Hannah Stephenson

Identification of 2 Loci Associated with Development of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels

Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. It is characterized by chronic progressive degenerative lesions of the mitral valve. The valve leaflets become thickened and prolapse into the left atrium resulting in mitral regurgitation (MR). MMVD is most prevalent in small to medium sized dog breeds, Cavalier King Charles Spaniels (CKCS) in particular. The onset of MMVD is highly age dependent, and at the age of 10 years, nearly all CKCS are affected. The incidence of a similar disease in humans-mitral valve prolapse-is 1-5%. By defining CKCSs with an early onset of MMVD as cases and old dogs with no or mild signs of MMVD as controls, we conducted a genome-wide association study (GWAS) to identify loci associated with development of MMVD. We have identified a 1.58 Mb region on CFA13 (P(genome) = 4.0 × 10(-5)) and a 1.68 Mb region on CFA14 (P(genome) = 7.9 × 10(-4)) associated with development of MMVD. This confirms the power of using the dog as a model to uncover potential candidate regions involved in the molecular mechanisms behind complex traits.

A Locus on Chromosome 5 Is Associated with Dilated Cardiomyopathy in Doberman Pinschers

Dilated cardiomyopathy (DCM) is a heterogeneous group of heart diseases with a strong genetic background. Currently, many human DCM cases exist where no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 cases and 70 controls collected in Germany we identified a genome-wide significant association to DCM on chromosome 5. We validated the association in an independent cohort collected in the United Kingdom. There is no known DCM candidate gene under the association signal. Therefore, DCM in Doberman Pinschers offers the chance of identifying a novel DCM gene that might also be relevant for human health.

A 16-bp deletion in the canine PDK4 gene is not associated with dilated cardiomyopathy in a European cohort of Doberman Pinschers

Source/description: Following a genome-wide association study (GWAS), a 16-bp deletion in the 5′ splice site of intron 10 of the pyruvate dehydrogenase kinase, isozyme 4 (PDK4) gene on CFA 14 has been reported to be associated with dilated cardiomyopathy (DCM) in Doberman Pinschers. This PDK4 variant was further reported to be absent from 100 dogs of other breeds. We have previously performed a GWAS in a European cohort of Doberman Pinschers and found a significant genome-wide association for DCM on CFA 5, but not on CFA 14. The objective of this study was to evaluate the association of the PDK4 variant on CFA 14 in our cohort of Doberman Pinschers.

Screening for Dilated Cardiomyopathy in Great Danes in the United Kingdom

BACKGROUND Great Danes (GD) are predisposed to dilated cardiomyopathy (DCM), but little is known about progression, clinical manifestations, or inheritance in dogs in the UK. For echocardiographic screening, breed-specific reference intervals (RI) are required. OBJECTIVES To document the prevalence, clinical manifestations, and inheritance of DCM in UK GD. To establish RI for Doppler echocardiography (ECHO) in GD. ANIMALS One hundred and seven client-owned GDs. METHODS Echocardiographic screening study. Dogs were scored on ECHO and ECG variables and classified as normal (NORM), equivocal (EQUIV), or affected (AFX). Forty NORM dogs were used to determine RI for ECHO. Pedigrees from all dogs were examined for mode of inheritance. RESULTS The prevalence of DCM in this population, based on score, was 35.6%. Significant differences in M mode left ventricular dimensions (MMLVD) were identified between male and female dogs (P < .011). RI for MMLVD and transformed MMLVD (allometric scaling) were lower than previously suggested. When dogs were reclassified using amended RI for MMLVD, prevalence increased to 47%. End-systolic volume index more reliably identified AFX dogs than other systolic function indices. Ventricular arrhythmias (VA) were commonly identified, with the highest prevalence in AFX dogs (54%). Pedigree analysis suggested an autosomal dominant mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE The prevalence of DCM in UK GD is higher than previously reported and autosomal dominant inheritance is likely. Sex or body weight-dependent RI should be used for ECHO in GD and current RI might underestimate ESVI in GD. VA might play an important role in GD with DCM.

Left atrial size, atrial function and left ventricular diastolic function in cats with hypertrophic cardiomyopathy

OBJECTIVES To describe left atrial size, left atrial volume, left atrial function and left ventricular diastolic function in healthy cats and those with hypertrophic cardiomyopathy without and with congestive heart failure. METHODS A retrospective study of 61 client-owned, 21 healthy, 21 asymptomatic hypertrophic cardiomyopathy and 19 with hypertrophic cardiomyopathy and congestive heart failure cats. Data were retrieved from clinical records and echocardiography archives. Left atrial diameter and volumes were measured. Left atrial function was investigated using changes in diameter (fractional shortening) and volume (Simpsons method; left atrial ejection fraction). Conventional echocardiographic indices of left ventricular diastolic function were recorded. RESULTS Left atrial diameter and left atrial volume measurements were significantly higher in hypertrophic cardiomyopathy with congestive heart failure cats compared with asymptomatic hypertrophic cardiomyopathy and healthy cats (P < 0·001). Left atrial passive, active and complete ejection fraction distinguished between hypertrophic cardiomyopathy with congestive heart failure and asymptomatic hypertrophic cardiomyopathy (P < 0·001). Hypertrophic cardiomyopathy with congestive heart failure cats had significantly lower mitral A wave velocity (P = 0·016) and atrial complete emptying based on diameter and volume measurements (P = 0·008 and P < 0·001, respectively) compared with asymptomatic hypertrophic cardiomyopathy cats. CLINICAL SIGNIFICANCE Left atrial volume is obtainable by echocardiography in cats. Left atrial volume and atrial function may indicate chronicity and severity of diastolic dysfunction associated with hypertrophic cardiomyopathy and congestive heart failure. Left atrial function was reduced in cats with hypertrophic cardiomyopathy and congestive heart failure compared with healthy and asymptomatic hypertrophic cardiomyopathy groups.

Retrospective evaluation of the use of amiodarone in dogs with arrhythmias (from 2003 to 2010)

OBJECTIVES To evaluate the efficacy of amiodarone in dogs with refractory supraventricular and ventricular arrhythmias and to document the side effects in treated dogs. METHODS Records of 28 dogs were retrospectively searched to document indication for amiodarone administration, heart rate, alkaline phosphatase, alanine aminotransferase, thyroxine (T4) and thyroid stimulating hormone values before and after starting treatment and during follow-up periods. RESULTS Sixteen dogs with supraventricular and 12 dogs with ventricular arrhythmias were treated with amiodarone. Amiodarone treatment significantly reduced the heart rate (P<0.001) and resulted in improvement in the severity of the arrhythmia and clinical signs in 26 dogs. There were no significant differences in alkaline phosphatase (P=0.596), alanine aminotransferase (P=0.842), T4 (P=0.789) and thyroid stimulating hormone (P=0.064) before and after starting amiodarone. On maintenance therapy, median amiodarone blood levels were within the accepted reference range (0.5 to 2.0 mg/L) at 0.8 mg/L (range 0.2 to 11.6 mg/L), but the majority of the desethylamiodarone levels were below normal at 0.1 mg/L (range 0.1 to 0.9 mg/L), based on human reference intervals (0.5 to 2.0 mg/L). CLINICAL SIGNIFICANCE Amiodarone may be an effective and safe alternative to treat supraventricular and ventricular arrhythmias in dogs, when common anti-arrhythmic drugs are not effective or contraindicated.

Assessment of mechanical ventricular synchrony in Doberman Pinschers with dilated cardiomyopathy.

OBJECTIVES Loss of temporal synchrony of myocardial contraction has been shown to reduce systolic function and be responsible for disease progression in people. The objective of this study is the assessment of inter- and intra ventricular synchrony in healthy Doberman Pinschers and those with dilated cardiomyopathy (DCM) by use of conventional Doppler and tissue velocity imaging. ANIMALS A total of 60 scans from 35 client-owned Doberman Pinschers presented for cardiac evaluation were analysed. METHODS Retrospective analysis of data. Using the European Society of Veterinary Cardiology DCM taskforce scoring system, Doberman Pinschers were classified into 4 groups: Control (Group 1; n=12), depressed systolic function other than DCM (Group 2; n=9), preclinical DCM (Group 3; n=8) and symptomatic DCM (Group 4; n=6). The time intervals between the beginning of the QRS complex and the peak velocity of pulmonic flow (Q-P) and the peak aortic flow (Q-Ao) were used to assess global synchrony between both ventricles. The time intervals between the beginning of the QRS complex and the peak myocardial systolic velocity (Q-peak S) and the onset of myocardial systolic velocity (Q-start S) were measured at the base of the right and left ventricular free wall (RVFW and LVFW) and interventricular septum (IVS), and used to determine segmental longitudinal inter- and intra ventricular synchrony. RESULTS No significant loss of global or segmental longitudinal inter- or intra ventricular synchrony was identified between the groups. CONCLUSION Impairment of longitudinal fibre synchrony does not appear to be significantly associated with clinical status of DCM in Doberman Pinschers, although it was identified in certain individuals.

Assessment of left ventricular function in healthy Great Danes and in Great Danes with dilated cardiomyopathy using speckle tracking echocardiography

OBJECTIVES Assess global circumferential and radial systolic and diastolic myocardial function with speckle tracking echocardiography (STE) in healthy Great Danes (GD) and in GD diagnosed with dilated cardiomyopathy (DCM). ANIMALS Eighty-nine GD were included in the study: 39 healthy (normal group [NORMg]) and 50 diagnosed with DCM (DCMg). METHODS This was a retrospective study. Signalment and echocardiographic diagnosis were obtained from the medical records of GD assessed between 2008 and 2012. Speckle tracking echocardiography analysis of circumferential (C) and radial (R) strain (St) and strain rate (SR) in systole (S), early (E) and late (A) diastole was performed at the levels of the mitral valve (MV), papillary muscles (PM) and apex (Ap) of the left ventricle. Univariable and multivariable analysis was performed to identify differences between groups. RESULTS Speckle tracking echocardiography variables increase from the MV towards the Ap of the left ventricle in both NORMg and DCMg dogs, some reaching statistical significance. Most of the variables (28/31) were lower in DCMg than in NORMg dogs: statistically significant variables included radial SR at the Ap in systole (p=0.029), radial strain at the PM (p=0.012), circumferential SR at the PM in systole (p=0.031), circumferential and radial SR at the MV in early diastole (p=0.019 and p=0.049, respectively). CONCLUSIONS There are significant differences in STE variables between NORMg and DCMg Great Danes, although the overlap between the two groups may indicate that these variables are not sufficiently discriminatory. STE variables are not sufficiently sensitive to use in isolation as a screening method.