Mitral Valve Disease and Cavalier King Charles Spaniels

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Canine Heart Valve Replacement & Repair Surgery

4DAVIS, CA: Dr. Leigh Griffiths, board certified veterinary cardiologist and surgeon, of the University of California at Davis' Veterinary Medical Teaching Hospital heads the UC Davis Cardiovascular Surgery Program, which includes canine mitral valve repair and replacement. He does not recommend implanting mechanical valves, due to the necessity of life-long anti-coagulation therapy and the threat of clotting in the event of any lapses in therapy. His group performs valve tissue replacement surgery, using either glutaraldehyde fixed porcine aortic or bovine pericardial valves. Dr. Griffiths warns that foreign tissue rejection is possible, and so he currently only recommends tissue valve placement in patients where valve repair is considered impossible.

Dr. Griffiths reports that the success rate of mitral repair is 70% of dogs surviving to leave the hospital, and of those which survive, the disease is essentially cured in 70%. Among the 30% which are not cured, he says that the disease is arrested (no more progression and stable medications) and they almost always die of other non-cardiac disease. So he rates surgery as very successful, but with a high initial risk. They do one open heart procedure a month.  Cost of the procedure is from $12,000- to $14,000.  Read more about this program at its website.

4FT. COLLINS, CO: Dr. E. Christopher Orton of the James L. Voss Veterinary Teaching Hospital at Colorado State University (CSU) in Ft. Collins, Colorado, heads an animal cardiac surgery program which reportedly has consistently and successfully completed life-saving, open-heart surgeries on canines. Dr. Orton and his surgical team have performed over 100 open-heart surgeries since1991 and began replacing heart valves in 1997. Valve surgery requires a team of six to eight people, additional staff in the critical care unit, and intensive monitoring of the dog before, during, and immediately after surgery, which limits the team's ability to conduct surgeries to only a few per month. The team replaces the defective valve with an artificial heart valve made from bovine pericardial tissue or with a mechanical valve prosthesis. The surgical procedure typically lasts about five hours, during which the new valve is placed in the dog's heart while its blood circulates through a heart-lung machine; then its heart is re-started, after which the dog is monitored in the surgical suite for two hours. The patient then is placed in the hospital's intensive care unit, where it is closely monitored for the next 72 hours.

The dog has to be monitored carefully for several months after it is discharged from the surgical unit. The surgery offers the dog the possibility of a lifelong cure, as long as the prosthetic valve continues to function well and does not develop complications, such as blood clots or tissue rejection. Dr. Orton's reports on his team's studies are cited below in Veterinary Resources. See 2004 MVD Surgery Report and 2005 MVD Surgery Report.

Beginning in July 2011, Dr. Orton and board certified veterinary cardiologist Dr. Allison K. Adams have been conducting clinical trials replacing the mitral valve with an artificial heart valve called MitralSeal developed by Avalon Medical, Ltd. This mechanical valve is designed to be installed using a minimally invasive approach into the beating heart. For details, click here.

Dr. Orton may be reached by telephone at 970-297-1250, and e-mail at corton@colostate.edu and Dr. Allison's email address is allison.adams@colostate.edu

4PITTSBURGH, PA: Research physicians at the University of Pittsburgh have conducted experimental mitral valve repairs on dogs, using radiofrequency ablation (RFA).  The RFA energy is applied to the deteriorating valve flaps and chords, resulting in controlled damage which has the affect of qualitatively reducing the leaflet surface and the chordal length.  The researchers found that the result of the application of RFA was to reduce the mitral regurgitation by statistically significant amounts.  Read the details below.

4COLLEGE STATION, TX: Dr. David A. Nelson of the Small Animal Medicine and Surgery Center at Texas A&M's College of Veterinary Medicine leads a similar veterinary surgical team which specializes in canine open heart surgery, including mitral valve repair. The surgical center is a part of the Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices. It is researching effective ways to repair the valves, rather than replace them, in smaller dogs.

Dr. Nelson advises that, to be eligible for surgery, the dog's heart function must still be preserved. Dogs that have reached the end point of a lengthy cardiac disease cycle are not considered as candidates. The total number of cases performed is still too low to offer any probability of success. There are still great risks involved, and each dog's case is different. A normal healthy young dog could likely undergo and recover from cardiac surgery without complication. One that is older, with cardiac disease or other organ involvement, presents a much more difficult challenge.

All candidates are referred by veterinarians, who will make the first contact to with the Texas A&M surgical team and send pertinent medical information that allows the team to make an initial determination. A cardiac work-up examination of the dog then is scheduled. The work-up may be scheduled in connection with a tentative surgery date. However, only after the work-up and consultation with the team is a final decision made as to recommend surgery.

A modest amount of mitral valve leakage may continue following the successful surgical mitral valve repair. Changing the disease from a rapidly progressive one to a static, manageable situation is considered a very acceptable result. Following surgery, the dog may remain on some cardiac medications.

The costs of surgery and aftercare is determined on a case by case basis. A current range of costs is from $5,000.00 to $10,000.00 or higher. Higher costs usually are due to increased intensive care unit charges. The team will make an accurate estimate after the dog's cardiac work-up examination. Due to the nature and expense of the service, the surgical center requires a deposit of $4,500.00 prior to surgery. Conventional types of credit cards are acceptable.

Dr. Nelson may be reached by telephone at 979-845-2351 and email dnelson@cvm.tamu.edu The surgical team's website is http://kndn.com/cv/

4LONDON, ENGLAND, UK: Heart surgeon Dan Brockman (BVSc, CVR, CSAO, MRCVS, Diplomate ACVS/ECVS) at the Royal Veterinary College, University of London, in England, has begun a animal cardiac surgery program, which includes open-heart mitral valve surgeries on canines. He has consulted with Dr. Orton at Colorado State University, and the two surgeons have been working together to advance heart surgeries in the UK.

Mr. Brockman may be reached at The Queen Mother Hospital for Animals, Hawkshead Campus, the Royal Veterinary College, telephone +44 (0)1707 666366, email qmhreception@rvc.ac.uk The website is www.rvc.ac.uk/Hospitals/QMH/Index.cfm

4FUJISAWA, JAPAN: Drs. M Nishida, M Uechi, T Mizukoshi, T Ebisawa, M Mizuno, T Mizuno, K Harada, M Fujiwara, N Nakayama of Nihon University, Fujisawa, Japan, have been conducting "mitral valve plasty" surgery on cavalier King Charles spaniels and other small dogs since 2006. Mitral valve plasty involves suture repairs to the mitral valve leaflets and includes the insertion of artificial chords made of a polymer, expanded polytetrafluoroethylene (e-PTFE). They report in a 2009 journal article, "Mitral Valve Plasty in 11 cavalier King Charles Spaniels", that "these results suggest that mitral valve plasty is beneficial in CKCS with MVD."

While two of their CKCS patients died during the post-operative study due to complications, and three were diagnosed with syringomyelia, the researchers found that among the nine survivors, "at 1 and 3 months after surgery, the left atrial to aortic root diameter ratio ... and the plasma atrial natriuretic peptide level ... were lower than those before surgery ... There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery ... and in the cardiac murmur grade ... ."

Read a 2010 report with updates of their surgeries.

See, also, a 2011 article by Masami Uechi, Nihon University, Kanagawa, Japan, that mitral valve repair surgeries of 50 dogs with heart enlargement, overall the heart rate decreased and mitral regurgitation reduced, resulting in reduction of the enlargement of the hearts.

4TOKYO, JAPAN: Drs. Midori Akiyama, Ryou Tanaka, Kohji Maruo, and Yoshihisa Yamane, of the Department of Veterinary Surgery, Tokyo University of Agriculture and Technology, in Tokyo, Japan, have conducted mitral valve repair surgery on at least one small dog, a 6-month-old, 15.6 lb., male Shiba Inu. They write in their 2005 article: A 6-month-old, 15.6 lb., male Shiba Inu with a cardiac murmur "due to an ostium primum septal defect, a ventricular septal defect, and mitral valve malformation with regurgitation. The mitral valve and tricuspid valve were separated and displaced at the same level as the ventricular septum. The mitral valve had a cleft in the septal cusp. ... An incision was made in the right atrium, and an ASD (25 x 15 mm in diameter) was identified in the lower portion of the atrial septum immediately above the ventricular septum. The mitral valve was seen through the ASD, and there was a cleft in the septal cusp. The cleft separated the septal cusps into two portions, both of which had thick edges. The cleft was repaired with mattress sutures of 5-0 polypropylenes. The ASD was then closed with sutures of 5-0 polypropylene using pledgets. A small VSD (5 mm in diameter) was observed behind the septal cusp of the tricuspid valve. The VSD was closed with simple mattress sutures of 5-0 polypropylene. The right atrium was sutured closed with a simple continuous pattern of 5-0 polypropylene." See their 2005 journal article. Their clinic is located at Department of Veterinary Surgery, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan; website: www.tuat.ac.jp/index-e.html

See also, a 2007 article by Drs. Koichi Tamura, Mayumi Murakami, and Makoto Washizu on post-mortem examinations of 12 dogs with suture-repaired mitral valve leaflets. Drs. Murakami and Washizu are at the Nippon Veterinary and Animal Science University, Tokyo, Japan, website: www.nvlu.ac.jp/e/index.html

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Current Research

4January 2012: UK cardiologists to compare MVD murmurs with echocardiograms of 200 CKCSs. UK cardiologists Simon Swift and Anne French announced that they will study in detail the incidence of MVD is 200 mature cavaliers, using echocardiography in combination with auscultation. They will evaluate the heart valves and heart chamber sizes. They also intend to collect DNA for analysis.

4November 2011: UK's Royal Veterinary College seeks cavaliers with asymptomatic MVD for cardiac MRIs. Drs. Julia Sargent, Virginia Luis Fuentes, and Holger Volk are leading a research team at Queen Mother Hospital for Animals which is enrolling cases for a cardiac MRI (cMRI) clinical study in order to validate a new echocardiographic scoring system for assessing the severity of degenerative mitral valve disease in asymptomatic dogs.

They have developed the new echocardiographic scoring system, based upon a number of different measurements that they believe can offer more reliable information on the severity of MVD than current echo protocols. They are testing their new scoring system by comparing it to cardiac magnetic resonance imaging (cMRI), which is considered the most reliable test for quantifying valve disease in humans.

Due to the necessity of anaesthetizing the dogs for the cMRIs, the researchers want to recruit dogs already scheduled for MRIs for other reasons, such as syringomyelia examinations. All dogs will undergo conventional echocardiography to assess their heart disease prior to anaesthesia and the MRI scan, and only dogs with stable heart disease will be recruited.

The researchers expect to be able to provide more accurate information for the individual dogs on the severity of their valve disease as a result of the MRI scan, and new echo score. They believe that the scoring system should be particularly useful for standardizing the severity of MVD at entry for clinical studies. Contact Dr.  Sargent at sargent@rvc.ac.uk and Dr. Luis Fuentes at vluisfuentes@rvc.ac.uk 

4November 2011: UK researchers fail to find genetic differences between early-onset and late-onset MVD in cavaliers.  A team of UK cardiologists and geneticists divided 36 CKCSs into groups of early and late onset MVD and assessed whether the distinction is determined by a small number of genetic factors. They report that they came up dry. They concluded:

"There were no regions of highly discrepant homo/heterozygosity in the two groups. Similarly, there was no evidence for loci associated with mitral valve murmur in a genome-wide association study. This analysis suggests that familial occurrence of mitral valve murmur in the CKCS breed is not due to a single major gene effect, indicating that breeding strategies to eliminate the disease cannot be based on genotype information at this time."

This seems to contradict a much more successful report issued in September 2011 by a team of veterinarians from Denmark, Sweden, Germany, England, and France. They reported that they identified two specific locations on cavaliers' chromosomes CFA13 and CFA14 which are associated the breed's hereditary mitral valve disease. They grouped 139 cavaliers with early-onset MVD and 102 old CKCSs with no or mild signs of MVD as controls. Then they conducted a genome-wide association study to find specific locations associated with development of MVD. Read more here.

4October 2011: Univ. of Penna. cardiologists study torsemide as alternative to furosemide. University of Pennsylvania veterinary cardiologists report that they have tested the loop diuretic torsemide as alternative to furosemide in dogs with advanced heart failure, including a 12 year old cavalier. They have found torsemide "has several characteristics that make it suitable for treatment of advanced heart failure including longer half-life, increased potency of diuretic action, and anti-aldosterone effects."

4September 2011: Swedish researchers find periodic x-rays of cavaliers can detect onset of congestive heart failure. A team of cardiologists at the Swedish University of Agricultural Sciences, including Drs. Kvart and Häggström examined periodic x-rays of 94 CKCSs to determine the value of the vertebral heart scale and its rate of increase per month, to predict the onset of congestive heart failure. They concluded in their report that the monthly rate of increase in heart size along the veterbral heart scale was a useful measurement for that purpose.

4September 2011: International study finds specific genetic locations for mitral valve disease in cavaliers. A team of veterinarians from Denmark, Sweden, Germany, England, and France report they have identified two specific locations on cavaliers' chromosomes CFA13 and CFA14 which are associated the breed's hereditary mitral valve disease. They grouped 139 cavaliers with early-onset MVD and 102 old CKCSs with no or mild signs of MVD as controls. Then they conducted a genome-wide association study to find specific locations associated with development of MVD. Read more here. They also stated:

"We will initiate studies of the most promising candidate genes in the 2 candidate regions which hopefully will lead us to the mutations affecting the development of mitral valve disease."

4August 2011: UK researchers conclude that leptin may play a role in canine cardiac disease. In an August 2011 report, a panel of UK cardiologists examined the relationship which leptin (a protein produced by dogs' fat cells) may have with MVD and other forms off cardiac disease. They found that dogs in congestive heart failure had significantly higher blood concentrations of leptin than dogs without cardiac disease. They concluded that leptin may "play a role in canine cardiac disease."

4August 2011: Belgium researchers find that spironolactone did not extend survival times of dogs with advanced heart failure. See report citation and abstract.

4July 2011: Dr. E. Christopher Orton, board certified veterinary surgeon at of the James L. Voss Veterinary Teaching Hospital at Colorado State University (CSU) in Ft. Collins, Colorado and board certified veterinary cardiologist Dr. Allison K. Adams have been conducting clinical trials replacing the mitral valve with an artificial heart valve called MitralSeal. This mechanical valve is designed to be installed using a minimally invasive approach into the beating heart. For details, click here.  Dr. Orton may be reached by telephone at 970-297-1250, and e-mail at corton@colostate.edu and Dr. Allison's email address is allison.adams@colostate.edu

4July 2011: Bayer's HECTOR Study fizzles out. Bayer Animal Health's HECTOR Study of a beta-blocker to treat MVD has quietly ended without success. The study, conducted since August 2009 (see introduction announcement) among at least eight veterinary schools and specialty clinics throughout the United States, has ended prematurely due to the interim statistics showing no significant difference between the beta-blocker and the placebo in extending time between grade 3 murmur and onset of heart failure.

4June 2011: Cytokine concentrations may indicate MVD progression in CKCSs. In a study of 41 cavaliers and 27 other dogs, Danish and Swedish cardiology researchers have found that certain cytokine concentrations either increase or decrease as the cavaliers' hearts enlarge due to MVD or mitral regurgitation increases. Cytokines are proteins released by cells that effect interactions between cells. The researchers have concluded that there may be a role for cytokines in canine MVD and congestive heart failure.

4June 2011: Enlarged heart size reduced after mitral valve replacement surgeries in Japan. Dr. Masami Uechi reports to the ACVIM that mitral valve repair surgeries of 50 dogs with heart enlargement, overall the heart rate decreased and mitral regurgitation reduced, resulting in reduction of the enlargement of the hearts.

4June 2011: Advanced electrocardiography can predict severity of MVD in cavaliers.  In a June 2011 study by Slovenian and Danish researchers, they were able to use advanced ECG to predict the severity of mitral regurgitation in dogs with MVD.  They reported:

"Our results indicate that for a cut-off criteria of MR [mitral regurgitation] 50% jet the five selected ECG parameters could predict the severity of MR caused by MMVD in CKCSs with sinus rhythm with sensitivity 65% (78% with age inclusion) and specificity 98% (92% with age inclusion) (P < 0.05)."

4March 2011: Holter monitoring study shows CKCSs have significantly higher heart rates than other small breeds. University of Copenhagen researchers obtained Holter recordings from 54 clinically healthy dogs: 23 cavaliers ("at high risk to develop MVD"), 18 wired-haired Dachshunds ("at moderate risk"), and 13 Cairn terriers ("at low risk"), to compare Holter readings between CKCS and the other breeds. The results showed that the cavaliers had "significantly higher" heart rates. They concluded: "However, further studies are required to clarify the possible influence of high HR [heart rate] in the development of MMVD in CKCS."  Read more here.

4February 2011: Vetmedin's EPIC trial begins. Pimobendan's developer and manufacturer, Boehringer Ingelheim GmbH, a German pharmaceutical company, which markets the drug under the registered brand name Vetmedin, has enlisted thirty-six board certified veterinary cardiologists throughout four continents, including eighteen in the United States and one in Canada, to participate in a long term study of 360 dogs with mitral valve murmurs, to determine if pimobendan can delay the onset of signs of congestive heart failure. The study, called "EPIC" (for "Evaluating Pimobendan in Cardiomegaly") by the sponsor, is expected to conclude in 2015. Half of the 360 MVD-affected dogs will be given a dose of pimobendan twice daily, while the other 180 MVD-affected dogs will be given a non-medicated placebo until they reach congestive heart failure.

[NOTE: In an April 2011 editorial, CavalierHealth.org has warned against cavaliers participating in this EPIC study, due to the unacceptable risk of the too-early administration of pimobendan to dogs which are  not yet in congestive heart failure.  If your cardiologist suggests that your cavalier participate in this EPIC Trial, beware and proceed at your dog's risk.]

4December 2010: Dr. Oyama studies links between cavaliers' giant platelets and MVD. Dr. Mark A. Oyama of the University of Pennsylvania is continuing his research into links between cavaliers' giant platelets and the breed's high incidence of mitral valve disease. His previous research has shown that CKCSs have elevated levels of serotonin (5-HT). The hypothesis is that 5-HT signaling is an important component of MVD in dogs. He suspects that the source of elevated serum 5HT is the blood platelets, since platelets are believed to contain 99% of all circulating 5-HT. It has been recently shown that platelet contents can activate disease changes within the heart muscle of experimental animals. The platelet, heart muscle, and valve-specific content of 5-HT in dogs with heart disease has not been previously reported. Dr. Oyama wants to determine if platelet 5-HT is the source of elevated serum 5-HT in cavaliers with MVD, as well as to quantify the amount of 5-HT in both the left ventricular muscle and mitral valve leaflets of affected dogs.  His report is due in December 2011.

 4October 2010: Vetmedin's "EPIC Trial" has begun. UK cardiologists are conducting a study (the "EPIC Trial") giving Vetmedin (pimobendan) to cavaliers with low grade MVD murmurs to see if the drug will slow the progression of MVD to congestive heart failure. About 300 dogs are participating, with half receiving pimo and the other half a placebo.

4October 2010: Japanese cardiologists successfully perform open heart MVD surgery on small dogs, using deep surface-induced hypothermia (sHT) and low-flow cardiopulmonary bypass (CPB). See report summary.

4September 2010: Swedish study shows watered-down MVD breeding protocol may not be working. Sweden's Kennel Club and its CKCS Club introduced a watered-down, but mandatory version of the MVD Breeding Protocol in 2001. In this program, dogs are not allowed to breed until four years of age and need a heart auscultation without murmurs within eight months before mating. However, dogs are allowed to breed at an age of 24 months, if the dog and its parents are examined and no murmurs are detected. Male dogs that have a heart auscultation at seven years of age without murmurs are allowed to breed without further heart evaluation. Breeding animals whose parents have heart murmurs before four years of age are not allowed to breed. The result from Dr. Clarence Kvart's investigation indicates that the prevalence of MMVD in six-year-old cavalier King Charles spaniels, born 2001 and 2003, is at least 50% and lacks signs of decrease despite the current breeding program introduced in Sweden 2001.

As a result, the Swedish clubs are considering toughening their relaxed protocol to follow the MVD protocol recommended by Lennart Swenson in 1998.

4July 2010: NC State's veterinary college seeks dogs with mild heart murmurs for activity study. The school's press release states: "Does your dog have a heart murmur? If so, he may be eligible for a new study of heart disease! We are enrolling dogs with early heart disease into a clinical trial to measure their activity at home. We will record their activity with a small device (the size of a quarter) that is attached to their collar. Activity will be recorded before, and during treatment with a medication used to treat heart disease. Requirements: The study will require an outpatient appointment with the cardiology service at the Veterinary Teaching Hospital. Your dog will then wear the collar/activity recording device for two weeks, then for another two weeks after twice-daily medication is started. Benefits to you: The study will pay $300 towards the cost of an evaluation by the cardiology service and the cost of the medication. The evaluation includes an extensive health screening. By comparing your pet’s activity before and after addition of the medication, and by comparing activity with that of a similar dog without heart disease, we hope to be able to measure any increase in your pet’s activity and vigor when treated with the medication." Contact Andrea Thomson, telephone 513-513-6854, email cvm_cprl@ncsu.edu

4May 2010: Dr. Sarah Blott issues her first report on using estimation of breeding values (EBVs). She writes in her May 2010 article:

"EBVs will allow breeders to distinguish between potential parents of high and low risk, after removing the influence of life history events. Analysis of current population structure, including numbers of dogs used for breeding, average kinship and average inbreeding provides a basis from which to compare breeding strategies. Predictions can then be made about the number of generations it will take to eradicate disease, the number of affected individuals that will be born during the course of selective breeding and the benefits that can be obtained by using optimisation to constrain inbreeding to a pre-defined sustainable rate."

4April 2010: Univ. of Pennsylvania MVD researchers need blood samples for gene study. The researchers are seeking to identify gene variation, and to verify it as the actual cause of MVD in the breed. Dr. Paula Henthorn asks for blood samples from cavaliers in these categories:

4CKCS with Grade 3 or louder murmur (by cardiologist) at age 5 years or younger.

4CKCS with no murmur (by cardiologist) at age 9 years or older.

4Older dogs which currently have a murmur but were cardiac clear at 9 years of age can be enrolled as long as a copy of the clearance at 9 years of age (or greater) is available.

If possible, they would also like a copy of the pedigree, but it is not necessary for enrollment. Click here for further information and the enrollment form.

If you are interested in making a financial donation to this research project, please send a check written to “Trustees of the University of Pennsylvania” with “Cavalier heart fund” in the memo to Dr. Paula Henthorn, Veterinary Hospital – Room 4033, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010; email: cmichel@vet.upenn.edu; telephone 215-898-8894; fax 215-573-2162. Donations are tax deductible. See also the September 2007 entry below for additional information about this research project.

4March 2010: UK researchers report early-onset MVD is "highly heritable" in cavaliers.  Drs. Tom Lewis, Simon Swift, John A. Woolliams, and Sarah Blott also found that "selection against the disease should be successful."  See report summary.

4March 2010: Swedish MVD researchers find cavaliers' most rapid heart enlargement only in last year before congestive heart failure. Drs. Clarence Kvart,  Jens Häggström, and others studied 24 cavalier King Charles spaniels with MVD for the rate of change of their heart size before congestive heart failure.  They found in their research journal article that "The left heart chambers increase in size rapidly only in the last year before the onset of congestive heart failure."

4March 2010:  Two recent studies examine connection between cardiac troponin I (cTnI) concentrations and severity of MVD. In a UK study soon to be published in The Veterinary Journal, 120 dogs, including cavaliers, were enrolled, and in a Swedish study in the Journal of Veterinary Internal Medicine, 81 dogs, including 67 CKCSs, were studied. Both groups observed that increases in cTnI concentrations in dogs with poor prognoses, and both also concluded that cTnI has potential in assessing the prognosis and severity of MVD and enlargement of the heart. Both reports also recommend more detailed future studies.

4January 2010: Dr. Mark Oyama summarizes research into the possible roles of serotonin (5HT) and transforming growth factor-b in transforming valvular interstitial cells (VIC) into a more active myofibroblast, which is an important component of MVD in cavaliers.  See his "insights".  Also check out his September 2009 entry, below. Dr. Oyama also suggests that ketaerin, a 5HT-R2A receptor blocker, or GR55562, a 5HT-R1B receptor blocker, may be effective in dealing with serotonin's affect on dogs' mitral valves.

4December 2009: Research physicians at the University of Pittsburgh conduct experimental mitral valve repairs on dogs, using radiofrequency ablation (RFA).  The RFA energy is applied to the deteriorating valve flaps and chords, resulting in controlled damage which has the affect of qualitatively reducing the leaflet surface and the chordal length.  The researchers found that the result of the application of RFA was to reduce the mitral regurgitation by statistically significant amounts.  Read the details below.

4November 2009: ACVIM's "Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease".  A panel of board certified veterinary cardiologists have published a "Consensus Statement, classifying the stages of MVD and the recommended treatment at each stage.

4September 2009: The Serotonin Concentration Studies Continue. "Healthy CKCS dogs had significantly higher serum [serotonin] 5HT concentrations than other healthy dogs predisposed to DMVD [degenerative mitral valve disease]," concludes the University of Pennsylvania team studying serontonin's connection to mitral valve disease (see the January 2009 Current Research entry below) in its report to be published in the November/December 2009 issue of the Journal of Veterinary Internal Medicine. They also found that "Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs."

4August 2009: Researchers need dogs with Grade 3 heart murmurs. [NOTE: See July 2011 entry: "HECTOR Study fizzles out"] HECTOR Study: Free screening tests -- a consultation ,an echocardiogram, chest radiographs, blood sample analysis and ECG -- are included. At several veterinary schools, the University of Pennsylvania's Veterinary Hospital (VHUP), in Philadelphia, PA, Washington State University's veterinary medicine's cardiology department, in Pullman, WA, the University of Missouri's veterinary medicine teaching hospital, in Columbia, MO, North Carolina State University's veterinary medicine cardiology department in Raleigh, NC, Cornell University's veterinary medicine cardiology department in Ithaca, NY, and Texas A&M University's (TAMU) veterinary medicine's cardiology department, in College Stations, TX, as well as the Animal Medical Center in New York City, and the MedVet Medical and Cancer Center for Pets in Worthington, Ohio, are recruiting dogs for a study evaluating a beta-blocker to treat heart disease due to MVD. All breeds are eligible. The dogs must have at least a Grade 3 murmur, be at least a year old, and have never had any clinical signs of heart disease of any kind.

Dogs included in the study will receive the beta-blocker or placebo, and will be required to return for rechecks four times the first year and twice yearly each year after. The study's title is “Clinical Evaluation of the Efficacy and Safety of a Beta-blocker Medication used to Treat Heart Disease due to Chronic Valvular Heart Disease”.

The beta-blocker being tested is not one of the ones commonly being prescribed and is administered in liquid form. It is a selective andrenoceptor blocker, identified as BAY 41-9202. The researchers hope to have up to 400 dogs participate in the study, over up to a four year period.  The study is sponsored by Bayer Animal Health.

Contacts:

The UPenn study in Philadelphia is being led by Dr. Mark A. Oyama. For more information, please contact Dana Durso by email or telephone 215-573-6553.

The Washington State U study in Pullman is led by Dr. Kate Meurs.  Email her or Becky Connors or call 509-335-6038.

The U. of Missouri study in Columbia is led by Dr. Deborah Fine.  You may contact her by email, or Ed Durham, or call 573-882-7821.

North Carolina State Univ. study in Raleigh contact is Allison Klein. Email her or call 919-513-6325.

Cornell University study in Ithaca contact is Dr. Syndey Moise. Email her or call 607-253-3081.

TAMU's study in College Station contact is led by Dr. Sonya Gale Gordon.  You may contact Kathy Glaze by email or call 979-845-2351.

The Animal Medical Center study in New York City is Dr. Philip Fox.  You may email him or contact him at telephone 212-329-8606.

The MedVet study in Ohio is being led by Dr. Linda Lehmkuhl. For more information, please contact her or Dr. Ann Bancroft by email or telephone, 614-431-4405.

4June 2009: Japan Surgeons Report Successful Repairs to CKCS Mitral Valves. Nihon University veterinary surgeons have been conducting "mitral valve plasty" surgery on cavalier King Charles spaniels and other small dogs since 2006. Mitral valve plasty involves suture repairs to the mitral valve leaflets and includes the insertion of artificial chords made of a polymer, expanded polytetrafluoroethylene (e-PTFE). They report in a 2009 journal article, "Mitral Valve Plasty in 11 Cavalier King Charles Spaniels", that "these results suggest that mitral valve plasty is beneficial in CKCS with MVD."

While two of their CKCS patients died during the post-operative study due to complications, and three were diagnosed with syringomyelia, the researchers found that among the nine survivors, "at 1 and 3 months after surgery, the left atrial to aortic root diameter ratio ... and the plasma atrial natriuretic peptide level ... were lower than those before surgery ... There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery ... and in the cardiac murmur grade ... ."

 4January 2009: Colorado State Univ. researchers to test drug inhibiting serotonin in mitral valves. Dr. E. Christopher Orton of the of Colorado State University's James L. Voss Veterinary Teaching Hospital and its Animal Heart Center in Ft. Collins, Colorado, and Dr. Sirilak Disatian, have issued a report on their study begun in June 2008, "Autocrine Serotonin and TGF-beta Signaling in Human Myxomatous Mitral Valve", which has been sponsored by the American Heart Association. The researchers have found that serotonin is created locally in heart mitral valves, thereby causing pathologic changes in the valves, resulting in their malfunction.

Serotonin is made by an enzyme called tryptophan hydroxylase 1 (TPH1). Serotonin then goes into the blood stream where it is picked up by platelets which are involved in blood clotting. Orton's group has shown that TPH1 is present in high levels in abnormal mitral valves from both dogs and humans.

Dr. Orton's group is seeking to find what triggers the enzyme in the valve which produces the serotonin. He plans to start a clinical trial on dogs to examine the impact of a drug that inhibits the enzyme that produces serotonin in the heart.

See also June 2008 entry for Dr. Mark Oyama.

4October 2008: UK Kennel Club to Add "Health Plan" to Cavalier King Charles Spaniel Breed Standard. The (UK) Kennel Club announced that it will include a "breed health plan" in the CKCS breed standard, to "ensure that no dog is bred for features that might prevent it from seeing, walking and breathing freely." A meeting to include representatives of the UK's cavalier club and cardiologists is set for December 1. The club expects to issue the CKSC health plan by early 2009.

The UK club also is asking the UK government to "give it statutory powers to make its established Accredited Breeder Scheme compulsory throughout the country. If successful, this would mean that all breeders who are not part of the scheme and who have not officially confirmed their willingness to follow the health standards set by the Kennel Club would be unable to produce or sell puppies within the law." Additionally, the UK's cavalier breed club is "now required to adopt the Kennel Club's Code of Ethics, to ensure that their practices fall in line with Kennel Club policy for putting the health and welfare of puppies first. This includes a clause that explicitly forbids the compulsory culling (killing) of healthy puppies." See website www.thekennelclub.org.uk

4September 2008: UK Kennel Club and British Veterinary Association Plan Possible Heart Testing Protocol for Cavalier Breeding Stock. On September 15, 2008, the UK Kennel Club and British Veterinary Association representatives met with representatives of UK cavalier King Charles spaniel clubs to discuss introducing a heart testing scheme, which would be applied to CKCS and three other breeds. The test results would be published in the Kennel Club's breed registration quarterly supplements and on the progeny's registration certificates. The group plans to meet again in December to consider adopting the scheme.  The UK Kennel Club also is looking at ways by which breeders could access health results of dogs/ bloodlines. This service will be available to breeders and pet owners.

4July 2008: ACVIM Announces "ARCH" -- New Registry of Cardiac Health. The board certified cardiologists of the American College of Veterinary Internal Medicine (ACVIM) have introduced a new registry, ARCH, to certify dogs' hearts are clear of mitral valve disease and other genetic heart disorders. ARCH certifications are issued only by board certified veterinary cardiologists. Look for the ARCH symbol and check out the website.

4June 2008: Serum Serotonin Concentration Is Elevated in CKCSs. University of Pennsylvania Drs. Jason W. Arndt, Mark A. Oyama, and C. A. Reynolds have completed initial research showing that CKCSs have higher levels of serotonin (5-HT) than other breeds which are pre-disposed to MVD. (CKCS, 903.9 [321.5] ng/ml vs. non-CKCS, 536.0 [153.7]; P50.004). The team studied 51 dogs, including 32 cavaliers, which either were affected with or pre-disposed to MVD (CKCSs as a breed are pre-disposed to MVD), plus 28 control dogs. They report: "In humans, elevated serotonin (5-HT) is associated with development of valvular lesions. Canine mitral valve cells demonstrate dose-dependent 5-HT-mediated ERK1/2 signaling, suggesting a possible link with canine DMVD. ... Our results suggest that 5-HT may play a role in the development of DMVD in small breed dogs, and in particular in the CKCS. Further studies involving the relationship between 5-HT, DMVD, breed, and platelet number, morphology, and function are warranted."

Meanwhile, at Colorado State University, Dr. E. Christopher Orton of the of CSU's James L. Voss Veterinary Teaching Hospital and its Animal Heart Center in Ft. Collins, Colorado, has started a study, "Autocrine Serotonin and TGF-beta Signaling in Human Myxomatous Mitral Valve", which is sponsored by the American Heart Association.

4May 2008: Auburn University Researchers Find Possible Link Between Oversized Platelets and MVD in Cavaliers. A team of researchers at Auburn University in Alabama (Drs. B. Davis, M. Toivio-Kinnucan, S. Schuller, M.K. Boudreaux) determined that "a mutation in the gene encoding β1-tubulin correlated with macrothrombocytopenia in CKCS." They concluded that "this information will aid in distinguishing inherited from acquired thrombocytopenia. It also provides insight into the mechanism of platelet production by megakaryocytes, and also may prove useful in understanding heart-related changes in macrothrombocytopenic CKCS with concurrent mitral valve regurgitation." See citation below.

4May 2008: Researchers Need Heart Tissue From Deceased MVD Canines. Dr. Allison M. Heaney, board certified veterinary cardiologist, heads a research program at the College of Veterinary Medicine at Washington State University studying the difference in the balance between these proteins affecting collagen in normal cultured mitral valve cells and mitral valve cells cultured from diseased leaflets. Differences that exist between normal and diseased valve cells will help target future research projects and aid in determining the cause of the breakdown of collagen in diseased valve cells.

Dr. Heaney is requesting mitral valve tissue from dogs of any breed that have died or have been euthanized that have significant degenerative MVD. The valve tissue will be used to culture cells from the tissue in order for the researchers to study the disease from a cell culture perspective. For inclusion in the study, dogs need to have a diagnosis of degenerative mitral valve disease from their veterinarian (if echocardiography findings are available, those should be provided as well) and the owner needs to be willing to let their referring veterinarian remove the mitral valve from the dog after it dies or is euthanized. The tissue should be removed within 2 hours of death or euthanasia.

She requests that the anterior mitral valve leaflet (the larger leaflet most associated with the septum and aorta) -- but if there is any confusion the entire mitral valve can be shipped and they can collect the anterior mitral valve leaflet once it arrives here. The sample should be shipped in phosphate buffered saline. If needed, the researchers can ship tubes of phosphate buffered saline for sample collection. The sample should be shipped on ice overnight to the address below. For more information, contact Dr. Heaney or her research technician, Marsha Robertson, at Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University 100 Dairy Road, Pullman, WA 99164-1120, telephone 509-335-0711, fax 509-335-0880, email aheaney@vetmed.wsu.edu, websites: www.vetmed.wsu.edu.This study is supported by AKC Canine Health Foundation, webpage www.akcchf.org/news/index.cfm?article_id=249

4May 2008: DNA Project Needs UK Cavaliers. Simon Swift, MA VetMB Cert SAC MRCV, at the University of Liverpool, heads a DNA study of cavalier King Charles spaniels. The study is based upon a novel genetic method intended to discover the genes behind mitral valve disease in the CKCS. The researchers need 100 cavaliers with early onset MVD (defined as developing mitral insufficiency before age 4 years or developed signs of heart failure before 8 years) and 100 CKCSs with late onset MVD (dogs over 10 years without a murmur or with very mild mitral insufficiency). The group also is currently working to locate qualified dogs in Sweden and Denmark, as well as the UK.

If you live in the UK and have a dog which meets these standards, contact Mr. Swift about obtaining blood samples and pedigrees: (1) Dogs under 4 years with a loud murmur. (2) Dogs under 8 years that have developed heart failure. This does not necessarily mean a cough. They should also have breathlessness, weight loss, and exercise intolerance. They should also need medication. (3) Dogs over 8 years with no murmur or a very quiet one. A cardiologist should examine the dog. There will no charge if the examination is coordinated with Mr. Swift at a participating centre. The researchers are prepared to travel to examine large groups of dogs. The team is rganising a health clinic in Bagworth on September 27, 2008. If you can attend with a suitable dog, please bring your pedigree.

You may contact Mr. Swift at: Small Animal Teaching Hospital, The University of Liverpool. Leahurst, Chester High Road, Neston, Cheshire CH64 7TE; telephone (0151) 795 6100, fax: (0151) 795 6101, email sath@liv.ac.uk, website www.liv.ac.uk/sath/index.htm

4March 2008: Reducing Rejection of Replacement Mitral Valves. Dr. E. Christopher Orton of Colorado State University’s Animal Heart Center in Ft. Collins, Colorado leads a team researching the use of "tissue engineering" to build a better replacement for canine heart valves. “All replacement heart valves in use today are based on non-living tissues and have limitations,” said Dr. Orton in an interview published in CSU's Insight magazine, Spring 2008 issue. “In humans, there are two options, a mechanical valve that requires the patient to be on blood thinners for the rest of their lives, or a bioprosthetic valve, using a pig valve fixed with glutaraldehyde. Humans can tolerate these valves, but dogs not so much. As a species, dogs are more likely to reject foreign tissue.” Dr. Orton’s work focuses on tissue engineering that studies methods for removing antigens from living tissues and repopulating the tissue with the animal’s own cells.

The team is developing new methods for screening a large number of proteins for antigenicity -- the degree to which a substance induces an immune response, across species. To accomplish this, Dr. Orton's team is using proteomics to look at all of the proteins in the tissues used for bioprosthetic heart valves.

Proteomics is a new focus in the field of biotechnology that enables a system-wide analysis of proteins produced by cells. With proteomics, researchers can detect proteins that elicit an immune response, and subsequently identify the protein antigen, categorize the antigens into broad groups according to their origin, and then place them into smaller categories according to structure, type, physical and chemical properties.

By exposing separated proteins to naturally-occurring and acquired antibodies, Dr. Orton seeks to determine which proteins are responsible for the antigenicity of biomaterials, and this knowledge can be used to develop strategies to selectively remove those proteins. This study is expected to provide important insights about the bioprostheses and about tissue transplantation in general.

4September 2007: Indentifying DNA markers and altered genes that predispose cavaliers to develop early-onset MVD: Drs. Margaret M. (Meg) Sleeper, Petra Werner, and James Buchanan, of the University of Pennsylvania's School of Veterinary Medicine, are conducting a genetic analysis of CKCS hearts and blood samples, with the goal to identify DNA markers and altered versions of genes that predispose cavaliers to develop early-onset mitral valve disease. The inclusion criteria are CKCSs that develop from grade 3 to grade 6 MVD murmurs before the age of 5 years; and their immediate relatives (parents, siblings, and grandparents); and dogs over age 6 years without murmurs. They are obtaining samples consisting of: 3 mls of EDTA blood. For more information about sending blood samples to this project, contact either the ACKCSC trust's Bettina M. Sterling, email Sterlingtoys@aol.com, or Dr. Werner, telephone number 215-898-8894, email cmichel@vet.upenn.edu. An application form is available at www.ackcsc.org/health/CKCS_owner_info_form.pdf  Drs. Sleeper and Buchanan are board certified cardiologists. Dr. Buchanan has contributed over sixteen years of his time to research of MVD in the CKCS. Dr. Werner, who has a doctorate in molecular genetics from the University of Zürich, has been leading a team of researchers at the Center for Comparative Medical Genetics and Section of Medical Genetics at the School of Veterinary Medicine, University of Pennsylvania for the past ten years in developing a genetic map of the canine genome.

The American Cavalier King Charles Spaniel Club's charitable trust's Darcy Fund is helping to underwrite this research, and the ACKCSC trust is actively participating in the project by collecting selected blood samples and pedigrees during health clinics around the United States. Financial donations to support this research project may be made by sending checks payable to "Trustees of the University of Pennsylvania", with "Cavalier Heart Fund" in the memo, directly to Dr. Petra Werner, Room 4033, Ryan Veterinary Hospital, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010. Donations are tax deductible.

4June 2007: Dogs needed for reduced rate Ohio State study to improve ultrasound imaging for diagnosing congestive heart failure: Dr. Karsten E. Schober of the cardiology department at the Ohio State University's College of Veterinary Medicine in Columbus, Ohio is looking for dogs with diagnosed heart disease to be a part of a non-invasive study titled: "Can better imaging predict heart failure?". The researchers seek to utilize cardiac ultrasound to identify and stage congestive heart failure (CHF) in dogs. Dogs with asymptomatic dilated cardiomyopathy (DCM) and degenerative mitral valve disease (MVD) and dogs with CHF caused by MVD or DCM will be enrolled.

Any dog with DCM or MVD -- unless treated with high doses of diuretics and no concurrent systemic disease -- is eligible. Participating dogs would be examined twice at the Ohio State Veterinary Hospital, five to fourteen days apart. During these two visits, the dogs will be given a complete physical examination, chest x-rays, an echocardiogram, blood pressure measurement, and a blood sample drawn. Benefits for dog owners include low cost examinations (50 percent cost reduction for the first visit and free second visit), short scheduling and waiting times, and important contribution to a research study that can improve the health of dogs. The results of this study may help to earlier diagnose CHF, better stratify cardiovascular risk, tailor therapy to specific dog needs, and reduce the exposure of personnel and animals to the ionizing radiation required for repeated thoracic radiography.

Contact: Dr. Schober, telephone 614-292-3551, email schober.4@osu.edu, or Laura Spayd, telephone 614-292-3551. Also visit http://www.vet.ohio-state.edu/2404.htm

4June 2007: 3-D echocardiographics and image reconstruction of cavaliers with MVD: Dr. Mark A. Oyama at the School of Veterinary Medicine, University of Pennsylvania, is leading a team of investigators to determine whether the heart valves of dogs with MVD possess inherently different geometrical characteristics when compared to those of non-affected dogs. They propose using a novel 3-D echocardiographic technique and specialized image reconstruction to visualize the geometry of the valve annulus and valve leaflets in greater detail. They intend to correlate the valve geometry with disease severity, ventricular function and geometry, and conventional 2-D echocardiographic measurements of mitral valve disease.

4Pathophysiological aspects of early mitral valve diseases in cavaliers: Dr. Inge Tarnow, at the University of Copenhagen's Department of Animal and Veterinary Basic Sciences, heads a group of specialists studying pathophysiological aspects of early mitral valve disease in cavaliers, including changes in platelet function, hemostatic changes, and prognostic factors. They currently are performing a large longitudinal study of 100 cavaliers with examinations (echocardiographic and blood tests) at ages 2, 4, and 8 years.

4DNA to discover genes causing MVD: Dr. Clare Rusbridge at the Stone Lion Veterinary Centre in the UK is coordinating an international group of geneticists and other specialists who are researching DNA samples from a variety of categories of cavalier King Charles spaniels throughout the world, in an effort to discover the genes causing mitral valve disease. In an April 2006 research update, Ms. Rushbridge reports that "a full genome scan looking for the causal gene/s of syringomyelia and mitral valve disease is underway!" The Cavalier Health Foundation (associated with the Cavalier King Charles Spaniel Club, USA) has contributed a grant to help underwrite this project. Donations are tax deductible. Donate to the Cavalier Health Foundation!

Also participating are Marie Pierre Dube, a genetics epidemiologist at the Montreal Heart Institute, and Dr. Zoha Kibar, the molecular geneticist in charge of fine mapping and identification of the gene(s) defective in MVD and syringomyelia in CKCSs, at Centre for the Study of Brain Diseases, CHUM – Montreal. Dr. Kibar reports in the April 2006 update:

"Both Syringomyelia and Mitral valve disease are particularly common in the cavaliers. Such high incidence in a particular breed as compared to other breeds suggests the involvement of genetic factors. The mode of inheritance including the number, identity and relative contribution of the causative genes is not determined yet. The etiology of both conditions could be further complicated by variable penetrance of the various genotypes and the involvement of environmental factors.

"The first step which is genetic mapping is currently underway. Due to the complex inbreeding in the CKCS, a preliminary genetic analysis was necessary to evaluate the informativeness of the genetic markers and hence the feasibility of a whole genome scan in such breed. Consequently, 10 dogs were selected for genotyping with 122 markers distributed among the 38 autosomes and X chromosome. The markers were found to be sufficiently polymorphic and informative. Next, 200 dogs were selected for a whole genome scan, primarily for Chiari malformation. However with additional phenotypic information on mitral valve disease, it is possible to use the same data to map the gene(s) defective in this disease. The whole genome scan was conducted at the Mammalian genotyping Center at the Marshfield Clinic in Wisconsin, USA. The genotyping data will now be analyzed using both linkage-based and association studies. In the latter, we will be taking advantage of the founder effect demonstrated for both these disorders in the CKCS breed.

"This strategy involves: 1) genetic mapping of the underlying gene(s), 2) identification of these defective gene(s) using the positional candidate gene approach and characterization of the mutation(s) and 3) initial functional characterization of the protein(s) encoded by the gene(s). This will help better understand the underlying pathogenic mechanisms for better diagnosis, prognosis and clinical management of these devastating conditions. These studies will also help unravel some of the complexity involved in this malformation in humans and in the embryonic development of the affected structures."

4Genomic expression patterns of mitral valve tissues from dogs with MVD: Dr. Mark A. Oyama at the School of Veterinary Medicine, University of Pennsylvania, and Sridar V. Chittur, PhD, Center for Functional Genomics, State University of New York at Albany, have published "Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease" in the August 2006 issue of the American Journal of Veterinary Research. Their conclusion is that "Evaluation of global expression patterns provides a molecular portrait of mitral valve disease, yields insight into the pathophysiologic aspects of DMVD [degenerative mitral valve disease], and identifies intriguing genes and pathways for further study."

4Repairing damaged heart cells by transplanting stem cells: Dr. Oyama also is investigating whether dogs' damaged heart cells can be repaired by transplanting the dogs' own stem cells into their hearts, a procedure called cardiac cellular transplantation.

4January 2007: Studying cellular changes that occur as the mitral valve deteriorates: Dr. Brendan M. Corcoran and Richard Han of the veterinary school at the University of Edinburgh, in collaboration with University College Galway, are conducting studies of the cell type of cavaliers afflicted with MVD, including the cellular changes that occur as the mitral valve deteriorates, assessing affected valves for the presence of a variety of markers that identify cell types, and determining if there is increased cell enzymatic activity which could result in valve destruction. The investigating panel suspects that that reason dogs develop MVD is because of a cell type, known as a valvular interstitial cell, which is malfunctioning and failing to produce normal structural components. These components are crucial to maintaining the valves structural rigidity, its shape and function, and to prevent it from leaking.

The study is looking at the structure and appearance of the valve cells using electron microscopy, thereby enabling the researchers to characterize the differences between normal and abnormal cells. The immediate aim of the studies is to prove these cells are abnormal, in what way they are abnormal, and why they are abnormal. In conjunction with that work, they are hope to determine procedures to isolate normal and abnormal cells and investigate the function of the cells in a controlled laboratory environment. See below a reference to Dr. Corcoran's 2004 article, "Identification of surface morphologic changes in the mitral valve leaflets and chordae tendineae of dogs with myxomatous degeneration", in the American Journal of Veterinary Research.

The Scottish study also involves evaluating the changes in the structural elements (collagen and elastin) in the valves, using routine and special stains for light microscopy, and looking at the expression of immunoglobulins in affected dogs. In a February 2006 interim report, the researchers stated that they are "confident that there are recognisable changes in the cell types that are crucial for maintaining healthy valves, and preliminary data suggests this is resulting in altered protein expression by the valve cells." According to the February 2006 interim report, Richard Han is leading two other projects related to the Scottish study. In the first, he is looking into "the structural change in the valve, particularly the spatial arrangement of the matrix, which gives the valves their structural rigidity and which is disorganised in disease." The researchers are using a powerful x-ray technique to investigate this problem.

Also, Mr. Han is leading a second related study, which is of innervation (nerve supply) of the mitral valve. Dr. Corcoran states that, "We know that a derangement of nerve supply has an adverse affect on valve function and we suspect on valve cells. This study is using immuno-histochemistry to map the innervation of the valve in normal and diseased dogs."

In their January 2007 report to the U.K.Cavalier King Charles Spaniel Club, the researchers state that their work is divided into five categories: (1) Immunohistochemical localization and identification of cell types in affected valves; (2) Quantification of cellular changes in diseased valves; (3) Identification of alteration in connective tissue elements and the factors that control these elements; (4) Evaluation of alteration in endothelial cell morphology and function; and (5) Analysis of differential protein and gene expression in diseased valves.

Dr. Corcoran concludes in his January 2007 report that, "We have identified fundamental changes in the valve that were not previously known and we have also identified the nature of change that occurs with disease progression. We have begun to look at the more fundamental changes that occur at the gene expression level and the consequence of changes in gene expression, namely what protein are expressed or absent. Like all research, this project has answered some questions, but has also raised new questions that will need investigation. Historically, we have known very little about the mitral valve disease in either dogs or humans and by its very nature this type of research slowly fills in the gaps in our knowledge hopefully eventually leading to the answer to the question of why does mitral valve disease occur."

Dr. Corcoran next (as of May 2007) is proceeding to investigate the phenomenon of interstitial cell phenotypic change further, using proteomics (two-dimensional gel electrophoresis) to identify potential proteins of interest. He states that, "From these data, in future studies we would use RT-PCR to identify differential gene expressions and identify potential genes of interest." The American Cavalier King Charles Spaniel Club's charitable trust's Darcy Fund, is helping to underwrite Dr. Corcoran's new area of research. Donations are tax deductible.

Dr. Corcoran may be reached at telephone 0131 650 6070, email Brendan.Corcoran@ed.ac.uk Mr. Han's telephone number is 0131 650 7680.

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Breeders' Responsibilities

Early-onset mitral valve disease has been found to be "highly heritable" in the cavalier King Charles spaniel breed, and "selection against the disease should be successful.", according to an April 2010 research report.

Due to the pervasiveness of MVD in the breed worldwide, cavalier King Charles spaniels under the age of five years should not be bred (with one limited exception -- see MVD Breeding Protocol). Also, no cavalier should be bred after age five years if it developed an MVD murmur before the age of five years. Any littermates of breeding stock having early-onset MVD (mitral valve murmurs before age 5 years) should be taken into very serious consideration. All CKCS breeding stock should be examined by board certified veterinary cardiologists at least annually and cleared by the veterinary specialists for MVD, the closer the examination to the breeding the better. It is recommended that all cavaliers, breeding stock or not, be examined annually by board certified veterinary cardiologists after age one year. See the current list of health clinics for upcoming cardiologist examinations.

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Mitral Valve Disease Seminars

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Related Links

MVD Breeding Protocol
Board Certified Veterinary Cardiologists
Diets
Questions for Breeders
Syncope
Canine Health Testing Clinics

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Two MVD support groups are Yahoo! Group: MVD in Cavaliers
and Karlin Lillington's CavalierTalk: SM and MVD Cavaliers Forum

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One cavalier's daily blog about her life with MVD: Darcy's Daily Blog
Darcy died at age 6 years in June 2006

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Laura Lang's CKCS Info Center webpage: Mitral Valve Disease

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American College of Veterinary Internal Medicine (ACVIM) Registry of Cardiac Health (ARCH)

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Veterinary Resources

Bradykinin stimulates afferent vagal C-fibres in intrapulmonary airways of dogs. Kaufman MP, Coleridge HM, Coleridge JCG, Baker DG. J Appl Physiol 1980;48:511-7.

Rapid shallow breathing evoked by selective stimulation of airway C fibres in dogs. H. M. Coleridge, J. C. G. Coleridge and A. M. Roberts. J Physiol 1983 Vol 340 pp 415-433.

Valvular incompetence in cavalier King Charles spaniels. Darke, PG. Vet Rec., Apr 1987; 120: 365 - 366.

Depressed contractile function due to canine mitral regurgitation improves after correction of the volume overload. K Nakano, M M Swindle, F Spinale, K Ishihara, S Kanazawa, A Smith, R W Biederman, L Clamp, Y Hamada, M R Zile, et al. Journal of Clinical Investigation 1991 June; 87(6): 2077–2086.

Understanding Mitral Valve Problems in Cavaliers. Buchanan J, Beardow A. CNE News & Views; Nov 1991.

Mitral valve replacement in dilated canine hearts with chronic mitral regurgitation. Importance of the mitral subvalvular apparatus. Yun KL, Rayhill SC, Niczyporuk MA, Fann JI, Zipkin RE, Derby GC, Handen CE, Daughters GT, Ingels NB, Bolger AF Circulation. 1991 Nov.; 84: 5 Suppl: III112-24.

Prevalence of mitral valve insufficiency in cavalier King Charles spaniels. Malik R, Hunt GB, Allan GS. Vet Rec., Apr 1992; 130: 302 - 303.

Chronic valvular disease in the cavalier King Charles spaniel in Sweden. Häggström J, Hansson K, Kvart C, L Swenson L. Vet Rec., Dec 1992; 131: 549 - 553.

Mitral Valve Disease in Cavalier King Charles Spaniels. Darke PG. 1993.

Chronic Mitral Valve Disease in Cavalier King Charles Spaniels: 95 Cases (1987-1991). Beardow A, Buchanan J. JAVMA 1993, Jan; 203(7): 1023-1029.

Plasma concentration of atrial natriuretic peptide in relation to severity of mitral regurgitation in Cavalier King Charles Spaniels. Häggström J, Hansson K, Karlberg BE, Kvart C, Olsson K. Am J Vet Res. 1994 May;55(5):698-703.

Tricuspid and mitral valvular disease: valve replacement. Breznock EM. Seminars in Vety Med & Surg (Small Anim). 1994 Nov;9(4):234-9.

Vertebral Scale System to Measure Canine Heart Size in Radiographs. Buchanan J, Bucheler J. JAVMA 1995, Jan; 206(2): 194-199.

Heart sounds and murmurs: changes related to severity of chronic valvular disease in the Cavalier King Charles spaniel. Häggström J, Kvart C, Hansson K. J Vet Intern Med. 1995 Mar-Apr;9(2):75-85.  Quote: "Auscultatory, phonocardiographic (PCG), radiographic, and echocardiographic evidence of chronic valvular disease (CVD) were studied in 79 Cavalier King Charles Spaniels with a mean age of 7.6 years (SD 2.6). Cardiac murmurs were present in 59 of the dogs and the intensity of the systolic cardiac murmur, assessed by auscultation (grade 1-6), was correlated (P < .001) to the severity of CVD (heart failure class) and to the echocardiographic dimensions of the heart (left atrial ratio, La/Ao-d, and left ventricular end diastolic diameter, LVEDD) (both P < .001). ...The relationship between cardiac dimensions (LVEDD and La/Ao-d) and S1a/S2a ratio was described by quadratic regression and found to be significant for both parameters (LVEDD; P < .001, R2 = .54 and La/Ao-d; P < .001, R2 = .63). The presence of a third heart sound (S3) was detected, using PCG, in 21 of the 68 dogs. The proportion of dogs exhibiting S3 increased with heart failure class (and increasing cardiac dimensions) (P < .001). These findings were confirmed by observations in 13 Cavalier King Charles Spaniels with cardiac failure progressing from heart failure class I to class II (Mean LVEDD from 30.2 to 35.2 mm and mean La/Ao-d from 1.09 to 1.43). An increase in intensity of the heart murmur, assessed by auscultation, increase in the ratio of the amplitudes of S1 and S2, as well as a shortening in Q-S2 and S1-S2 intervals (all P < .01) were found in these dogs."

Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: Results of invasive multicenter prosepective veterinary evaluation of enalapril study. IMPROVE Study Group. J Vet Intern Med 1995; 9:234-242.

Controlled clinical evaluation of enalapril in dogs with heart failure: Results of the cooperative veterinary enalapril study group. Cove Study Group. J Vet Intern Med 1995; 243-252.

Mitral valve replacement for the treatment of congenital mitral dysplasia in a bull terrier. White R.N., Stepien R.L., Hammond R.A., Holden D.J., Milner H.R., Cobb M.A., Hellens S.H. The Journal of Small Animal Practice 1995: 36, 407–410.

Activation of the renin-angiotensin system in dogs with asymptomatic and mildly symptomatic mitral valvular insufficiency. Pedersen HD, Koch J, Poulsen K, Jensen AL, Flagstad A. J Vet Intern Med. 1995 Sep-Oct;9(5):328-31.

Mitral valve prolapse in 3-year-old healthy Cavalier King Charles Spaniels. An echocardiographic study. H D Pedersen, B O Kristensen, K A Lorentzen, J Koch, A L Jensen, and A Flagstad. Can J Vet Res. 1995 October; 59(4): 294–298.  Quote: "Clinical studies have shown that Cavalier King Charles Spaniels (CKCS) have a high prevalence of mitral valvular insufficiency (MVI). Echocardiography has the potential to disclose early valvular changes, and the present prospective study was designed to investigate the occurrence of mitral valve prolapse (MVP) in young CKCS without heart murmurs, and to correlate the degree of MVP with the clinical status of the dogs by including CKCS with MVI as well. The study was based on blinded evaluations of echocardiographic recordings of mitral valves from 34 CKCS and 30 control dogs. Thirteen (87%) of 15 three-year-old CKCS without heart murmurs had MVP (2 total and 11 partial), as compared with 1 (7%) of 15 three-year-old normal Beagle dogs (P < 0.0001), and none of 15 three-year-old normal Medium Size Poodles (P < 0.0001). Of 19 CKCS with MVI, MVP was found in 84% of the entire group and in 100% of dogs with pulmonary congestion or edema. The occurrence of total MVP tended to be higher in the group with MVI (47%, 9/19), when compared with the younger CKCS without heart murmurs (13%, 2/15, P = 0.06). MVP was positively associated with excessive heart rate variability (P = 0.003). The radius of curvature of the anterior mitral valve leaflet in systole was significantly reduced in dogs with MVP when compared with those without (P < 0.0001). In conclusion, this study shows that CKCS at an early age have a high occurrence of MVP. This suggests: 1) A genetic predisposition of CKCS to MVP; and 2) That MVP is a pathogenetic factor in the development of mitral valvular insufficiency. Follow up studies may add further support to these proposals, and clarify whether echocardiography may be an aid in selecting CKCS for future breeding."

Relationship Between Parental Cardiac Status in Cavalier King Charles Spaniels and Prevalence and Severity of Chronic Valvular Disease in Offspring. Swenson L, Häggström J, Kvart C, Juneja RK. JAVMA 1996, Jan; 208(12): 2009-2012.

Heart rate variability in relation to severity of mitral regurgitation in Cavalier King Charles spaniels. Häggström J, Hamlin RL, Hansson K, Kvart C. J Small Anim Pract. 1996 Feb;37(2):69-75.  Quote: "Heart rate variability was measured in 81 Cavalier King Charles spaniels to investigate if it could be used to evaluate the severity of mitral regurgitation and to predict decompensation. Heart rate variability was assessed by the natural logarithm of the variance of the R-R intervals for 20 consecutive beats obtained from electrocardiographic recordings. Twenty-two of the dogs were clinically normal and 59 had mitral regurgitation caused by chronic valvular disease. The severity of mitral regurgitation was evaluated by echocardiography and thoracic radiography. Heart rate variability was found to be reduced (P < 0.001) among dogs with severe left atrial and ventricular dilatation and clinical signs of congestion. No significant differences in heart rate variability were found among normal dogs, dogs with only cardiac murmur, and dogs with echoradiographic evidence of slight to moderate left atrial and ventricular dilatation. Overall, an association was found between heart rate variability and left atrial to aortic root ration and left ventricular end diastolic diameters (r = 0.72 and 0.64, respectively, P < 0.001), as well as heart and respiratory rate (r = 0.80 and 0.69, respectively, P < 0.001). Multiregression analysis showed that, in order of importance, heart rate, left atrial diameter and respiratory rate had significant effects on heart rate variability. Among these parameters, heart rate variability and left atrial diameter were found to be most efficient in separating decompensated dogs from compensated. It is concluded that heart rate variability may provide the clinician with valuable information when assessing the severity of mitral regurgitation caused by chronic valvular disease."

Cavalier About Cavalier Heart Disease? Minors S. CKCSCC Newsletter. 1996.

Chronic Valvular Disease in Cavalier King Charles Spaniels: Epidemilogy, inheritance, and pathophysiology. Jens Häggström. Thesis, Swedish Univ. Ag. Sci., Uppsala, 1996.

The problem of inherited diseases. 5: Valvular disease in Cavalier King Charles spaniels. Swift, S., 1996. Journal of Small Animal Practice; 37:505-506.

Port-access mitral valve replacement in dogs. Pompili MF, Stevens JH, Burdon TA, Siegel LC, Peters WS, Ribakove GH, et al. J Thorac Cardiovasc Surg 1996; 112: 1268–1274.

Effects of enalapril on exercise tolerance and longevity in dogs with heart failure produced by iatrogenic mitral regurgitation. Hamlin, RL, Benitz, AM, Ericsson, GF, et al. J Vet Intern Med 1996; 10:85-87.

Mitral Valve Disease in Cavalier King Charles Spaniels. Darke, P., Fuentes VL, Kvart C, Häggström J. Swenson L.  Proceedings, Seminar by Intervet UK Ltd and The Cavalier King Charles Spaniel Club UK. November 1996.

Effects of long-term treatment with enalapril or hydralazine on the reninangiotensin-aldosterone system and fluid balance in dogs with naturally acquired mitral valve regurgitation. Haagstrom, J, Hansson, K, Bengt, E, et al.  Amer J Vet Res 1996; 57:1645-1652.

Effects of naturally acquired decompensated mitral valve regurgitation on the renin-angiotensin-aldosterone system and atrial natriuretic peptide concentration in dogs. Häggström J, Hansson K, Kvart C, Karlberg BE, Vuolteenaho O, Olsson K. Am J Vet Res. 1997 Jan;58(1):77-82.

Update on Mitral Valve Disease. Kvart C, Häggström J. Proceedings, 15th ACVIM Forum, 1997.

Chronic Valvular Disease in Cavalier King Charles Spaniels. Jacobs G. Outline of Lecture to CKCSC,USA 1997.

The cardiac effects of pimobendan (but not amrinone) are preserved at rest and during exercise in conscious dogs with pacing-induced heart failure. Ohte N, Cheng CP, Suzuki M, Little WC. J. Pharmacol. Exp. Ther. 1997 Jul;282(1):23-31.

International Symposium on Chronic Cardiac Valve Disease in the Cavalier King Charles Spaniel. Beardow A, Buchanan J, Fuentes VL, Keene B, Swenson L. Transcript of Private Recording of Proceedings, CKCSC,USA. May 1998.

Effects of enalapril on survival in dogs with naturally acquired heart disease: Results of the long-term investigation of veterinary enalapril (LIVE) study group. LIVE Study Group. J Am Vet Med Assoc 1998;213:1573–1577.

Hypomagnesemia and mitral valve prolapse in Cavalier King Charles spaniels.  Pedersen HD, Mow T.; Zentralbl Veterinarmed A. 1998 Dec;45(10):607-14. Effects of renal impairment on the disposition of orally administered enalapril, benazepril, and their metabolites. Lefebvre, HP, Laroute, V, Concordet, D, Toutain, P. J Vet Intern Med 1999Jan-Feb;13(1):21-27.

Auscultation in Mild Mitral Regurgitation in Dogs: Observer Variation, Effects of Physical Maneuvers, and Agreement with Color Doppler Echocardiography and Phonocardiography. Pedersen HD, Häggström J, Falk T, Mow T, Olsen LH, Iversen L, Jensen AL. J Vet Intern Med. 1999 Jan-Feb;13(1):56-64.

Echocardiographic mitral valve prolapse in cavalier King Charles spaniels: epidemiology and prognostic significance for regurgitation. Pedersen HD, Lorentzen KA, Kristensen BO. Vet Rec., Mar 1999; 144: 315 - 320.

Textbook Of Canine And Feline Cardiology: Principles And Clinical Practice.  Fox P., Sisson D. D., Moise N. S., Saunders (Elsevier) 1999.

Renal safety of chronic enalapril therapy in dogs with compensated mitral regurgitation. VETPROOF Study Group. J Vet Intern Med 1999; 13:246.

The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: results of a multi center, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial. The BENCH Study Group. J Vet Cardiol 1999;1:5–18.

No Expression of Angiotensin II Receptors and Angiotensin-Converting Enzyme in Myxomatous Canine Mitral Valve Leaflets. An Autoradiographic Study. Mow T., Pedersen H.D. J. Vet. Med. Series A; Oct 1999; 46(8):465-472.

 "Acquired valvular heart disease." (Kvart C, Häggström J.) in: Textbook of Veterinary Internal Medicine. 5thed., Ettinger SJ, Feldman EC, eds.;WB Saunders, 2000:787-800.

New Insights on Effect of Kidney Insufficiency on Disposition of Angiotensin-Converting Enzyme Inhibitors: Case of Enalapril and Benazepril in Dogs. Pierre-Louis Toutain, Hervé P. Lefebvre and Valérie Laroute. J. Pharmacology & Experimental Therapeutics; March 2000; 292(3):1094-1103.

Nutritional Therapy in the Treatment of Heart Disease in Dogs. Robert S. Dove. Alternative Medicine Review; 6 Supp.: S/38-S/45; 2001.

Increased platelet aggregation response in Cavalier King Charles spaniels with mitral valve prolapse.  Olsen,L.H., Kristensen, A.T., Häggström, J., Jensen, A.L., Klitgaard, B., Hansson, H., Pedersen, H.D. J.Vet. Internal Med. 2001, 15:209-216.

Use of breed-specific ranges for the vertebral heart scale as an aid to the radiographic diagnosis of cardiac disease in dogs. Lamb CR, Wikeley H, Boswood A, Pfeiffer DU. Vet Rec. 2001 Jun 9;148(23):707-11.

Ultrastructural morphologic evaluation of the phenotype of valvular interstitial cells in dogs with myxomatous degeneration of the mitral valve. Black A., French A.T., Dukes-McEwan J., Corcoran B.M. AmJ.Vet.Res., 2001 Nov; 66(8):1408-1414.

Effect of age and body weight on neurohumoral variables in healthy Cavalier King Charles Spaniels. Eriksson A.S., Järvinen A.-K., Eklund K.K., Vuolteenaho O.J., Toivari M.H., Nieminen M.S. Am.J.Vet.Res. 2001 Nov,62(11):1818-1824.

Efficacy of Enalapril for Prevention of Congestive Heart Failure in Dogs with Myxomatous Valve Disease and Asymptomatic Mitral Regurgitation. Kvart C, Häggström J, Pedersen HD, Hansson K, Eriksson A, Jarvinen AK, Tidholm A, Bsenko K, Ahlgren E, Ilves M, Ablad B, Falk T, Bjerkfas E, Gundler S, Lord P, Wegeland G, Adolfsson E, Corfitzen J. J Vet Intern Med. 2002 Jan-Feb;16(1):80-88.

A Double-Blind, Randomized, Placebo-Controlled Study of Pimobendan in Dogs with Dilated Cardiomyopathy. Fuentes V. L.,Corcoran C., French A., Schober K. E., Kleemann R. , Justus C.; J Vet Intern Med. 2002 May;16(3):255–261.

Left atrial to aortic root indices using two-dimensional and M-mode echocardiography in cavalier King Charles spaniels with and without left atrial enlargement. Hansson, K., Häggström, J., Kvart, C. & Lord, P. Vet. Rad. & Ultra. (2002) 43:568–575.

Chronic valvular heart disease in dogs. Rush J.E.. In: Proceedings of the 26th Annual Waltham Diets; OSU Symposium for the Treatment of Small Animal Cardiology, pp. 1-7, 2002.

Enalapril monotherapy in asymptomatic mitral regurgitation: results of VETPROOF (Veterinary Enalapril Trial to Prove Reduction in Onset Of Failure). Atkins CE. ACVIM Forum Presentation, 75-76, 2002.

Effects of long-term administration of enalapril on clinical indicators of renal function in dogs with compensated mitral regurgitation. Atkins CE, Brown WA., Coats JR, et al.; JAVMA 2002 Sept; 221(5):654-658.

Clinical and Echo Doppler Follow-Up of a Mitral Valve Stenosis Corrected by Open Heart Surgery in a Dog. Carlos C, Daniel P, Borenstein N.; Proceedings, 37th World Small Animal Vet. Assn., Oct 2002.

A Clinical Trial about the Efficacy of Pimobendan in Comparison to Enalapril in Dogs with Mitral Valve Endocardiosis.  Deinert M, Ripken A; Proceedings, 37th World Small Animal Vet. Assn., Oct 2002.

Regurgitant Fraction Measured by Using the Proximal Isovelocity Surface Area Method in Dogs with Chronic Myxomatous Mitral Valve Disease.  Kittleson M. D., Brown, W. A.; J Vet Intern Med. 2003 Jan;17(1):84-88.

Spectral analysis of heart rate variability in dogs with mild mitral regurgitation. Fujii Y., Wakao Y. AmJ.Vet.Res. 2003 Feb; 64(2):145-148.

Brain Natriuretic Peptide Concentration in Dogs with Heart Disease and Congestive Heart Failure. Kristin A. MacDonald, Mark D. Kittleson, Coralie Munro, and Philip Kass. J Vet Intern Med. 2003 Mar;17(2):172–177.

Decreased Plasma Concentration of Nitric Oxide Metabolites in Dogs with Untreated Mitral Regurgitation.  Pedersen H. D., Schütt T., Søndergaard R., Qvortrup K., Olsen L. H., Kristensen A. T. J Vet Intern Med. 2003 Mar;17(2):178-184.

Spectral analysis of heart rate variability in dogs with mild mitral regurgitation. Fujii Y, Wakao Y. Am J Vet Res 2003;64:145–148.

Decreased Platelet Function in Cavalier King Charles Spaniels with Mitral Valve Regurgitation.  Tarnow I., Kristensen A. T., Texel H., Olsen L. H., Pedersen H. D.; Vol. 17, No. 5, pp. 680–686. J Vet Intern Med. 2003 Sep;17(5):680-686.

Investigation of pimobendan versus benazepril in canine myxomatous valvular disease. Boswood A, McEwan JD, French A, Little C, Swift S, Smith S, Patteson M. Vet Rec. 2003 Oct 4;153(14):439-40.

Clinical investigation of Ramipril(VASOTOP) on canine chronic heart failure. Okusa Kiyoshi, Inoue Midori, Kurita Tooru, Takehara Kazutaka, Sasagawa Kazuyasu, Nameki Yoshikazu, Yonezawa Satoru, Kanno Shigeyuki. Jap.J.Sm.An.Prac. 2003; 22(2):93-103 Quote: "The efficacy of ramipril(Vasotop) was confirmed in a clinical investigation conducted in 26 small-animal hospitals using 89 dogs with chronic heart failure. 74 dogs were received ramipril and the other 15 dogs were received placebo tablets. Two of 74 dogs didn't visit the hospital for the last evaluation, other two dogs died of morbid pulmonary edema and one dog was terminated administration at 7th day due to vomit, polydipsia & polyuria, anorexia and decrease of activity. Ramipril was administered orally once a day for 28 consecutive days to achieve a minimum dosage of 0.125mg/kg. The daily dosage in the ramipril group(69 dogs) ranged from 0.125 to 0.313mg/kg. The clinical effectiveness of ramipril was evaluated using the five parameters as activity, exercise tolerance, breathing difficulties, cough and NYHA class. As a result, 1) Significant improvement was observed in ramipril group at 7th day after treatment. 2) Effective rate of ramipril treatment was 87.0%. And even a plain administration of ramipril(without concomitant drug) indicated curative properties as equal as 85.9%. 3) The improvement of the symptoms was observed in all 7 dogs, which showed high BUN value before administration(>35mg/dl). As for BUN values of these dogs, they showed decline or no change except one uremia dog. Accordingly, the clinical efficacy of ramipril orally given at 0.125-0.25mg/kg once daily on canine chronic heart failure was confirmed significantly. In the context of safety, no adverse drug reactions potentially inhibiting clinical applications were observed."

Assessment of the Ability of Pimobendan to Increase the Frequency of Ventricular Ectopy in Dogs with CHF Due to DCM and Chronic Mitral Valve Insufficiency. MR O’Grady, SL Minors, ML O'Sullivan, R Horne. J Vet Intern Med; May/June 2004;18(3) (ACVIM 22st Ann. Vet. Med. Forum Abstract Program: Abstract 258).

Identification of surface morphologic changes in the mitral valve leaflets and chordae tendineae of dogs with myxomatous degeneration. Corcoran BM, Black A, Anderson H, Dukes-McEwan J, French A, Smith P, Devine C. Am J Vet Res 2004;65:198–206.

Evaluation of techniques and outcomes of mitral valve repair in dogs. Griffiths LG, Orton EC, Boon JA. J Am Vet Med Assoc. 2004 Jun 15;224(12):1941-5.

Differences between breeds of dog in a measure of heart rate variability. Doxey S, Boswood A. Vet Rec. 2004 Jun 5;154(23):713-7.

Caractéristiques épidémiologiques, cliniques, écho-doppler de l’endocardiose mitrale chez le Cavalier King Charles en France: étude rétrospective de 451 cas (1995 à 2003). Valérie Chetboul, Renaud Tissier, Florence Villaret, Audrey Nicolle, Eric Déan, Thierry Benalloul, Jean-Louis Pouchelon. Can Vet J 2004;45:1012–1015. Quote: "A study performed on 451 Cavalier King Charles showed that 40.6% of dogs had a left apical systolic heart murmur, whose prevalence increased with age (. 11-year-old, 100%), but was not different between males and females. Mitral valve endocardiosis represented 93.3% of the ultrasonographic abnormalities."

Breed Predispositions to Disease in Dogs & Cats.  Alex Gough, Alison Thomas. 2004; Blackwell Publ. 44-45.

Use of pimobendan in the management of heart failure. Fuentes VL. Vet Clin North Am Small Anim Pract. 2004 Sep;34(5):1145-55.

New insights into degenerative mitral valve disease in dogs. Jens Häggström, Henrik Duelund Pedersen, and Clarence Kvart. Vet. Clinics of No.h Amer.: Small Anim.Pract.2004 Sep;34(5):1209-26.

Experimental models and mechanisms of enhanced coughing. Donald C. Bolser. Pulmonary Pharmacology & Therapeutics 17 (2004) 383–388. Quote: "Enhanced coughing can be produced in a variety of animal models, including the guinea pig, cat, dog and pig. Typically, airway inflammation has been produced by sensitization, exposure to cigarette smoke, sulphur dioxide or angiotensin-converting enzyme inhibitors. In some of these models, inflammatory mediators such as bradykinin and tachykinins have been shown to contribute to the enhanced coughing."

Comparison of the effects of imidapril and enalapril in a prospective, multicentric randomized trial in dogs with naturally acquired heart failure. Amberger C, Chetboul V, Bomassi E, et al. J Vet Cardiol 2004;6:9-16.

Angiotensin-converting enzyme inhibitors in the therapy of renal diseases. Lefebvre, H. P. & Toutain, P. L. J. Vet. Pharm. & Therap., Oct.2004; 27(5):265-281.

Assessment of changes in hemostatic markers in Cavalier King Charles Spaniels with myxomatous mitral valve disease. Tarrow I, Kristensen AT, Olsen LH, Pedersen HD. Am J Vet Res 2004 Dec.;65(12):1644–1652.

Epidemiological, clinical, echo-doppler characteristics of mitral valve endocardiosis in Cavalier King Charles in France: a retrospective study of 451 cases (1995 to 2003). Chetboul V, Tissier R, Villaret F, Nicolle A, Dean E, Benalloul T, Pouchelon JL. Can Vet J. 2004 Dec;45(12):1012-5.

Non-invasive real-time measurements of cardiac vagal tone in dogs with cardiac disease. Little C,J,, Julu P.O., Hansen S., and Reid S.W. Vet Rec., Jan 2005; 156: 101 - 105.

Canine Heart Failure - Current Concepts: Strengths and Weaknesses. Atkins C. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 111-113.

Carvedilol and the Heart - A Promising Therapy. Miller M. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 125, 130.

Future Directions for Diagnosis Treatment and Management Strategies. Miller M. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 131-133.

Pimobendan A New Drug for Heart Failure Management. Miller M. Proceedings, 19th No. Am. Vet. Conf., Jan. 2005: 129.

Mortality in over 350,000 Insured Swedish dogs from 1995–2000: I. Breed-, Gender-, Age- and Cause-specific Rates. BN Bonnett, A Egenvall, Å Hedhammar, P Olson. Acta Vet Scand. 2005; 46(3): 105–120. Quote: "As an example, in Cavalier King Charles spaniels ... deaths ... in the diagnostic category heart ... account for 52% of all deaths in that breed."

Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs With Long-Term Pimobendan Therapy. R. Tissier; V. Chetboul; R. Moraillon; A. Nicolle; C. Carlos; B. Enriquez; J-L. Pouchelon. Cardiovascular Toxicology; March 2005; 5(1):43-52(10). Quote: "The aim of this article is to describe original adverse effects in two dogs chronically treated with the inodilator pimobendan. We report a German shepherd (i.e., dog 1) and a poodle (i.e., dog 2) that were referred to our cardiology unit after receiving pimobendan for 10 and 5 mo, respectively. In both dogs, conventional echo-Doppler examination demonstrated mitral valve regurgitation and myocardial hypertrophy. Tissue Doppler imaging (TDI) was performed in the first case and revealed an abnormal relaxation phase. After the first examination, pimobendan administration was stopped in both cases and dogs were re-examined 3 and 1 mo later, respectively. Mitral valve regurgitation assessed by echocardiography decreased in both dogs, and the systolic heart murmur disappeared in dog 1. Importantly, most echocardiographic and TDI parameters tended to normalize in dog 1, suggesting, at least partial reversal of both myocardial hypertrophy and relaxation abnormality produced during inodilator therapy. This is the first report to describe an increase in mitral regurgitation under clinical conditions in dogs treated with pimobendan. We also suggest that pimobendan may induce ventricular hypertrophy. However, prospective studies are needed to confirm this observation."

Degenerative Mitral Valve Disease Prevalence in King Charles Spaniels. Odhelius A. Master thesis 2005:1, Swedish Univ. of Agricultural Sciences. An Approach to Asymptomatic Acquired Heart Disease in Dogs and Cats. Clarke E. Atkins. World Small Animal Veterinary Association, 30th World Small Animal Vet. Assn., May 2005.

Efficacy and safety of pimobendan in canine heart failure caused by myxomatous mitral valve disease. Smith P J.; French A T.; Van Israël N; Smith S G.W.; Swift S T.; Lee A J.; Corcoran B M.; Dukes-McEwan J. J Small Animal Practice, 31 March 2005, 46(3):121-130(10). Quote: "Treatment with pimobendan was well tolerated compared with treatment with ramipril. Pimobendan dogs were 25 per cent as likely as ramipril dogs to have an adverse heart failure outcome ... These results should be interpreted cautiously ... [and] warrants further investigation."

Hemodynamic effects of orally administered carvedilol in healthy conscious dogs. Abbott JA, Broadstone RV, Ward DL, Pyle RL. Am J Vet Res 2005;66:637–641. Interobserver Variability of Vertebral Heart Size Measurements in Dogs with Normal and Enlarged Hearts, Kerstin H, Häggström J, Kvart C, Lord P, Veterinary Rad. & Ultrasound, Mar. 2005, 46(2): 122.

Surgical Correction of a Partial Atrioventricular Septal Defect With a Ventricular Septal Defect in a Dog. Midori Akiyama, DVM, Ryou Tanaka, DVM, PhD, Kohji Maruo, DVM, PhD and Yoshihisa Yamane, DVM, PhD. J.Amer. Animal Hosp. Assn.41:137-143 (2005). (A 6-month-old, 15.6 lb., male Shiba Inu with a cardiac murmur "due to an ostium primum septal defect, a ventricular septal defect, and mitral valve malformation with regurgitation. The mitral valve and tricuspid valve were separated and displaced at the same level as the ventricular septum. The mitral valve had a cleft in the septal cusp. ... An incision was made in the right atrium, and an ASD (25 x 15 mm in diameter) was identified in the lower portion of the atrial septum immediately above the ventricular septum. The mitral valve was seen through the ASD, and there was a cleft in the septal cusp. The cleft separated the septal cusps into two portions, both of which had thick edges. The cleft was repaired with mattress sutures of 5-0 polypropylenes. The ASD was then closed with sutures of 5-0 polypropylene using pledgets. A small VSD (5 mm in diameter) was observed behind the septal cusp of the tricuspid valve. The VSD was closed with simple mattress sutures of 5-0 polypropylene. The right atrium was sutured closed with a simple continuous pattern of 5-0 polypropylene.")

Mitral valve prolapse in Cavalier King Charles Spaniel: A review and case study. Hyun C. J. Vet. Sci. 2005 Mar;6(1):67-73.

Technique and outcome of mitral valve replacement in dogs. Orton EC, Hackett TB, Mama K, Boon JA. J Am Vet Med Assoc. 2005 May 1;226(9):1508-11, 1500.

Evaluation of a New Brain Natriuretic Peptide Assay in Dogs. William E. Herndon, Justine A. Lee, Kenneth J. Drobatz, Matthew J. Ryan. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 68).

Short-term Hemodynamic Effects of Chronic Oral Carvedilol in Cavalier King Charles Spaniels with Asymptomatic Chronic Degenerative Valve Disease. S.G. Gordon, A. Bahr, M.W. Miller, D.M. Boothe, & K. Glaze. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 69).

Biomarkers of Platelet Activation in Cavalier King Charles Spaniels. D.F. Hogan, D.J. Weiss, C.A. Thompson, M.P. Ward. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 175).

Long-term Effects of Pimobendan and Benazepril On Several Echocardiographic and Tissue Doppler Imaging Variables in Dogs with Asymptomatic Myxomatous Mitral Valve Disease. V. Chetboul, H.P. Lefebvre, C. Carlos Sampedrano, A.P. Nicolle, V. Saporano, V. Gouni, D. Concordet, J.-L. Pouchelon. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 199).

Circulating Concentrations of Insulin-Like Growth Factor-1 in Dogs with Naturally Occurring Mitral Regurgitation.  Pedersen H. D., Falk T., Häggström J., Tarnow I., Olsen L. H., Kvart C., Nielsena M. O.; J Vet Intern Med. 2005 Jul;19(4):528-532.

Dogs with Heart Diseases Causing Turbulent High-Velocity Blood Flow Have Changes in Platelet Function and von Willebrand Factor Multimer Distribution.  Tarnow I., Kristensen A. T., Olsen L. H., Falk T., Haubro L., Pedersen L. G.,Pedersen H. G.; J Vet Intern Med. 2005 Jul-Aug;19(4):515-521. Quote: "The purpose of this prospective study was to investigate platelet function using in vitro tests based on both high and low shear rates and von Willebrand factor (vWf) multimeric composition in dogs with cardiac disease and turbulent high-velocity blood flow. Client-owned asymptomatic, untreated dogs were divided into 4 groups: 14 Cavalier King Charles Spaniels (Cavaliers) with mitral valve prolapse (MVP) and no or minimal mitral regurgitation (MR), 17 Cavaliers with MVP and moderate to severe MR, 14 control dogs, and 10 dogs with subaortic stenosis (SAS). Clinical examinations and echocardiography were performed in all dogs. PFA100 closure times (the ability of platelets to occlude a hole in a membrane at high shear rates), platelet activation markers (plasma thromboxane B2 concentration, platelet surface P-selectin expression), platelet aggregation (in whole blood and platelet-rich plasma with 3 different agonists), and vWf multimers were analyzed. Cavaliers with moderate to severe MR and dogs with SAS had longer closure times and a lower percentage of the largest vWf multimers than did controls. Maximal aggregation responses were unchanged in dogs with SAS but enhanced in Cavaliers with MVP (regardless of MR status) compared with control dogs. No significant difference in platelet activation markers was found among groups. The data suggest that a form of platelet dysfunction detected at high shear rates was present in dogs with MR and SAS, possibly associated with a qualitative vWf defect. Aggregation results suggest increased platelet reactivity in Cavaliers, but the platelets did not appear to circulate in a preactivated state in either disease."

Quantitative Echocardiographic Evaluation of Mitral Endocardiosis in Dogs Using Ratio Indices. Brown D.J., Rush J.E., MacGregor J., Ross J.N.Jr., BrewerB., and Rand W.M. J Vet Intern Med 2005 Jul-Aug;19 (4):542–552.

Neurohormonal and Circulatory Effects of Short-Term Treatment with Enalapril and Quinapril in Dogs with Asymptomatic Mitral Regurgitation. Moesgaard S.G., Pedersen L.G., Teerlink T., Häggström J., Pedersen H.D. J. Vet. Intern. Med. 2005 Sep-Oct; 19(5): 712-719.

Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs. Arsenault, W.G., Boothe, D.M., Gordon, S.G., Miller, M.W., Chalkley J.R., Petrikovics, I. Am J Vet Res 2005;66:2172–2176.

Updates on the Diagnosis and Treatment of Canine Heart Disease. Gordon, Sonya G. Proceedings, 20th No. Am. Vet. Conf., Jan. 2006: 216-218.

Role of Positive Inotropic Agents for Managing Dogs with Mitral Valve Disease. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 221.

Value of Measuring Cardiac Troponins in Your Practice. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 222.

Diagnostic and Prognostic Variables in Mitral Valve Disease in Dogs. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 226-227.

How I Treat Heart Failure Due to Mitral Regurgitation. Häggström, Jens. Proceedings, No. Am. Vet. Conf., Vol. 20, Jan. 2006: 228.

Pimobendan in Heart Failure Therapy – A Silver Bullet? Gordon S.G., Miller M.W., and Saunders A.B. J. Am. Animal Hosp. Assn. March/April 2006; 42:90-93. Pharmacodynamics of Carvedilol in Conscious, Healthy Dogs. Sonya G. Gordon, Wendy G. Arsenault, Mike Longnecker, Dawn M. Boothe, Matthew W. Miller, and Jeff Chalkley. J Vet Intern Med March/April 2006;20:297–304.

Efficacy of oral tadalafil, a new long-acting phosphodiesterase-5 inhibitor, for the short-term treatment of pulmonary arterial hypertension in a dog. Serres F, Nicolle AP, Tissier R, Gouni V, Pouchelon JL, Chetboul V. J Vet Med A Physiol Pathol Clin Med. 2006 Apr;53(3):129-33.

C-Reactive Protein Concentration in Dogs with Chronic Valvular Disease. John E. Rush, Nathan D. Lee, Lisa M. Freeman, and Barbara Brewer. J Vet Intern Med; May/June 2006;20:635–639.

Acute Cardiovascular Effects of Pimobendan in Dogs with Stable Congestive Heart Failure Due To Chronic Degenerative Atrioventricular Valve Disease. RM Roland, SG Gordon, A Bahr , MW Miller, AB Saunders. J Vet Intern Med; May/June 2006;20(3) (ACVIM 24th Ann. Vet. Med. Forum Abstract Program: Abstract 75).

Physiological Flow Murmurs in Cavalier King Charles Spaniels.  LH Olsen, R Hjarbaek, HD Pedersen. J Vet Intern Med; May/June 2006;20(3) (ACVIM 24th Ann. Vet. Med. Forum Abstract Program: Abstract 136).

Cardiovascular effects of a phosphodiesterase III inhibitor in the presence of carvedilol in dogs. Uechi M, Hori Y, Fujimoto K, Ebisawa T, Yamano S, Maekawa S. J Vet Med Sci. 2006 Jun;68(6):549-53.

Clinical Efficacy of Pimobendan Versus Benazepril for the Treatment of Acquired Atrioventricular Valvular Disease in Dogs. Christophe W. Lombard, Olaf Jöns, and Claudio M. Bussadori. J. Am. Anim. Hosp. Assoc., July/August 2006; 42: 249 - 261.

Heart Disease as a Cause of Death in Insured Swedish Dogs Younger Than 10 Years of Age. Agneta Egenvall, Brenda N. Bonnett, and Jens Häggström. J Vet Intern Med July/August 2006;20:894–903.

Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease. Mark A. Oyama, and Sridar V. Chittur. Am. J.Vet. Research; Aug. 2006, 67:8, 1307-1318.

Effects of Dietary Modification in Dogs with Early Chronic Valvular Disease. Lisa M. Freeman, John E. Rush, and Peter J. Markwell. J Vet Intern Med, Sep 2006;20:(5)1116–1126.  Quote: "The potential benefits of nutritional modification in early canine cardiac disease are not known. We hypothesized that echocardiographic, neuroendocrine, and nutritional variables will differ between dogs with asymptomatic chronic valvular disease (CVD) and healthy controls, and that a moderately reduced sodium diet enriched with antioxidants, n-3 fatty acids, taurine, carnitine, and arginine will alter these variables in dogs with CVD. Echocardiography was performed and blood was collected. After baseline comparison with healthy controls, all dogs with CVD were fed a low-sodium run-in diet for 4 weeks, reevaluated, and then randomized to receive either the cardiac diet or a placebo diet for 4 weeks. RESULTS: At baseline, dogs with CVD (n = 29) had significantly lower circulating sodium, chloride, arginine, and methionine concentrations and higher plasma concentrations of atrial natriuretic peptide compared to healthy controls. In dogs with CVD, plasma aldosterone concentration and heart rate increased significantly after 4 weeks of eating the run-in diet. The cardiac diet group (n = 14) had larger increases in levels of cholesterol (P = .001), triglycerides (P = .02), eicosapentaenoic acid (P < .001), docosahexaenoic acid (P < .001), total omega-3 fatty acids (P < .001), vitamin C (P = 0.04), alpha-tocopherol (P < .001), and gamma-tocopherol (P < .001) compared to the placebo diet group (n = 15). The cardiac diet group also had larger reductions in maximal left-atrial dimension (P = .003), left-ventricular internal dimension in diastole (P = .03), and weight-based maximal left-atrial dimension (P = .03). CONCLUSIONS AND CLINICAL IMPORTANCE: Observed changes in both blood variables and echocardiographic measurements warrant additional studies on dietary modifications in dogs with early CVD."

Echocardiographic estimation of systemic systolic blood pressure in dogs with mild mitral regurgitation. SP Tou, DB Adin, AH Estrada. J Vet Intern Med, Sep 2006;20:1127-1131.

Comparison of Canine Cardiac Troponin I Concentrations as Determined by 3 Analyzers. Darcy B. Adin, Mark A. Oyama, Margaret M. Sleeper, and Rowan J. Milner. J. Vet Intern Med, Sep 2006;20:1136–1142.

Recurrent syncope: only the heart was considered. Peter Stiefelhagen. MMW Fortschr Med. 2006 Sep 28;148 (39):21.

Pimobendan: Understanding its cardiac effects in dogs with myocardial disease. Justin D. Thomason, Tiffany K. Fallaw, and Clay Calvert. Vet. Med. Oct. 2006.

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B-Type Natriuretic Factor, Endothelin, and Cardiac Troponin-I. Robert Prosek, D. David Sisson, Mark A. Oyama, and Philip F. Solter. J Vet Intern Med 2007;21:238–242.

Prospective Clinical Evaluation of an ELISA B-Type Natriuretic Peptide Assay in the Diagnosis of Congestive Heart Failure in Dogs Presenting with Cough or Dyspnea. Teresa C. DeFrancesco, John E. Rush, Elizabeth A. Rozanski, Bernard D. Hansen, Bruce W. Keene, Dominic T. Moore, and Clarke E. Atkins. J Vet Intern Med 2007;21:243–250.

Beating Heart Mitral Valve Replacement with a Bovine Pericardial Bioprosthesis for Treatment of Mitral Valve Dysplasia in a Bull Terrier. Luc Behr, Valérie Chetboul, Carolina Carlos Sampedrano, Gouni Vassiliki, Jean-louis Pouchelon, François Laborde, and Nicolas Borenstein. Veterinary Surgery, Volume 36, Issue 3: 190-198, 2007.

Healing of wound sutures on the mitral valve: an experimental study. Koichi Tamura, Mayumi Murakami, and Makoto Washizu. J. Gen. Thoracic and Card. Surg.; 55(3): pp. 98-104; March, 2007. Quote: "Objective: The aim of this study was to examine the histopathological changes that occur during the heading process of a sutured wound on the mitral valve. Methods In 12 mongrel dogs, an incision was made at a right angle to the annulus at the center of the free edge of the anterior mitral leaflet and then sutured. Animals were killed 2–16 weeks later and the wounds were examined histologically. Results: Two weeks after the operation, fibrin thrombi were found on the atrial surfaces of the wound, and organized thrombi became part of the neointima thereafter. There were capillaries in the thrombi, but only a few extended from the valvular ring. On the ventricular surfaces, fibrous neointima extending from adjacent intima without capillary proliferation covered the wound at 2 weeks. These heading processes started from the valvular ring side of the wound. Processes were delayed near the free edge area, and myxomatous granulation tissue extended from the adjacent spongiosa. There were abundant collagen fibers obscuring the suture line at 4 weeks in the basal region and at 12–16 weeks near the free edge. Calcified deposits with cartilage were found in a thick scar in the basal region at 4 weeks and extended to the central area thereafter. Conclusion: The healing of mitral valvular wounds is slow, especially near the free edge area. The wound is covered by organized thrombi at the atrial surface and by fibrous sheaths at the ventricular surface. These processes should be taken into consideration during the patients’ care after valvoplasty, especially during the first several months after surgery."

Clinical evaluation of imidapril in congestive heart failure in dogs: results of the EFFIC study. B. Besche, V. Chetboul, M.-P. Lachaud Lefay, E. Grandemange. J. Small An. Prac. 48 (5), 265–270, May 2007. Quote: "The success rate in the imidapril group was 66 compared with 68 per cent in the benazepril group. Regarding safety, 35 dogs in each group experienced at least one adverse event. Nine dogs in each group experienced at least one serious adverse event. The difference between these results was not statistically significant. ... Imidapril is as efficacious and safe as the reference product, benazepril".

Natriuretic Peptides Are Elevated in Cavalier King Charles Spaniels with Congestive Heart Failure but Not in Dogs with Clinically Inapparent Mitral Valve Disease. I. Tarnow, H.D. Pedersen, C. Kvart, K. Hoglund, T.S. Kamstrup, L.H. Olsen, J. Häggström. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 54). Quote: "These data confirm previous findings of elevated plasma ANP and BNP in dogs with CHF. However, the data do not support the relevance of NT-proBNP and proANP assays in blood-based detection of clinically inapparent MVD."

Frequency of Ventricular Ectopy in Dogs with Chronic Mitral Valve Disease and Congestive Heart Failure Treated with Pimobendan or Benazepril. M.L. O’Sullivan, M.R. O’Grady, C. Walker. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 55). Quote: "Pimobendan did not result in an increase in frequency of ventricular arrhythmias in comparison to benazepril."

Brain Naturetic Peptide for Discrimination of Respiratory Distress Due to Congestive Heart Failure or Primary Pulmonary Disease. D.M. Fine, .E. Declue, C.R. Reinero. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 56).

The Utility of NT-proBNP to Differentiate Cardiac And Respiratory Causes of Coughing or Dyspnea In Dogs. G. Wess, N. Timper, J. Hirschberger. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 131).

Acute Hemodynamic Effects of Oral Tadalafil in Dogs with Severe Mitral Valve Disease and Pulmonary Hypertension. JS Orvalho, WP Thomas, PH Kass. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 137). Quote: "These data suggest that oral tadalafil, when added to conventional heart failure therapy, decreases the pulmonary artery pressure in this group of dogs."

Evaluation of Pimobendan in the Treatment of Early Mitral Valve Disease. Ouellet M, Difruscia R, Bélanger MC. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 138). Quote: "... data suggest a possible non-sustained positive inotropic effect and a reduction of the (mitral regurgitation fraction) at 90 days with the administration of pimobendan in early chronic MVD."

Pharmacokinetics of Bisoprolol Versus Carvedilol in Dogs. G Beddies, PR Fox, M Papich, V-R Kanikanti, R Krebber, BW Keene. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 139). Quote: "These dramatic differences suggest that bisoprolol has less inter-individual pharmacokinetic variability than carvedilol in the dog. The pharmacokinetic advantages of bisoprolol versus carvedilol should be considered when contemplating clinical application of these agents."

The Effect of Pimobendan on the Reninangiotensin-Aldosterone System and Arrhythmogensis in the Dog. M.A. Booth, C.E. Atkins, Y. Fujii, A.K. Adams, T.C. DeFrancesco, B.W. Keene. J Vet Intern Med. 2007; 21(3) (ACVIM 25th Ann. Vet. Med. Forum Abstract Program: Abstract 140). Quote: "We conclude that there is no significant increase in ventricular ectopy in healthy dogs given a combination of furosemide and pimobendan and, as postulated, that pimobendan does not activate the RAAS. However, pimobendan given concurrently with furosemide does not prevent RAAS activation."

Quantification of mitral valve regurgitation in dogs with degenerative mitral valve disease by use of the proximal isovelocity surface area method. Vassiliki Gouni, François J. Serres, Jean-Louis Pouchelon, Renaud Tissier, Hervé P. Lefebvre, Audrey P. Nicolle, Carolina Carlos Sampedrano, Valérie Chetboul. J Am Vet Med Assn Aug 2007;231(3): 399-406. Quote: "Results suggested that regurgitant fraction (RF) is a repeatable and reproducible variable for noninvasive quantitative evaluation of mitral valve regurgitation in awake dogs. Regurgitation fraction also correlated well with disease severity. It appears that this Doppler echocardiographic index may be useful in longitudinal studies of MVD in dogs."

Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study. Valérie Chetboul, Hervé P Lefebvre, Carolina Carlos Sampedrano, Vassiliki Gouni, Vittorio Saponaro, François Serres, Didier Concordet, Audrey P Nicolle, Jean-Louis Pouchelon. J Vet Intern Med. 2007; 21 (4):742-53. Quote: "A significant treatment effect was observed as soon as day 15 with increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening (P < .0001) and tissue Doppler variables (P = .001). Concurrently, the maximum area and peak velocity of the regurgitant jet signal increased (P < .001), whereas these variables remained stable in the BNZ group. Histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group. Moreover, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group. ... PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD. Additional investigation in dogs with symptomatic MVD is now warranted."

Collagen Organization in Canine Myxomatous Mitral Valve Disease: An X-Ray Diffraction Study. Mojtaba Hadian, Brendan M. Corcoran, Richard I. Han, J. Gunter Grossmann, and Jeremy P. Bradshaw. Biophysical J. Oct. 2007; 93:2472–2476. Quote: "Collagen fibrils, a major component of mitral valve leaflets, play an important role in defining shape and providing mechanical strength and flexibility. Histopathological studies show that collagen fibrils undergo dramatic changes in the course of myxomatous mitral valve disease in both dogs and humans. However, little is known about the detailed organization of collagen in this disease. This study was designed to analyze and compare collagen fibril organization in healthy and lesional areas of myxomatous mitral valves of dogs, using synchrotron small-angle x-ray diffraction. The orientation, density, and alignment of collagen fibrils were mapped across six different valves. The findings reveal a preferred collagen alignment in the main body of the leaflets between two commissures. Qualitative and quantitative analysis of the data showed significant differences between affected and lesion-free areas in terms of collagen content, fibril alignment, and total tissue volume. Regression analysis of the amount of collagen compared to the total tissue content at each point revealed a significant relationship between these two parameters in lesion-free but not in affected areas. This is the first time this technique has been used to map collagen fibrils in cardiac tissue; the findings have important applications to human cardiology."

Modulation of the tissue reninangiotensin-aldosterone system in dogs with chronic mild regurgitation through the mitral valve. Yoko Fujii, Kensuke Orito, Makoto Muto, Yoshito Wakao. Am J Vet Research Oct 2007;68(10): 1045-1050. Quote: "The tissue renin-angiotensin-aldosterone system (RAAS) was modulated without changes in the plasma RAAS in dogs with mild mitral valve regurgitation during the chronic stage of the condition. An ACE-dependent pathway may be a major route for production of angiotensin II during this stage of the condition."

Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. Clarke E. Atkins, Bruce W. Keene, William A. Brown, Julie R. Coats, Mary Ann Crawford, Teresa C. DeFrancesco, N. Joel Edwards, Phillip R. Fox, Linda B. Lehmkuhl, Michael W. Luethy, Kathryn M. Meurs, Jean-Paul Petrie, Frank S. Pipers, Steven L. Rosenthal, Jennifer A. Sidley, Justin H. Straus. J Amer Vet Med Assn, Oct 2007;231(7): 1061-1069. Quote: "Chronic enalapril treatment of dogs with naturally occurring, moderate to severe mitral regurgitation (MR) significantly delayed onset of congestive heart failure (CHF), compared with placebo, on the basis of number of CHF-free days, number of dogs free of CHF at days 500 and study end, and increased time to a combined secondary endpoint of CHF-all-cause death. Improvement in the primary endpoint, CHF-free survival, was not significant. Results suggest that enalapril modestly delays the onset of CHF in dogs with moderate to severe MR."

Blood pressure in the Cavalier King Charles Spaniel. Anna Franzén. Thesis, Swedish Univ. Ag. Sci., Uppsala, 2007.

A study of the utility of NT-proBNP in distinguishing animals with heart disease and heart failure from animals with respiratory disease and normal animals. Adrian Boswood. To be published in 2007(?).

The Cough Reflex in Animals: Relevance to Human Cough Research. Brendan J. Canning. Lung; Feb 2008; Vol 186:Supp 1: pp. 23-28. Quote: "All mammalian species studied cough or display some similar respiratory reflex upon aerosol challenge with tussigenic stimuli such as citric acid or capsaicin. Animals cough to the same stimuli that evoke coughing in humans, and therapeutic agents that display antitussive effects in human studies also prevent coughing in animals."

Pimobendan – What You Need to Know. Amara Estrada. FVMA convention Apr 2008. http://2008.fvmaconvention.com/data/papers/EstradaPimobendan.pdf  Quote: "... There is evidence that treatment with a positive inotropic agent such as pimobendan prior to the development of systolic myocardial failure can have deleterious effects. Experimental data have shown that valvular and parietal endocardial jet lesions could be induced within 4 weeks in healthy dogs even in the absence of previous valvular disease. Additionally, clinical reports of dogs chronically treated with pimobendan have described adverse cardiac effects, such as increased regurgitant fraction and left atrial enlargement, which were in part reversed following cessation of pimobendan therapy. Moreover, a recent prospective study in dogs with naturally occurring mild, asymptomatic mitral valve disease treated with pimobendan demonstrated increased regurgitant fraction and induction of mitral valve lesions including acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinea with glycosaminoglycans. These reports raise an important issue: is pimobendan indicated in dogs without systolic myocardial dysfunction? While the answer is not entirely clear at this point in time, careful case selection when deciding when and how to use pimobendan is advised and at present, it should be reserved for use when systolic myocardial failure is detected or suspected."

Vetmedin (Pimobendan). George A. Kramer. atlanticcoastvet.com/news/vetmedin May 2008. Quote: "Pimobendan should be used only in dogs that are symptomatic for heart failure (modified NYHA class II-IV). ... It may have more value in dogs with DCM due to the positive inotropic effect since all dogs with DCM have decreased myocardial contractility. Most dogs with chronic valvular heart disease do not have decreased contractility and do not need positive inotropic support. ... According to Boehringer-Ingelheim, "treatment should be initiated only in symptomatic cases which will benefit from increased myocardial contractility (positive inotropy). ... ... There is a report out of Europe that documents negative effects on the heart and worsening of the mitral regurgitation in dogs chronically treated with pimobendan for valvular disease. The changes were reversed when the drug was discontinued. There is also a concern that the drug could predispose the heart to tachyarrhythmias and lead to an increased incidence of sudden death. Although pimobendan has been shown to cause a dose-dependent tachycardia, no studies to date have documented an increased risk of sudden death. One study comparing pimobendan to enalapril showed an increase in ventricular ectopy after 14 days of treatment."

Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity. Mark A. Oyama, Philip R. Fox, John E. Rush, Elizabeth A. Rozanski, Mike Lesser. J. Amer. Vet. Med. Assn. May 15, 2008; 232(10): pp. 1496-1503. Quote: "Objective—To determine whether serum N-terminal pro-B-type natriuretic (NT-proBNP) concentration could be used to identify cardiac disease in dogs and to assess disease severity in affected dogs. ... 119 dogs with mitral valve disease, 18 dogs with dilated cardiomyopathy, and 40 healthy control dogs. ... Results—Serum NT-proBNP concentration was significantly higher in dogs with cardiac disease than in control dogs, and a serum NT-proBNP concentration > 445 pmol/L could be used to discriminate dogs with cardiac disease from control dogs with a sensitivity of 83.2% and specificity of 90.0%. In dogs with cardiac disease, serum NT-proBNP concentration was correlated with heart rate, respiratory rate, echocardiographic heart size, and renal function. For dogs with cardiac disease, serum NT-proBNP concentration could be used to discriminate dogs with and without radiographic evidence of cardiomegaly and dogs with and without congestive heart failure. Conclusions and Clinical Relevance—Results suggested that serum NT-proBNP concentration may be a useful adjunct clinical test for diagnosing cardiac disease in dogs and assessing the severity of disease in dogs with cardiac disease."

Mutation in β1-Tubulin Correlates with Macrothrombocytopenia in Cavalier King Charles Spaniels. B. Davis, M. Toivio-Kinnucan, S. Schuller, M.K. Boudreaux. J.Vet.Int.Med. May-June 2008;22(3): 540-545. Quote: "Background: Cavalier King Charles Spaniels (CKCS) have a high prevalence of inherited macrothrombocytopenia. The purpose of this study was to determine if a mutation in β1-tubulin correlated with presumptive inherited macrothrombocytopenia. Hypothesis: A mutation in β1-tubulin results in synthesis of an altered β1-tubulin monomer. α-β tubulin dimers within microtubule protofilaments are unstable, resulting in altered megakaryocyte proplatelet formation. ... Methods: DNA was used in polymerase chain reaction (PCR) assays to evaluate β1-tubulin. Platelet numbers and mean platelet volume (MPV) were evaluated for a correlation with the presence or absence of a mutation identified in β1-tubulin. Platelets obtained from homozygous, heterozygous, and clear CKCS were further evaluated using electron microscopy and immunofluorescence. Results: A mutation in the gene encoding β1-tubulin correlated with macrothrombocytopenia in CKCS. Electron microscopy and immunofluorescence studies suggest that platelet microtubules are present but most likely are unstable and decreased in number. Conclusions and Clinical Importance: The macrothrombocytopenia of CKCS correlated with a mutation in β1-tubulin. α–β tubulin dimers within protofilaments most likely are unstable, leading to altered proplatelet formation by megakaryocytes. This information will aid in distinguishing inherited from acquired thrombocytopenia. It also provides insight into the mechanism of platelet production by megakaryocytes, and also may prove useful in understanding heart-related changes in macrothrombocytopenic CKCS with concurrent mitral valve regurgitation."

Effect of Benazepril on Survival and Cardiac Events in Dogs with Asymptomatic Mitral Valve Disease: A Retrospective Study of 141 Cases. J.-L. Pouchelon, N. Jamet, V. Gouni, R. Tissier, F. Serres, C. Carlos Sampedrano, M. Castaignet, H. P. Lefebvre, V. Chetboul. J.Vet.Int.Med. July-Aug 2008;22(4): 905-914. Quote: "BNZ [benazepril] had beneficial effects in asymptomatic dogs other than CKC [Cavalier King Charles spaniels] and KC [King Charles spaniels] affected by MVD with moderate-to-severe MR. Breed distribution should be taken into account for interpretation of clinical trials performed in dogs with cardiac disease."

Serum Serotonin Concentration Is Elevated in Dogs with Degenerative Mitral Valve Disease. JW Arndt, MA Oyama, JM Connolly, CA Reynolds, RJ Levy. J Vet Intern Med. 2008; 22(3) (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract 58). Quote: "Little is known concerning the molecular mechanisms involved in degenerative mitral valve disease (DMVD). In humans, elevated serotonin (5-HT) is associated with development of valvular lesions. Canine mitral valve cells demonstrate dose-dependent 5-HT-mediated ERK1/2 signaling, suggesting a possible link with canine DMVD. We sought to measure serum 5-HT concentration in dogs with DMVD, dogs predisposed to DMVD (small breed dogs weighing < 10 kg and without a murmur), and healthy large breed control dogs. ... Seventy-nine dogs were enrolled (27 affected, 24 predisposed, and 28 controls), with 17/27 affected and 15/24 predisposed dogs being Cavalier King Charles Spaniels (CKCS). ... Subgroup analysis revealed that predisposed CKCS had greater mean serum 5-HT than predisposed non-CKCS (CKCS, 903.9 [321.5] ng/ml vs. non-CKCS, 536.0 [153.7]; P50.004). We conclude that dogs with clinically apparent DMVD as well as CKCS that are predisposed to DMVD have elevated serum 5-HT. Our results suggest that 5-HT may play a role in the development of DMVD in small breed dogs, and in particular in the CKCS. Further studies involving the relationship between 5-HT, DMVD, breed, and platelet number, morphology, and function are warranted."

NT-pro-BNP Concentration in Preclinical (ISACHC 1A & 1B) Chronic Degenerative Atrioventricular Valve Disease. LT Drourr, SG Gordon, RM Roland, AB Saunders, SE Achen and MW Miller. J Vet Intern Med. 2008; 22(3) (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract 192). Quote: "This study reports the NT-proBNP median and range in dogs with various degrees of cardiac remodeling due to preclinical CVD and the correlation between NT-proBNP and various echocardiographic and radiographic indices of cardiac remodeling and Doppler derived E:Ea as an index of cardiac filling pressures. ... Eighteen dogs with preclinical CVD were evaluated a total of 24 times; 15 of the 18 dogs were CKCS, mean age was 8.2 ± 2.8 years, and 60% were male. NT-proBNP concentrations were not normally distributed. The median NT-proBNP was 508 with an interquartile range of 323–793, a minimum of 200, and maximum of 2255. Dogs with an increased LVIDd and/or LVIDs (7/24) had significantly elevated NT-proBNP when compared to those whose LVIDd and LVIDs were normal, with a median NT-proBNP of 1247 (interquartile range 503–1861) and 371 (interquartile range 279–626) respectively. There was a significant correlation between NT-pro-BNP and 2D derived La:Ao ratio. There was no significant correlation between NT-pro BNP and VHS, M-mode derived La:Ao ratio, LVIDd and LVIDs (indexed to body surface area), or Doppler derived E:Ea ratio. NT-proBNP is elevated to various degrees in preclincal CVD and is not correlated to many common indices of cardiac remodeling. Its true utility may lie in its correlation to important clinical endpoints such as onset of congestive heart failure. Larger prospective studies are warranted to further evaluate the clinical utility of this novel test."

Plasma and Urinary Levels of 6-keto-Prostaglandinf1a in Dogs with Myxomatous Mitral Valve Disease. CE Rasmussen, AV Sundqvist, CT Kjempff, I Tarnow, M jelgaard-Hansen, TS Kamstrup, A Sterup, TM Soerensen and LH Olsen. J Vet Intern Med. 2008; 22(3) (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract 195). Quote: "Endothelial dysfunction might be involved in the pathogenesis of myxomatous mitral valve disease (MMVD) in dogs. A decreased plasma concentration of the nitric oxide metabolites nitrate and nitrite have been found in Cavalier King Charles Spaniels (CKCS) with mitral regurgitation, suggesting an endothelial dysfunction in dogs with MMVD. It is speculated that the vasodilator prostacyclin also plays a role in the pathogenesis of MMVD. The aims of this study were to validate an enzyme immunoassay for a metabolite of canine prostacyclin (6-keto-prostaglandin(PG)F1a) and to compare plasma and urinary 6-keto-PGF1a in dogs with different degrees of MMVD. The study included 76 privately owned dogs: 34 CKCS, 32 Dachshunds and 10 control dogs of different breeds not predisposed to MMVD. All dogs went through clinical and echocardiographic examination. ... In conclusion, the enzyme immunoassay seemed valid for measuring canine 6-keto-PGF1a in plasma and urine. Plasma or urinary 6-keto-PGF1a does not appear to be influenced by the degree of MMVD in CKCS or Dachshunds. However, the cause of lower creatinine standardized urinary 6-keto-PGF1a in control dogs compared to CKCS and Dachshunds remains to be established."

Stem Cell Treatments of Mitral Valve Disease in Cavalier King Charles Spaniels. Jane Mercer, Medlink 2008, www.medlink-uk.com/_global/downloads/results_2008/MercerJ.pdf  Quote: "As Mitral Valve Disease in Cavalier King Charles Spaniels is a degenerative disease, it could be possible to use stem cells to regenerate the affected mitral valve in the heart. From the research previously conducted, it is shown that bone marrow stromal cells can be differentiated and specialised under specific conditions into different types of cell, and can therefore be developed into cardiac muscle. These cells have been induced by external factors, such as introduction to hormones, and will become cells with the specific function of beating cells in the heart. The stem cells will divide and multiply to produce more cardiac muscle and therefore regenerate and repair the mitral valve. As the muscle is repairing, it is suggested in other reports that more stem cells from the bone marrow will naturally migrate to the heart to aid the process of reparation. In spite of this, Mitral Valve Disease is polygenetic, hence stem cells will not be able to prevent the disease from affecting the dogs, as only DNA modification can stop the passing on of the alleles which cause the disease. Stem cells will, however, enable the treatment of the disorder and therefore prevent any further suffering and discomfort to the Cavalier King Charles Spaniels. Hypothetically, it is potentially possible to take stem cells from any body tissue and, under suitable conditions, induce them to become specialised cells which can repair and regenerate damaged muscle. New data suggests that stem cells may exist in the heart and can repair damage, preventing scar tissue from permanently replacing the functioning heart muscle. By injecting bone marrow stromal cells into the diseased heart, there is hope in the future that the stem cells, with the right stimulus, could potentially regenerate the heart muscle."

Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study. Häggström J, Boswood A, O'Grady M, Jöns O, Smith S, Swift S, Borgarelli M, Gavaghan B, Kresken JG, Patteson M, Ablad B, Bussadori CM, Glaus T, Kovačević A, Rapp M, Santilli RA, Tidholm A, Eriksson A, Belanger MC, Deinert M, Little CJ, Kvart C, French A, Rønn-Landbo M, Wess G, Eggertsdottir AV, O'Sullivan ML, Schneider M, Lombard CW, Dukes-McEwan J, Willis R, Louvet A, Difruscia R. J Vet Intern Med. Sept-Oct 2008; 22(5). Quote: "Two hundred and sixty client-owned dogs in CHF caused by Myxomatous mitral valve disease (MMVD) were recruited from 28 centers in Europe, Canada, and Australia. ... A prospective single-blinded study with dogs randomized to PO receive pimobendan (0.4–0.6 mg/kg/d) or benazepril hydrochloride (0.25–1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. Results: ... One hundred and twenty-four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL] = 0.516–0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. Conclusions and Clinical Importance: Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy."

Feasibility of Myxomatous Mitral Valve Repair Using Direct Leaflet and Chordal Radiofrequency Ablation. Jeffrey L. Williams, Yoshiya Toyoda, Takeyoshi Ota, Dmitry Gutkin, William Katz, Marco Zenati, and David Schwartzman. J Interv Cardiol. 2008 December ; 21(6): 547–554. Quote: "Objective: Minimally invasive repair of mitral valve prolapse (MVP) causing severe mitral regurgitation (MR) should reduce mitral regurgitation and have chronic durability. Our ex-vivo, acute in-vivo, and chronic in-vivo studies suggest that direct application of radiofrequency ablation (RFA) to mitral leaflets and chordae can effect these repair goals to decrease MR. Methods: A total of seven canines were studied to assess the effects of RFA on mitral valve structure and function. RFA was applied ex-vivo (n=1), acutely in-vivo using a right lateral thoracotomy and cardiopulmonary bypass (n=3), and chronically in-vivo using percutaneous access to the heart (n=3). RFA was applied to the mitral valve and its associated chordae. Mitral valve structure and function (in-vivo preparations) were then assessed. Results: Ex-vivo application of RFA resulted qualitative reduction in mitral leaflet surface area and chordal length. Acute in-vivo application of RFA to canines found to have MVP causing severe MR demonstrated a 43.7–60.7% statistically significant (p=0.039) reduction in post-ablation MR. Chronic, in-vivo, percutaneous application of RFA was found to be feasible and the engendered alterations durable. Conclusion: These data suggest that myxomatous mitral valve repair using radiofrequency energy delivered via catheter is feasible."

Autocrine Serotonin and Transforming Growth Factor β1 Signaling Mediates Spontaneous Myxomatous Mitral Valve Disease. Sirilak Disatian, E. Christopher Orton. J Heart Valve Dis 18:44-51, Jan. 2009. Quote: "Background and aim of the study: Although serotonin and serotoninergic drugs are known to cause myxomatous-like valvulopathy, the role of serotonin in spontaneous myxomatous valve disease (MVD) remains unclear. Tryptophan hydroxylase 1 (TPH1) is the limiting enzyme for peripheral serotonin synthesis, and its expression in myxomatous valves could implicate an autocrine serotonin signaling mechanism. Studies in cultured cells demonstrate a close coupling between serotonin and transforming growth factor β1 (TGFβ1) signaling. The study aim was to investigate serotonin and TGFβ1 signaling in spontaneous MVD. Methods: In canine normal and myxomatous mitral valves, target signaling proteins including TPH1, serotonin 2B receptor (5HT2BR), serotonin transmembrane transporter (SERT), total and phosphorylated extracellular signaling-regulated kinase (ERK) 1/2, latent TGFβ1 and TGFβ1 receptors I and II, were studied using immunohistochemistry and immunoblot analysis. In human myxomatous valves, TPH1 was determined using immunofluorescence and immunoblot analysis. Results: In canine mitral valves, both 5HT2BR and TPH1 were increased in myxomatous valves, whereas SERT, a key protein in serotonin metabolism, was decreased in myxomatous valves. Phosphorylated, but not total, ERK 1/2 was increased in myxomatous valves, consistent with an enhanced active serotonin signaling. The expression of TGFβ1 receptors I and II, and of latent TGFβ1, was increased in myxomatous valves. Human myxomatous mitral valves expressed TPH1. Conclusion: The expression of TPH1 by canine and human myxomatous valves demonstrates a capacity for local serotonin production. Key signaling protein expression patterns support active serotonin and TGFβ1 signaling in canine myxomatous valves. These findings implicate an autocrine serotonin and TGFβ1 mechanism in the pathogenesis of spontaneous MVD."

Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease. M. Ouellet, M.C. Bélanger, R. DiFruscia, G. Beauchamp. J Vet Int Med March/April 2009; 23(2):258-263. Quote: "Background: Pimobendan (PIMO) is a novel inodilator that has shown promising results in the treatment of advanced mitral valve disease (MVD), but little is known about its hemodynamic effects, especially regarding the mitral regurgitant volume in naturally occurring MVD. Hypothesis: The addition of pimobendan to treatment decreases the regurgitant fraction (RF) in dogs with asymptomatic MVD. Animals: Twenty-four client-owned dogs affected by International Small Animal Cardiac Health Council class Ib MVD. Methods: Prospective, blinded, and controlled clinical trial. Dogs were assigned to a PIMO treatment group (n = 19) (0.2–0.3 mg/kg q12h) or a control group (n = 5). Echocardiographic evaluations were performed over a 6-month period. Results: The addition of PIMO to treatment did not decrease the RF of dogs affected by asymptomatic class 1b MVD over the study period (P= .85). There was a significant increase in the ejection fraction of the PIMO treated dogs at 30 days (80.8 ± 1.42 versus 69.0 ± 2.76, corrected P= .0064), and a decrease in systolic left ventricular diameter (corrected P= .011) within the PIMO group compared with baseline. However, this improvement in systolic function was not sustained over the 6-month trial period. Conclusion and Clinical Importance: This study did not identify beneficial long-term changes in the severity of mitral regurgitation after addition of PIMO to angiotensin converting enzyme inhibitor treatment of dogs with asymptomatic MVD."

Predictive value of natriuretic peptides in dogs with mitral valve disease. Tarnow I, Olsen LH, Kvart C, Hoglund K, Moesgaard SG, Kamstrup TS, Pedersen HD, Häggström J. Vet J. 2009 May;180(2):195-201. Quote: "Natriuretic peptides are useful in diagnosing heart failure in dogs. However, their usefulness in detecting early stages of myxomatous mitral valve disease (MMVD) has been debated. This study evaluated N-terminal (NT) fragment pro-atrial natriuretic peptide (NT-proANP) and NT-pro-brain natriuretic peptide (NT-proBNP) in 39 Cavalier King Charles Spaniels (CKCS) with pre-clinical mitral valve regurgitation (MR), sixteen dogs with clinical signs of heart failure (HF) and thirteen healthy control dogs. Twenty seven CKCS and ten control dogs were re-examined 4 years after the initial examination and the status of the dogs 5 years after the initial examination was determined by telephone calls to the owner. All dogs were evaluated by clinical examination and echocardiography. CKCS with severe MR had higher NT-proANP and NT-proBNP compared to controls and CKCS with less severe MR. Dogs with clinical signs of HF had markedly elevated NT-proANP and NT-proBNP. Plasma concentrations of the natriuretic peptides measured at re-examination could predict progression in regurgitant jet size."

Expression of Genes Encoding Matrix Metalloproteinases (MMPs) and their Tissue Inhibitors (TIMPs) in Normal and Diseased Canine Mitral Valves. H. Aupperle, J. Thielebein, B. Kiefer, I. März, G. Dinges, H.-A. Schoon, A. Schubert. J. of Comparative Pathology; May 2009; 140(4):271-277. Quote: "The pathogenesis of canine chronic valvular disease (CVD) is not fully characterized. The present study investigates the expression of genes encoding matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in normal and diseased mitral valves (MVs). Samples from normal (n = 15) or diseased (n = 10) canine MVs were subject to real-time polymerase chain reaction (PCR) for quantification of mRNA encoding MMP-1, -2, -9 and -14 and TIMP-2, -3 and -4. In normal valves there was low expression of mRNA encoding MMP-2, -9 and -14 and TIMP-3. In the valves from dogs with CVD there was significantly increased transcription of mRNA encoding MMP-1 and -14 and TIMP-2, -3 and -4, but no elevation in mRNA encoding MMP-2 and -9. MMPs and TIMPs are therefore likely to be involved in extracellular matrix metabolism in normal canine MVs and there are significant alterations in the expression of genes encoding these molecules during CVD."

The Effect of Furosemide and Pimobendan on the Renin-Angiotensin-Aldosterone System (RAAS) in Dogs. AC Lantis, CE Atkins, TC DeFrancesco, BW Keene.  J Vet Intern Med 2009;23; (ACVIM 26th Ann. Vet. Med. Forum Abstract Program: Abstract #2). Quote: "We have shown that pimobendan, at the labeled dosage, does not accentuate furosemide- induced RAAS activation. We observed a three-fold increase in RAAS activity with furosemide alone and in combination with pimobendan. Therefore, furosemide, with or without pimobendan, is not recommended for chronic use in the absence of concurrent therapy to blunt RAAS activity, such as ACEI, aldosterone receptor blockers, or angiotensin II type I receptor blockers."

Long-term Survival of Two Dogs after Mitral Valve Plasty Using Expanded Polytetrafluoroethylene Chords: Pathological Study. Mnishida, M Uechi, T Mizukoshi, T Ebisawa, M Mizuno, T Mizuno, K Harada, M Fujiwara, N Nakayama. J Vet Intern Med 2009;23:749 (ACVIM 27th Ann. Vet. Med. Forum Abstract Program: Abstract 219). Quote: "Mitral valve plasty is one of the treatment options for mitral regurgitation (MR). Expanded polytetrafluoroethylene (e-PTFE) is a polymer, which has been widely used to make artificial chords. In this study, we report autopsy and histological findings in two dogs that underwent cardiopulmonary bypass for mitral annuloplasty using e-PTFE sheets and chordoplasty using e-PTFE sutures. Case 1 was a neutered, 7-year-and-5-month-old male Cavalier King Charles Spaniel with severe MR. Postoperative progress was favorable until 10 months later when the dog showed severe diastolic dysfunction with significantly decreased fractional shortening by echocardiography. The dog died unexpectedly at 23 months after surgery. Case 2 was a 10-year-and-3-month-old female Maltese with severe MR. Postoperative progress was also satisfactory, but the dog died at 26 months after surgery from respiratory failure caused by intrathoracic fibrosarcoma. By histopathological examination, the structural integrity of both atrial and ventricular muscle fibers was maintained in Case 1, with no evidence of degeneration, fibrosis or fiber disarray. In Case 2, mild fibrosis was noted at the base of the left ventricular papillary muscle, indicating an old myocardial infarct. In both cases, e-PTFE sheets and sutures were not damaged and well integrated in the surrounding, highly differentiated connective tissues. There was no evidence of reactive changes around e-PTFE. These results suggest that e-PTFE is excellent in tissue compatibility and durability and useful for canine mitral valve plasty."

Mitral Valve Plasty in 11 Cavalier King Charles Spaniels. M Nishida, M Uechi, T Mizukoshi, T Ebisawa, M Mizuno, T Mizuno, K Harada, M Fujiwara. J Vet Intern Med 2009;23:749 (ACVIM 27th Ann. Vet. Med. Forum Abstract Program: Abstract 220). Quote: "This study aimed at retrospectively assessing the effectiveness of mitral valve plasty in Cavalier King Charles Spaniel (CKCS), a breed predisposed to mitral valve disease (MVD). Eleven CKCS (5 males and 6 females; bodyweight, 8.8 1.4 kg; age, 110 26.7 months) underwent cardiopulmonary bypass for mitral valve plasty ... Postoperative complications included 1 case of tricuspid valve insufficiency and 3 cases of left atrial thrombosis (one had a preexisting thrombus at the time of surgery). In 3 cases, neurological symptoms became evident after surgery due to preexisting syringomyelia. The mean survival time was 10.4 6.8 months. One dog died from a suspected cardiac cause at 22 months after surgery, and another from possible thromboembolism at 4 months after surgery. Nine dogs were still alive at the time of the report. At 1 and 3 months after surgery, the left atrial to aortic root diameter ratio (1.76 0.36 and 1.68 0.33, respectively; n57) and the plasma atrial natriuretic peptide level (117.9 54.8 and 85.8 38.2 pg/mL, respectively; n54) were lower than those before surgery (2.60 0.61 and 198.0 109.9 pg/mL). There were also significant improvements in the number of prescribed cardiovascular drugs 1 month after surgery (1.6 1.3 vs. 4.5 1.6 preoperatively, po0.05; n511) and in the cardiac murmur grade (2.5 0.8 vs. 5.1 0.6 preoperatively, po0.05; n59). These results suggest that mitral valve plasty is beneficial in CKCS with MVD."

Intra- and Post-operative Complications in 47 Dogs That Underwent Mitral Valve Plasty. T Mizuno, M Uechi, T Ebisawa, M Mizuno, T Mizukoshi, K Harada, M Nishida, M Fujiwara, T Nakayama. J Vet Intern Med 2009;23:749 (ACVIM 27th Ann. Vet. Med. Forum Abstract Program: Abstract 221). Quote: "To assess the incidence of intra- and post-operative complications, we retrospectively reviewed 47 cases that underwent MVP with CPB at the Nihon University Animal Medical Center between August 2006 and September 2008. The subjects were 47 dogs [22 males and 25 females, age: 62–175 (123 25) months, bodyweight: 1.8–13.5 (5.7 3.0) kg]. The mean age of the 10 dogs that died within 4 months after surgery was 140 21 (range: 115–175) months, which was significantly higher compared to those that survived beyond 4 months postsurgery [119 25 (range: 62–157) months]. The 4-month postoperative mortality was 29% for dogs aged 10 years or older and 11% for those younger than 10 years. The causes of death were surgical technical problems (2 cases), thrombosis (4 cases), pancreatitis (2 cases), pulmonary hypertension (1 case) and unknown (1 case). Of the 37 cases that survived for 4 months or longer, 4 cases had postoperative complications (thrombotic cerebral infarction, pulmonary infarction, cerebellar infarction and aspiration pneumonitis; 1 case each). Thrombus formation (including those in the left atrium) was observed in 12 cases and was the most frequent causes of postoperative complication and/or death. These results suggest that prevention of thrombosis is an important strategy for improving the surgical outcome of MVP. For dogs over 10 years old, in addition, preoperative stabilization and postoperative management are critical, and earlier surgery is recommended."

Association of Plasma N-Terminal Pro-B-Type Natriuretic Peptide Concentration with Mitral Regurgitation Severity and Outcome in Dogs with Asymptomatic Degenerative Mitral Valve Disease. V. Chetboul, F. Serres, R. Tissier, H.P. Lefebvre, C. Carlos Sampedrano, V. Gouni, L. Poujol, G. Hawa, and J.L. Pouchelon. J Vet Intern Med 2009;23(5):984-994. Quote: "Background: The clinical outcome of dogs affected by degenerative mitral valve disease (MVD) without overt clinical signs is still poorly defined, and criteria for identification of animals that are at a higher risk of early decompensation have not yet been determined. Hypothesis: N-terminal pro-B-type natriuretic peptide plasma concentration (NT-proBNP) is correlated with mitral regurgitation (MR) severity and can predict disease progression in dogs with asymptomatic MVD. Animals: Seventy-two dogs with asymptomatic MVD, with or without heart enlargement (International Small Animal Cardiac Health Council: ISACHC classes 1a and 1b), and a control group of 22 dogs were prospectively recruited. ... Results: ... NT-proBNP was higher in dogs with MVD (ISACHC classes 1a and 1b) compared with the control group (P= .025 and < .001, respectively). The difference was not significant when only dogs from ISACHC class 1a with RF < 30% were considered. Lastly, NT-proBNP was higher in dogs that underwent MVD decompensation at 12 months (P < .05). Conclusions and Clinical Importance: NT-proBNP is correlated with MVD severity and prognosis in dogs with asymptomatic MVD."

Aldosterone receptor antagonists – how cardiovascular actions may explain their beneficial effects in heart failure. P. Ovaert, J. Elliott, F. Bernay, E. Guillot, & T. Bardon. J. vet. Pharmacol. Therap.(2009) 33:109–117.

Effects of Short-term Treatment with Pimobendan in Dogs with Myxomatous Valve Disease. A. Caro, E. Ynaraja, J.A. Montoya. J. Appl. Anim. Res.;June 2009;35:113-117.

Acute Effect of Pimobendan and Furosemide on the Circulating Renin-Angiotensin-Aldosterone System in Healthy Dogs. M.B. Sayer, C.E. Atkins, Y. Fujii, A.K. Adams, T.C. DeFrancesco, and B.W. Keene. J Vet Intern Med 2009;23(5):1003-1006. Quote: "Background: The renin-angiotensin-aldosterone system (RAAS) is activated in states of decreased cardiac output and by certain cardiovascular therapeutic agents, such as loop diuretics and vasodilators. Hypothesis: Short-term treatment with the inodilator, pimobendan, will not activate the circulating RAAS because its vasodilatory action will be offset by its positive inotropic property, thereby ameliorating RAAS stimulation at the juxtaglomerular apparatus. Furthermore, pimobendan will suppress RAAS activation produced by furosemide. Animals: Nine healthy laboratory dogs were used in this study. Methods: Experimental, cross-over study. Dogs were administered pimobendan (0.5 mg/kg q12h) for 4 days followed by furosemide (2 mg/kg q12h) and then, after a wash-out period, a combination of the drugs. Aldosterone : creatinine (A : Cr) was measured at the end of each treatment cycle. Results: There was no significant increase in the average urinary A : Cr with the administration of pimobendan (control urinary A : Cr = 0.46, standard deviation (SD) 0.33; pimobendan A : Cr = 0.48, SD 0.28). There was a significant increase in the average urinary A : Cr after administration of furosemide (urinary A : Cr = 1.3, SD 0.70) and with the combination of furosemide and pimobendan (urinary A : Cr = 2.9, SD 1.6). Conclusions and Clinical Relevance: Short-term administration of high-dose pimobendan, does not activate the RAAS in healthy dogs. Pimobendan did not prevent RAAS activation associated with furosemide therapy. These results in healthy dogs suggest that furosemide therapy, with or without pimobendan, should be accompanied by RAAS suppressive therapy."

ACVIM Consensus Statement: Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease. C. Atkins, J. Bonagura, S. Ettinger, P. Fox, S. Gordon, J. Häggström, R. Hamlin, B. Keene (Chair), V. Luis-Fuentes, and R. Stepien. J Vet Intern Med. Nov/Dec 2009;23(6):1142–1150. Download pdf version here.  Quote: "Cavalier King Charles Spaniels are predisposed to developing CVHD at a relatively young age, but the time course of their disease progression to heart failure does not appear to be markedly different from that of other small breed dogs except for the early age of onset. ... The classification system presented below and used in these guidelines is meant to complement, not replace, functional classification systems. The new system describes 4 basic stages of heart disease and failure: (a) Stage A identifies patients at high risk for developing heart disease but that currently have no identifiable structural disorder of the heart (e.g., every Cavalier King Charles Spaniel without a heart murmur); (b) Stage B identifies patients with structural heart disease (e.g., the typical murmur of mitral valve regurgitation is present), but that have never developed clinical signs caused by heart failure. Because of important clinical implications for prognosis and treatment, the panel further subdivided Stage B into Stage B1 and B2; (i) Stage B1 refers to asymptomatic patients that have no radiographic or echocardiographic evidence of cardiac remodeling in response to CVHD; (ii) Stage B2 refers to asymptomatic patients that have hemodynamically significant valve regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided heart enlargement; (c) Stage C denotes patients with past or current clinical signs of heart failure associated with structural heart disease. Because of important treatment differences between dogs with acute heart failure requiring hospital care and those with heart failure that can be treated on an outpatient basis, these issues have been addressed separately by the panel. Some animals presenting with heart failure for the 1st time may have severe clinical signs requiring aggressive therapy (eg, with additional afterload reducers or temporary ventilatory assistance) that more typically would be reserved for those with refractory disease (see Stage D); (d) Stage D refers to patients with end-stage disease with clinical signs of heart failure caused by CVHD that are refractory to ‘‘standard therapy’’ (defined later in this document). Such patients require advanced or specialized treatment strategies in order to remain clinically comfortable with their disease. As with Stage C, the panel has distinguished between animals in Stage D that require acute, hospital-based therapy and those that can be managed as outpatients. ... Diagnosis for Stage A -- Consensus recommendations: (a) Small breed dogs, including breeds with known predisposition to develop CVHD (e.g., Cavalier King Charles Spaniels, Dachshunds, Miniature and Toy Poodles) should undergo regular evaluations (yearly auscultation by the family veterinarian) as part of routine health care. (b) Owners of breeding dogs or those at especially high risk, such as Cavalier King Charles Spaniels, may choose to participate in yearly screening events at dog shows or other events sponsored by their breed association or kennel club and conducted by board-certified cardiologists participating in an ACVIM-approved disease registry."

Evaluation of pimobendan and N-terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs. Atkinson, K. J.; Fine, D. M.; Thombs, L. A.; Gorelick, J. J.; Durham, H. E. J Vet Intern Med Nov/Dec 2009; 23(6):1190-1196.  Quote: "Background: Pimobendan is a positive inotrope and vasodilator that may be useful in the treatment of pulmonary hypertension (PHT) secondary to degenerative mitral valve disease. Hypothesis: Pimobendan decreases the severity of PHT measured echocardiographically and improves quality-of-life scores. Changes in N-terminal probrain natriuretic peptide (NT-proBNP) concentrations will reflect improvement in severity of PHT. Animals: Ten client-owned dogs with peak tricuspid regurgitant flow velocity (TRFV) ≥3.5 m/s. Methods: Prospective short-term, double-blinded, crossover design, with a long-term, open-label component. Short term, dogs were randomly allocated to receive either placebo or pimobendan (0.18-0.3 mg/kg PO q12 h) for 14 days. After a 1-week washout, they received the alternative treatment for 14 days, followed by pimobendan open-label for 8 weeks. Results: Short-term comparison: peak TRFV decreased in all dogs on pimobendan compared with placebo from a median of 4.40 (range, 3.2-5.6) to 3.75 (range, 2.4-4.8) m/s (P<.0001). NT-proBNP concentration decreased after treatment with pimobendan from a median of 2,143 (range, 450-3,981) to 1,329 (range, 123-2,411) pmol/L (P=.0009). All dogs improved their quality-of-life score (P=.006). In the long-term comparisons, peak TRFV decreased in all dogs from a median of 4.28 (range, 3.5-5.7) to 3.52 (range, 2.4-5.0) m/s (P<.0001). No significant changes in NT-proBNP or quality-of-life scores were detected. Conclusions and Clinical Importance: Pimobendan lowered severity of measurable PHT, improved quality-of-life scores, and decreased NT-proBNP concentrations short-term. Long term, only the reduction in TRFV was maintained."

Serum Serotonin Concentrations in Dogs with Degenerative Mitral Valve Disease. Arndt JW, Reynolds CA, Singletary GE, Connolly JM, Levy RJ, Oyama MA. J Vet Intern Med. Nov/Dec 2009;23(6) 1208-1213. Quote: "Background: Increased serotonin (5HT) signaling has been implicated in valvular disease of humans and animals, including canine degenerative mitral valve disease (DMVD). High circulating 5HT concentration is a potential source of increased signaling, and serum 5HT concentrations have not been previously reported in dogs with DMVD. Hypothesis: Dogs with DMVD and small breed dogs predisposed to DMVD have higher serum 5HT concentrations than large breed controls. Animals: Fifty dogs affected with DMVD, 34 dogs predisposed to DMVD but without cardiac murmur or echocardiographic evidence of DMVD, and 36 healthy large breed control dogs. Methods: Prospective analysis. Serum 5HT concentration was measured by an ELISA test. Results: Median serum 5HT concentration was significantly higher in dogs with DMVD and in dogs predisposed to DMVD as compared with controls (DMVD, 765.5 ng/mL [interquartile range, 561.3-944.4]; predisposed, 774.9 ng/mL [528.3-1,026]; control, 509.8 ng/mL [320.8-708.8]; P= .0001). Subgroup analysis of predisposed dogs indicated significantly higher serum 5HT concentrations in Cavalier King Charles Spaniel (CKCS) dogs than in other breeds (CKCS, 855.0 ng/mL [635.8-1,088]; non-CKCS, 554.2 ng/mL [380.6-648.4]; P= .0023). Age, platelet count, and platelet morphology were not correlated with 5HT concentration in any group. Conclusions and Clinical Importance: Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs. Healthy CKCS dogs had significantly higher serum 5HT concentrations than other healthy dogs predisposed to DMVD. Additional investigation into a possible role of 5HT in the pathogenesis of DMVD is warranted."

Study of collagen structure in canine myxomatous mitral valve disease. Mojtaba Hadian. Thesis 2009, Div. Vet. Biomed. Sci., Med. & Vet. Sci. College, Univ. Edinburgh. Download at http://www.era.lib.ed.ac.uk/handle/1842/4383 Quote: "Myxomatous mitral valve disease (MMVD) is the single most common acquired cardiac disease of dogs, and is a disease of significant veterinary importance. It also bears close similarities to mitral valve prolapse in humans and therefore is a disease of emerging comparative interest. Realising the importance of collagen fibres in mitral heart valves and considering the paramount significance of myxomatous mitral valve disease, a better understanding of the pathogenesis of MMVD is essential. Thus, this study was designed to investigate the changes in collagen molecules, including fibril structure, fibril orientation, d-spacing, collagen density, collagen content, thermal stability, and the status of mature and immature crosslinks. A combination of biophysical and biochemical tools such as x-ray diffraction, neutron diffraction, HPLC were utilised in order to fulfil the objectives. Biochemical assay of hydroxyproline revealed a 10% depletion of collagen in mildly affacted (grade I and II) leaflets, while a 20% depletion of fibrillar collagen was revealed by mapping the collagen fibrils onto the anatomy of cardiac leaflets using x-ray data. Differential scanning calorimetry showed that there were no significant differences in the onset temperature of denaturation of collagen between the healthy and affected leaflets. However, in affected areas of leaflets, the enthalpy of denaturation significantly dropped by 20%. In the affected regions, neutron diffraction results showed an increase in the immature reducible cross-links though the low number of the samples can be considered a limiting factor in this regard. However, the HPLC results showed a 25% decrease in the number of mature cross-links. Additionally, the recently introduced imaging technologies to biology and medicine such as differential enhancing imaging (DEI) and coherent anti-Stokes Raman scattering spectroscopy (CARS) were, to the author’s best knowledge, applied for the first time to this disease. In doing so, this thesis furthers our understanding of the pathogenesis of MMVD, especially in relation to the collagen. The thesis provides new findings about MMVD and demonstrates the potential of biophysical tools for studying similar conditions."

VP Client Information Sheets: Pimobendan (Vetmedin). Mark Rishniw, www.veterinarypartner.com/Content.plx?P=A&A=2715&S=0&EVetID=3001843 Quote: "Pimobendan is not currently recommended for use in dogs with heart disease prior to the onset of congestive heart failure. One study in dogs with early mitral valve disease suggested an increase in valve damage in the dogs given pimobendan."

Molecular changes in fibrillar collagen in myxomatous mitral valve disease. Mojtaba Hadian, Brendan M. Corcoran, and Jeremy P. Bradshaw. Cardiovascular Pathology, Sep. 2010; 19(5):e141-e148. Quote: "Introduction: Myxomatous mitral valve disease (MMVD) is the single most common acquired cardiac disease of dogs and is a disease of significant veterinary importance. It also bears close similarities to mitral valve prolapse in humans and therefore is a disease of emerging comparative interest. We have previously mapped the structure of collagen fibrils in valve leaflets using synchrotron X-rays and have demonstrated changes in collagen structure associated with the regions of disease. Methods: Differential scanning calorimetry (DSC), biochemical assay of collagen content, high-performance liquid chromatography (HPLC), and neutron diffraction were combined with further analysis of our previous X-ray data to elucidate molecular changes in fibrillar collagen in mild to moderately affected MMVD dogs. Results: Comparing diseases and adjacent grossly uninvolved areas in the same leaflets, there was a 20% reduction in collagen fibrils, but only a 10% depletion of collagen content. The enthalpy of collagen denaturation was reduced in affected areas. Chromatography showed a 25% decrease in mature nonreducible covalent cross-links in the affected samples, and neutron diffraction data showed fewer reducible immature covalent cross-links in grossly uninvolved tissue samples. Conclusions: Mild to moderate MMVD in the dog is associated with a marginal decline in collagen content in overtly diseased areas of valves, but more importantly is associated with an increase in immature collagen content. These changes will contribute to the mechanical dysfunction of the leaflet, and this study provides important information on the structure–mechanical alterations associated with this disease. The data suggests MMVD involves a dyscollagenesis process in the development of valve pathology."

Cardiac troponin I as a marker for severity and prognosis of cardiac disease in dogs. S. Fonfara, J. Loureiro, S. Swift, R. James, P. Crippse and J. Dukes-McEwan. The Veterinary Journal. doi:10.1016/j.tvjl.2009.04.004. Quote: "The use of cardiac troponin I (cTnI) to assess the severity of disease and prognosis in 120 dogs presented for cardiac evaluation was analysed. cTnI concentrations were measured using a commercially available assay. Dogs were placed into three groups: group 1, cTnI 0.15 ng/mL; group 2, cTnI 0.151–1.0 ng/mL; group 3, cTnI>1.01 ng/mL. Dogs in group 1 were significantly younger (P < 0.0001) and had no or stable cardiac diseases and longest survival times, whereas those in groups 2 and 3 had severe cardiac diseases and significantly reduced survival times (P < 0.0001). Thirty dogs with initially increased cTnI concentrations had a repeat assay less than 2 months later with significant reductions in cTnI concentrations (P = 0.005). Initial cTnI concentrations could not differentiate dogs that survived in group 3 from those that did not. However, dogs that survived showed significant cTnI reductions (P = 0.015) in the repeated assay in contrast to the dogs that died (P = 0.22). It was concluded that cTnI is useful in assessing the prognosis and severity of cardiac diseases in dogs, and progression and response to treatment can be assessed by repeat sampling. cTnI concentrations >1.0 ng/mL and persistent increases in cTnI concentrations are indicators of a poor prognosis in dogs with cardiac disease."

Insights into Serotonin Signaling Mechanisms Associated with Canine Degenerative Mitral Valve Disease. M.A. Oyama and R.J. Levy. J Vet Intern Med Jan/Feb 2010;24(1):27–36. Quote: "In Cavalier King Charles Spaniels, the time from onset of a heart murmur to death because of congestive heart failure can be quite accelerated, highlighting the rapid nature of disease progression in this particular breed. ... Little is known about the molecular abnormalities associated with canine degenerative mitral valve disease (DMVD). The pathology of DMVD involves the differentiation and activation of the normally quiescent mitral valvular interstitial cell (VIC) into a more active myofibroblast phenotype, which mediates many of the histological and molecular changes in affected the valve tissue. In both humans and experimental animal models, increased serotonin (5-hydroxytryptamine, 5HT) signaling can induce VIC differentiation and myxomatous valve damage. In canine DMVD, numerous lines of evidence suggest that 5HT and related molecules such as transforming growth factor-b play a critical role in the pathogenesis of this disease. A variety of investigative techniques, including gene expression, immuno-histo-chemistry, protein blotting, and cell culture, shed light on the potential role of 5HT in the differentiation of VIC, elaboration of myxomatous extracellular matrix components, and activation of mitogen-activated protein kinase pathways. These studies help support a hypothesis that 5HT and its related pathways serve as an important stimulus in canine DMVD. This review describes the pathological characteristics of canine DMVD, the organization and role of the 5HT pathway in valve tissue, involvement of 5HT in human and experimental models of valve disease, avenues of evidence that suggest a role for 5HT in naturally occurring DMVD, and finally, a overarching hypothesis describing a potential role for 5HT in canine DMVD. ... Interestingly, activation of canine VIC could be inhibited by coincubation with either ketanserin, a 5HT-R2A receptor blocker, or GR55562, a 5HT-R1B receptor blocker, indicating that these 2 receptor types are potentially involved in 5HT-induced changes. ... Interestingly, Cavalier King Charles Spaniels, which are highly predisposed to DMVD as well as macrothrombocytosis, had significantly higher serum 5HT concentrations than did other breeds of dogs."

Cardiac Troponin I Is Associated with Severity of Myxomatous Mitral Valve Disease, Age, and C-Reactive Protein in Dogs. I. Ljungvall, K. Höglund, A. Tidholm, L.H. Olsen, M. Borgarelli, P. Venge, and J. Häggström. J Vet Intern Med, Jan/Feb 2010;24(1):153–159. Quote: "Background: Concentrations of cardiac troponin I (cTnI) and C-reactive protein (CRP) might be associated with cardiac remodeling in dogs with myxomatous mitral valve disease (MMVD). Age- and sex-dependent variations in cTnI concentration have been described. Objective: To investigate whether plasma concentrations of cTnI and CRP are associated with severity of MMVD, and investigate potential associations of dog characteristics on cTnI and CRP concentrations. Animals: Eighty-one client-owned dogs with MMVD of varying severity [including 67 Cavalier King Charles spaniels]. Methods: Dogs were prospectively recruited for the study. Dogs were classified according to severity of MMVD. Plasma cTnI was analyzed by a high sensitivity cTnI assay with a lower limit of detection of 0.001 ng/mL, and plasma CRP was analyzed by a canine-specific CRP ELISA. Results: Higher cTnI concentrations were detected in dogs with moderate (0.014 [interquartile range 0.008–0.029] ng/mL, P 5 .0011) and severe (0.043 [0.031–0.087] ng/mL, Po.0001) MMVD, compared with healthy dogs (0.001 [0.001–0.004] ng/mL). Dogs with severe MMVD also had higher cTnI concentrations than dogs with mild (0.003 [0.001–0.024] ng/mL, P o .0001) and moderate (P 5 .0019) MMVD. There were significant associations of age, CRP, heart rate, and left ventricular end-diastolic diameter, on cTnI concentration C-reactive protein did not differ among severity groups, butwas significantly associated with cTnI, breed, and systolic blood pressure on CRP concentration. Conclusions and Clinical Importance: Analysis of cTnI concentration has potential to increase knowledge of overall cardiac remodeling in dogs with MMVD. However, effect of age on cTnI needs consideration when assessing cTnI."

Efficacy of Spironolactone on Survival in Dogs with Naturally Occurring Mitral Regurgitation Caused by Myxomatous Mitral Valve Disease. F. Bernay, J.M. Bland, J. Häggström, L. Baduel, B. Combes, A. Lopez, and V. Kaltsatos. J Vet Intern Med, Mar/Apr 2010;24(2):331-341.Quote: "Hypothesis: Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Animals: ... 212 dogs with moderate to severe mitral regurgitation (MR) caused by MMVD (International Small Animal Cardiac Health Council classification classes II [n = 190] and III [n = 21]). Methods: Double-blinded, field study conducted with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin converting enzyme inhibitor, plus furosemide and digoxin if needed). Primary endpoint was a composite of cardiac-related death, euthanasia, or severe worsening of MR. Results: Primary endpoint reached by 11/102 dogs (10.8%) in the spironolactone group (6 deaths, 5 worsening) versus 28/110 (25.5%) in control group (14 deaths, 8 euthanasia, 6 worsening). Risk of reaching the composite endpoint significantly decreased by 55% (hazard ratio [HR] = 0.45; 95% confidence limits [CL], 0.22–0.90; log rank test, P= .017). Risk of cardiac- related death or euthanasia significantly reduced by 69% (HR = 0.31; 95% CL, 0.13–0.76; P= .0071). Number of dogs not completing the study for cardiac and other miscellaneous reasons similar in spironolactone (67/102) and control groups (66/110). Conclusion and Clinical Importance: Spironolactone added to conventional cardiac therapy decreases the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe MR caused by MMVD."

Rate of change of heart size before congestive heart failure in dogs with mitral regurgitation. P. Lord, K. Hansson, C. Kvart, and J. Häggström. J Small An Prac; Apr 2010; 51(4):210-218. Quote: "Objectives: The objective of the study was to examine the changes in vertebral heart scale, and left atrial and ventricular dimensions before and at onset of congestive heart failure in cavalier King Charles spaniels with mitral regurgitation. Methods: Records and radiographs from 24 cavalier King Charles spaniels with mitral regurgitation were used. Vertebral heart scale (24 dogs), and left atrial dimension and left ventricular end diastolic and end systolic diameters (18 dogs) and their rate of increase were measured at intervals over years to the onset of congestive heart failure. They were plotted against time to onset of congestive heart failure. Results: Dimensions and rates of change of all parameters were highest at onset of congestive heart failure, the difference between observed and chance outcome being highly significant using a two-tailed chi-square test (P<0·001). Clinical significance: The left heart chambers increase in size rapidly only in the last year before the onset of congestive heart failure. Increasing left ventricular end systolic dimension is suggestive of myocardial failure before the onset of congestive heart failure. Rate of increase of heart dimensions may be a useful indicator of impending congestive heart failure."

Optimisation of breeding strategies to reduce the prevalence of inherited disease in pedigree dogs. Lewis, T.W.; Woolliams, J.A.; Blott, S.C. Animal Welfare 19(Supp 1):93-98(6), May 2010. Quote: "One option for improving the welfare of purebred dog breeds is to implement health breeding programmes, which allow selection to be directed against known diseases while controlling the rate of inbreeding to a minimal level in order to maintain the long-term health of the breed. The aim of this study is to evaluate the predicted impact of selection against disease in two breeds: the Cavalier King Charles spaniel (CKCS) .... Heritabilities for mitral valve disease, syringomyelia in the CKCS ... were estimated to be 0.64 (± 0.07), 0.32 (± 0.125) ... respectively, which suggest encouraging selection responses are feasible based upon the estimation of breeding values (EBVs) if monitoring schemes are maintained for these breeds. Although using data from disease databases can introduce problems due to bias, as a result of individuals and families with disease usually being over-represented, the data presented is a step forward in providing information on risk. EBVs will allow breeders to distinguish between potential parents of high and low risk, after removing the influence of life history events. Analysis of current population structure, including numbers of dogs used for breeding, average kinship and average inbreeding provides a basis from which to compare breeding strategies. Predictions can then be made about the number of generations it will take to eradicate disease, the number of affected individuals that will be born during the course of selective breeding and the benefits that can be obtained by using optimisation to constrain inbreeding to a pre-defined sustainable rate."

Evaluation of plasma and urinary levels of 6-keto-prostaglandin F1α as a marker for asymptomatic myxomatous mitral valve disease in dogs. Rasmussen, C.E., Sundqvist, A.V., Kjempff, C.T., Tarnow, I., Kjelgaard-Hansen, M., Kamstrup, T.S., Sterup, A.L., Soerensen, T.M., Olsen, L.H. Vet. J. May 2010; 184(2):241–246. Quote: "Endothelial dysfunction might be involved in the pathogenesis of myxomatous mitral valve disease (MMVD). The aims of this study were (1) to validate an enzyme immunoassay (EIA) for canine 6-keto-prostaglandin (PG)F1α (prostacyclin metabolite and marker for endothelial function) and (2) to compare plasma and urinary 6-keto-PGF1α in dogs with asymptomatic MMVD. The study included two breeds predisposed to MMVD and two control groups (Cairn terriers and dogs of different breeds). Echocardiography was used to estimate the severity of MMVD. The intra- and inter-assay coefficients of variation were between 3.1% and 24.5% in the assay range. No echocardiographic parameter was correlated with plasma or urinary 6-keto-PGF1α (P > 0.05), but all control dogs had lower urinary 6-keto-PGF1α (P < 0.02) and the Cairn terriers had higher plasma 6-keto-PGF1α (P < 0.02). The EIA appeared valid for measuring canine 6-keto-PGF1α in plasma and urine. It is suggested that 6-keto-PGF1α levels are related to breed and not MMVD in asymptomatic stages."

Cardiac troponin I as a marker for severity and prognosis of cardiac disease in dogs. S. Fonfaraa, J. Loureiroa, S. Swifta,R. Jamesa, P. Crippse and J. Dukes-McEwan. Vet.J. June 2010; 184(3): 334-339. Quote: "The use of cardiac troponin I (cTnI) to assess the severity of disease and prognosis in 120 dogs presented for cardiac evaluation was analysed. cTnI concentrations were measured using a commercially available assay. Dogs were placed into three groups: group 1, cTnI 0.15 ng/mL; group 2, cTnI 0.151–1.0 ng/mL; group 3, cTnI>1.01 ng/mL. Dogs in group 1 were significantly younger (P < 0.0001) and had no or stable cardiac diseases and longest survival times, whereas those in groups 2 and 3 had severe cardiac diseases and significantly reduced survival times (P < 0.0001). Thirty dogs with initially increased cTnI concentrations had a repeat assay less than 2 months later with significant reductions in cTnI concentrations (P = 0.005). Initial cTnI concentrations could not differentiate dogs that survived in group 3 from those that did not. However, dogs that survived showed significant cTnI reductions (P = 0.015) in the repeated assay in contrast to the dogs that died (P = 0.22). It was concluded that cTnI is useful in assessing the prognosis and severity of cardiac diseases in dogs, and progression and response to treatment can be assessed by repeat sampling. cTnI concentrations >1.0 ng/mL and persistent increases in cTnI concentrations are indicators of a poor prognosis in dogs with cardiac disease."

Thromboelastography in Dogs with Asymptomaticmyxomatous Mitral Valve Disease. I Tarnow, LH Olsen, SG Moesgaard, AU Martinsen, AC Birkegaard, AT Kristensen, B Wiinberg. J Vet Intern Med 2010;24:--- (ACVIM 28th Ann. Vet. Med. Forum Abstract Program: Abstract 11). Quote: "Changes in platelet aggregation responses and von Willebrand factor multimer levels have been reported in dogs with asymptomatic heart disease. Alterations in hemostatic pathways may be involved in the progression of canine mitral valve disease by causing microthrombosis and vessel changes in the myocardium, and it is being debated whether dogs with heart disease could benefit from antithrombotic therapy. We hypothesized that a global hypercoagulability is present in dogs with asymptomatic mitral valve disease. The study investigated Kaolin and Tissue Factor activated thromboelastographic (TEG) tracings in 3 groups of dogs: 11 Cavalier King Charles Spaniels (CKCS) with no or minimal mitral regurgitation (MR) (age 5.0 1.8 years), 14 CKCS with severe MR (regurgitant jet size by echocardio-graphy 50%) (age 7.1 1.6 years), and 8 healthy Beagles with no or minimal MR (age 7.7 2.3 years). ... These data do not support the hypothesis that a global hypercoagulability is present in CKCS with asymptomatic myxomatous mitral valve disease. Moreover, prospective longitudinal trials are needed to demonstrate a benefit of anti-thrombotic therapy in dogs with asymptomatic heart disease. The data supports previous findings that CKCS with macrothrombocytopenia have a normal coagulation response despite low platelet counts."

To Give or Not to Give... Ace Inhibitors. Hervé P. Lefebvre 2010 WSAVA Congress. www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2010&Category=8387&PID=56301&O=Generic  Quote: "Adverse effects of ACE inhibitors are rare. Renal safety of ACE inhibitors was an early concern, but their impact on renal function in adult normohydrated animals is minimal. The risk of hyperkalemia is very limited. ACE inhibitors are contraindicated in pregnant animals and neonates, as renal RAAS indeed plays a pivotal role in nephrogenesis and renal development. Although ACE inhibitors are mildly hypotensive agents in dogs and cats, they are contraindicated in animals with pre-existing hypotension, hypovolemia, hyponatremia and acute renal failure. Drug interactions mentioned in the literature include potential adverse effects of dual therapy with NSAIDs and ACEI. This interaction is clinically relevant as osteoarthritis and CKD can occur concomitantly in the same patient. COX inhibition induces a vasoconstriction of the afferent arteriole while ACE inhibitors, by blocking angiotensin II synthesis, induce vasodilation of the efferent arteriole. The drop in glomerular capillary pressure may lead to a decrease in GFR, and consequently to acute renal failure. Nevertheless, the contraindication for use of NSAIDs in a patient treated with ACE inhibitor is only relative in IRIS stage II and III, but a very careful monitoring of renal function is recommended when such a dual therapy is initiated."

Proposal For a New Simple Echo Index Predicting Congestive Heart Failure (CHF) in Mitral Valve Disease (MVD). Gerard Le Bobinnec. 2010 WSAVA Congress. www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2010&Category=8386&PID=56113&O=Generic  Quote: "MVD has a very variable progression, and there is a question still unsolved: when must we start the treatment? For it's now well demonstrated that if ACE inhibitors improve clinical status and prolong longevity in dogs with symptomatic MVD, unfortunately they have no preventive effect in asymptomatic stages; 3 successive publications demonstrated it now unquestionably: Kvart, SVEP trial 2002; Atkins, VETPROOF, 2007; Pouchelon, JVIM, 2008. Therefore, we evidently need a 'key' to predict the risk and time to onset of CHF, just to permit a precocious intervention and then to really improve outcome. Many attempts were published, not really convincing, except one of the latest (Reynolds, ACVIM, 2008) using Left Atrium and Aorta ratio ( LA/Ao) and serum NT-proBNP: 45% probability of CHF when LA/Ao = 1,8 & NT-proBNP = 1086 ; 100% probability of CHF when LA/ Ao = 2,8 & NT-proBNP = 2192. Two shortcomings in this statistical model: 1) It provides a probability, but not a threshold. 2) Serum NT-proBNP dosage is not yet a routine one, immediately accessible to all practitioners. A few years ago (ICVS, Paris, 2004), we underlined the interest of the Left Ventricular Internal Diameter in diastole (LVd) calculated on a standard transventricular M-mode as an interesting measurement correlated with many other parameters: murmur, class of CHF, LA/Ao (Häggström, JVIM, 1995), prognosis and mortality prediction (Moonarmat, JSAP, 2010). But because raw measurement are not available between dogs, we were very interested with the M-mode echographic ratio indices published by Brown et al (JVIM, 2003), and particularly with the LVd/Ao ratio: in normal dog, LVd/Ao = 1,6 +/- 0,2 , that means LV dilation starts over 1,8 (and then NT-proBNP secretion too). Because La/Ao and LVd/Ao separately failed to discriminate asymptomatic and symptomatic MVD (classes 1a-1b from classes 2-3a), despite a good linear correlation of these 2 indexes with CHF classes, our idea was to add the 2 indexes: we realised it on 397 dogs with MVD, and the results seem to be promising: Left Chambers on Aorta ratio (LC/Ao) = LA/Ao + LVd/Ao = in Class 1a: 3,12; Class1b: 4,01; Class 2: 4,59; Class 3a: 5,04 (see tables for details). It means that if you have an asymptomatic MVD with a LC/Ao > 4,5, you may immediately start treatment with ACE inhibitors, Pimobendan, or even Spironolactone more usefully than with a blind approach."

Canine Degenerative Myxomatous Mitral Valve Disease: Natural History, Clinical Presentation and Therapy. Michele Borgarelli, Jens Häggström. Vet. Clinics of No. America: Sm. An. Prac.; July 2010; 40(4)651-663. Quote: "Myxomatous mitral valve disease is a common condition in geriatric dogs. Most dogs affected are clinically asymptomatic for a long time. However, about 30% of these animals present a progression to heart failure and eventually die as a consequence of the disease. Left atrial enlargement, and particularly a change in left atrial size, seems to be the most reliable predictor of progression in some studies, however further studies are needed to clarify how to recognize asymptomatic patients at higher risk of developing heart failure. According to the published data on the natural history of the disease and the results of published studies evaluating the effect of early therapy on delaying the progression of the disease, it seems that no currently available treatment delays the onset of clinical signs of congestive heart failure (CHF). Although the ideal treatment of more severely affected dogs is probably surgical mitral valve repair or mitral valve replacement, this is not a currently available option. The results of several clinical trials together with clinical experience suggest that dogs with overt CHF can be managed with acceptable quality of life for a relatively long time period with medical treatment including furosemide, an angiotensin-converting enzyme inhibitor, pimobendan, and spironolactone."

Genetics of Cardiac Disease in the Small Animal Patient. Kathryn M. Meurs. Vet. Clinics of No. America: Sm. An. Prac.; July 2010; 40(4)701-715. Quote: "There is increasing evidence that many forms of congenital and acquired cardiovascular disease in small animal patients are of familial origin. The large number of familial diseases in domestic purebred animals is thought to be associated with the desire to breed related animals to maintain a specific appearance and the selection of animals from a small group of popular founders (founder effect). Clinicians can use knowledge that a particular trait or disease may be inherited to provide guidance to owners and animal breeders to reduce the frequency of the trait. Even if the molecular cause is not known, identification of a pattern of inheritance and information on clinical screening can be useful for a breeder trying to make breeding decisions. Common forms of inheritance for veterinary diseases include autosomal recessive, autosomal dominant, X-linked recessive, and polygenic. These genetic traits and their possible involvement in cardiac disease in small animals are discussed in this article."

Associations between cardiac pathology and clinical, echocardiographic and electrocardiographic findings in dogs with chronic congestive heart failure. Torkel Falk, Lennart Jönsson, Lisbeth H. Olsen, Inge Tarnow, and Henrik D. Pedersen. Vet. J. July 2010; 185(1)68-74. Quote: "The objective of this study was to correlate defined pathological features with clinical findings in dogs with naturally occurring congestive heart failure (CHF). Fifty-eight dogs with CHF were examined clinically and using echocardiography and electrocardiography. Detailed cardiac post-mortem examination was used to assess intra-myocardial arterial narrowing, myocardial fibrosis and atrophy and myxomatous mitral valve degeneration (MMVD). Arterial narrowing significantly correlated with fibrosis (P < 0.0001) and with fractional shortening, an indicator of systolic function (P = 0.002). The grade of fibrosis was associated with shorter survival time (P = 0.002), and the papillary muscle fibrosis score tended to correlate with proximal isovelocity surface area radius (P = 0.03). Data from this study lend support to the hypothesis that naturally occurring canine CHF is affected by several factors such as MMVD, myocardial atrophy and fibrosis, and by arteriosclerosis. Further, more extensive research will be required to establish cause–effect relationships between these cardiac lesions and the pathophysiology of CHF in dogs."

Molecular changes in fibrillar collagen in myxomatous mitral valve disease. Mojtaba Hadian, Brendan M. Corcoran, and Jeremy P. Bradshaw. Cardiovascular Pathology, Sep. 2010; 19(5):e141-e148. Quote: "Introduction: Myxomatous mitral valve disease (MMVD) is the single most common acquired cardiac disease of dogs and is a disease of significant veterinary importance. It also bears close similarities to mitral valve prolapse in humans and therefore is a disease of emerging comparative interest. We have previously mapped the structure of collagen fibrils in valve leaflets using synchrotron X-rays and have demonstrated changes in collagen structure associated with the regions of disease. Methods: Differential scanning calorimetry (DSC), biochemical assay of collagen content, high-performance liquid chromatography (HPLC), and neutron diffraction were combined with further analysis of our previous X-ray data to elucidate molecular changes in fibrillar collagen in mild to moderately affected MMVD dogs. Results: Comparing diseases and adjacent grossly uninvolved areas in the same leaflets, there was a 20% reduction in collagen fibrils, but only a 10% depletion of collagen content. The enthalpy of collagen denaturation was reduced in affected areas. Chromatography showed a 25% decrease in mature nonreducible covalent cross-links in the affected samples, and neutron diffraction data showed fewer reducible immature covalent cross-links in grossly uninvolved tissue samples. Conclusions: Mild to moderate MMVD in the dog is associated with a marginal decline in collagen content in overtly diseased areas of valves, but more importantly is associated with an increase in immature collagen content. These changes will contribute to the mechanical dysfunction of the leaflet, and this study provides important information on the structure–mechanical alterations associated with this disease. The data suggests MMVD involves a dyscollagenesis process in the development of valve pathology."

Evaluation of the Swedish breeding program for cavalier King Charles spaniels. Tobias Lundin, Clarence Kvart. Acta Veterinaria Scandinavica, Sept. 2010, 52:54. Quote: "The Swedish Kennel club and the Special club for cavalier King Charles spaniels (SCKCS) started a breeding program in 2001 with the aim of reducing MMVD in the Swedish population of CKCS. In this program, dogs are not allowed to breed until four years of age and need a heart auscultation without murmurs within eight months before mating. However, dogs are allowed to breed at an age of 24 months, if the dog and its parents are examined and no murmurs are detected. Male dogs that have a heart auscultation at seven years of age without murmurs are allowed to breed without further heart evaluation. Breeding animals whose parents have heart murmurs before four years of age are not allowed to breed. The aim of this investigation was to study the prevalence of heart murmurs in the Swedish population of six-year-old CKCS born 2001 and 2003, and to estimate if prevalence has decreased since the breeding program was introduced 2001. ... In this investigation 353 CKCS were selected as a sample of the population and 150 were examined by auscultation for heart murmurs when they reached the age of six years in 2007 and 2009. ... The effect of the breeding program was evaluated by comparing the prevalence of heart murmurs in the two groups. In 2007, the prevalence of heart murmurs was 52% (50% for females and 54% for males) and in 2009, the prevalence was 55% (44% for females and 67% for males). No significant difference was found in the prevalence of heart murmurs between 2007 and 2009 (P=0.8). For all six-year-old CKCS, the prevalence of heart murmur was 53% (females 46% and males 61%), which is higher than previous Swedish investigations. ... The result from this investigation indicates that the prevalence of MMVD in six-year-old cavalier King Charles spaniels, born 2001 and 2003, is at least 50% and lacks signs of decrease despite the current breeding program introduced in Sweden 2001."

Open Heart Surgery with Deep Hypothermia and Cardiopulmonary Bypass in Small and Toy Dogs. Isamu Kanemoto, Daisuke Taguchi, Satoko Yokoyama, Masashi Mizuno, Hiromi Suzuki, and Tougaku Kanamoto. Vet. Surgery 2010; 39:674–679. Quote: "Objective: To evaluate open heart surgery with deep surface-induced hypothermia (sHT) and low-flow cardiopulmonary bypass (CPB) in small and toybreed dogs. Animals: Small breed dogs (n=8) weighing o5.5 kg with naturally occurring cardiac disease. [None were Cavaliers.] ... Conclusion: Deep sHT with low-flow rate CPB may be used for open heart surgery in small dogs weighing o5.5 kg. Clinical Relevance: Open heart surgery for selected congenital defects and acquired defects in small and toy-breed dogs may be successfully performed using deep sHT and CPB."

Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs. Schuller, S., Van Israël, N., Vanbelle, S., Clercx, C., McEntee, K. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2010.01235.x.

Breed Predispositions to Disease in Dogs & Cats (2d Ed.). Alex Gough, Alison Thomas. 2010; Wiley-Blackwell Publ. 51.

Myxomatous Degenerative Mitral Valve Disease: An Update. Sirilak Disatian. Thai J. Vet. Med. 2010 40(2): 151-157. Quote: "This article was written to summarize an update of canine MVD concerning clinical approach, etiology, and treatment. ... canine MVD is the number one acquired heart disease in dogs. Although MVD is a common disease easily found in veterinary hospitals, its etiology is still unknown. To date, treatments goals have been to correct circulatory disturbances secondary to mitral valve regurgitation, improve quality of life and prolong survival time. A better understanding in the pathogenesis of valve degeneration will guide a treatment protocol to treat the actual lesions as well as to prevent the degenerative progression rather than to control resultant circulatory disturbances which may help MVD dogs to have a better quality of life with a longer time before developing heart failure or death."

Detection of Congestive Heart Failure in Dogs by Doppler Echocardiography. K.E. Schober, T.M. Hart, J.A. Stern, X. Li, V.F. Samii, L.J. Zekas, B.A. Scansen, and J.D. Bonagura. J Vet Intern Med 2010;24:1358–1368. Quote: "Background: Echocardiographic prediction of congestive heart failure (CHF) in dogs has not been prospectively evaluated. Hypothesis: CHF can be predicted by Doppler echocardiographic (DE) variables of left ventricular (LV) filling in dogs with degenerative mitral valve disease (MVD) and dilated cardiomyopathy (DCM). Animals: Sixty-three client-owned dogs. Methods: Prospective clinical cohort study. Physical examination, thoracic radiography, analysis of natriuretic peptides, and transthoracic echocardiography were performed. Diagnosis of CHF was based upon clinical and radiographic findings. Presence or absence of CHF was predicted using receiver-operating characteristic (ROC) curve, multivariate logistic and stepwise regression, and best subsets analyses. Results: Presence of CHF secondary to MVD or DCM could best be predicted by E: isovolumic relaxation time (IVRT) (area under the ROC curve [AUC]50.97, P o .001), respiration rate (AUC50.94, P o .001), Diastolic Functional Class (AUC50.93, P o .001), and a combination of Diastolic Functional Class, IVRT, and respiration rate (R250.80, P o .001) or Diastolic Functional Class (AUC51.00, P o .001), respiration rate (AUC51.00, P o .001), and E: IVRT (AUC50.99, P o .001), and a combination of Diastolic Functional Class and E: IVRT (R250.94, P o .001), respectively, whereas other variables including N-terminal pro-brain natriuretic peptide, E: Ea, and E: Vp were less useful. Conclusion and Clinical Importance: Various DE variables can be used to predict CHF in dogs with MVD and DCM. Determination of the clinical benefit of such variables in initiating, modulating, and assessing success of treatments for CHF needs further study."

The Cardiac Biomarker Sodium-Calcium Exchanger (NCX-1) Can Differentiate between Heart Failure and Renal Failure: A Comparative Study of NCX-1 Expression in Dogs with Chronic Mitral Valvular Insufficiency and Azotemia. S.-J. Nam, S.-H. Han, H.-W. Kim, C. Hyun. J.Vet.Int.Med. Nov/Dec 2010;24(6):1383-1387. Quote: "The sodium-calcium exchanger (NCX-1), an established cardiac biomarker, was postulated previously as differentiating between heart failure (HF) and renal failure (RF) in dogs. The effect of azotemia on NCX-1 expression has not been studied. In contrast to other cardiac biomarkers (eg, N-terminal-proBNP), we hypothesized that the expression level of NCX-1 is not influenced by either azotemia or decreased renal clearance. Fifteen client-owned healthy control dogs, 14 dogs with chronic mitral valvular insufficiency (CMVI), classified based on severity of the disease by the established International Small Animal Cardiac Health Council classification system, and 15 dogs with RF, grouped according to the International Renal Interest Society stage classification. A comparative study of the expression levels of NCX-1, evaluated in peripheral blood samples from dogs with HF, RF, and healthy controls by quantitative PCR. NCX-1 expression was significantly increased in moderate (2.99 ± 0.61 [fold changes relative to normal group]) to severe (4.35 ± 1.44) CMVI dogs (P < .01). In contrast, NCX-1 expression was not increased in the azotemic dogs. Furthermore, there was also no correlation between increased concentrations of creatinine and urea nitrogen in serum and NCX-1 expression in the RF group. Azotemia likely does not affect NCX-1 expression."

Pulmonary Blood Volume in Mitral Regurgitation in Cavalier King Charles Spaniels. A. Eriksson, K. Hansson, J. Häggström, A.-K. Järvinen, P. Lord. J.Vet.Int.Med. Nov/Dec 2010;24(6):1393-1399. Quote: "Pulmonary edema and venous congestion are well-recognized signs of congestive heart failure (CHF) in advanced canine chronic mitral regurgitation (MR). However, little is known about pulmonary blood volume (PBV), blood pulmonary transit time (PTT), and the regulation of these. Objectives: To measure and evaluate the relationships of PBV, forward stroke volume (FSV), and heart rate normalized blood pulmonary transit time (nPTT) in healthy dogs and dogs with MR. ... 33 Cavalier King Charles Spaniels; 11 healthy, 4 in modified New York Heart Association (NYHA) class I, 11 in class II, and 7 in CHF were studied. ... Increased PBV, not decreased FSV, is the main cause of increased nPTT in MR. Increased nPTT can be used as an indicator of abnormal cardiopulmonary function in dogs with MR."

Evaluation of pimobendan in dogs with cardiomegaly caused by preclinical mitral valve disease. Adrian Boswood, Sarah Smith, Mark Patteson. Vet Rec; Feb. 2011;168:222. Quote: "We wish to announce the launch of a new study called EPIC (Evaluation of Pimobendan In dogs with Cardiomegaly caused by preclinical mitral valve disease [MVD]). EPIC is a global, randomised, double-blinded, parallel group, placebo-controlled study conducted within Good Clinical Practice guidelines. The study has been designed to assess whether using pimobendan in the preclinical phase of MVD extends the time to the onset of clinical signs of congestive heart failure. Colleagues will be aware that pimobendan is already licensed, and widely used, for the treatment of congestive heart failure attributable to both valvular insufficiency and dilated cardiomyopathy."

The Effect of Furosemide on Left Atrial Pressure in Dogs with Mitral Valve Regurgitation. S. Suzuki, T. Ishikawa, L. Hamabe, D. Aytemiz, H. Huai-Che, R. Fukushima, N. Machida, R. Tanaka. JVIM; Mar/Apr 2011;25(2):244–250. "The effects of furosemide on left atrial pressure (LAP) in dogs with mitral regurgitation (MR) have not been documented in a quantitative manner and between different routes of administration. Objective: To document LAP and echocardiographic parameters in MR dogs administered furosemide IV or PO, in order to document changes in LAP after furosemide treatment. ... Conclusions: LAP was decreased in proportion to the dosage of furosemide, which did not significantly differ between IV and PO of the same dosages. E wave and E/Ea might be useful for the treatment evaluation of furosemide."

Heritability of premature mitral valve disease in Cavalier King Charles spaniels. Tom Lewis, Simon Swift, John A. Woolliams, and Sarah Blott. Vet J, April 2011, 188(1):73-76. Quote: "Mixed model analysis of 1252 records of cardiac auscultation of ≥4- to <5-year-old Cavalier King Charles spaniels (CKCS) from 1991 to 2008 in conjunction with the Kennel Club pedigree records of all dogs registered from the mid 1980s to September 2007 was used to estimate variance parameters of premature mitral valve disease (MVD). Data were limited to dogs 4 and <5 years of age to ensure diagnostic distinction between early and late onset MVD. Cardiac murmurs were detected in 108/1252 (8.6%) dogs. Heritability estimates of 0.67 (standard error, SE 0.071) for the grade of murmur and 0.33 (SE 0.072) for the presence/absence of murmur were calculated. The variance due to clinician was 0.02 (SE 0.012) for grade and 0.03 (SE 0.017) for presence/absence of murmur. These results indicate that the presence and severity of MVD, as assessed by cardiac auscultation, in 4- to 5-year-old CKCS is highly heritable and that selection against the disease should be successful."

Holter Monitoring in Clinically Healthy Cavalier King Charles Spaniels, Wire-Haired Dachshunds, and Cairn Terriers. C.E. Rasmussen, S. Vesterholm, T.P. Ludvigsen, J. Häggström, H.D. Pedersen, S.G. Moesgaard, L.H. Olsen. J.Vet.Int.Med. May 2011; 25(3):460–468. "Objectives: To investigate influence of breed, age, sex, body weight, degree of recording artifact, and mitral valve prolapse (MVP) on Holter recordings of 3 breeds of small dogs that have differing predispositions for myxomatous mitral valve disease. The study also assessed if heart rate (HR) at clinical examination (HRex) was associated with HR during Holter monitoring and evaluated the reproducibility of Holter variables. Animals: This study included 54 privately owned dogs: 23 Cavalier King Charles Spaniels (CKCS) (at high risk to develop MMVD), 18 wirehaired Dachshunds (wD) (at moderate risk to develop MMVD) and 13 Cairn Terriers (CT) (at low risk to develop MMVD). All dogs were between two and nine years old and clinical healthy based on history, clinical examination, echocardiography, serum biochemistry and complete blood count. ... Results: Fifteen out of 27 Holter derived variables were significantly associated with breed (P < .03), but not with age (P > .7), sex (P > .2), body weight (P > .7), degree of recording artifact (P > .4), or MVP (P > .6). CKCS had a significantly higher HRex (mean 121 ± SD 12 bpm) compared to wD (94 ± 18 bpm) (P > 0.0001) and CT (102 ± 16 bpm) (P = 0.0009). The minimum HR (HRmin) measured during Holter recording was significantly higher in CKCS (51 ± 10 bpm) compared to wD (42 ± 7 bpm) (P = 0.001) and CT (45 ± 7 bpm) (P 5 0.05). In addition, CKCS had a higher mean HR (HRmean) during Holter recording (83 ± 13 bpm) compared to would (68 ± 8 bpm) (P > 0.0001) and CT (75 ± 10 bpm) (P = 0.04). Both HRmean (P > 0.0001) and HRmin (P = 0.001) were positively correlated with HRex. Second-degree atrioventricular-block (AV) and single, sporadic, uniform ventricular premature complexes (VPC) occurred in 63.0% and 40.7% of the dogs, respectively. The occurrence of second-degree AV-block and VPC showed no breed difference. In conclusion, HR parameters were higher in CKCS compared to wD and CT. HRmean and HRmin were correlated with Hrex. However, further studies are required to clarify the possible influence of high HR in the development of MMVD in CKCS. Second degree AV-block and single, sporadic, uniformed VPC, were common in CKCS, wD and CT but not related to breed."

ACE-Inhibitors, Emerging & Established Roles in the Treament of Heart Failure. Clarke E. Atkins. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 048). Quote: "... Future uses of ACE-I include the use of other drugs concurrently in the advent of aldosterone escape. Reciprocally speaking, the use of ACE-I to suppress the activation of RAAS as is seen with amlodipine and furosemide will become more important as it is better understood. The discovery and better understanding of tissue RAAS activators will help us to suppress the tissue RAAS which makes up 90-99% of the body’s RAAS. Electronic remodeling during arrhythmias can be blocked in part with ACE-I, so this drug group will play a role in management of arrhythmias in the future. Lastly, ACE-I will likely find greater use in combination with pimobendan (which have to date only been studied in designs comparing their efficacy, without concern for additive benefit) and beta-blockers which show promise in treatment of heart failure and slowing the progression of asymptomatic heart disease."

Beta Blockers: Emerging & Established Roles in the Treatment of Heart Failure. Jonathan A. Abbott. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 049). Quote: "... The efficacy of BAA (beta-adrenergic antagonists) in heart failure has been unequivocally demonstrated in people with HF and experimental evidence favors the use of BAAs in dogs with systolic dysfunction. Based on this, the cautious use of BAA in veterinary patients can be justified. However, beta-blockade in canine patients with systolic dysfunction is currently an unproven therapy. Furthermore, BAA can have catastrophic effects in patients with severe myocardial dysfunction who may be critically dependent on a limited inotropic reserve in order to maintain adequate cardiac output.The author considers the use of BAA, generally metoprolol or carvedilol, in patients with echocardiographic evidence of myocardial dysfunction who have not developed congestive signs or in those in which congestive signs have resolved with therapy. Unwillingness on the part of the pet-owner to contend with frequent dosage adjustments or accept the potential for adverse effects is a relative contraindication."

Inodilators: Emerging & Established Roles in the Treatment of Heart Disease. Sonya Gordon.  J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 050). Quote: "... Currently, pimobendan is available as an oral formulation and milrinone and levosimendan are available as intravenous (IV) preparations. ... The clinical veterinary indication for milrinone is for acute cardiovascular support in dogs with HF, however in most cases dobutamine is the preferred agent for this indication. No clinical studies of the effects of intravenous milrinone administration for acute myocardial failure in dogs or cats have been performed. Clinical studies of the effects of chronic oral administration have been performed but this form of the drug has not been approved for veterinary use and is not available for human use. ... Milrinone is chemically incompatible with furosemide and thus should not be administered in the same intravenous line without flushing adequately in between. ... Overall, pimobendan enhances systolic function by improving the efficiency of contraction, limiting the arrhythmogenic side effects of positive inotropes whose sole mechanism of action is to increase myocardial intracellular calcium. Pimobendan inhibits PDE-III in vascular smooth muscle resulting in dilation of both arteries and veins leading to a reduction of both cardiac preload and afterload. Pimobendan has also been demonstrated to have additional vasodilatory properties that are reportedly endothelium mediated (nitric oxide) and may involve inhibition of PDE-V. ... This product [pimobendan] in not currently available as an IV preparation however the oral preparation is rapidly absorbed with peak effects in 2-4 hours. The recommended canine dose is 0.25-0.3 mg/kg twice daily. In later stages of heart failure or when clinical signs become refractory the dose (0.25-0.3 mg/kg) is frequently increased to three times daily. ... Levosimendan exerts its positive inotropy predominantly through calcium sensitization. It appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependant manner. ... It is used for the acute/short-term support of decompensated heart failure. An oral formulation of levosimendan was recently developed for evaluation in the treatment of canine congestive heart failure but to date no clinical trial results have been reported. ... Pimobendan has been proven to prolong survival and reduce clinical signs in dogs with congestive heart failure secondary to both CVD and DCM.8-10 According to the ACVIM consensus statement guidelines for the diagnosis and treatment of CVD pimobendan should be considered a cornerstone of multimodal therapy in dogs with Stage C and D heart failure due to CVD. ... Pimobendan is currently used off label for the treatment of both right and left heart failure due to a variety of underlying etiologies. It is used as a rescue agent on a case by case basis in patients with symptomatic heart failure when conventional heart failure therapy is failing and/or when the underlying cardiac disease (based on echocardiogram) is characterized by ventricular systolic dysfunction or myocardial failure. ... Pimobendan has recognized use in the emergency treatment of congestive heart failure but this indication could be better evaluated for this indication if an IV formulation were available. The availability of an IV formulation would likely lead to its evaluation for short-term support of the cardiovascular system in dogs with recognized heart disease (e.g. Stage B2 CVD and DCM) that require general anesthesia. ... "

Regulation of Cardiac β-1, β-2, and β-3 Adrenergic Receptors in Canine Valvular Heart Disease. OL Nelson, J Häggström, K Höglund, I Ljungvall, C Kvart. Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 155B). Quote: "... Use of β- receptor blocking drugs in dogs with heart failure has been disappointing as compared to results in people. Dogs with overt congestive failure do not tolerate the hemodynamic drug effects, and clinical trials in subclinical heart disease have not shown clear benefit in survival or disease progression. It is therefore logical to hypothesize that the canine species may express β- adrenergic receptors in different proportions than humans, and these receptor proportions may regulate differently in canine heart disease. We also hypothesized that dogs with CHF would have upregulation of β1 & 3 adrenergic receptors compared to healthy dogs. We quantified mRNA expression of β1, 2, and 3 adrenergic receptors in atrial and ventricular myocardium of 13 dogs that were euthanized at various stages of degenerative mitral valvular disease (DMVD) and congestive heart failure (CHF). The mean age of DMVD dogs was 10.1 (6 males, 7 females). Breeds of dogs with DMVD were 1 border collie, 1 beagle, 1 miniature poodle and 10 Cavalier King Charles Spaniels (CKCS). Six healthy mix breed dogs (mean age, 5.5years; mean weight, 15.9kg; 3 males, 3 females) without cardiac disease were used as controls. Normal canine LV myocardium expressed similar proportions of β1 and β2 adrenergic receptors, whereas β3 receptors were slightly less. Δ Ct values did not differ in LV myocardium between healthy dogs and CHF dogs for RPS5 (housekeeping gene), β1 or β3 adrenergic receptors. β2 adrenergic receptor was significantly upregulated in LV myocardium of CHF dogs. The LA myocardium results were very similar to the LV myocardium. Six CKCS did not register β1 receptor signal for LA or LV myocardium. These results may suggest that upregulation of β2 adrenergic receptors are a predominant finding in the dog, which could explain the differences in tolerance of beta-blocking drugs in dogs compared to humans (which predominately upregulate β1). We also postulate that some CKCS may have polymorphisms of their β1 adrenergic receptor to account for lack of amplification. These results could be further investigated by quantifying β adrenergic receptor protein in myocardium and sequencing the β1 receptor in the CKCS. Understanding regulation of β- adrenergic receptors in various stages of canine heart disease will elucidate answers to these common questions regarding the use of β -receptor blocking drugs for heart failure therapy in canine patients."

Identification of Two Deletion Polymorphisms Within the Canine Beta-1 Adrenoceptor Gene. BA Maran, KM Meurs, SL Lahmers, OL Nelson.  J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum: Abstract C-08).  Quote: "... The field of pharmacogenomics, which is the influence of genetics on drug response, is very new in the dog and very little is known about breed specific or family variation in the genes that impact cardiac drug function. The hypothesis of this study is that polymorphisms are present in the canine ß1-AR gene, which could result in an altered pharmacologic response to beta-blocker therapy. The objective of the study was to sequence the canine ß1-AR gene in unrelated dogs of several different breeds to evaluate for the presence of polymorphisms. The canine ß1-AR gene was amplified with specifically designed and optimized primers using the canine ß1-AR sequence, standard PCR techniques, and PCR-based genomic sequencing. DNA samples from 40 dogs of five breeds were evaluated. Computer modeling (POLYVIEW3D) was performed to evaluate the structural impact of any observed polymorphisms. We identified two polymorphisms within the canine ß1-AR gene that may alter responsiveness to commonly administered beta-blockers. We sequenced 40 DNA samples from five breeds (Newfoundland, Boxer Dog, Doberman Pinscher, King Charles Cavalier (CKCS), Great Dane) of dogs and identified two separate deletion polymorphisms, with some individuals displaying both deletions. One polymorphism, a six to nine base pair deletion, was identified in five Boxer dogs, six Newfoundlands, seven Great Danes, seven Doberman Pinschers, and one CKCS. This deletion correlates to a loss of two to three aspartic acids. A second polymorphism was identified in four Newfoundlands, four Great Danes, and two CKCS and consists of a 24 base pair deletion. This deletion correlates to a loss of eight amino acids, a repeating strand of glycine and alanine. Computer modeling (POLYVIEW3D) of these deletions determined substantial tertiary structural change within the intracellular domain that has the potential to alter receptor function. Although the clinical significance of these deletions are unknown, additional investigation into the pharmacogenomics of beta-blockers in dogs is warranted as these polymorphisms may alter the commonly accepted therapeutic strategies for various cardiac diseases in dogs."

Bronchomalacia in Dogs with Myxomatous Mitral Valve Degeneration. MK Singh, LR Johnson, MD Kittleson, RE Pollard. William R. Pritchard. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-12). Quote: "Coughing in the small breed dog may be related to cardiac causes associated with myxomatous mitral valve degeneration (MMVD) including pulmonary edema and compression of the mainstem bronchus by a severely enlarged left atrium, or due to respiratory causes such as tracheal and/or bronchial collapse or chronic bronchitis. The purpose of this study was to evaluate the association between left atrial enlargement and large airway collapse in dogs with MMVD and chronic cough. We hypothesized that airway collapse was independent of degree of left atrial enlargement. ... Preliminary results failed to identify an association between left atrial enlargement and airway collapse in dogs with MMVD but did suggest that airway inflammation is common in affected dogs. Further studies are needed to identify factors contributing to airway collapse in dogs with and without MMVD."

Reverse Remodeling after Mitral Valve Repair under Cardiopumonary Bypass in Dogs. Masami Uechi. . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract 157A). Quote: "We evaluated cardiac reverse remodeling after mitral valve repair under cardiopulmonary bypass (CPB) for mitral regurgitation in small breed dogs. Fifty dogs (body weight 1.8–9.3 kg, age 5–14 years) with mitral regurgitation were treated between August 2006 and November 2009. The cardiac murmur was grade 4/6–6/6. The preoperative chest X-rays showed cardiac enlargement (vertebral heart scale (VHS) 11.0–13.1). Echocardiography showed severe mitral regurgitation and left atrium enlargement (LA/Ao 2.0–4.2). After inducing anesthesia, a thoracotomy was performed in the fifth intercostal space. CPB was started by using a CPB circuit connected to carotid artery and jugular vein catheters. After inducing cardiac arrest, the left atrium was sectioned and chordae tendineae rupture confirmed. The chordae tendineae were replaced with expanded polytetrafluoroethylene. A mitral annulus plasty was also done, and the left atrium was closed. After de-clamping for restarting the heart, the chest was closed. Heart rate decreased from 118–164 bpm to 75–138 bpm. The grade of cardiac murmur was reduced to 0/6–3/6 three months postoperatively, and the heart shadow was reduced (VHS 9.8–11.5) in the chest x-rays. Echocardiography confirmed the marked reduction in mitral regurgitation and the left atrial dimensions (LA/Ao 1.2–2.2). Mitral valve repair reduced enlarged cardiac size by reduction of regurgitant rate."

Associations Between N-terminal Procollagen Type III (PIIINP) and Ventricular Remodelling in Dogs with Mitral Valve Disease.  MJ Hezzell, A Boswood, J Elliott. . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-17). Quote: "PIIINP is a serum biomarker of collagen biosynthesis and is described as a marker of myocardial fibrosis in human patients. We hypothesised that PIIINP concentrations would vary according to the degree of remodelling demonstrable in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Serum PIIINP concentrations (mg/ml) were measured in dogs with MMVD and healthy controls using a validated commercially available radioimmunoassay. Results are reported as (Mean ± SD). Non-normally distributed variables were logarithmically transformed. Comparisons of continuous variables were made between groups using t-tests and one-way ANOVAs with Tukey’s post-hoc comparisons. Univariable analyses were used to evaluate associations between PIIINP and clinical characteristics (age, breed [cavalier King Charles spaniel (CKCS) yes/ no], sex, weight, heart rate [measured from ECG], treatment with ACEi [yes/ no], treatment with diuretics [yes/ no] and echocardiographic measurements [LA/Ao, LVEDD/ LVFWd, LVEDDN, LVESDN]). Multivariable analysis was initially performed with all dogs included and then repeated excluding all dogs receiving therapy. Dogs with MMVD were divided into those with no cardiomegaly (NC) (LA/Ao < 1.5 and LVEDDN < 1.8), those with cardiomegaly (LA/Ao 1.5 and/ or LVEDDN 1.8) but no clinical signs (C) and those dogs with cardiomegaly requiring treatment for congestive heart failure (CHF). One hundred and fifty-four dogs with MMVD and 23 control dogs were studied. There was no difference in age (P = 0.870) or weight (P = 0.606) between the MMVD and control groups. There was a significant difference in serum PIIINP (P 5 0.034) between normal (11.2 ± 3.66), NC (11.6 ± 4.57), C (10.1 ± 3.44) and CHF (9.4 ± 3.06) groups. Post-hoc comparisons demonstrated a difference between NC and CHF groups (P = 0.038). There was no difference in serum PIIINP between genders (P = 0.228). In the univariable analysis CKCS (yes/ no) (P = 0.016) was positively associated with serum PIIINP. Age (P < 0.0001), Log (LA/Ao) (P = 0.002) and LVEDDN (P = 0.002) were negatively associated with serum PIIINP. In the multivariable model including all dogs, LVEDDN (P o 0.0001, B =-4.04 (95%CI = -6.11 to -1.97)), age (P = 0.006, B = -0.28 (95%CI = -0.47 to -0.08)) and CKCS (yes/ no) (P = 0.003, B 5 2.01 (95%CI = 0.67 to 3.34)) were independently associated with serum PIIINP. In the multivariable model including only dogs not receiving therapy (n 5 141), LVEDDN(P50.006, B= -4.30 (95%CI = -7.32 to-1.29)), age (P = 0.011, B = -0.31 (95%CI = -0.55 to -0.07)) and CKCS (yes/ no) (P = 0.034, B = 1.75 (95%CI = 0.13 to 3.37)) were independently associated with serum PIIINP. In conclusion, serum PIIINP decreases with age and with increasing LVEDDN. CKCS have higher serum PIIINP measurements independent of age and LVEDDN, which may reflect a difference in collagen turnover in this breed."

Advanced Electrocardiography Can Predict Mitral Regurgitation in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease. M Spiljak, AD Petric, LH Olsen, A Stepancic, T Falk, CE Rasmussen, V Starc. . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-32). Quote: "Recently, multiple advanced resting electrocardiographic (ECG) techniques have been applied in humans for detection of cardiac autonomic and repolarisation function. This has improved the diagnostic and/or prognostic value of short-time ECG in detection of common human cardiac diseases even before onset of symptoms or changes in the standard ECG. Therefore, this study investigates, if advanced ECG can predict the severity of mitral regurgitation (MR) in dogs with myxomatous mitral valve disease (MMVD) and thereby improve the diagnostic value of ECG. The study included 77 privately owned Cavalier King Charles Spaniels (CKCSs) (age 6.0 ± 2.7 years; 30 males and 47 females). All dogs were examined by echocardiography and a short-time (3–5 min) high-fidelity 12-lead ECG, with the dog in a resting position and in sinus rhythm. Dogs were divided into 5 groups according to the degree of MR estimated as the percentage of the left atrium area using color Doppler mapping (0%; 0% < jet 15%; 15% < jet 50%; jet > 50%; jet = 100% and with clinical signs of congestive heart failure). ECG recordings were evaluated via custom software programs to calculate 76 different parameters, including heart rate variability (HRV), QT variability (QTV), T-wave complexity, wave morphology and 3-D ECG. One-way ANOVA determined 21 ECG parameters, which were significantly different (P < 0.05) between the 5 dog groups. Principal component factor analysis identified a 5- factor model with 83.2% explained variability. QRS dipolar voltage and two repolarization indices of QTV increased significantly with MR severity, whereas total power of the frequency spectrum of RR interval and the standard deviation of QTV decreased significantly with MR severity. For the 5 selected parameters the prediction of MR jet value was tested by multiple linear regression. A correlation coefficient (R) of 0.65 indicated that the prediction value was significant (P < 0.01). If age was included in the multiple linear regression the prediction value was further increased (R = 0.80). Our results indicate that for a cut-off criteria of MR 50% jet the five selected ECG parameters could predict the severity of MR caused by MMVD in CKCSs with sinus rhythm with sensitivity 65% (78% with age inclusion) and specificity 98% (92% with age inclusion) (P < 0.05)."

Heart Rate and Heart Rate Variability in Dogs with Different Degrees of Myxomatous Mitral Valve Disease. CE Rasmussen, T Falk, NE Zois, SG Moesgaard, HD Pedersen, J Häggström, and LH Olsen. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-42). Quote: "Heart rate variability (HRV) is an indirect measurement of the autonomic modulation of heart rate (HR). Reduced HRV measured from short-time electrocardiography is seen in dogs with heart failure (HF) secondary to myxomatous mitral valve disease (MMVD). However, HRV is suggested to increase with disease severity at early stages of MMVD. The aims of this study were 1) to associate HR and HRV with severity of MMVD in Cavalier King Charles Spaniels (CKCS) and 2) to compare HR and HRV between CKCS and other dog breeds in a group of dogs in HF secondary to MMVD. One-hundred dogs were examined by echocardiography and 24-hour electrocardiography. The dogs were divided into five groups: 1) CKCS with no/minimal mitral regurgitation (MR) (MR jet 15% of the left atrial area using color Doppler mapping) and no murmur, 2) CKCS with mild MR (20% < jet 50%), 3) CKCS with moderate/severe MR (jet > 50%) and no clinical signs of HF, 4) CKCS in HF (HF defined as left atrium to aortic root ratio (LA/Ao) > 1.5, clinical signs of HF and furosemide responsiveness) and 5) non-CKCS in HF. Dogs in HF were allowed HF therapy. Both HR and HRV were analyzed over a 24-hour period, while HRV were also analysed over a 6-hour nightly period. Analyses of variance were performed with HR or HRV as response variables and the explanatory variables dog group and echocardiographic indices of MMVD were included separately. All P-values were Bonferroni corrected. Minimum- and mean HR were significantly higher in CKCS with moderate/severe MR and in HF compared to CKCS with no/minimal and mild MR (all P < 0.001). Seven out of 26 HRV variables were significantly decreased in CKCS with moderate/severe MR and in HF compared to CKCS with no/minimal and mild MR (all P < 0.02). Another 10 HRV variables showed the same groupwise differences (all P < 0.02), except that the difference between CKCS with mild MR and CKCS with moderate/severe MR did not reach statistical significance. M minimum HR, mean HR and the HRV variables (7 and 10) differing between dog groups, also consistently decreased with increasing MR, LA/Ao and the proximal isovelocity surface area in CKCS. Non-CKCS in HF had a lower minimum HR compared to CKCS in HF (P = 0.03) and a higher triangular index measured in both periods (all P < 0.04). In conclusion, HR increased and most HRV variables decreased with increasing severity of MMVD in CKCS, even prior to the development of HF. Other breeds in HF secondary to MMVD had lower minimum HR, but higher triangular index compared to CKCS in HF."

Dynamics of the Renin-angiotensin-aldosterone System (RAAS) after Oral Administration of Benazepril in Dogs. J Mochel, G Strehlau, R Mohamed, M Peyrou . J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract P-1). Quote: "In dogs, RAAS activation is a major feature of congestive heart failure (CHF). Benazepril (Fortekor) is a potent ACE inhibitor with well-documented effectiveness in canine CHF. Although ACE activity (ACE[A]) has been used in preclinical studies as a surrogate marker of efficacy, some authors have reported a poor correlation between plasma ACE[A] and changes in angiotensin II (AII) or aldosterone (AL). The purpose of this study was to investigate the effect of benazepril on canine plasma renin activity/concentration (PRA/PRC), angiotensin I (AI), AII, AL, and fractional excretion of potassium (UfeK), sodium (UfeNa) and aldosterone (UfeAL). Sixteen beagle dogs were fed a low-sodium diet and dosed with placebo or benazepril tablets (10 mg PO, q24h) for 5 days. Blood and urine samples were collected on day 1 (D1) and day 5 (D5) over 24-hour periods. Data were analyzed by repeated measures ANOVA of baseline corrected values, and ANOVA of AUC[24hours]. Compared with placebo, benazepril induced a significant increase in PRA and AI at D1 (p-value [PRA]:0.001, p-value [AI]:0.002) and D5 (p-value [PRA]:0.001, p-value [AI] < 0.001). No differences in PRC were noticed. Based on AUC[24hours], AII levels were 34% lower in the benazepril group at D5 (p-value [AII]:0.01). UfeAL and AL decreased by up to 27% and 24% at D1 and D5, respectively, though differences did not reach statistical significance. Benazepril markedly influences RAAS dynamics in dogs. Decreased exposure to AII and AL are likely to be the key events required to counteract pathological remodeling of the heart in CHF."

Serum Serotonin Concentration in Relation to Severity of Spontaneous Degenerative Mitral Valve Disease in Dogs. S.J. Lim, S.H. Lee, H.J Park, D.W. Jung, H.J. Choi, H.Y Youn, H.M. Park, D.H. Kim, K.H. Song. J Vet Intern Med 2011;--- (ACVIM 29th Ann. Vet. Med. Forum Abstract Program: Abstract C-37). Quote: "... Serotonin and serotonin-related mechanisms have been implicated as a cause of valvular disease in human and animals, including spontaneous DMVD in dogs. Increased circulating 5HT concentration as a potential source of heightened 5HT signaling is demonstrated in small dogs with DMVD. The aim of this study was to investigate whether serum 5HT concentrations were associated with severity of naturally occurring DMVD in small dogs and to investigate potential associations of dog characteristics on serum 5HT concentrations in our study population. Forty-eight dogs were included in this study and were classified into control and DMVD groups according to the results of physical and echocardiographic examinations. ... Significantly higher 5HT concentrations were observed in dogs with moderate (P < .05) and severe (P < .05) DMVD, compared with concentration in control group. Additionally, 5HT concentration in dogs with moderate DMVD were significantly higher (P < .05) than concentration in dogs with mild DMVD. Also, dogs with severe DMVD had significantly higher 5HT concentration than dogs with mild (P < .05) and moderate (P < .05) DMVD. There was no significant association of age, platelet, and LVIDd, on serum 5HT concentration, however, weak correlation between serum 5HT increased significantly and LA:Ao ratio (R² = .211, P < .05) was observed. The results of this study indicate that serum 5HT concentrations were higher with increasing severity of spontaneous DMVD, which may be the potential cause to advance the progression of DMVD. Further studies should be performed to reveal the role of 5HT in inducing and accelerating spontaneous DMVD and to investigate if lowering serum 5HT concentration could alter the progression of DMVD."

Circulating cytokine concentrations in dogs with different degrees of myxomatous mitral valve disease. Nora E. Zois, Sophia G. Moesgaard, Mads Kjelgaard-Hansen, Caroline E. Rasmussen, Torkel Falk, Christine Fossing, Jens Häggström, Henrik D. Pedersen, and Lisbeth H. Olsen. Vet.J. June 2011. Quote: "Cytokines have been associated with the progression of congestive heart failure (CHF) in humans and may be implicated in the pathophysiology of myxomatous mitral valve disease (MMVD) in dogs. The aim of this study was to determine the serum concentrations of cytokines in dogs with MMVD. The study included 16 Cairn terriers with no or minimal mitral regurgitation (MR), 41 Cavalier King Charles Spaniels (CKCS) with different degrees of MR and 11 dogs of different breeds with CHF due to MMVD. Granulocyte–macrophage colony-stimulating factor, interferon-ã, interleukin (IL)-2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, keratinocyte-derived chemokine, interferon-ã-induced protein and monocyte chemoattractant protein-1 (MCP-1) were measured using a canine-specific multiplex immunoassay. CHF dogs had significantly higher MCP-1 concentrations than dogs with no or minimal MR. Among the CKCS, IL-2 and IL-7 decreased with increasing left atrial size and IL-7 also decreased with increasing MR. IL-8 decreased with increasing left ventricular end-systolic internal dimensions. MCP-1 was increased in CHF dogs compared to healthy control dogs and IL-2, IL-7 and IL-8 decreased with increasing indices of disease severity. The results suggest a role for these cytokines in canine MMVD and CHF."

Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs. Schuller, S., Van Israël, N., Vanbelle, S., Clercx, C., McEntee, K. J. vet. Pharmacol. Therap. Aug 2011; 34(4):322–331. Quote "Aldosterone plays an important role in the pathophysiology of heart failure. Aldosterone receptor blockade has been shown to reduce morbidity and mortality in human patients with advanced congestive left ventricular heart failure. This study was designed to assess the efficacy and tolerance of long-term low-dose spironolactone when added to conventional heart failure treatment in dogs with advanced heart failure. Eighteen client-owned dogs with advanced congestive heart failure due to either degenerative valve disease (n = 11) or dilated cardiomyopathy (n = 7) were included in this prospective, placebo-controlled, double-blinded, randomized clinical study. After initial stabilization including furosemide, angiotensin-converting enzyme inhibitors, pimobendan and digoxin, spironolactone at a median dose of 0.52 mg/kg (range 0.49–0.8 mg/kg) once daily (n = 9) or placebo (n = 9) was added to the treatment, and the dogs were reassessed 3 and 6 months later. Clinical scoring, echocardiography, electrocardiogram, systolic blood pressure measurement, thoracic radiography, sodium, potassium, urea, creatinine, alanine aminotransferase, aldosterone and aminoterminal atrial natriuretic propeptide were assessed at baseline, 3 and 6 months. Survival times were not significantly different between the two treatment groups. Spironolactone was well tolerated when combined with conventional heart failure treatment."

Effects of treatment on respiratory rate, serum natriuretic peptide concentration, and Doppler echocardiographic indices of left ventricular filling pressure in dogs with congestive heart failure secondary to degenerative mitral valve disease and dilated cardiomyopathy. Karsten E. Schober, Taye M. Hart, Joshua A. Stern, Xiaobai Li, Valerie F. Samii, Lisa J. Zekas, Brian A. Scansen, John D. Bonagura. JAVMA Aug 2011;239(4):468-479. Quote: "Objective: To evaluate the effects of treatment on respiratory rate, serum natriuretic peptide concentrations, and Doppler echocardiographic indices of left ventricular filling pressure in dogs with congestive heart failure (CHF) secondary to degenerative mitral valve disease (MVD) and dilated cardiomyopathy (DCM). Design: Prospective cohort study. Animals: 63 client-owned dogs [45 with MVD of which 13 were cavalier King Charles spaniels]. Procedures: Physical examination, thoracic radiography, analysis of natriuretic peptide concentrations, and Doppler echocardiography were performed twice, at baseline (examination 1) and 5 to 14 days later (examination 2). Home monitoring of respiratory rate was performed by the owners between examinations. Results: In dogs with MVD, resolution of CHF was associated with a decrease in respiratory rate, serum N-terminal probrain natriuretic peptide (NT-proBNP) concentration, and diastolic functional class and an increase of the ratio of peak velocity of early diastolic transmitral flow to peak velocity of early diastolic lateral mitral annulus motion (E:Ea Lat). ... Only respiratory rate predicted the presence of CHF at examination 2 with high accuracy. Conclusions and Clinical Relevance: Resolution of CHF was associated with predictable changes in respiratory rate [In the present study, all dogs with CHF had high respiratory rate and resolution of heart failure was accompanied by a predictable decrease of respiratory rate to values equivalent to or below the respiratory rate of dogs without clinical signs of CHF. ... The clinical relevance of this is that in addition to predicting successful short-term treatment of CHF, the respiratory rate measured at home may allow both clinicians and owners to more accurately tailor home treatment to a target respiratory rate and to avoid excessive or insufficient diuresis. This study suggests that veterinarians should instruct owners to monitor respiratory rate and that respiratory rate is useful for both diagnosis and management of dogs with CHF.], serum NT-proBNP concentration, and selected Doppler echocardiographic variables in dogs with DCM and MVD. ... Home monitoring of respiratory rate is simple and very useful in the assessment of CHF in dogs with either DCM or MVD. The use of respiratory rate, analysis of serum NT-proBNP concentration, and transthoracic Doppler echocardiography for clinical guidance in the treatment of CHF merits further study."

NT-proBNP, NT-proANP and cTnI concentrations in dogs with pre-capillary pulmonary hypertension. Heidi B. Kellihan, Brian A. MacKie, Rebecca L. Stepien. J Vet Cardio. Quote: "Objectives: To compare [NT-proBNP], [NT-proANP] and [cTnI] between control dogs with respiratory disease without pulmonary hypertension (PH) and dogs with pre-capillary PH, and to assess the accuracy of [NT-proBNP], [NT-proANP], [cTnI] to predict Doppler-derived peak tricuspid regurgitation (TR) gradient. Animals: 20 dogs. 8 control dogs with respiratory disease with no PH and 12 with pre-capillary PH. Methods: [NT-proBNP], [NT-proANP] and [cTnI] were compared between the 2 groups and simple linear regression analysis was used to predict peak TR gradients from various blood biomarkers. Results: Median [NT-proBNP] was higher in the dogs with PH (2011 pmol/L, 274–7713 pmol/L) compared to control dogs (744 pmol/L; 531–2710 pmol/L) (p = 0.0339). [NT-proBNP] was associated with peak TR gradient (R2 = 0.7851, p = 0.0001). Median [NT-proANP] did not differ between dogs with PH (1747 fmol/L; 894–2884 fmol/L) and control dogs (1209 fmol/L; 976–1389 fmol/L (p = 0.058). [NT-proANP] was not associated with peak TR gradient (R2 = 0.2780, p = 0.0781). Median [cTnI] did not differ between dogs with PH (0.2850 ng/mL; 0.19–1.13 ng/mL) and control dogs (0.2 ng/mL; 0.19–0.82 ng/mL, p = 0.3051). Median [TnI] was not associated with peak TR gradient (R2 = 0.024, p = 0.6307). Conclusions: [NT-proBNP] concentration is significantly higher in dogs with pre-capillary PH when compared to dogs with respiratory disease without PH, and [NT-proBNP] may be useful to predict the severity of estimated PH. Elevations in [NT-proBNP] due to pre-capillary PH may complicate the interpretation of [NT-proBNP] elevations in patients presenting with cardiorespiratory abnormalities. [NT-proANP] and [cTnI] were not elevated in dogs with pre-capillary PH."

Identification of 2 Loci associated with development of myxomatous mitral valve disease in cavalier king charles spaniels. Madsen MB, Olsen LH, Häggström J, Höglund K, Ljungvall I, Falk T, Wess G, Stephenson H, Dukes-McEwan J, Chetboul V, Gouni V, Proschowsky HF, Cirera S, Karlskov-Mortensen P, Fredholm M. J Hered. 2011 Sep-Oct;102 Suppl 1:S62-7. Quote: "Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. It is characterized by chronic progressive degenerative lesions of the mitral valve. The valve leaflets become thickened and prolapse into the left atrium resulting in mitral regurgitation (MR). MMVD is most prevalent in small to medium sized dog breeds, Cavalier King Charles Spaniels (CKCS) in particular. The onset of MMVD is highly age dependent, and at the age of 10 years, nearly all CKCS are affected. The incidence of a similar disease in humans-mitral valve prolapse-is 1-5%. By defining CKCSs with an early onset of MMVD as cases [139 CKCSs] and old dogs with no or mild signs of MMVD as controls [102 CKCSs], we conducted a genome-wide association study (GWAS) to identify loci associated with development of MMVD. We have identified a 1.58 Mb region on CFA13 (P(genome) = 4.0× 10(-5)) [CFA 13q2.2.3] and a 1.68 Mb region on CFA14 (P(genome) = 7.9× 10(-4)) [CFA 14q1.3] associated with development of MMVD. ... Twenty protein-coding genes have been annotated in the candidate region of CFA 13 (1.68 Mb) and in the homologous region of HSA 4, whereas 11 protein-coding genes have been annotated in the CFA 14 region (1.58 Mb) and in the homlogous HSA 7 region. ...This confirms the power of using the dog as a model to uncover potential candidate regions involved in the molecular mechanisms behind complex traits. ... We will initiate studies of the most promising candidate genes in the 2 candidate regions which hopefully will lead us to the mutations affecting the development of mitral valve disease."

Leptin Expression in Dogs with Cardiac Disease and Congestive Heart Failure. Fonfara, S., Hetzel, U., Tew, S., Dukes-Mcewan, J., Cripps, P. and Clegg, P. J Vet Int Med Sept 2011; 25(5):1017–1024.  Quote: "Leptin belongs to the group of adipokines and has recently attracted attention because of its effects on the cardiovascular system. Increased leptin concentrations are reported in obese dogs but its role in cardiac disease (CD) is not known. Therefore, we investigated leptin expression in blood samples from dogs with congestive heart failure (CHF), and from myocardial samples of dogs with CDs. Leptin mRNA was analyzed from blood samples of 8 dogs presented for cardiac screening in which no abnormalities were detected and 8 dogs in CHF. In addition, myocardial samples (interventricular septum, right and left atria, and ventricles) of 10 dogs with no cardiac abnormalities (controls), 7 dogs with acquired and 3 dogs with congenital CDs were investigated using real-time polymerase chain reaction (PCR). Results: Dogs with CHF had significantly higher blood concentrations of leptin mRNA than dogs without CD (P = .013). Myocardial leptin expression was significantly increased in acquired (P = .035) and decreased in congenital CD (P = .016) in comparison to controls. Dogs in heart failure stage D showed higher myocardial leptin concentrations than dogs in stage C3 and B (P = .031). Differences according to myocardial region (P < .05) were detected and higher leptin concentrations were present in the atria in comparison to the ventricles in dogs with CD (P = .005). Comparing male and female dogs with CD revealed higher leptin concentrations in female dogs (P = .001). Conclusions: These results indicate leptin mRNA concentrations vary with CD, severity of CD, myocardial region, and possibly sex. Therefore, leptin might play a role in canine CD."

Radiographic Heart Size and Its Rate of Increase as Tests for Onset of Congestive Heart Failure in Cavalier King Charles Spaniels with Mitral Valve Regurgitation. P.F. Lord, K. Hansson, C. Carnabuci, C. Kvart, J Häggström. J Vet Int Med Sept 2011; 25(6):1312-1319.  Quote: "Background: In canine mitral regurgitation (MR) the rate of heart enlargement increases in the last year before congestive heart failure (CHF). Measurement of heart size and its rate of increase may be useful tests for CHF in MR. Objectives: To determine the value of vertebral heart scale (VHS) and its rate of increase (∆VHS units/month) for diagnosing the presence and predicting the onset of CHF. Animals: Longitudinal study of 94 Cavalier King Charles Spaniels (CKCS). Methods: VHS was measured at intervals before CHF. ∆VHS/month was calculated from sequential pairs of VHS measurements and the interval between them. Diagnostic accuracy and utility were determined by the areas under receiver operating characteristic plots (AUROC), and likelihood ratios (LR). Results: AUROC for VHS at the onset of CHF was 0.93 (95% CI, 0.96–0.90), to predict CHF 1–12 months before CHF was 0.74 (95% CI, 0.81–0.66), and for ∆VHS/month at CHF was 0.98 (95% CI, 0.99–0.96). Interval LRs and their cutoff values for CHF were for VHS: 13 (95% CI, 20–7.3) at ≥12.7; 1.2 (95% CI, 2.0–0.68) between 12.7 and 12.0; 0.04 (95% CI, 0.18–0.01) at ≤12.0, and for ∆VHS/month: 15 (95% CI, 30–7.7) at ≥0.08; 0.72 (95% CI, 2.0–0.25) between 0.08 and 0.06; and 0.05 (95% CI, 0.13–0.02) at ≤0.06. Conclusions and Clinical Importance: Under the conditions of this study, VHS and particularly ∆VHS/month are useful measurements for detecting onset of CHF in CKCS with MR."

Mitral Valve Disease - Alternative Therapies Such as Beta Blockers, Amlodipine and Pimobendan. Christophe W. Lombard. WSAVA 2011 Congress. http://www.vin.com/proceedings/Proceedings.plx?&CID=WSAVA2011&PID=pr69346&O=Generic

Use of the loop diuretic torsemide in three dogs with advanced heart failure. Mark A. Oyama, Gordon D. Peddle , Caryn A. Reynolds, and Gretchen E. Singletary. J Vet Cardio; Oct 2011; doi:10.1016/j.jvc.2011.10.001. Quote: "Diuretics are a mainstay of therapy in dogs with heart failure. In dogs with advanced heart failure, moderate to high doses of loop diuretics such as furosemide are used with diminishing effects as profound activation of neuroendocrine systems promote signs of congestive heart failure. The loop diuretic torsemide has several characteristics that make it suitable for treatment of advanced heart failure including longer half-life, increased potency of diuretic action, and anti-aldosterone effects. ... This case series describes 3 dogs [including a 12 year-old cavalier King Charles spaniel] with advanced heart disease that despite treatment with multiple cardiac medications and moderate to high doses of furosemide experienced frequently recurring episodes of CHF. ... In each dog, replacement of furosemide with a torsemide dose, in terms of mg/kg, at one-tenth to one-thirteenth of the daily furosemide dose were associated with apparent resolution of CHF for relatively long durations of time. We speculate that when switching to torsemide, restoration of diuretic response was the most likely cause of this observation. In these and other cases managed by the authors, pet owners report notable increases in their dog’s diuresis and water consumption following institution of torsemide. In a small prospective blinded cross-over study,13 dogs with heart failure experienced significantly higher serum albumin and significantly lower urine specific gravity when receiving torsemide as compared to furosemide, suggesting that torsemide is associated with a relatively greater diuretic response. ... Torsemide’s safety and superior efficacy have previously been established in human patients with CHF. ... The restoration of diuretic responsiveness and the accompanying volume depletion that follows torsemide administration might increase risk for renal insufficiency, and care should be taken to limit or reduce administration of concurrent diuretics such as hydrochlorothiazide and to closely monitor renal function when administering torsemide. The authors also recommend that owners of dogs receiving torsemide closely monitor their dog’s urine production, water consumption, and appetite. ... Torsemide has several attractive pharmacologic properties that might aid in the long-term treatment of canine heart disease. Clinical guidelines or recommendations involving torsemide should follow from prospective clinical trials demonstrating the long-term safety and potential superiority of torsemide over furosemide and other commonly used diuretics. "

Genome-wide analysis of mitral valve disease in Cavalier King Charles Spaniels. Anne T. French, Rob Ogden, Cathlene Eland, Gibran Hemani, Ricardo Pong-Wong, Brendan Corcoran, Kim M. Summers. Vet J; Nov 2011; doi:10.1016/j.tvjl.2011.09.011 Quote: "The Cavalier King Charles Spaniel (CKCS) is prone to severe early onset mitral valve disease. In this study, 36 purebred CKCS dogs were evaluated for mitral valve murmur and divided into early and late onset groups. A genome-wide genetic approach was used to assess whether the condition is determined by a small number of genetic factors. There were no regions of highly discrepant homo/heterozygosity in the two groups. Similarly, there was no evidence for loci associated with mitral valve murmur in a genome-wide association study. This analysis suggests that familial occurrence of mitral valve murmur in the CKCS breed is not due to a single major gene effect, indicating that breeding strategies to eliminate the disease cannot be based on genotype information at this time."

Pimobendan and Its Use in Treating Canine Congestive Heart Failure. Danielle Bowles and Darren Fry. Compendium; Nov 2011; 33(11). View article on-line here.

Cardiology: Validating an echocardiographic scoring system for mitral valve disease. Julia Sargent, Virginia Luis Fuentes and Holger Volk. Vet Rec Nov 2011;169(22):590. Quote: "We are currently enrolling cases for a cardiac MRI (cMRI) clinical study in order to validate a new echocardiographic scoring system for assessing the severity of degenerative mitral valve disease in asymptomatic dogs." Contact: vluisfuentes@rvc.ac.uk

Flow-Mediated Vasodilation Measurements in Cavalier King Charles Spaniels with Increasing Severity of Myxomatous Mitral Valve Disease. S.G. Moesgaard1, C. Klostergaard, N.E. Zois1, T. Teerlink, M. Molin, T. Falk, C.E. Rasmussen, V. Luis Fuentes, I.D. Jones, L.H. Olsen. JVIM Dec 2011. Quote: "Background: Cardiovascular disease is associated with endothelial dysfunction in humans and studies of plasma biomarkers suggest that dogs with myxomatous mitral valve disease (MMVD) might also have endothelial dysfunction. Hypothesis: That progression of mitral regurgitation (MR) is associated with development of endothelial dysfunction. Animals: Forty-three Cavalier King Charles Spaniels (CKCS) with MR of varying severity. Methods: Privately owned CKCS were prospectively recruited and divided in 4 groups: (1) 12 CKCS with minimal MR; (2) 9 CKCS with mild MR; (3) 11 CKCS with moderate-severe MR; and (4) 11 CKCS with moderate-severe MR and clinical signs compatible with heart failure. Dogs underwent blood sampling, echocardiography, blood pressure (BP) recordings, and flow-mediated vasodilation (FMD) measurements. The effect of progressive MR on FMD was determined by multivariate analyses. Results: Flow-mediated vasodilation decreased with progression of MR. Group 4 (4.79 ± 3.22%) had significantly lower FMD than groups 1 (10.40 ± 4.58%) and 2 (10.14 ± 3.67%) (P < .005) and group 3 (6.79 ± 3.98%) had a significantly lower FMD than group 1 (P = .03). Increasing left ventricular end-diastolic diameter (P = .0004, R2 = 0.27) and the combination of age (P = .01) and body weight (P = .002) (R2 = 0.31) were significantly associated with reduced FMD. FMD did not correlate with sex, BP, or plasma markers. Conclusions and Clinical Importance: Reduced FMD indicates that increased disease severity in CKCS with MMVD is associated with development of endothelial dysfunction which might be a future therapeutic and/or diagnostic target."

Advanced Electrocardiographic Parameters Change with Severity of Mitral Regurgitation in Cavalier King Charles Spaniels in Sinus Rhythm. M. Špiljak Pakkanen, A. Domanjko Petrič, L.H. Olsen, A. Stepančič, T.T. Schlegel, T. Falk, C.E. Rasmussen, V. Starc. JVIM Dec 2011. Quote: "Background: Multiple advanced resting ECG (A-ECG) techniques have improved the diagnostic or prognostic value of ECG in detecting human cardiac diseases even before onset of clinical signs or changes in conventional ECG. Objective: To determine which A-ECG parameters, derived from 12-lead A-ECG recordings, change with severity of mitral regurgitation (MR) caused by myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCSs) in sinus rhythm. Animals: Seventy-six privately owned CKCSs. Methods: Dogs were prospectively divided into 5 groups according to the degree of MR (estimated by color Doppler mapping as the percentage of the left atrial area affected by the MR jet) and presence of clinical signs. High fidelity approximately 5-minute 12-lead ECG recordings were evaluated using custom software to calculate multiple conventional and A-ECG parameters. Results: Nineteen of 76 ECG parameters were significantly different (P < .05) across the 5 dog groups. A 4-parameter model that incorporated results from 1 parameter of heart rate variability, 2 parameters of QT variability, and 1 parameter of QRS amplitude was identified that explained 82.4% of the variance with a correlation coefficient (R) of 0.60 (P < .01). When age or murmur grade was included in the statistical model the prediction value further increased the R to 0.74 and 0.85 (P < .01), respectively. Conclusion: In CKCSs with sinus rhythm, 4 selected A-ECG parameters further improve prediction of MR jet severity beyond age and murmur grade, although the predictive increment in this study probably is not sufficient to warrant utilization in clinical veterinary practice."

Survival Characteristics and Prognostic Variables of Dogs with Preclinical Chronic Degenerative Mitral Valve Disease Attributable to Myxomatous Degeneration. M. Borgarelli, S. Crosara, K. Lamb, P. Savarino, G. La Rosa, A. Tarducci, J. Häggström. JVIM Dec 2011; DOI: 10.1111/j.1939-1676.2011.00860.x Quote: "Background: Preclinical myxomatous mitral valve degeneration (MMVD) includes a heterogeneous group of dogs. Therefore, identifying risk factors for progression of the disease is of clinical importance. Objectives: To investigate survival time and risk factors for clinical and echocardiographic variables taken at initial examination for clinical progression in preclinical MMVD dogs. Animals: A total of 256 dogs with stage B1 or B2 MMVD. Materials and Methods: Medical records of 256 dogs with preclinical MMVD were reviewed retrospectively. Long-term outcome was assessed by telephone interview. Dogs alive at the time of phone interview were asked to return to the hospital for re-evaluation of their cardiac status. Results: Seventy of 256 (27.3%) dogs died during the observation period. The median survival time, regardless of cause of death, was 588 (range 75–1,668) days. The presence of a murmur was associated with an increased risk of death (AHR 2.14; 95% CI 1.12, 4.11; P = 0.022). Thirty (12%) deaths were considered cardiac related. LA/Ao > 1.4 was the only negative predictor (AHR 2.64; 1.13, 6.13; P = 0.024) for cardiac-related deaths. Eighty-three dogs were re-examined, of which 34 progressed to a more advanced stage of MMVD. The presence of Emax > 1.2 (AHR 2.75; 95% CI 1.01, 7.48; P = 0.047) and cough (AHR 7.89; 95% CI 3.18, 20.07; P < 0.001) were significant in the multivariate analysis. Conclusions and Clinical Importance: Preclinical MMVD represents a relatively benign condition in dogs. Clinicians might find stratification of this dog population according to risk factors based on clinical and echocardiographic findings helpful in determining treatment."

Heart Rate, Heart Rate Variability, and Arrhythmias in Dogs with Myxomatous Mitral Valve Disease. C.E. Rasmussen, T. Falk, N.E. Zois, S.G. Moesgaard, J. Häggström, H.D. Pedersen, B. Åblad, H.Y. Nilsen, L.H. Olsen. J.Vet.Int.Med. Jan/Feb 2012;26(1):76-84. Quote: "Background: Autonomic modulation of heart rhythm is thought to influence the pathophysiology of myxomatous mitral valve disease (MMVD). Hypotheses: (1) Holter-derived variables reflecting autonomic modulation of heart rhythm change with MMVD severity in Cavalier King Charles Spaniels (CKCS); (2) Holter-derived variables can identify MMVD severity in CKCS; and (3) Holter-derived variables in CKCS in congestive heart failure (CHF) secondary to MMVD differ from those in dogs of other breeds in CHF. Animals: Ninety privately owned dogs: 70 CKCS with variable MMVD severity and 20 non-CKCS in CHF secondary to MMVD. Methods: Dogs were prospectively recruited and divided into 5 MMVD severity groups based on history, breed, and physical and echocardiographic examination findings. Holter-derived variables included heart rate variability (HRV), heart rate (HR), and arrhythmia evaluated from 24-hour Holter recordings. Results: In CKCS, 18 of 26 HRV (all P < .0002) and 3 of 9 arrhythmia (all P < .0004) variables decreased with increasing MMVD, whereas minimum and mean HR (all P < .0001) increased with increasing MMVD severity. An arrhythmia variable representing sinus arrhythmia (“premature normals”) (P < .0001) and the HRV variable triangular index (TI) (P < .0001) could distinguish CKCS with moderate or severe mitral regurgitation from CKCS in CHF in specific intervals. Among dogs in CHF, Holter-derived variables did not differ among breeds. Conclusions and Clinical Importance: In CKCS, Holter-derived variables changed with MMVD severity. “Premature normals” and TI showed diagnostic potential. Breed differences were not seen among dogs in CHF secondary to MMVD."

Renal Resistive Index in 55 Dogs with Degenerative Mitral Valve Disease. V. Chetboul, T. Daste, V. Gouni, D. Concordet, E. Trehiou-Sechi, F. Serres, J.L. Pouchelon, C.A. Germain, C. Layssol-Lamour, H.P. Lefebvre. J.Vet.Int.Med. Jan-Feb 2012; 26(1):101-108. Quote: "Background: Azotemia occurs frequently in dogs with degenerative mitral valve disease (DMVD). It could indicate changes in renal hemodynamics. Hypothesis/Objectives: To assess the renal resistive index (RI) in dogs with DMVD, and the statistical link between heart failure class, azotemia, echo-Doppler parameters, several plasma variables, and RI. Animals: Fifty-five dogs [including 15 cavaliers] with naturally occurring DVMD were used (ISACHC class 1 [n = 28], 2 [n = 19], and 3 [n = 8]). Methods: Observational, blinded study, performed under standardized conditions. Physical examination, renal ultrasonography, and echo-Doppler examinations were performed in awake dogs. The RI of the renal, interlobar, and arcuate arteries were measured. Plasma creatinine, urea, and N-terminal pro-B-type natriuretic peptide concentrations (NT-proBNP) were determined. Statistical links between variables and RI were tested by means of a general linear model. Results: Although the RI of renal and arcuate arteries were unaffected by ISACHC class, the left interlobar RI increased (P < .001) from 0.62 ± 0.05 (mean ± SD) in class 1 to 0.76 ± 0.08 in class 3. It was also higher (P < .001) in azotemic (0.74 ± 0.08) than in non-azotemic (0.62 ± 0.05) dogs. Similar findings were observed for right interlobar RI. Univariate analysis showed a positive statistical link between NT-proBNP (P = .002), urea (P < .001), creatinine (P = .002), urea-to-creatinine ratio (P < .001), left atrium-to-aorta ratio (P < .001), regurgitation fraction (P < .001), systolic pulmonary arterial pressure (P < .001), shortening fraction (P = .035), and RI. Conclusion and Clinical Importance: In dogs with DMVD, interlobar RI increases with heart failure severity and azotemia but a cause and effect relationship remains to be established."

Advanced Electrocardiographic Parameters Change with Severity of Mitral Regurgitation in Cavalier King Charles Spaniels in Sinus Rhythm. M. Sˇ piljak Pakkanen, A. Domanjko Petricˇ , L.H. Olsen, A. Stepancˇ icˇ , T.T. Schlegel, T. Falk, C.E. Rasmussen, and V. Starc. J.Vet.Int.Med.; Jan 2012;26(1):93-100. Quote: "Background: Multiple advanced resting ECG (A-ECG) techniques have improved the diagnostic or prognostic value of ECG in detecting human cardiac diseases even before onset of clinical signs or changes in conventional ECG. Objective: To determine which A-ECG parameters, derived from 12-lead A-ECG recordings, change with severity of mitral regurgitation (MR) caused by myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCSs) in sinus rhythm. Animals: 76 privately owned CKCSs. Methods: Dogs were prospectively divided into 5 groups according to the degree of MR (estimated by color Doppler mapping as the percentage of the left atrial area affected by the MR jet) and presence of clinical signs. High fidelity approximately 5-minute 12-lead ECG recordings were evaluated using custom software to calculate multiple conventional and A-ECG parameters. Results: Nineteen of 76 ECG parameters were significantly different (P < .05) across the 5 dog groups. A 4-parameter model that incorporated results from 1 parameter of heart rate variability, 2 parameters of QT variability, and 1 parameter of QRS amplitude was identified that explained 82.4% of the variance with a correlation coefficient (R) of 0.60 (P < .01). When age or murmur grade was included in the statistical model the prediction value further increased the R to 0.74 and 0.85 (P < .01), respectively. Conclusion: In CKCSs with sinus rhythm, 4 selected A-ECG parameters further improve prediction of MR jet severity beyond age and murmur grade, although the predictive increment in this study probably is not sufficient to warrant utilization in clinical veterinary practice."

Characterisation and cardiac directed differentiation of canine adult cardiac stem cells. Hannah M. Hodgkiss-Geere, David J. Argyle, Brendan M. Corcoran, Bruce Whitelaw, Elspeth Milne, David Bennett, Sally A. Argyle. Vet.J.; Feb 2012;191(2):176-182. Quote: "This study describes the isolation and characterisation of adult canine cardiac stem cells, and explores their ability to differentiate into cardiac myocytes. Direct comparisons are also made with available human data. Atrial cardiac explants were taken from dogs post-mortem and cultured to isolate adult stem cells. Cells were able to survive successive passages in serum-free media, were able to form cardiospheres, and under controlled culture conditions were capable of clonal expansion, demonstrating their ability for self-renewal. Characterisation of these cells demonstrated the following marker profile: c-kit, GATA 4 and flk-1 positive; cardiac troponin T and NKx2.5 low. Cardiac lineage directed differentiation was performed based on the published literature. Gene expression studies demonstrated that cardiac directed differentiation was partially achieved, with up-regulation of cardiac troponin T and NKx2.5, and down-regulation of c-kit and endothelial lineage markers. However the cells did not express the ryanodine receptor or β1-adrenergic receptors and did not contract spontaneously."

The rapidly evolving field of biomarkers of cardiac function and injury in dogs: Challenges and next steps. Wayne R. Buck, Bruce E. LeRoy, Eric A.G. Blomme. Vet.J. Jan 2012;191(1):13-14. Quote: "[B]iomarkers have received a similar level of attention, in particular the two natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). While ANP can be measured directly, BNP release is most often evaluated indirectly through the measurement of the inactive amino terminal of the prohormone ProBNP (NT-proBNP), which has a longer circulating half-life, higher concentration in the circulation and higher stability than BNP. ... The value of any biomarker is not only based on its biological nature, but also on the assay used to measure it. Hence, it is critical for authors to thoroughly describe or document the nature and analytical performance of assays used and, when appropriate, their associated reference values."

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