HEART MUSCLE DISEASE IN DOGS

Transcription

1 Vet Times The website for the veterinary profession HEART MUSCLE DISEASE IN DOGS Author : Simon Swift Categories : Vets Date : January 21, 2013 SIMON SWIFT considers the potential causes, disease progression and specific treatment options for dogs presenting with a cardiomyopathy CARDIOMYOPATHIES are diseases of the heart muscle 1 that result from many different causes, including genetic defects, cardiac myocyte injuries and infiltrative diseases. In some cases, the phenotype is well recognised and this has resulted in a series of clinical syndromes being identified. These have been classified by a World Health Organisation task force in humans 2. However, in dogs, although the clinical appearance can be similar, the underlying cause can be very different and this may result in differing progression, response to treatment and ultimately prognosis. Unfortunately, in canine cardiology, the underlying cause is rarely identified, so decisions concerning treatment and prognosis have to be based on the clinical syndrome. Recognised syndromes 3 include: dilated cardiomyopathy (DCM); arrhythmogenic right ventricular cardiomyopathy (ARVC); hypertrophic cardiomyopathy (HCM); and myocarditis. 1 / 8

2 Restrictive and unclassified cardiomyopathies seen in cats are rarely documented in dogs. Dilated cardiomyopathy DCM is characterised by ventricular dilatation ( Figure 1 ) and reduced systolic function, usually affecting the left ventricle. The left ventricle has increased mass, but the dilatation results in thin walls. In most cases, the disease is likely to have a genetic origin, although despite much research effort the cause in most cases is elusive. Recently, two genes have been suggested in Dobermanns with DCM. The LUPA study 4 identified an abnormality on chromosome 5 while an American group identified a splice site mutation on pyruvate dehydrogenase kinase 4, a mitochondrial protein 5. Other breeds have their own variation of DCM with characteristic features such as in Irish wolfhounds, great Danes and cocker spaniels. Portuguese water spaniels have a juvenile form, but most cases of DCM present in middle to old age (four to eight years). It is important to exclude other causes of reduced systolic function. These include nutritional deficiencies such as carnitine or taurine, tachycardiomyopathy and toxicity, for example, doxorubicin. Diagnosis in symptomatic cases is usually straightforward based on the echocardiographic evidence of dilatation and reduced systolic function (Panel 1). However, it is likely most dogs have an asymptomatic phase that may last for years, and identification of affected dogs for breeding programmes can be problematic. Guidelines have been proposed but remain to be validated 6. Normal ranges for some breeds have been identified, but an allometric scaling method 7 is used for others. To complicate matters, some athletic breeds have a lazy heart on echocardiography when not in work or training. As the disease generally has a poor prognosis and a median survival time of six months 8 once heart failure develops, drugs aimed at delaying the onset of heart failure should improve longevity as well as quality. A recent prospective, randomised, blinded, placebocontrolled trial 9 involving 76 Dobermanns screened from more than 1,000 dogs proved that pimobendan could delay the onset of failure or sudden cardiac death from 441 to 718 days. A retrospective study 10, also in Dobermanns, indicated that ACE inhibitors, in this case benazepril, would also prolong the diseasefree interval compared to placebo (425 versus 339 days). The problem we face is identifying the asymptomatic cases. Detection of a murmur consistent with mitral regurgitation secondary to dilation of the annulus, or the presence of a gallop rhythm or arrhythmia, should prompt further investigations. Screening at-risk breeds should be considered once they reach middle age and older. Dogs with equivocal findings should be re-evaluated in six months to assess progression. 2 / 8

3 Once heart failure develops, diuretics such as furosemide are added to the treatment regime to control the congestion. Pimobendan and an ACE inhibitor are started unless the dog is already receiving them. An anti-aldosterone antagonist, spironolactone, is used by many cardiologists although evidence 11 is weak and there is no licence for its use in DCM. Spironolactone causes vasodilation, decreasing fluid retention and potassium loss, normalising the autonomic nervous system and reducing the myocardial hypertrophy and fibrosis. Heart failure can develop because of decreasing systolic function, so the increased filling pressures required to maintain output result in pulmonary oedema and/or ascites. Alternatively, in many large and giant breed dogs, heart failure is precipitated by the development of atrial fibrillation ( Figure 2 ). This results in a tachycardia, decreasing filling time, and the loss of atrial contraction, which may be contributing 25 per cent to 30 per cent of left ventricle filling. The benefits of cardioversion are likely to be short-lived as most dogs return to atrial fibrillation after a brief period of time due to their underlying structural heart disease (large atria). Hence we use rate control rather than rhythm control. Digoxin and diltiazem are the drugs of choice and a recent study 12 suggested better rate control was achieved using a combination of the two. Digoxin takes three to five days to have an effect due to the long half-life, with peak levels achieved by day five to seven. Serum levels are usually checked after one week. The vagal effects are present at doses under the normal therapeutic range suggested by commercial laboratories and this may explain the benefits seen in humans 13. Diltiazem is more rapidly active, but, being a calcium channel blocker, it has negative inotropic activity that could be detrimental in the setting of heart failure and systolic dysfunction. The dog may need a rapid heart rate to maintain output. Starting diltiazem at the lower end of the therapeutic range and increasing to effect would be a sensible treatment regime. Mean heart rate targets are under 140bpm in the clinic and under 120bpm 14 with a Holter monitor because of the known detrimental effect of tachycardia on the heart muscle. ARVC ARVC is a disease of boxers and Birman cats, and infrequently recognised in others. Classically, the heart muscle is replaced with a fibrofatty infiltrate. This occurs in both ventricles, but the ventricular arrhythmias ( Figure 3 ) that result are usually right ventricular in origin (positive in lead II). The initial report 15 on boxer cardiomyopathy identified three phenotypes: ventricular arrhythmias, systolic dysfunction and those with both. The first group had the best prognosis of two years and the other two groups, one year and six months respectively. It is likely this disease has a genetic basis. However, it is unclear whether all boxers have the same defect or those with ventricular arrhythmias have a different disease to those with systolic dysfunction. 3 / 8

4 In humans, some genetic defects have been shown to cause different cardiomyopathies 16 so this is not unreasonable. Also, in the colony of Maine coon cats with HCM due to a myosin-binding protein C defect in the United States, some cats without the defect have developed HCM, suggesting a second, as yet unidentified, defect. A deletion in the 3 -untranslated region of striatin has been suggested as a cause in some American boxers 17, although the situation in the UK appears confused. Striatin is a desmosomal protein that colocalises with plakophilin, a protein frequently involved in human ARVC. Incomplete penetrance has been suggested as a reason for the disparity between genotype and phenotype and this is recognised in humans. Because of the ventricular ectopy, Holter monitoring can be used to screen for the disease. Current ACVIM guidelines18 indicate lower than 50 ventricular premature contractions (VPCs) per 24 hours is normal, 30 to 50 per 24 hours is equivocal and more than 300 or runs of ventricular tachycardia is abnormal. Suggestions for commencement of antiarrhythmic treatment include more than 1,000 VPCs per 24 hours even if the dog is asymptomatic or lower than 1,000 VPCs/24 hours if the morphology is complex. It should be remembered considerable daily variation exists in the number of VPCs, so a reduction of more than 85 per cent is needed for success 19. Unfortunately, no antiarrhythmic drugs are licensed for the treatment of ventricular arrhythmias in dogs. Class-three drugs with potassium channel blocking properties such as sotalol (0.5 mg/kg to 3mg/kg BID) have been shown to be effective 20. Sotalol, in its racemic form, also has beta-blocking actions, so care should be taken if systolic function is compromised. As with all drugs with betablocking properties, sotalol should be started at the lower end of the dosage range and titrated up to effect. If necessary, a class-one agent with sodium channel blocking properties, such as mexiletine (4mg/kg to 8mg/kg bid-tid), can be added. Unfortunately, it is becoming more difficult to obtain. Amiodarone, another classthree agent with some classone, two and four actions, can be used, but significant side effects can be seen, for example, hepatopathy, hypothyroidism and thrombocytopaenia. Omega-3 fatty acids may have a role in decreasing arrhythmia frequency 21. HCM Although hypertrophic cardiomyopthy is the most common acquired cardiac disease in cats, it is rarely diagnosed in dogs. It is characterised by concentric hypertrophy of the left ventricular walls without a fixed outflow tract obstruction or systemic hypertension. With the variation in sizes of dogs presented, this again can 4 / 8

5 cause problems identifying hypertrophy. Normal values have been published for some breeds and for other and crossbreeds, a scaling system can be applied 7. It is important to exclude other causes of hypertrophy, especially if that hypertrophy is symmetrical. The disease must be differentiated from subaortic stenosis (SAS). Breeds predisposed to SAS include Newfoundlands, boxers, golden retrievers and German shepherd dogs. We have reported HCM 22 in young dogs usually presented when a systolic murmur up to grade four in intensity was identified. The murmur was due either to dynamic outflow tract obstruction with the classic scimitar shape on Doppler echocardiography ( Figure 4 ) or mitral regurgitation with anterior systolic motion of the mitral valve, as seen in cats. Overall, the disease seemed to have a benign self-limiting course; some were treated with beta-blockers and this has been reported by other authors 23. Terrier breeds may be predisposed. Myocarditis Myocarditis is characterised by myocardial inflammation, degeneration and necrosis. Causes can be physical, chemical or infectious agents. Unfortunately, identification of the underlying cause may require an endomyocardial biopsy and this is rarely performed. If the inflammatory episode is not recognised, the end result may be chamber dilatation and decreased systolic function so the syndrome then resembles DCM. A variety of tachyarrhythmias and bradyarrhythmias can be seen, but, most commonly, ventricular premature complexes and ventricular tachycardia are identified on ECG ( Figure 5 ). Toxoplasma and Neospora are occasionally identified, but the endemic tick-borne diseases less so. Leishmania, fungal myocarditis and Chagas disease, caused by Trypanosoma cruzi, are rarely diagnosed in the UK. Parvoviral myocarditis is also rarely identified. The virus has a predilection for dividing cells, and most puppies are protected by maternally derived antibodies during the critical time period when myocardial cells are dividing. A peracute form is seen at three to eight weeks of age with severe dyspnoea due to left-sided congestive heart failure. Those that survive this insult may develop a DCM-like disease before 12 months of age. A form of myocarditis affecting the atria has been reported in dogs. Atrial arrhythmias, including atrial fibrillation, are common although heart block has also been reported, especially in young English springer spaniels requiring pacemaker implantation 24. Cardiac troponin-1 is part of the sarcomere and regulates interaction between actin and myosin. It is released into the circulation in cases of myocardial cell damage. The levels correlate with the degree of damage and prognosis and a reduction in the levels may suggest a decrease in the ongoing damage 25. Therefore, serial samples may be helpful in tracking disease progression. 5 / 8

6 Conclusion Many diseases can affect the heart muscle of dogs. The ability to diagnose these allows specific treatment to be targeted to increase longevity and quality of life. This is an active area of ongoing research and more information is likely to emerge over the next few years. References 1. Hare J (2008). The dilated, restrictive and infiltrative cardiomyopathies. In Libby P, Bonow R O, Mann D L, Zipes D P (eds) Braunwald s Heart Disease (8th edn), Saunders: 1,739-1, Richardson P et al (1996). Report of the 1995 World Health Organization/ International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies, Circulation 93: Meurs K M (2010). Myocardial disease : canine. In Ettinger S and Feldman E (eds), Textbook of Veterinary Internal Medicine (7th edn) Elsevier: 1,320-1, Mausberg T B et al (2011). A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman pinschers, PLoS ONE 6(5): e 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(8): 1,319-1, Dukes-McEwan J et al (2003). Proposed guidelines for the diagnosis of canine idiopathic dilated cardiomyopathy, JVC 5: Cornell C C et al (2004). Allometric scaling of M-mode cardiac measurements in normal and adult dogs, JVIM 18: Martin M W et al (2010). Canine dilated cardiomyopathy: a retrospective study of prognostic findings in 367 clinical cases, JSAP 51: 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), JVIM 26: 1,337-1, O Grady M R et al (2009). Efficacy of benazepril hydrochloride to delay the progression of occult dilated cardiomyopathy in Doberman pinschers, JVIM 23: Swift S (2010). Aldosterone inhibitors. In Ettinger S and Feldman E (eds), Textbook of Veterinary Internal Medicine (7th edn) Elsevier: 1,223-1, Gelzer A R M et al (2009). Combination therapy with digoxin and diltiazem controls ventricyular rate with chronic atrial fibrillation in dogs better than digoxin or diltazem monotherapy: a randomized crossover study in 18 dogs, JVIM 23: Digitalis Investigation Group (1997). The effect of digoxin on mortality and morbidity in patients with heart failure, NEJM 336: MacGregor J (2012). Cardiologists treatment of canine tachyarrhythmias, Proceedings ACVIM Forum, New Orleans. 15. Harpster N K (1983). Boxer cardiomyopathy. In Kirk R W (ed) Current Veterinary 6 / 8

7 Therapy (8th edn) Saunders: Keren A et al (2008). Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression, Nature Clinical Practice Cardiovascular Medicine 5(3): Meurs K M (2010). Genomewide association identifies a deletion in the 3 untranslated region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy, Human Genetics 128(3): Meurs K M (2012). Electrocardiography in the staging and assessment of canine myocardial diseases: ambulatory ECG, Proceedings of International Cardiology Veterinary Symposium, Dubai: Spier A W et al (2004). Evaluation of the spontaneous variability in the frequency of ventricular arrhythmias in boxers with arrhythmogenic right ventricular cardiomyopathy, JAVMA 224: Meurs K M et al (2002). Comparison of the effect of four antiarrhythmic treatments for familial ventricular arrhythmias in boxers, JAVMA 221: Smith C E et al (2007). Omega-3 fatty acids in boxer dogs with arrhythmogenic right ventricular cardiomyopathy, JVIM 21: Loureiro J et al (2008). Canine dynamic left ventricular outflow tract obstruction: assessment of myocardial function and clinical outcome, JSAP 49: Connolly et al (2003). Dynamic obstruction of the left ventricular outflow tract on four young dogs, JSAP 44: Fonfara S et al (2010). English springer spaniels with significant bradyarrhythmiaspresentation, troponin-1 and follow after pacemaker implantation, JSAP 51: Fonfara S et al (2010). Cardiac troponin-1 as a marker for severity and prognosis of cardiac disease in dogs, Vet Journal 184: Stephenson H M et al (2012). Screening for dilated cardiomyopathy in great Danes in the United Kingdom, JVIM 26: 1,140-1, Serres F et al (2008). Comparison of three ultrasound methods for quantifying left ventricular systolic function: correlation with disease severity and prognostic value in dogs with mitral disease, JVIM 22: PANEL 1: ECHO PARAMETERS OF DECREASED SYSTOLIC FUNCTION Fractional shortening under 25 per cent, this may decrease to 20 per cent for giant breed dogs 26. E point septal separation over 7mm. LV end diastolic and systolic dimension derived from M mode, ejection fraction and end systolic volume index in excess of normal range. Volumes and ejection fraction should be derived from modified Simpson formulae not Teichholz / 8

8 Powered by TCPDF ( Systolic time interval: pre-ejection period to LV ejection time ratio of more than Sphericity index (ratio of LV end diastolic length to width) of lower than 1.6. PANEL 2: POINTS TO NOTE ON TREATMENT Dogs with asymptomatic DCM should receive pimobendan and an ACE inhibitor. Once heart failure develops, furosemide and spironolactone should be added. Rate control of atrial fibrillation is best achieved with diltiazem and digoxin combined. ARVC is recognised in the boxer breed and RV origin VPC or VT are frequently seen. Sotalol +/ mexiltine are the antiarrhythmic agents of choice HCM is infrequently diagnosed, may require beta blocking agents and generally has a benign prognosis. Dogs with myocarditis frequently have raised troponin-i and ventricular arrhythmias. Outcome depends on the underlying disease. 8 / 8