CANINE ACQUIRED HEART DISEASE: ADVANCES IN MEDICAL TREATMENT

Vet Times The website for the veterinary profession https://www.vettimes.co.uk CANINE ACQUIRED HEART DISEASE: ADVANCES IN MEDICAL TREATMENT Author : Emily Dutton, Simon Swift Categories : Vets Date : July 8, 2013 EMILY DUTTON, SIMON SWIFT discuss how skills in recognising and treating canine acquired heart disease have increased, especially in valvular and mycocardial disease THE most commonly diagnosed acquired heart disease in dogs is degenerative mitral valve disease (DMVD) with cavalier King Charles spaniels, Yorkshire terriers, miniature poodles and dachshunds being over-represented1, 2. Although DMVD is a common disease of older dogs, only a small percentage develop clinical signs of congestive heart failure (CHF) and require treatment2. On investigation of a systolic apical heart murmur, echocardiography is the cornerstone of diagnosing DMVD (Figures 1 and 2). It also allows identification of individual dogs at high risk of developing complications as a result of their disease. In a large retrospective study2, the left atrial/aorta (LA/Ao) ratio was the most significant independent predictor of cardiac-related death. Comparing the rates of change of echocardiographic variables in naturally-occurring DMVD3, left ventricular diastolic and systolic diameter, mitral regurgitant velocity and LA/Ao ratio were greater in the year before succumbing to cardiac death than in dogs that died of other causes. Hence, serial echocardiography every six to 12 months is likely to help detect disease progression. Predicting the onset of heart failure would be very helpful and risk factors in dogs with DMVD4 included high vertebral heart sum, LA/Ao ratio and N-terminal prohormone of brain natriuretic peptide (NTproBNP). However, the weekly variability of NT-proBNP in healthy dogs has been 1 / 16

reported to be as high as 500pmol/L5. Those dogs with DMVD that develop CHF most commonly show clinical signs of breathlessness. A study has shown no statistical association between coughing and CHF as identified by radiological evidence of cardiogenic pulmonary oedema6. This is not surprising as cough receptors occur in the proximal parts of the respiratory tree (for example, larynx, trachea, bronchi). Coughing will only occur if the amount of fluid is sufficient to flood the upper airways, for example, with peracute cardiogenic pulmonary oedema. The concomitant presence of airway disease represented a higher risk factor for coughing in dogs with DMVD. Pulmonary hypertension (PH) is a common finding in dogs with DMVD, with prevalence ranging from 14 per cent to 53 per cent7. Diagnosis can be made noninvasively with echocardiography (Figures 3 and 4). In those cases with clinical signs of PH, such as collapse or ascites, then a phosphodiesterase V inhibitor (such as sildenafil) may improve symptoms8. In canine patients with simultaneous PH and concurrently treated left-sided heart failure due to DMVD, the addition of pimobendan reduced estimated PH severity as compared to placebo and improved quality of life in the short term9. Arrhythmias and, in particular, atrial arrhythmias, as a consequence of atrial stretch secondary to valvular incompetence, are also common in dogs with DMVD. Treatment of atrial fibrillation (AF) is aimed at rate control rather than rhythm control as there is underlying structural heart disease (Figure 5). Digoxin is a vagomimetic agent that slows conduction through the atrioventricular (AV) node, thus is a negative chronotropic agent. It is also a weak positive inotrope with a narrow therapeutic index. Digoxin toxicity can occur hence, starting at low doses with close monitoring is advisable. The ideal therapeutic range is 0.5ng/ml to 1.0ng/ml as the vagal effects can be seen at these lower levels. Diltiazem is a calcium channel blocker with negative chronotropic actions. It has mildly negative inotropic effects and should be used with caution in those patients with heart failure and impaired systolic function, with doses being slowly titrated upwards after starting at the lower end of the therapeutic range. Digoxin and diltiazem are often administered together and used to treat AF. The combination of the two drugs has been shown to provide better rate control than either drug alone in dogs10. Hopefully, this will translate into improved survival times. Controlling heart rate in dogs with AF can significantly improve cardiac output by increasing diastolic filling time as well as preventing tachycardiainduced cardiomyopathy, which can occur following sustained elevations in heart rates. Finally, measuring systemic blood pressure is recommended as hypertension might accelerate 2 / 16

progression of mitral regurgitation and hypotension might influence treatment choices11. Dilated cardiomyopathy Dilated cardiomyopathy (DCM) is an acquired idiopathic myocardial disease of large to giant-breed dogs, such as Dobermann pinschers, boxers, Scottish deerhounds, Irish wolfhounds, great Danes and Newfoundlands, although it has also been seen in smaller breeds, such as cocker spaniels12,13. The prevalence of DCM in individual breeds can be high and is estimated to be between 25 per cent and 50 per cent in Dobermann pinschers14. It is characterised by ventricular dilation (Figure 6) and impaired contractility, which may lead to exercise intolerance, collapse, congestive heart failure and sudden death13,15. The diagnosis of DCM requires the exclusion of other diseases that may induce a similar phenotype, such as hypothyroidism, tachycardia-induced cardiomyopathy and taurine or carnitine 18 19 deficiency16-. In humans, a proportion of DCM cases are thought to be inherited. In dog breeds, such as the Dobermann and the boxer, genetic mutations have been suggested and research is -23. 20 ongoing in predisposed breeds with familial DCM Diagnosis is made using echocardiography to detect dilatation and reduced systolic function and is often not made until an animal has developed symptoms. The preclinical stage, prior to the onset of clinical signs, may be characterised by a systolic heart murmur, due to mitral incompetence (Figure 7 ), gallop rhythm and ventricular arrhythmias, which can be detected with a 24-hour ECG (Holter monitor). The combination of NT-proBNP assay and Holter is highly accurate for the detection of preclinical DCM24. Angiotensin-converting enzyme inhibitors (ACEIs) and pimobendan have been shown to delay the onset of heart failure in Dobermanns with preclinical DCM. Pimobendan was shown to delay the onset of heart failure or sudden cardiac death from 441 to 718 days14 and benazepril prolonged the disease-free interval from 339 to 425 days25. As the median survival time for dogs with DCM once failure develops is four to six months13,26, delaying the onset of failure is likely to be beneficial. Cocker spaniels have a longer survival of approximately one to two years13. Ventricular arrhythmias are common, especially in certain breeds such as Dobermanns, great Danes and boxers. None of the drugs used to control arrhythmias are licensed. Antiarrhythmic drugs also have the potential to be pro-arrhythmic. AF also occurs commonly in these dogs as a result of atrial stretch. The benefits of rhythm control with DC cardioversion are usually short-lived due to the underlying structural heart disease so, again, rate control with drug therapy is the treatment of choice. 3 / 16

Treatment of congestive heart failure If a dog presents with acute congestive heart failure (CHF; Figure 8), furosemide is the drug of choice and should be administered intravenously. Oxygen administration is also recommended, as well as an angiotensin-convertingenzyme inhibitor (ACEI) and pimobendan to reduce preload and afterload and to provide inotropic support27. Injectable pimobendan is now available in the UK for dogs and is likely to be helpful in an acute CHF. It may be particularly useful in the short term in those dogs with ascites and decreased intestinal absorption, or anxious patients who may not tolerate oral medications. DCM and the associated reduced cardiac output will cause activation of the renin angiotensin aldosterone system (RAAS). In addition, furosemide stimulates RAAS due to a reduction in glomerular filtration rate28. RAAS stimulation does help to maintain blood pressure, but it also has deleterious side effects, such as excessive sodium and water retention (promoting the development of effusions), vasoconstriction (increasing afterload on the failing heart) and potentiating myocardial fibrosis. An ACEI should therefore be prescribed to normotensive dogs with CHF. The beneficial effects of using an ACEI and pimobendan in addition to furosemide for those 31 DMVD patients with chronic heart failure have been demonstrated29-. However, there is no evidence to show dogs treated with all three drugs survive longer than those just treated with furosemide and pimobendan. Dogs treated with furosemide and an ACEI had shorter survival times29. There is some evidence the use of spironolactone is weaker32. From a practical point of view, a recently licensed combination ACEI with spironolactone is available and may help improve owner compliance. Spironolactone is an aldosterone antagonist, which reduces myocardial fibrosis as well as a weak potassiumsparing diuretic. Theoretically, an aldosterone antagonist, such as spironolactone, should be beneficial and may reduce myocardial fibrosis, which occurs in heart failure patients. However, the UK licence is for DMVD, but not DCM. In those cases with refractory CHF, additional diuretics (such as thiazides) may be cautiously used to achieve sequential nephron blockade. Close monitoring of renal parameters and serum electrolytes in these cases is required. Arrhythmogenic right ventricular cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy (ARVC) is classically an adult-onset myocardial disease seen in boxers and bulldogs. ARVC is a familial disease in boxers inherited as an autosomal dominant trait33. It is characterised by fibrofatty infiltration of the myocardium, which leads to dilation particularly of the right cardiac chambers, ventricular arrhythmias and sudden 4 / 16

death. Three clinical categories have been identified: the concealed form with arrhythmias, but no clinical signs; the overt form with symptomatic ventricular arrhythmias, but no CHF; and the myocardial dysfunction form, which includes those dogs with both ventricular arrhythmias and CHF34. The myocardial dysfunction form has been shown to be the most prevalent in the UK, with syncope the most common clinical sign35. Syncope in boxers with ARVC has been shown to be a poor prognostic indicator and is thought to be often, but not always, caused by ventricular tachycardia35,36. Holter monitoring is recommended for symptomatic patients, but also for screening for preclinical disease. Arrhythmias that are commonly seen include ventricular premature complexes (VPCs) usually right ventricular in origin, or runs of ventricular tachycardia (Figure 8). Treatment with anti-arrhythmic medication is often initiated if there are more than 1,000 VPCs per 24 hours, the morphology is complex, or the dog is symptomatic. Intravenous lidocaine (class 1B drug) should be administered to control ventricular tachycardia. Oral class 1B drugs, such as mexiletine, are becoming difficult to obtain so other drugs, such as sotalol, are often considered for longterm management36,37. Sotalol has class II and class III actions with negative inotropic effects and should, therefore, be used with caution in those dogs with systolic dysfunction. There is little published evidence to suggest anti-arrhythmic treatment reduces the likelihood of sudden death or prolongs life expectancy. Advice from a specialist is recommended. Conclusions The ability to diagnose and treat acquired heart diseases in dogs is an active area of ongoing research. In particular, improving quality of life as well as increasing longevity is very important. Early detection of acquired heart disease and effective, targeted monitoring of the condition is important to help optimise the treatment plan long term. Please note some medicines mentioned in this article are not licensed for use in dogs. References 1. Borgarelli M and Haggstrom J (2010). Canine degenerative myxomatous mitral valve disease : natural history, clinical presentation and therapy, Vet Clin Small Anim40: 651-663. 2. Borgarelli M et al (2008). Survival characteristics and prognostic variables of dogs with mitral regurgitation attributable to myxomatous valve disease, J Vet Internal Med22: 120-128. 3. Hezzell M J et al (2012). Selected echocardiographic variables change more rapidly in dogs that die from myxomatous mitral valve disease, J Vet Cardiol14: 269-279. 4. Reynolds C A et al (2012). Prediction of first onset of congestive heart failure in dogs with 5 / 16

degenerative mitral valve disease: The PREDICT cohort study, J Vet Cardiol 14: 193-202. 5. Kellihan H B et al (2009). Weekly variability of plasma and serum NTproBNP measurements in normal dogs, J Vet Cardiol 11 (Suppl 1): S93-S97. 6. Ferasin L et al (2013). Risk factors for coughing in dogs with naturally acquired myxomatous mitral valve disease, J Vet Internal Med 27: 286-292. 7. Kellihan H B and Stepien R L (2012). Pulmonary hypertension in canine degenerative mitral valve disease, J Vet Cardiol 14: 149-164. 8. Kellum H B and Stepien R L (2007). Sildenafil citrate therapy in 22 dogs with pulmonary hypertension, J Vet Internal Med 21: 1,258-1,264. 9. Atkinson K J et al (2009). Evaluation of pimobendan and N-Terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs, J Vet Internal Med 23: 1,190-1,196. 10. Gelzer A R et al (2009). Combination therapy with digoxin and diltiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized crossover study in 18 dogs, J Vet Internal Med 23: 499-508. 11. Kvart C et al (2002). Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation, J Vet Intern Med 16: 80-88. 12. Dukes McEwan J et al (2003). Proposed guidelines for the diagnosis of canine idiopathic dilated cardiomyopathy, J Vet Cardiol 5: 7-19. 13. Martin M W S et al (2009). Canine dilated cardiomyopathy: a retrospective study of signalment, presentation and clinical findings in 369 cases, J Small Anim Pract 50: 23-29. 14. Summerfield N J et al (2012). Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in doberman pinschers with preclinical dilated cardiomyopathy (the PROTECT study), J Vet Intern Med 26: 1,337-1,349. 15. Richardson P et al (1996). Report of the 1995 world health organisation. International society and federation of cardiology task force on the definition and classification of cardiomyopathies, Circulation 93: 841-842. 16. Fascetti A J et al (2003). Taurine deficiency in dogs with dilated cardiomyopathy: 12 cases (1997 2001), J Am Vet Med Assoc 223: 1,137-1,141. 17. Phillips D E and Harkin K R (2003). Hypothyroidism and myocardial failure in two great Danes, J Am Anim Hosp 39: 133-137. 18. Keene B W et al (1991). Myocardial L-carnitine deficiency in a family of dogs with dilated cardiomyopathy, J Am Vet Med Assoc 198: 647-650. 19. Karkkainen S and Peuhkurinen K (2007). Genetics of dilated cardiomyopathy, Ann Med 39: 91-107. 20. Mausberg T B et al (2011). A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman pinschers, PLOS ONE 6: e20042. 21. Meurs K M et al (2012). A splicesite mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher, Human Genetics 131: 1,319-1,325. 22. Meurs K M (2012). Genomewide association identifies a deletion in the 3 untranslated 6 / 16

region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy, Human Genetics 128: 315-324. 23. Stephenson H M et al (2013). Screening for dilated cardiomyopathy in great Danes in the United Kingdom, J Vet Intern Med 26: 1,140-1,147. 24. Singletary G E et al (2012). Prospective evaluation of NT-proBNP assay to detect occult dilated cardiomyopathy and predict survival in Doberman pinschers, J Vet Intern Med 26: 1,330-1,336. 25. O Grady M R (2009). Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman pinschers, J Vet Intern Med 23: 977-983. 26. Tidholm (2006). Survival in dogs with dilated cardiomyopathy and congestive heart failure treated with digoxin, furosemide and propranolol : a retrospective study of 62 dogs, J Vet Cardiol 8: 41-47. 27. Atkins C et al (2009). Guidelines for the diagnosis and treatment of canine chronic valvular heart disease, ACVIM consensus statement, J Vet Internal Med 23: 1,142-1,150. 28. Fett D L et al (1993). Low-dose atrial natriuretic factor and furosemide in experimental acute congestive heart failure, J Am Soc Nephrol 4: 162-167. 29. Haggstrom J et al (2008). 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, J Vet Internal Med 22: 1,124-1,135. 30. COVE study group (1995). Controlled clinical evaluation of enalapril in dogs with heart failure: results of the cooperative veterinary enalapril study group, J Vet Internal Med 9: 243-252. 31. The BENCH Study Group (1999). The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial, J Vet Cardiol 1: 5-18. 32. Bernay F et al (2010). Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease, J Vet Internal Med 24: 331-341. 33. Meurs K M et al (1999). Familial ventricular arrhythmias in boxers, J Vet Intern Med 13: 437-439. 34. Harpster N (1991). Boxer cardiomyopathy, Vet Clin N Am Small Anim Pract 21: 989-1,004. 35. Palermo V (2011). Cardiomyopathy in Boxer dogs: A retrospective study of the clinical presentation, diagnostic findings and survival, J Vet Cardiol 13: 45-55. 36. Caro-Vadillo A et (2013). Arrhythmogenic right ventricular cardiomyopathy in boxer dogs: a retrospective study of survival, Vet Rec 172: 268. 37. Meurs K M et al (2002). Comparison of the effect of four antiarrhythmic treatments for familial ventricular arrhythmias in boxers, J Am Vet Med Assoc 221: 522-527. 7 / 16

Figure 1. Right parasternal long axis view from a seven-year-old Dobermann showing dilated, rounded left atrium and ventricle. 8 / 16

Figure 2. Similar view from the same dog. Colour flow shows mitral regurgitation that occurs secondary to dilation of the mitral annulus and causes the systolic murmur. 9 / 16

Figure 4. Right parasternal long axis view from an eight-yearold CKCS with DMVD. Note the dilated rounded left ventricle and massively dilated left atrium. The anterior valve leaflet is thickened and prolapsing into the left atrium indicating rupture of a chorda tendineae. 10 / 16

Figure 5. Colour image from the same dog showing a large jet of tricuspid regurgitation. Doppler interrogation of this indicated the dog had pulmonary hypertension. 11 / 16

Figure 5. A six-lead ECG of a seven-year-old dog with a heart rate more than 210 bpm. No P waves are visible on any limb lead. The rate is fast and the rhythm is irregular. This is consistent with atrial fibrillation 50mm/s and 10mm/mV. 12 / 16

Figure 6 (left). Right parasternal long axis view from an eight-year-old cavalier King Charles spaniel showing a large jet of mitral regurgitation secondary to degenerative valve disease with a dilated left atrium. 13 / 16

Figure 7 (right). Left cranial long axis view from a 15-year-old Shetland sheepdog of the right atrium and right ventricle. This systolic frame shows tricuspid valve prolapsed. About 30 per cent of dogs with DMVD have tricuspid involvement. 14 / 16

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Figure 8. A six-lead ECG from a dog that presented as an emergency with rapid ventricular tachycardia. The complexes are wide and bizarre. 50mm/s and 10mm/mV. 16 / 16 Powered by TCPDF (www.tcpdf.org)