Analysis of 8 Sarcomeric Candidate Genes for Feline Hypertrophic Cardiomyopathy Mutations in Cats with Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats. Causative mutations have been identified in the Maine Coon (MC) and Ragdoll breed in the cardiac myosin binding protein C gene (MYBPC3). HCM is thought to be inherited in other breeds.
Hypothesis: That a causative mutation for HCM in the British Shorthair (BSH), Norwegian Forest (NWF), Siberian, Sphynx, or MC cats would be identified in the exonic and splice site regions of 1 of 8 genes associated with human familial HCM.
Animals: Three affected BSH, NWF, Siberians, Sphynx, 2 MC (without the known MC mutation), and 2 Domestic Shorthair cats (controls) were studied.
Methods: Prospective, observational study. Exonic and splice site regions of the genes encoding the proteins cardiac troponin I, troponin T, MYBPC3, cardiac essential myosin light chain, cardiac regulatory myosin light chain, α tropomyosin, actin, and β–myosin heavy chain were sequenced. Sequences were compared for nucleotide changes between affected cats, the published DNA sequences, and control cats. Changes were considered to be causative for HCM if they involved a conserved amino acid and changed the amino acid to a different polarity, acid-base status, or structure.
Results: A causative mutation for HCM was not identified, although several single nucleotide polymorphisms were detected.
Conclusions and Clinical Importance: Mutations within these cardiac genes do not appear to be the only cause of HCM in these breeds. Evaluation of additional cardiac genes is warranted to identify additional molecular causes of this feline cardiac disease.     

Assessment of Left Ventricular Systolic Function by Strain Imaging Echocardiography in Various Stages of Feline Hypertrophic Cardiomyopathy

Background: Diastolic dysfunction occurs in many cats with hypertrophic cardiomyopathy (HCM). Less is known about systolic function in various stages of HCM. Myocardial strain analysis by tissue Doppler imaging (TDI) is a noninvasive echocardiographic method to assess systolic function that has not been reported previously in cats. Objectives: To evaluate systolic function in various stages of feline HCM by measurement of myocardial strain. Animals: Two hundred and sixty‐three cats. Methods: Cats were classified by echocardiography into one of the following groups: clinically healthy (control) group (n = 160), mild HCM (n = 22), moderate HCM (n = 39), and severe HCM (n = 42). Peak myocardial strain, measured by TDI in the basal and midventricular segment of the interventricular septal wall (IVS) and the left ventricular posterior wall (LVPW), was compared among different HCM and control groups. Results: Whereas conventional echocardiography demonstrated an apparently normal or supernormal contractile state based on percentage of fractional shortening, myocardial strain in all HCM groups was significantly decreased compared with the control group (P < .001). There was a significant correlation between strain values and wall thickness (P < .001). Reproducibility of strain analysis was 6.3% in the IVS and 9.7% in the LVPW. Conclusions and Clinical Importance: Myocardial strain analysis is a new, valuable, and reproducible method in cats. This method allows noninvasive detection of abnormal systolic deformation in cats with HCM despite apparently normal left ventricular systolic function as assessed by conventional echocardiography. The abnormal systolic deformation already was present in mild HCM and increased with progressive left ventricular concentric hypertrophy.     

Muscular dystrophy in female dogs

The most common form of muscular dystrophy in dogs and humans is caused by mutations in the dystrophin gene. The dystrophin gene is located on the X chromosome, and, therefore, disease-causing mutations in dystrophin occur most often in males. Therefore, females with dystrophin deficiency or other forms of muscular dystrophy may be undiagnosed or misdiagnosed. Immunohistochemistry was used to analyze dystrophin and a number of other muscle proteins associated with muscular dystrophy in humans, including sarcoglycans and laminin alpha2, in muscle biopsy specimens from 5 female dogs with pathologic changes consistent with muscular dystrophy. The female dogs were presented with a variety of clinical signs including generalized weakness, muscle wasting, tremors, exercise intolerance, gait abnormalities, and limb deformity. Serum creatine kinase activity was variably high. One dog had no detectable dystrophin in the muscle; another was mosaic, with some fibers normal and others partly dystrophin-deficient. A 3rd dog had normal dystrophin but no detectable laminin alpha2. Two dogs could not be classified. This study demonstrates the occurrence of dystrophin- and laminin alpha2-associated muscular dystrophy and the difficulty in clinical diagnosis of these disorders in female dogs.     

Increased Serum Growth Hormone Concentration in Feline Hypertrophic Cardiomyopathy

Serum growth hormone concentration was measured by radioimmunoassay in 31 cats with hypertrophic cardiomyopathy, 38 normal cats, and 35 cats with other cardiac disease. Cats with hypertrophic cardiomyopathy had a significantly increased serum growth hormone concentration when compared with normal cats and cats with other cardiac disease. The serum growth hormone concentration in cats with hypertrophic cardiomyopathy was less than that previously reported in cats with growth hormone secreting pituitary tumors. Pituitary tumors were not identified in eight of the cats with hypertrophic cardiomyopathy examined at necropsy. An increased serum growth hormone concentration may be measured in cats with hypertrophic cardiomyopathy but it is unclear if the increased serum growth hormone concentration is a cause or effect of hypertrophic cardiomyopathy.     

Feline Pododermatoses

Abstract— Pododermatoses are uncommon in the cat. Diagnosis is based on a detailed and thorough history including progression of the disease, its response to previous therapy, involvement of other animals or people, and the cats' environment. Physical examination of both the skin and the body, as a whole, is essential because feline pododermatoses are often associated with systemic disease such as feline leukaemia virus (FeLV), feline immunodefiency virus (FIV) and diabetes mellitus. Laboratory tests include skin scrapings, Wood's light examination, fungal culture, lesion smears, and skin biopsy. The latter is often the key to the diagnosis of feline pododermatoses. Other tests may include the intradermal skin test, patch testing and evaluation of endocrine function. Successful therapy of feline pododermatoses is dependent upon obtaining a definitive diagnosis. Résumé— Les pododermatites sont peu fréquentes chez le chat. Le diagnostic repose sur une anamnèse soignée comprenant l'évolution de la maldie, sa réponse aux traitements antérieurs l'atteinte d'autres animaux on de personnes et l'environnement du chat. L'examen clinique, de la peau et de l'enseble du corps comme un tout, est essentiel, les pododermatites félines étant souvent associées à des maladies générales telles que le FeLV, le FIV ou le diabète sucré. Les examens complémentaires comportent des raclages cutanés, un examen à la lampe de Wood, une culture fongique, des caiques des lésions et des biopsies. Cette derrière est souvent la clef du diagnostic d'une pododermatite féline. Les autres examens complémentaires peuvent ètre des intradermopréactions, des tests épicutanés et des tests hormonaux. Le succès du traitement d'une pododermatite féline dépend de la possibilité d'établir un diagnostic définitif. Zusammenfassung— Pododermatitis bei Katzen ist selten. DieDiagnose beruht auf einer detaillierten und sorgfältig erhobenen Anamnèse einschließlich des Verlaufs der Erkrankung, ihrem Ansprechen auf bereits durchgeführte Therapien, die Erkrankung weiterer Tiere oder Menschen sowie Angaben über die Lebensumstände der Katze. Die klinische Untersuchungen von Haut und dem Körper als Ganzes ist ein wesentlicher Punkt, da feline Pododermatosen oft mit systemischen Erkrankungen wie FeLV, FIV und Diabetes mellitus vergesellschaftet sind. Laboruntersuchungen schließben Hautgeschabsel, Untersuchungen mit der Wood-Lampe, Pilzkultur, Abklatschpräparate, der Hautveränderungen und Hautbiopsien mit ein. Letztere sind oft der Schlüssel zur Diagnose der felinen Pododermatitis. Andere diagnostische Methoden können intradermale Hauttests, Patchtests und überprüfung endokriner Organfunktionene beinhalten. Die erfolgreiche Behandlung der felinen Pododermatitis hängt davon ab, ob eine definitive Diagnose erstellt werden kann. Resumen Pododermatosis es un hallazgo infrequente en el gato. El diagnóstico se basa en una historia detallada y completa incluyendo el curso de la enfermedad, respuesta a la terapia instaurada, si ha afectado a otros animales o personas, y el medio ambiente que rodea al gato. El examen fisico de ambos, piel y cuerpo, como si se tratase de una entidad única, és esencial, ya que las pododermatosis felinas se asocian frequentemente a enfermedades sistémicas como FeLV, FIV y diabetes mellitus. Los exámenes de laboratorio incluyen raspados cutáneos, investigación con la lámpara de wood, cultivos fungales, examinación microscópica directa del exudado, y biopsia cutánea. Esta última es frecuentemente la clave en el diagnóstico de la pododermatosis felina. Otros tests a llevar a cabo podrían ser pruebas cutáneas intradérmicas, tests de sensibilidad de contacto, y evalucación de la función endocrina. El éxito de la terapia depende de la obtención de un diagnóstico correcto.     

Platelet Aggregation in Feline Cardiomyopathy

Platelet aggregation in response to adenosine diphosphate (ADP) was evaluated in 16 healthy cats and in 10 cats with cardiomyopathy. The minimum threshold concentration of ADP required to induce irreversible (2nd-phase) aggregation was determined in each cat. The minimum ADP concentration needed for 2nd-phase aggregation in platelets from healthy cats ranged from 1 microM to 100 microM ADP, with 56% (9/16) requiring 100 microM ADP. Of the remaining seven normal cats, three had platelets responding irreversibly to 10 microM ADP, and four had platelets responding to 1 microM ADP. In cats with cardiomyopathy, the threshold concentrations ranged from 0.01 microM ADP to 10 microM ADP. Two cats had platelets responding irreversibly to 0.01 microM ADP, whereas another cat had a threshold response at 0.1 microM ADP. Platelets from the remaining seven cats with cardiomyopathy exhibited 2nd-phase aggregation in response to 1 microM ADP (five cats) or 10 microM ADP (two cats). Platelet counts ranged from 210,000/mm3 to 630,000/mm3 in healthy cats and from 218,000/mm3 to 624,000/mm3 in cats with cardiomyopathy. There was no apparent correlation between the platelet count and the magnitude of the threshold aggregation response, as measured by lag phase and slope of the aggregation curves. The results indicate that some cats with cardiomyopathy have platelets that are hyperaggregable to ADP in vitro.     

Cardiac Troponin I and T as Prognostic Markers in Cats with Hypertrophic Cardiomyopathy

Background

Myocardial injury detected by cardiac troponin I and T (cTnI and cTnT) in cardiac disease is associated with increased risk of death in humans and dogs.

Hypothesis

Presence of myocardial injury predicts long‐term death in cats with hypertrophic cardiomyopathy (HCM), and ongoing myocardial injury reflects change in left ventricular wall thickness over time.

Animals

Thirty‐six cats with primary HCM.

Methods

Prospective cohort study. Cats with HCM were included consecutively and examined every 6 months. Echocardiography, ECG, blood pressure, and serum cTnI and cTnT were evaluated at each visit. Cox proportional hazards regression analysis was performed to evaluate prognostic potential of serum troponin concentrations at admission and subsequent examinations. Correlations were used to examine associations between troponin concentrations and cardiac hypertrophy.

Results

Troponin concentrations at admission were median [range] 0.14 [0.004–1.02] ng/mL for cTnI, and 13 [13–79.5] ng/L for cTnT. Both were prognostic for death (P = .032 and .026) as were the last available concentrations of each (P = .016 and .003). The final cTnT concentration was a significant predictor of death even when adjusting for the admission concentration (P = .043). In a model containing both markers, only cTnT remained significant (P = .043). Left ventricular free wall thickness at end‐diastole (LVFWd) at admission was correlated with cTnI at admission (r = 0.35, P = .035), however no significant correlations (r = 0.2–0.31, P = .074–.26) were found between changes in troponin concentrations and left ventricular thickness over time.

Conclusions and Clinical Importance

Myocardial injury is part of the pathophysiology leading to disease progression and death. Low sensitivities and specificities prevent outcome prediction in individual cats.     

Feline bartonellosis and cat scratch disease

Bartonella species are important emerging zoonotic pathogens. Transmission of these organisms in nature may be much more complex than is currently appreciated. Cats can be infected with five Bartonella species, including, Bartonella henselae, Bartonella clarridgeae, Bartonella bovis, Bartonella koehlerae and Bartonella quintana. In addition to cats, numerous domestic and wild animals, including bovine, canine, human, and rodent species can serve as chronically infected reservoir hosts for various intra-erythrocytic Bartonella species. In addition, an increasing number of arthropod vectors, including biting flies, fleas, keds, lice, sandflys and potentially ticks have been implicated in the transmission of various Bartonella species to animals or human beings. In the reservoir host, Bartonella species cause chronic intra-erythrocytic and vascular endothelial infections, with a relapsing bacteremia documented in experimentally infected cats. Although the immunopathology induced by Bartonella infection requires additional study, the organisms can localize to the heart valve (endocarditis), cause granulomatous inflammation in lymph nodes, liver or spleen, induce central nervous system dysfunction with or without cerebrospinal fluid changes, and may contribute to inflammatory polyarthritis. Hematological abnormalities are infrequent, but thrombocytopenia, lymphocytosis, neutropenia, and eosinophilia have been reported in B. henselae-infected cats. Serology, PCR and culture can be used to support a diagnosis of feline bartonellosis, however, due to the high rate of sub-clinical infections among various cat populations, documenting causation in an individual cat is difficult, if not impossible. Response to treatment can be used in conjunction with serology or organism isolation to support a clinical diagnosis of feline bartonellosis. As fleas are involved in the transmission among cats, the use of acaracide products to eliminate fleas from the environment is of critical importance to decrease the risk of B. henselae transmission among cats and to humans.     

Feline visceral hemangiosarcoma

BACKGROUND: Feline visceral hemangiosarcoma (HSA) is an uncommon tumor, and the clinical progression and outcome are rarely reported. HYPOTHESIS: The prognosis of feline visceral HSA is poor because of severe clinical signs, anemia, and a high rate of metastasis. ANIMALS: The medical records of 26 client-owned cats with visceral HSA were reviewed. METHODS: Multi-institutional retrospective study. RESULTS: The most common historical findings and clinical signs included lethargy, anorexia, respiratory difficulty, collapse, and vocalizing. Eighty-two percent of cats were anemic, and aspartate transaminase was increased in 53% of the study population. Metastatic lung disease was noted in 33% of affected cats. In 75% of the cats, abdominal ultrasonography identified a specific location of HSA. However, ultrasound identification of all multifocal lesions was successful only in 3/9 cats (33%). Tumor location was identified in the following organs: liver (35%), small intestine (31%), large intestine (31%), abdominal lymph node (31%), mesentery (27%), spleen (23%), lung (19%), omentum (12%), brain (8%), pancreas (8%), and diaphragm (8%). Multifocal HSA was noted in 77% of cats. Three cats received adjuvant chemotherapy (doxorubicin). Seventy-one percent of euthanized cats were euthanized within 1 day of diagnosis. The median survival time of the remaining cats (n = 6) was 77 days (range, 23-296 days). CONCLUSION AND CLINICAL IMPORTANCE: Feline visceral HSA is most often multifocal at the time of diagnosis. The prognosis appears poor, and the number of cats receiving chemotherapy is low.     

Evaluation of the Calcium Channel-Blocking Agents Diltiazem and Verapamil for Treatment of Feline Hypertrophic Cardiomyopathy

To determine the efficacy of and clinical response to several pharmacologic agents for treatment of idiopathic hypertrophic cardiomyopathy in cats, 17 symptomatic cats were randomized to treatment with either propranolol, diltiazem, or verapamil. Clinical, laboratory, radiographic, electrocardiographic, and echocardiographic data were obtained before treatment and after 3 and 6 months of chronic oral therapy. Too few of the cats receiving propranolol or verapamil survived long enough to obtain long-term data needed to make statistical comparisons between groups. However, all 12 cats ultimately treated with diltiazem became asymptomatic, and no adverse effects from this drug were noted in any of these cats. Treatment with diltiazem was associated with a significant reduction of pulmonary congestion assessed radiographically (P less than 0.01), and improved ventricular filling based on echocardiographic measurements of left atrial size (P less than 0.05), left ventricular internal diastolic dimension (P less than 0.05), and relaxation time index (P less than 0.001). There was also a drug-related improvement in jugular venous oxygen tension (P less than 0.001) and blood lactate concentration (P less than 0.01) suggesting improved peripheral perfusion in the cats receiving diltiazem. The results indicate that diltiazem provides an effective and apparently safe treatment for the management of feline hypertrophic cardiomyopathy.     

Platelet Activation in Cats with Hypertrophic Cardiomyopathy

Background

Cats with hypertrophic cardiomyopathy (HCM) are at risk for development of systemic thromboembolic disease. However, the relationship between platelet activation state and cardiovascular parameters associated with HCM is not well described.

Objectives

To characterize platelet activation by flow cytometric evaluation of platelet P‐selectin and semiquantitative Western blot analysis of soluble platelet‐endothelial cell adhesion molecule‐1 (sPECAM‐1).

Animals

Eight normal healthy cats (controls) owned by staff and students of the School of Veterinary Medicine and 36 cats from the UC Davis Feline HCM Research Laboratory were studied.

Methods

Platelet‐rich plasma (PRP) was used for all flow cytometry studies. Platelet surface CD41 and P‐selectin expression were evaluated before and after ADP stimulation. sPECAM‐1 expression was evaluated by Western blot analysis of platelet‐poor plasma that had been stabilized with aprotinin. Standard echocardiographic studies were performed.

Results

Resting platelets from cats with severe HCM had increased P‐selectin expression compared to controls, and expressed higher surface density of P‐selectin reflected by their increased mean fluorescence intensities (MFI). Stimulation with ADP also resulted in significantly increased P‐selectin MFI of platelets from cats with severe HCM. Increased P‐selectin expression and MFI correlated with the presence of a heart murmur and end‐systolic cavity obliteration (ESCO). sPECAM‐1 expression from cats with moderate and severe HCM was significantly increased above those of control cats.

Conclusions and Clinical Importance

P‐selectin and sPECAM expression may be useful biomarkers indicating increased platelet activation in cats with HCM.     

Heterogeneity of Hypertrophy in Feline Hypertrophic Heart Disease

Eighty-six cats with non-dilated left ventricular myocardial hypertrophy were studied retrospectively. Cats were categorized by two-dimensional echocardiography as having symmetric ventricular hypertrophy (Type I), asymmetric with predominant septal thickening hypertrophy (Type II), and asymmetric hypertrophy with predominant free-wall thickening (Type III). The distribution of hypertrophy was judged subjectively and objectively. Subjective and objective results were similar (P= 0.03) although overlap existed between groups. Morphologic patterns (Types I, II, and III) were compared with breed, age, sex, heart rate, percent fractional shortening, left atrial size, serum creatinine concentration, and the presence (yes/no) of pleural effusion, pulmonary edema, pericardial effusion, heart murmur, dyspnea, thromboembolism, hyperthyroidism, and being alive at the time of study. Interventricular septal thickness, left ventricular free wall thickness, percent fractional shortening, and left atrial size additionally were compared to 3-month survival. Cats with Type HI hypertrophy were more likely to experience thromboembolism than cats with Type II hypertrophy (P= 0.05) and cats with Type I hypertrophy were more likely to have heart murmurs than cats with Type III (P= 0.02). No other significant associations were found in comparison to pattern of hypertrophy. Both left atrial size and percent fractional shortening significantly correlated with 3-month survival (P < 0.001 for each). The degree of interventricular septal wall thickness was associated with 3-month survival (P= 0.02) when known hyperthyroid cats were excluded from the study group, while left ventricular free wall thickness consistently was not associated with survival. This study demonstrates the heterogeneity of hypertrophy in cats with hyper-trophic heart disease and provides predictors of survival (left atrial size, percent fractional shortening, and interventricular septal wall thickness when compared with euthanasia/spontaneous death data).     

猫肥厚型心肌病与心肌纤维化

肥厚型心肌病是猫最常见的原发性心脏疾病,典型特征为心脏左心室肥厚。心肌纤维化是猫肥厚型心肌病的标志性病理变化,其可导致心脏功能障碍和节律异常,是心肌病患猫预后不良的重要因素。对于猫肥厚型心肌病与心肌纤维化,目前缺乏针对性治疗,新型治疗方法亟需开发。本综述总结了猫肥厚型心肌病的病理特征以及目前关于猫心肌纤维化发病机制的研究进展,拟通过探索心肌纤维化的发病机制,从而为猫肥厚型心肌病新型治疗药物的开发寻找突破点。     

Evidence for Genetic Involvement in Feline Dilated Cardiomyopathy

Quantitative genetic evaluation of clinical dilated cardiomyopathy (DCM) was conducted in a large cattery with known history. Data showed that clinically affected cats were significantly more interrelated than randomly chosen case-control populations from the same colony. The results of this study suggest that quantitative inheritance, either interactive with or independent of nutrition or presently unknown factors, is involved in feline dilated cardiomyopathy. (Journal of Veterinary Internal Medicine 1993; 7:383–387. Copyright © 1993 by the American College of Veterinary Internal Medicine.)