Philip R. Fox

Echocardiographic Assessment of Spontaneously Occurring Feline Hypertrophic Cardiomyopathy: An Animal Model of Human Disease

BACKGROUNDnNecropsy studies in domestic cats have suggested the occurrence of a primary cardiac disease resembling hypertrophic cardiomyopathy (HCM) in humans. We used two-dimensional echocardiography to define morphological and functional features of HCM during life in 46 domestic cats evaluated in a subspecialty veterinary clinic. Cats were 8 months to 14 years old (mean, 6 years).nnnMETHODS AND RESULTSnDuring the follow-up period of as long as 49 months, 18 cats died (or were euthanatized) due to congestive heart failure, peripheral embolization, or both, and 3 other cats experienced out-of-hospital sudden, unexpected death. Echocardiography showed a small left ventricular cavity, associated with a variety of patterns of hypertrophy. Wall thickening was most often diffuse (involving ventricular septum and free wall) in 31 cats (67%) and segmental in 15 (33%), including 12 with thickening confined to anterior septum; wall thickening was judged to be asymmetrical in 42 and symmetrical (concentric) in 4. In 30 cats (65%), marked mitral valve systolic anterior motion produced dynamic obstruction to left ventricular outflow (Doppler estimated gradients, 25 to 110 mm Hg). Compared with survivors, cats with HCM that died with heart failure had greater left ventricular thickness (8.1 +/- 1.5 versus 7.3 +/- 0.9 mm; P < .05) and larger left atria (20.1 +/- 4.6 versus 16.8 +/- 3.4 mm; P = .01) and more often had the nonobstructive form (89% versus 48%; P < .01).nnnCONCLUSIONSnA spontaneously occurring disease of domestic cats was identified by echocardiography and was similar in its phenotypic expression to HCM in humans; it was characterized by unexplained left ventricular hypertrophy in a variety of patterns with or without evidence of outflow obstruction. Unfavorable prognosis was associated with greater magnitude of hypertrophy and absence of outflow obstruction. Feline HCM may prove to be a valuable animal model of the human disease.

Arrhythmogenic Right Ventricular Cardiomyopathy Causing Sudden Cardiac Death in Boxer Dogs A New Animal Model of Human Disease

Background—Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary familial heart muscle disease associated with substantial cardiovascular morbidity and risk of sudden death. Efforts to discern relevant pathophysiological mechanisms have been impaired by lack of a suitable animal model. Methods and Results—ARVC was diagnosed in 23 boxer dogs (12 male; 9.1±2.3 years old). Clinical events alone or in combination included sudden death (n=9; 39%), ventricular arrhythmias of suspected right ventricular (RV) origin (n=19; 83%), syncope (n=12, 52%), and heart failure (n=3; 13%). Right ventricular enlargement or aneurysms occurred in 10 (43%). Striking histopathological abnormalities were present in each boxer dog but not in controls, including severe RV myocyte loss with replacement by fatty (n=15, 65%) or fibrofatty (n=8, 35%) tissue. Focal fibrofatty lesions were also present in both atria (n=8) and the left ventricle (LV) (n=11). Fatty replacement occupied substantially greater RV wall area in ARVC dogs than controls (40.4±18.8% versus 13.8±3.4%, respectively) (P <0.001); residual myocardium was correspondingly reduced (56.6±19.2% versus 84.8±3.8% in controls) (P <0.001). MRI demonstrated bright anterolateral and/or infundibular RV myocardial signals, confirmed as fat by histopathology. Myocarditis appeared in the RV (n=14, 61%) and LV (n=16, 70%) and in each dog with sudden death, but not in controls. Familial transmission was evident in 10 of the 23. Conclusions—We describe a novel, spontaneous, and genetically transmitted animal model of ARVC associated with sudden death in the boxer dog, closely resembling the human disease. This model may aid in understanding the pathogenic mechanisms of ARVC.

Spontaneously Occurring Arrhythmogenic Right Ventricular Cardiomyopathy in the Domestic Cat A New Animal Model Similar to the Human Disease

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disease of incompletely resolved pathogenesis and is a largely unappreciated cause of sudden death in the young. Methods and ResultsClinical features of 12 domestic cats with ARVC (7 male; 1 to 20 years old, mean 7.3±5.2 years) were right-sided congestive heart failure (n=8), supraventricular tachyarrhythmias (n=5), ventricular tachycardia (n=3), polymorphic ventricular arrhythmias (n=6), and right bundle-branch block (n=5). ARVC was suspected in all 8 cats examined with echocardiography by marked enlargement of the right ventricle (RV) and right atrium and tricuspid regurgitation. Eight died of cardiovascular disease and 4 died of noncardiac conditions. At autopsy, hearts of ARVC cats were characterized grossly by moderate-to-severe RV cavity enlargement and wall thinning (n=12) and apical aneurysm formation (n=6). Histology demonstrated pronounced RV lesions in all 12 ARVC cats, including marked myocardial injury (myocyte death and atrophy) and repair (fibrous and/or fatty replacement). Injury and repair were also evident in the left ventricle (LV) in 10 cats, and 2 had involvement of both atria. Myocarditis was present in 10 of the 12 ARVC cats. Apoptosis was detected in 9 ARVC cats (mean apoptotic index, 28±23% RV, 21±19% LV, and 17±15% ventricular septum) but not in controls. ConclusionsIn the common domestic cat, we identified a clinically relevant cardiomyopathy that closely mimics ARVC in humans. This unique feline model of human disease will be relevant to defining pathogenesis and investigating mechanisms responsible for disease progression in ARVC.

Hypertrophic cardiomyopathy. Clinical and pathologic correlates.

Hypertrophic cardiomyopathy is a primary myocardial disease with a wide range of clinical and morphologic characteristics. It is characterized by increased cardiac mass associated with a non-dilated, hypertrophied left ventricle. Phenotypic variability is substantial and includes both diffuse and segmental forms of left ventricular hypertrophy. Histopathologic features consist of myofiber disorganization, intramural arteriosclerosis, and pathologic fibrosis and matrix connective tissue. Associated functional derangements include dynamic obstruction to left and right ventricular outflow and diastolic dysfunction, including heart failure.

Endomyocardial fibrosis and restrictive cardiomyopathy: pathologic and clinical features.

Restrictive cardiomyopathy (RCM) is a primary myocardial disorder characterized by diastolic dysfunction and wide phenotypic heterogeneity. Clinicopathologic features in cats are currently poorly defined. One form of RCM is associated with endomyocardial fibrosis. The hallmark feature of endomyocardial fibrosis RCM is severe endomyocardial scar that may diffusely involve the left ventricle, or appear as a distinct lesion bridging the ventricular septum and left ventricular free wall. In some cases this may reduce left ventricular chamber volume or result in apical or mid chamber stenosis with associated pressure gradients. Left atrial enlargement is generally severe. Ventricular hypertrophy is variable and is often associated with wall or chamber remodeling. Histopathologic features include striking endocardial scar, myocardial interstitial fibrosis, and in some instances, endomyocarditis.

Molecular Screening by Polymerase Chain Reaction Detects Panleukopenia Virus DNA in Formalin-Fixed Hearts from Cats with Idiopathic Cardiomyopathy and Myocarditis

n Abstractn n Viral myocarditis has been suggested as an etiology for cardiomyopathy in several mammalian species. Myocarditis and idiopathic cardiomyopathy have been reported in the domestic cat, although a viral etiology has not been demonstrated. Because of the continuing interest in the potential relationship between viral myocarditis and cardiomyopathy, we evaluated hearts from cats with spontaneous, idiopathic cardiomyopathy for viral genomic material within myocytes by polymerase chain reaction, and for the presence of myocarditis by light microscopy. Thirty-one (31) formalin-fixed hearts from domestic cats who died of idiopathic cardiomyopathy were randomly selected from pathology archives. Seventeen (17) formalin-fixed hearts from healthy cats were similarly selected as normal controls. The polymerase chain reaction (PCR) was used to evaluate myocardial tissue for the presence of viral genome from feline panleukopenia virus, herpes virus, calici virus, and corona virus. Hearts were examined using light microscopy for histologic evidence of myocarditis according to the Dallas criteria. Panleukopenia virus was identified by PCR in 10 of 31 cats with cardiomyopathy but in none of the controls. Neither cardiomyopathic or control cats tested positive by PCR for herpes virus, calici virus, and corona virus. Myocarditis was detected by histologic examination in 18 of 31 cardiomyopathic cats and in none of 17 control cats. Myocarditis and or feline panleukopenia virus genome was detected in felines with idiopathic hypertrophic, dilated, and restrictive cardiomyopathy, suggesting a possible role of viral infection and inflammation in the pathogenesis of cardiomyopathy in this species.n n

Spontaneously occurring restrictive nonhypertrophied cardiomyopathy in domestic cats: a new animal model of human disease.

BACKGROUNDnSpontaneously occurring small animal models of myocardial disease, closely resembling the human condition, have been reported for hypertrophic cardiomyopathy (in cats) and arrhythmogenic right ventricular cardiomyopathy (in cats and boxer dogs). Nonhypertrophied restrictive cardiomyopathy (RCM) is a well-recognized but relatively uncommon primary heart muscle disease causing substantial morbidity in humans. We describe RCM occurring in felines here as a potential model of human disease.nnnMETHODSnWe used two-dimensional and Doppler echocardiography to define morphologic and functional features of RCM in 35 domestic cats (25 male; 10±4 years old) presenting to a subspecialty veterinary clinic. Ten underwent complete necropsy examination. Echocardiographic parameters of diastolic filling were compared to those in 41 normal controls.nnnRESULTSnThe 35 cats presented with congestive heart failure (n=32), lethargy (n=2), or syncope (n=1), associated with thromboembolism in 5 and supraventricular tachyarrhythmias in 8. During an average 4.4-year follow-up period, 18 died or were euthanized due to profound heart failure, and 3 died suddenly; survival from clinical presentation to death was 0.1 to 52 months. Echocardiographic and necropsy examination showed biatrial enlargement, nondilated ventricular chambers, and normal wall thicknesses and atrioventricular valves. Histopathology demonstrated disorganized myocyte architecture and patchy replacement myocardial fibrosis. Pulsed Doppler demonstrated restrictive physiology with increased early (E) mitral filling velocity (1.1±0.3 m/s) and peak E to peak late (A) flow ratios (4.3±1.2), reduced A filling velocity (0.3±0.1 m/s), and shortened mitral deceleration time (40.7±9.3 ms; all P<.001 vs. controls), with preserved left ventricular systolic function.nnnCONCLUSIONSnA primary myocardial disease occurring spontaneously in domestic cats is remarkably similar to restrictive nondilated and nonhypertrophied cardiomyopathy in man and represents another potential animal model for human disease.

Dilated Cardiomyopathy in Juvenile Doberman Pinschers

BACKGROUNDnCanine dilated cardiomyopathy (DCM) is an acquired heart muscle disease of unknown etiology characterized by commonly adult onset of arrhythmias, congestive heart failure(CHF), and sudden death. Myocardial failure associated with myocarditis has been well documented in puppies infected with parvovirus. While a form of DCM has recently been described in juvenile Portuguese Water Dogs it has not been reported in juvenile Doberman pinschers, a breed known for its high prevalence of DCM.nnnMETHODSnWe examined 7 Doberman pinscher puppies that were referred for cardiovascular examination. Six were from a litter of 8 (2 of the 8 died earlier with congestive heart failure) and an additional puppy was from an unrelated litter. Clinical assessment included physical examination, electrocardiography and echocardiography. Autopsy was performed on 3 puppies from the same litter with echocardiographic documented DCM. Cardiac tissues were evaluated histologically and by PCR analysis for parvovirus.nnnRESULTSnIn the litter of 8 puppies, 6 were affected with DCM between 10 days and 4 weeks of age. Of these 6 dogs, 2 died with acute pulmonary edema; 3 were euthanized at 4 weeks of age due to an advanced stage of DCM; 1 was diagnosed with DCM at 11 weeks of age. The latter survived for 2.5 years until it developed CHF and was euthanized. The remaining 2 dogs were unaffected and survived to adulthood. Another puppy from an unrelated litter developed DCM and CHF at 13 weeks of age, and was euthanized 4 weeks later. PCR analysis performed on myocardial tissue was negative for parvovirus genome. Cardiac histopathology revealed extensive myocytolysis involving myocytes and conduction fibers, hyperplasia of myocytes and smooth muscle cells, and attenuated myocytes separated by extracellular edematous ground substance (wavy fibers).nnnCONCLUSIONSnA juvenile form of DCM with high morbidity was detected in 6 Doberman pinscher puppies from one litter and in a puppy from an unrelated litter. Congestive heart failure occurred in most of the affected puppies between 10 days and 17 weeks of age.

Comparison of the pharmacokinetic properties of bisoprolol and carvedilol in healthy dogs

OBJECTIVEnTo compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation beta1-adrenoceptor-selective blocking agent, with those of carvedilol, a third-generation beta1/beta2 and alpha1-adrenoceptor blocking agent, in dogs.nnnANIMALSn12 healthy adult Beagles.nnnPROCEDURESnA prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed.nnnRESULTSnAfter oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 microg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 microg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 microg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 microg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol.nnnCONCLUSIONS AND CLINICAL RELEVANCEnAfter oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.

Time for pathology renaissance.

N ot long ago, diagnosing heart disease relied principally upon the history, physical examination, ECG and radiography. While diagnosis could always be verified or established at the time of autopsy, current advances in medical technology now provide for a more friendly avenue to patient analysis. In particular, refinements in diagnostic imaging have been dramaticso much so, that today, we are able to conduct pre-mortem, non-invasive ‘virtual’ autopsies utilizing two-dimensional and Doppler echocardiography, magnetic resonance imaging, and computed tomography scanning. It is nonetheless true that because heart failure is a syndrome and not a disease, it resists classification by any one test alone. While much information and data can be generated through noninvasive testing, the current reality is, that the degree to which many of these data correlate with risk factors, disease progression, or outcome await evidencebased validation. Despite technical advances, deficiencies in our current methods are underscored by the fact that success in reducing cardiovascular morbidity and mortality has been slow to develop. In view of this reality, we need to refine our current tools and develop new approaches to more accurately assess and more effectively manage heart disease.