Chronic valvular disease in dogs

Introduction

CVD, which may also be described as “degenerative valve disease”, “myxomatous valve disease” or “endocardiosis”, causes progressive thickening and malformation of the heart valve leaflets, with the mitral valve most commonly affected. In many cases, similar changes are present on the tricuspid valve.

Epidemiology

CVD is a disease of middle-aged to older dogs, although earlier onset has been noted in some breeds (e.g., Cavalier King Charles spaniels). Although the etiology has not been ascertained in most dogs, a genetic tendency toward development of CVD has been proven in Cavalier King Charles Spaniels and Dachshunds 1,2, and a genetic basis for at least some of the changes noted is suspected in other breeds. All breeds can be affected, but the disease most commonly results in clinical signs in small and medium breeds.

Pathology

The histologic changes to the valve consist of degenerative changes in collagen (“myxomatous degeneration”) and development of valvular fibrosis. Grossly, the affected valve leaflets in patients with CVD are thickened, white to yellow in color, with nodular edges that may be curled 3. In contrast to valvular changes associated with valve leaflet infection (i.e., bacterial endocarditis), the endocardial surface of the irregular valve leaflets is typically intact with a smooth surface. The degenerative changes often affect the chordae tendineae as well as the leaflet itself, and the stretching and thickening may result in chordal rupture (Figure 1). In the atrioventricular valves, the distortion of the leaflets caused by this remodeling results in incomplete closure of the valves, and regurgitation of blood during systole. Chronically, mitral and tricuspid regurgitation cause atrial and ventricular dilation on the affected sides of the heart. Secondary damage within the atrium may include jet lesions (roughened areas of endocardium at the point of contact with the regurgitant jet) and in some cases, partial rupture of the atrial endocardium (Figure 2) or complete left atrial rupture.

Echocardiographic findings

The echocardiographic appearance of CVD in dogs can be divided into anatomic and functional changes to the valve leaflets/valve apparatus, and changes to the size, shape and function of the cardiac chambers that occur secondary to the volume loading due to valvular regurgitation.

Valvular changes

Changes to the anatomy include thickening of the valve leaflets with variable increases in echogenicity. The anterior mitral valve leaflet often seems to be more distorted than the posterior leaflet, and may appear to be curved or “hockey-stick” shaped when open. When closed, mitral valve prolapse may be noted, with portions of the valve leaflet ballooning backward into the atrium in systole. Mitral valve prolapse may occur as chordal structures elongate or rupture. Rupture of a more major chord may result in a “flail” mitral valve leaflet, in which an untethered edge of the leaflet flips backward into the atrium in systole, causing acute worsening of valvular regurgitation (Figures 3 a-d). Mitral regurgitation (MR) secondary to these anatomic changes may be documented using color-flow Doppler mapping (Figure 4 a,b).

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Figure 3. Echocardiographic images from dogs with chronic valvular disease, illustrating various echocardiographic features of the disease. In all figures, LA: left atrium, LV: left ventricle.
(a) Right parasternal long axis view (diastolic frame). The arrow indicates the thickened anterior mitral valve leaflet. Note globoid appearance of left atrium and ventricle, reflecting eccentric hypertrophy due to chronic volume loading. 
© Dr. Heidi B. Kellihan
(b) Right parasternal long axis view of the mitral and tricuspid valves (systolic frame). The arrow indicates the thickened and prolapsing septal tricuspid valve leaflet. The asterisk identifies a segment of mitral valve prolapse on the anterior mitral valve leaflet. 
© Dr. Heidi B. Kellihan
(c) Right parasternal long axis view of the mitral valve (end-diastolic frame). The arrow indicates a prolapsed segment of the anterior mitral valve leaflet. 
© Dr. Rebecca L. Stepien
(d) Right parasternal long axis view of the mitral valve (systolic frame). The arrow indicates a flailed portion of the anterior mitral valve leaflet. 
© Dr. Rebecca L. Stepien

Grading of the severity of the valve changes may take into account the degree of anatomic change to the valve, the presence/absence of mitral valve prolapse and flail, the size of the color-mapped mitral jet (especially at its source at the valve leaflet) and the presence of left atrial enlargement 4. With CVD of the tricuspid valve, the septal leaflet often appears to be more affected than the mural leaflet, with changes similar to the mitral valve (thickening, increased echogenicity, prolapse, Figure 3b). As with the mitral valve, evidence of right atrial dilation usually indicates more severe tricuspid regurgitation.

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Figure 4. 
(a) Right parasternal long axis view optimized for the left ventricular inflow tract (systolic frame). The small arrows identify the mitral valve leaflets. The color jet in the left atrium during systole indicates the presence of mitral regurgitation. LA: left atrium, LV: left ventricle. 
© Dr. Rebecca L. Stepien
(b) Left apical parasternal long axis view optimized for the left ventricular inflow tract (systolic frame). The arrow indicates the point at which the width of the mitral regurgitation jet can be assessed as an indicator of severity. LA: left atrium, LV: left ventricle, IVS: interventricular septum, RA: right atrium. 
© Dr. Rebecca L. Stepien

Other echocardiographic findings

Cardiac remodeling secondary to chronic atrioventricular valvular regurgitation is common and the degree of remodeling is affected by the severity of the regurgitation. If moderate to severe MR is present, the left atrium becomes progressively dilated. The left ventricle dilates and becomes more spherical in appearance (i.e., eccentric hypertrophy, Figure 3a). Initially, the left ventricular free wall may be mildly thickened, but later in the disease, when ventricular dilation occurs, both free wall and interventricular septum may become thinned. Moderate to severe tricuspid regurgitation results in similar changes in the right heart (Figure 3b).

Systolic function, as measured by fractional shortening, may appear to be increased in the moderate stages of MR; it remains unclear if these apparent beneficial functional changes are an artifact of decreased afterload or represent actual increases in systolic function (Figure 5). As CVD progresses and the ventricle dilates further, the fractional shortening may become normal once again; this may indicate the early stages of myocardial systolic failure. Severe MR may lead to secondary pulmonary hypertension due to chronically elevated left atrial pressure. If pulmonary hypertension is present, the right atrium and right ventricle become dilated and eventually develop systolic failure (“right heart failure secondary to left heart failure”).

Clinical evaluation

The American College of Veterinary Internal Medicine (ACVIM) guidelines for staging of heart disease in dogs (Figure 6) are a helpful guide when discussing CVD in clinical patients 5 and are a useful reference for both diagnosis and therapy of CVD, as clinical findings allow classification and thus can guide therapy.

Approach to patients at risk for development of CVD (ACVIM Stage A)

Patients at risk for development of CVD are commonly recognized to be small to medium breed, older dogs, with males more frequently affected than females. “At risk” breeds may be presented at screening events for routine or pre-breeding evaluations. The Stage A population, i.e., patients identified as “at risk” based on breed/ breed type but with no cardiac abnormalities identified on physical examination, require no therapy, but the owners or breeders should be informed about the future risk of the disease, and alerted to clinical signs that may indicate development of heart disease or congestive heart failure (e.g., cough, increased respiratory rate or effort, signs of fatigue). Annual physical examination and careful auscultation of breeds at risk are especially recommended for early detection of heart murmurs that may indicate the onset of CVD.

Approach to the patient with a heart murmur and no clinical signs (ACVIM Stage B1 or B2) 

History

Dogs with CVD may have detectable changes on auscultation (typically, systolic murmurs) evident for 3-5 years prior to the onset of clinical signs. During these preclinical years, the patient usually has no cough, difficulty breathing, syncope or fatigue, and the murmurs are detected during routine physical examination. Some dogs in the later stages of preclinical CVD will have gallop sounds or arrhythmias (irregular heart rhythm with associated pulse deficits) detected. Pulse strength is usually normal. As cardiomegaly progresses in dogs with large airway compromise (e.g., inflammatory airway disease or bronchomalacia), a hacking, non-productive cough may develop due to impingement of the enlarged left atrium on the left mainstem bronchus. A paroxysmal, hacking, non-productive cough without changes in respiratory rate or effort in a dog suspected of having MR is usually indicative of cardiomegaly rather than CHF.

Physical examination

The most common method of detecting CVD for the first time is by identifying a heart murmur on routine physical examination. In the early stages of CVD (Stage B1 or B2), the heart rate is normal and a regular rhythm or a sinus arrhythmia may be present. The murmur of MR is usually heard best at the left apex of the heart (where the apex beat may be palpated) and occurs during systole – confirmed when the murmur is heard simultaneously with the palpated femoral pulse. Murmurs are graded on a scale from 1-6 in dogs, with grades 1 and 2 representing soft murmurs, grades 3 and 4 representing moderate intensity murmurs and grades 5 and 6 representing the loudest murmurs. Grade 5 or 6 murmurs are accompanied by a palpable systolic “thrill” (vibration) over the area of maximal murmur intensity. In dogs with CVD the intensity of the murmur is associated with the severity of regurgitation, with murmurs of grades 4 to 6 representing more severe disease. In the case of tricuspid regurgitation (TR), a systolic murmur may be identified with the point of maximal intensity at the right cardiac apex (approximately at intercostal space 4 on the right thorax). When mitral and tricuspid regurgitation co-exist in a patient, it may be difficult to differentiate a TR murmur from the referred sound of the MR murmur. A jugular pulse with every heartbeat supports a diagnosis of hemodynamically significant tricuspid regurgitation.

Diagnostic testing in the early stages of CVD may be offered to the client with the aim of confirming the diagnosis, staging the disease severity and establishing other baseline information (e.g., serum biochemical analysis) that may become useful for comparison in the future or for establishing normal organ function if therapy is contemplated.

Radiography

Thoracic radiography is an essential part of evaluating the patient, allowing determination of heart size via the Vertebral Heart Score [VHS] assessment (6, Figure 7) and scrutiny of pulmonary vasculature and parenchyma for evidence of pulmonary infiltrates and vascular engorgement typical of CHF. In the patient without clinical signs, the size of the heart, assessed over time, can be used to estimate the likelihood of CHF development in the near future; a VHS > 12 or an increase in VHS between visits of approximately > 0.7 VHS units/month indicates impending CHF 7,8. In patients without clinical signs, baseline radiographs may reveal a normal-sized heart (Stage B1 disease) or cardiac enlargement (Stage B2) that may be mild to severe. Knowledge of a patient’s degree of cardiomegaly allows the clinician to educate the client as to monitoring their pet for development of signs of CHF. Patients diagnosed at Stage B1 may have no clinical signs for 2-4 years, while those with some degree of cardiac enlargement may develop signs of CHF sooner. The prognosis for CVD patients without clinical signs is fairly optimistic; 70% of preclinical dogs in one study were alive 6 years later 9.

Echocardiography

Echocardiography is not required for tentative diagnosis of CVD in its early stages if the signalment and physical examination findings in a patient without clinical signs present a picture consistent with MR and/or TR. Nevertheless, obtaining an echocardiogram at first detection of a murmur allows confirmation of the tentative diagnosis of CVD. In addition, in dogs also at risk for occult dilated cardiomyopathy (e.g., large-breed dogs), echocardiography is the diagnostic test of choice to differentiate these conditions. Lastly, if unexpected clinical findings are noted (e.g., irregular heart rhythm in a dog without other clinical signs), echocardiography can provide important additional information.

Other diagnostic testing

Measurement of biomarkers, specifically NT-proBNP concentration, has been assessed in this type of patient and may be useful for identifying dogs at increased risk of development of CHF within one year 8; currently the test is not considered diagnostic in a non-clinical CVD patient but it may add information 10. Other methods can be recommended for individuals based on clinical findings (e.g., an ECG if an irregular heart rhythm is detected) or concurrent known illnesses (e.g., blood pressure measurement if renal disease is present).

Monitoring

When a patient is diagnosed with Stage B2 disease, introduction of the concept of home “resting respiratory rate” (RRR) monitoring is helpful (Table 1); owners can be counseled to monitor the RRR of their pet, and contact their veterinarian if the rate exceeds the normal (or the reference) range (< 25 breaths per minute) 11.

Table 1. Monitoring a dog’s RRR at home can provide early warning of developing problems and allow the caretaker to assess the efficacy of medications. The following pointers may be useful.

Approach to the patient with CVD and clinical signs of CHF (ACVIM Stage C or D)

History

Dogs with CVD and CHF may have had a heart murmur recognized previously but have not had any clinical signs until the CHF presentation. Alternatively, some dogs with MR will have had a dry hacking cough previously with little effect on quality of life. A recent history that should cause the clinician to suspect CHF may include varying degrees and combinations of respiratory abnormalities (increased rate and effort), fatigue or easy tiring with exercise, or (rarely) syncope. General signs of systemic illness, including weight loss and changes in behavior (i.e., less playful or quieter), may be present. Note that CVD dogs with previous CHF are still considered to be Stage C since medications are required to maintain a compensated state.

Physical examination

If CHF is present (Stage C or D), heart murmurs are detected as in the early stages of disease, but other physical findings reflecting low cardiac output or fluid retention are present. For dogs with left-sided CHF,increased respiratory effort and coughing may be noted due to pulmonary edema. In severe CHF, the patient may be cyanotic and coughing up blood-tinged white foam. Lung sounds are usually abnormal, and range from increased large airway sounds to easily detected pulmonary crackles, suggesting the presence of alveolar fluid accumulation. Ascites and jugular distention usually indicate right-sided CHF, which may be due to tricuspid CVD, development of pulmonary hypertension secondary to left-sided disease, or a combination of both. Irregular heart rhythms may accompany severe CVD with or without CHF. Common arrhythmias usually ascribed to severe atrial dilation include atrial premature complexes, atrial tachycardia or atrial fibrillation. Less commonly, CVD patients may develop ventricular ectopy.

Once CHF is suspected in a patient with a heart murmur consistent with CVD, further evaluation is required to estimate the severity of the heart failure and establish the best course of therapy. In general, thoracic radiography provides information about the presence/absence/severity of CHF, while echocardiography provides information regarding the underlying disease and the development of complications such as pulmonary hypertension.

Radiography

The initial evaluation of heart size in conjunction with findings of left-sided heart failure (i.e., interstitial or alveolar pulmonary infiltrates in the presence of left atrial enlargement and pulmonary venous engorgement) in a patient with new clinical signs establishes a diagnosis of CHF and serves as a baseline for comparison once therapy is initiated (Figure 8). In patients with clinical signs of right-sided CHF (particularly ascites), radiography allows for screening for pleural effusion as well as assessment of right-sided cardiac structures (including pulmonary arteries) for evidence of pulmonary hypertension. Where left-sided heart disease has resulted in the development of pulmonary hypertension and subsequent right-sided heart failure, enlargement of both left and right heart structures may be present. Serial radiographs are invaluable to assess the success of therapy as well as to monitor the status of a CHF patient over time.

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Figure 8. Left lateral thoracic radiographs obtained from a dog with Stage C chronic valvular disease. (a) Film obtained on emergency presentation; note significant cardiomegaly and severe, patchy alveolar infiltrates representing acute pulmonary edema (arrows). 
© University of Wisconsin
(b) The same patient after 48 hours’ therapy with furosemide and oxygen. The pulmonary infiltrates have resolved. Note the impingement of the severely enlarged left atrium on the left mainstem bronchus (arrow). 
© University of Wisconsin 

Echocardiography

Echocardiography at the time of diagnosis of CHF (obtained once the patient is stable) adds valuable information to the patient’s record. If not previously performed, it can establish the exact anatomic/functional diagnosis of CVD and be used to estimate the severity of disease as well as screen for complications such as pulmonary hypertension, chordae tendineae rupture or left atrial rupture. Echocardiography in CVD patients is often most helpful as a diagnostic tool at specific time points rather than a monitoring tool for the presence of heart failure over time.

Biomarkers

Serum NT-proBNP concentration may be useful to establish a diagnosis of CHF in dogs with known CVD and respiratory distress when it is not clear if the respiratory compromise is due to CHF or respiratory disease. Although there is some variability between studies in exact values, an elevated NT-proBNP concentration (e.g., > ~1000 pmol/L) is supportive of CHF as a cause of dyspnea, whereas a normal level suggests a respiratory cause for dyspnea 12. In all cases, NT-proBNP assessment should be considered supportive rather than diagnostic of cardiac disease 10.

Therapy for dogs with CVD

ACVIM Stage A heart disease

As noted above, patients at risk for CVD without clinical findings require no specific treatment, and no therapy has been proven to prevent or delay the onset of CVD in these patients. Screening for physical evidence of CVD (e.g., a systolic heart murmur) should be performed at each physical examination, accompanied by discussion of the risks.

ACVIM Stage B1 heart disease

As with Stage A CVD, Stage B1 patients require no specific therapy, but more owner education is essential since the disease is already present, and it is a good time to optimize the patient’s weight and body condition if not already ideal. Discussion with owners about diet and exercise, as well as likely clinical signs of CVD, provides inducement for closer management and observation of their pet.

ACVIM Stage B2 heart disease

As CVD progresses, cardiac enlargement occurs and will progress at a variable rate, individual to the dog. In early Stage B2, cardiomegaly is identified via radiography or echocardiography, but may not be severe. Most cardiologists do not recommend any specific therapy at this point.

When cardiomegaly worsens, recommendations for therapy become less uniform. Important factors to consider are the degree of cardiomegaly and concurrent findings on radiography, and the presence or absence of a cough due to mainstem bronchial compression with or without underlying large airway abnormalities. When cardiomegaly is severe and CHF seems likely in the near future, the author typically recommends initiation of angiotensinconverting enzyme inhibitor (ACEI) therapy 13. In patients with cough due to cardiomegaly, ACEI therapy, antitussive therapy (e.g., butorphanol) or a combination of the two may be used. Currently there is no proven benefit to routine initiation of pimobendan therapy at this stage.

ACVIM Stage C heart disease (CHF)

The diagnosis of CHF in a dog with CVD is usually the moment when direct therapy for CHF begins. Acute therapy of the emergency patient with respiratory distress differs slightly from chronic CHF therapy (see below). Most therapy for CHF is lifelong, although the number and choice of medications, as well as dosing regimens, may change over time.

Acute CHF

Dogs with acute CHF due to CVD are usually presented in respiratory distress. Immediate oxygen therapy (e.g., oxygen cage or “blow by” oxygen supplementation) should be provided while developing a tentative diagnosis. If CHF is suspected based on history and physical examination, thoracic radiography can confirm the presence of fluid suggestive of pulmonary edema but may not be obtainable if the patient’s condition is unstable.

In these cases, immediate parenteral administration of furosemide can be life-saving. Dogs that can tolerate oral medication may receive pimobendan as soon as feasible. An injectable form of pimobendan, to be administered intravenously, is available in some countries and may provide an alternative for dogs unable to be given oral medication. After initial furosemide has been administered, the patient should be observed with minimal handling until respiratory rate and effort improve. A second parenteral dose of furosemide can be administered if no urination is observed within 30-60 minutes of injection. In very anxious patients, low doses of butorphanol can be administered SC or IM to provide very mild sedation. Dogs with significant ascites causing discomfort can have abdominocentesis performed to relieve pressure on the diaphragm that may be limiting ventilation. Some dogs will become hypotensive if the full amount of ascites is removed; removal of approximately 75% of the ascitic fluid acutely is usually tolerated. Cage rest with minimal exercise and oxygen supplementation is recommended until acute pulmonary edema has resolved.

Chronic management of CHF

Once a CHF patient has improved to the point where oxygen therapy is no longer needed, home-administered oral treatments are possible, and several medications have proven survival benefits 14,15,16,17. Left-sided congestive heart failure is initially treated with “triple therapy” (furosemide, pimobendan and ACEI), with the addition of spironolactone chronically in many patients. Of these medications, furosemide and pimobendan should be administered first and are essential for early treatment of pulmonary edema due to left-sided CHF. Once a patient is rehydrated (reliably signaled by the return of appetite), an ACEI may be administered safely. Dehydrated patients may develop pre-renal azotemia if given ACEI; in this case the drug should be stopped while the patient is rehydrated, restarting the drug once the dog is stabilized. Like ACEI, spironolactone is considered a chronic, rather than acute, therapy for CHF. Administering spironolactone as a neurohormonal blocker early in the course of chronic CHF decreases sodium and water retention and may increase survival 17. Once the patient is stable at home, a gradual return to normal exercise can be initiated, although strenuous exercise (e.g., prolonged ball-chasing, competitive sports) may not be tolerated.

ACVIM Stage D heart disease (refractory CHF)

A CVD patient that has been stable on chronic therapy may appear to become refractory to therapy over time. This presentation may include a recurrence of heart failure despite stable medications, or incomplete resolution of heart failure on triple therapy. The owners should be questioned carefully with regard to exact medication dosing, with special attention to any inadvertent lapses in administration that may have occurred. In addition, careful patient evaluation may reveal evidence of other findings suggestive of systemic disease, arrhythmia or development of complications such as pulmonary hypertension. Metabolic changes such as dehydration or hypokalemia may interfere with CHF therapy. Complications such as arrhythmias or pulmonary hypertension require diagnostic testing for full evaluation and direct therapy as necessary. If recurrence of CHF is due to progression of CVD (i.e., other causes have been ruled out), additional oral arterial vasodilators such as amlodipine for further “offloading” of the left side of the heart may be required. Animals with severe recurrent CHF may require short-term hospitalization with oxygen support and temporary use of parenteral inotropic drugs like dobutamine. Consultation with, or referral to, a specialist for management of these cases may be beneficial. A consensus paper regarding diagnosis and therapy of canine CVD has been published 5; Table 2 sets out common drugs, usage and dosage, and a useful formulary may be found online*.

* https://cardiaceducationgroup.org/resource/formularies/ 

Table 2. Dosage of medications used in acute and chronic therapy of CVD in dogs.

Dietary considerations for valvular disease patients

Dietary recommendations for canine patients with chronic valvular heart disease continue to evolve. Previously, diets with severe sodium and protein restrictions were commonly discussed for these patients, but more recent considerations suggest that diets with high quality protein and moderate sodium restriction, along with supplementation of omega-3 fatty acids, are likely to be helpful to manage chronic disease. Omega-3 fatty acid supplementation, delivered separately or as part of a commercial diet, is thought to have beneficial effects in dogs both before heart failure occurs 18 and during clinical heart failure 19, likely due to the anti-inflammatory and anticachexia effects of these essential fatty acids 20. Feeding a diet with moderate sodium restriction and enhanced with omega-3 fatty acids and amino acids like taurine and carnitine may be beneficial even in early valvular disease (Stage B) before congestive heart failure occurs 18.

Prognosis for CVD

The clinical course of canine CVD is unpredictable, especially in the early stages. Although clients should be informed about the disease and possible clinical signs at the time a diagnosis of heart disease is made (e.g., at the time a murmur is detected), they should also be informed that many dogs with CVD will never develop CHF. The disease tends to be progressive over time, but the rate of progression is individual to the dog. The amount of time to onset of CHF, if it occurs, is also related to how early the disease is detected; animals with very soft (≤ grade 2/6) murmurs of MR and no cardiomegaly usually remain free of clinical signs longer than those with loud (≥ grade 4/6) murmurs or cardiomegaly at diagnosis. Overall, preclinical CVD dogs may remain without clinical signs of CHF for 2-4 years 9,21,22.

Once CHF occurs, survival depends on choice of therapy 14,15, but other factors have an impact. Dogs whose owners monitor them closely and notice problems early, and dogs that tolerate the medications easily tend to survive longer and have better quality of life. In general, dogs treated optimally with triple therapy can be expected to live approximately 6-18 months post-CHF.