Researchers Study Causes & Treatment For Degenerative Mitral Valve Disease

Chris and Renee Coney are Chihuahua lovers.

 “Dexter,” who turns 14 in July, is their second pet Chihuahua. When the smooth coat Chihuahua was diagnosed with a heart murmur three years ago, the couple, who live in Turner Falls, Mass., did not know what to expect. Their spunky Dexter couldn’t have heart disease, they thought.  

“Just because a dog has a murmur does not mean they’re symptomatic or that they are going to be anytime soon,” explains Dexter’s heart specialist, Nancy Morris, D.V.M., DACVIM, who practices at Mass. Veterinary Cardiology Services in Agawam. “Dogs with murmurs can go years without showing signs of disease.”

As it turned out, learning about Dexter’s heart murmur meant the Coneys could help monitor the dog’s health and look for signs of the slow, progressive degenerative mitral valve disease (DMVD), also known as chronic valvular disease. If necessary, medi­ca­tions could be given to help manage the fluid in the lungs and the arrhythmia, or irregular heartbeats, which often accompany the disease. The best part was learning that Dexter might never develop the severe form of the disease that requires medications.

Most owners do not learn their dog has DMVD until they reach the advanced stage. Coughing, tiring after exercise and a rapid respiratory rate clue them in that something could be wrong. Although 30 percent of small breeds over the age of 10 develop DMVD, the reasons they are prone to the disorder are a mystery. Because the affected breeds have other diseases associated with connective tissue problems, such as luxating patella and collapsing trachea, and because the mitral valve has a lot of connective tissue, it is possible these conditions are somehow related.

Believed to be a polygenic disorder involving many genes, DMVD is transmitted by carrier dogs to their offspring. Besides Chihuahua, other affected breeds are Cavalier King Charles Spaniel, Cocker Spaniel, Japanese Chin, Lhasa Apso, Miniature and Toy Poodle, and Norfolk Terrier. Cavaliers, which have the greatest risk, develop an early-onset form that progresses rapidly.

Researchers at the veterinary schools at the University of Penn­sylvania and Cornell University are working to discover the causes of DMVD. Could high levels of the neuro­transmitter serotonin in the mitral valve be to blame? What if genes that code for small size affect the structure and function of specific regions of the heart muscle and affect the stress on the mitral valve contributing to its degeneration?

Deciphering the Disease Process

Located between the left atrium and left ventricle of the heart, the mitral valve helps regulate the flow of blood in and out of the heart and prevents a back flow from going into the atrium. The mitral valve is made of thin flaps of tissue, or valve leaflets, attached by long, tendon-like structures, the chordae tendineae, to the muscles of the left ventricle. These valve leaflets open and close to regulate the flow of blood, but as the disease progresses, they begin to thicken, contract and lose flexibility.

When the mitral valve functions correctly, blood in the left ventricle is pumped to the body as the heart contracts. As the mitral valve degrades, it cannot close properly and small amounts of blood leak back into the left atrium. Over time, the valve degrades until the heart can no longer compensate. Stress from the leak causes the heart to enlarge, eventually resulting in congestive heart failure. In severe cases, the chordae tendineae may rupture, damaging or causing the complete collapse of the mitral valve.

People also can develop mitral valve disease. Although surgery can be performed to replace the mitral valve in people, it is not currently a treatment option for dogs due to the expense and limited availability. This may change in the future as a research team at Nihon University in Tokyo has had good results with valve repairs in dogs using open-heart surgery. 

An increase in serotonin, a neurotransmitter that is important in maintaining normal cardiovascular functions throughout the body, has been found in the mitral valves of dogs and people with mitral valve disease. For example, some people who took the Fen-Phen combination diet pill that was popular in the early 1990s later developed mitral valve disease, which was attributed to an increase in serotonin activity.

Mark Oyama, D.V.M., DACVIM-Cardiology, professor of clinical studies and chief of cardiology at the Uni­ver­sity of Pennsylvania, has been involved in research investigating the role of serotonin in dogs with DMVD. Oyama and his colleagues have reported that dogs with DMVD had more serotonin in their blood than dogs without disease. The research, which was published in 2009 and 2013 in the Journal of Veterinary Internal Medicine, suggests that serotonin signaling may play a role in the progression of early stages of DMVD. 

“The most recent study, led by collaborators at the Swedish Agricultural University in Uppsala, examined the blood of 120 dogs and found that those with DMVD had higher levels of serotonin,” Oyama says. “Higher levels of serotonin are associated with higher levels of glyco­sa­minoglycan, one of the pathological molecules that is common in DMVD valves. Serotonin is found not only in the brain and nerves but also in blood platelets and the heart. It is interesting that high serotonin levels are found in the heart and platelets of dogs with DMVD because other studies have shown that high serotonin can damage the valves." 

Similar comparative research at Cornell University College of Veterinary Medicine involves studying the mech­anical differences of the heart and mitral valve of normal dogs and those with DMVD. N. Sydney Moise, D.V.M., DACVIM, professor of medicine and cardiology section chief, hypothesizes that since DMVD affects small-breed dogs, the same genes that affect size or bone structure may also affect the heart contributing to the disease.

“The stress on the leaflets of the mitral valve may be different in dogs that have a higher rather than lower prevalence of severe valvular degeneration,” Moise says. “The altered stress could trigger other factors that accelerate degeneration. The disease is likely multifactorial involving genetics, mechanics and aging.”

The Moise laboratory and collaborator Jonathan Butcher of the Bio­medical Engineering Department at Cornell University found altered function in mitral valve cell cultures. This research was published in 2012 in the Journal of Veterinary Cardiology. Moise and her research team are now evaluating echocardiograms, or ultrasounds, of the hearts of high-risk small-breed dogs between 1 and 2 years of age and a group of low-risk large-breed dogs. “By observing how the valves move, we hope to detect differences in their motion and thus recognize stress levels of dogs at high risk versus those at low risk for this disease,” she says.

The researchers are seeking older small-breed dogs that do not have disease for the study. “We want to see if older small dogs free of disease have hearts more like to those of the low-risk large-breed dogs,” says Moise.

Diagnosis & Treatment

Most cases of DMVD are recognized by veterinarians who detect a heart murmur during an auscultation exam by listening to the heart with a stethoscope. This usually is followed by an echocardiogram to visualize early changes in the mitral valve, chest radiograph to determine whether the heart is becoming enlarged, and/or an electro­cardiogram to pick up arrhythmias.

An earlier study by Oyama and his research team found that 12 of 48 Norfolk Terriers considered clinically normal actually showed evidence of DMVD on an echocardiogram despite not having a detectable heart murmur from an auscultation examination by a veterinary cardiologist. The study raised the question whether an echo­cardiogram rather than an auscultation could be used to identify dogs for the disease.

The University of Pennsylvania researchers then followed dogs suspected of early disease over time to see if they eventually progressed to developing a heart murmur. They found that some dogs have subtle, mild changes in the shape and function of the mitral valve — the early signs of DMVD — despite the absence of a heart murmur.

“We discovered that dogs with mild changes on their echocardiogram eventually developed a heart murmur, suggesting that early detection of disease could be done in the absence of a heart murmur,” Oyama says.

There is no cure and limited treatment options are available for dogs with DMVD. To help manage the disease, veterinarians prescribe medications on an individual basis to help slow its progression. Dogs may be given:

  • diuretics, such as furosemide and spironolactone, to help remove excess fluid from the lungs
  • an ACE (angiotensin-converting-enzyme) inhibitor to help prevent enlargement of the heart and congestive heart failure by relieving strain on the heart and lowering blood pressure
  • pimobendan to dilate blood vessels and improve the strength of the heart muscle

Oyama and his research team are looking at pharmaceuticals that could potentially block the effect of serotonin on the mitral valve. They also are evaluating the effect of a new diuretic in helping to manage dogs with the disease.

“This new diuretic has the potential to be more effective at treating and then preventing the recurrence of heart failure and fluid accumulation in the lungs or abdomen than existing diuretics,” Oyama says. “This diuretic is less likely to build up resistance by the patient, and thus may be more effective and safe. We are interested in learning whether this diuretic can improve a dog’s quality of life and longevity.

“Many dogs will never develop the severe form of the disease that causes the clinical signs requiring medications. A relatively small percentage will have progressive heart enlargement and be at risk for heart failure.”

After being diagnosed with DMVD in 2011, Dexter remained asymptomatic for a year and then was given medi­cations to help manage the condition. Morris, his heart specialist, says, “The timing of medications is key to disease management. There is no benefit to providing medications early in the disease when there isn’t any atrial enlargement. The best time is when there is moderate left atrial enlargement of the heart.”

Meanwhile, Dexter, who will be 14 years old in July, continues to live a spunky, fulfilling life. “Dexter is doing well, and he hasn’t had any side effects from the medications,” Renee Coney says. “I think he is an example of how this disease can be managed successfully.”  

Purina appreciates the support of the Chihuahua Club of America and particularly Lauren A. Payne, chair of the CCA Health Related Issues Committee, in helping to identify topics for the Purina® Pro Club® Chihuahua Update newsletter.

Signs of Advanced DMVD 

  • Excessive panting when exercising
  • Shortness of breath
  • Coughing
  • Distended abdomen
  • Loss of appetite
  • Weight loss

Breeding Recommendations for Dogs with DMVD

Degenerative mitral valve disease (DMVD) is believed to be a polygenic disease involving several genes. The disorder likely results from genetics, aging and mechanical damage that occurs to the heart over time.

Dr. Mark Oyama, of the University of Pennsylvania School of Veterinary Medicine, says, “Affected dogs should not be automatically removed from breeding programs. Doing so would further limit the already small gene pool.”

Genetic counselor Jerold Bell, D.V.M., clinical associate professor of veterinary genetics at Tufts Cummings School of Veterinary Medicine, agrees. “Breeders can minimize the risk of producing the disease without limiting genetic diversity. Affected dogs should be replaced in a breeding program with a normal littermate, parent or close relative. These should then be bred to echocardiogram-tested normal dogs that have a clearer familial history of DMVD. This reduces the carrier risk by half while maintaining the bloodline’s good genes.”