Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis. METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts. RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.

Randomized, double-blinded, controlled trial of the effects of coenzyme Q10 supplementation on plasma coenzyme Q10 concentration in dogs with myxomatous mitral valve disease.

OBJECTIVE: To determine the dose of coenzyme Q10 (CoQ10) needed to achieve at least a 3-fold increase in plasma CoQ10 concentration in dogs with myxomatous mitral valve disease (MMVD) and congestive heart failure (CHF). ANIMALS: 18 dogs with CHF due to MMVD and 12 healthy dogs. PROCEDURES: In a randomized, double-blinded, controlled trial, dogs with MMVD were given 50 or 100 mg of water-soluble CoQ10 (ubiquinone; total daily dose, 100 mg [n = 5] or 200 mg [6]) or a placebo (7), PO, twice a day for 2 weeks in addition to regular cardiac treatment. Plasma CoQ10 concentration was measured in dogs with MMVD before (baseline) and at various time points after supplementation began and in healthy dogs once. Concentrations were compared among and within groups. RESULTS: No significant difference in median baseline plasma CoQ10 concentration was detected between healthy dogs and dogs with MMVD. Fold increases in plasma CoQ10 concentrations ranged from 1.7 to 4.7 and 3.2 to 6.8 for individual dogs in the 100-mg and 200-mg groups, respectively. The change in plasma CoQ10 concentration after supplementation began was significantly higher than in the placebo group at 4 hours and 1 and 2 weeks for dogs in the 200-mg group and at 1 and 2 weeks for dogs in the 100-mg group. CONCLUSIONS AND CLINICAL RELEVANCE: A daily CoQ10 dose of 200 mg was sufficient to achieve at least a 3-fold increase in plasma CoQ10 concentration and may be used in CoQ10 supplementation studies involving dogs with CHF due to MMVD.

Plasma coenzyme Q10 concentration, antioxidant status, and serum N-terminal pro-brain natriuretic peptide concentration in dogs with various cardiovascular diseases and the effect of cardiac treatment on measured variables.

OBJECTIVE To determine the plasma total antioxidant capacity, erythrocyte superoxide dismutase activity, whole blood glutathione peroxidase activity, and plasma coenzyme Q10 (CoQ10) concentration in dogs with various stages of cardiovascular diseases and in healthy dogs; assess the influence of cardiac treatment on the levels of antioxidant variables, plasma CoQ10 concentration, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, and determine any correlation between the disease severity (NT-proBNP concentration) and antioxidant variables or CoQ10 concentration. ANIMALS 43 dogs with various types and stages of cardiovascular diseases (congenital and acquired) and 29 healthy dogs. PROCEDURES Blood samples were collected from all dogs for spectrophotometric assessment of antioxidant variables. Plasma CoQ10 concentration was determined with a high-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry method. Serum NT-proBNP concentration was measured with an ELISA. RESULTS Values for antioxidant variables did not differ among groups of dogs with cardiovascular diseases, regardless of disease stage or treatment. Plasma CoQ10 concentration was significantly increased in treated dogs with congestive heart failure (CHF), compared with untreated patients. However, plasma CoQ10 concentration did not differ among heart failure classes. A significant, negative correlation between serum NT-proBNP and plasma CoQ10 concentrations was identified in treated CHF-affected dogs, suggesting that low plasma CoQ10 concentration may be associated with increased severity of CHF. CONCLUSIONS AND CLINICAL RELEVANCE The antioxidant variables evaluated were not altered in dogs with CHF, regardless of cardiac disease stage or treatment. Further investigation into the possible effects of CoQ10 supplementation in dogs with advanced stages of CHF is warranted.

Two-dimensionally-guided M-mode and pulsed wave Doppler echocardiographic evaluation of the ventricles of apparently healthy cats.

OBJECTIVE: To determine two-dimensionally-guided (2D-guided) M-mode and pulsed-wave (PW) Doppler echocardiographic reference intervals range of healthy non-sedated cats. ANIMALS: Fifty-three healthy, unsedated domestic cats. MATERIALS AND METHODS: Cats were interrogated via standard imaging planes with 2D-guided PW Doppler, using 5.0 and 7.5 MHz duplex imaging transducers. Left ventricular (LV) M-mode measurements and intracardiac PW Doppler data were acquired using ACVIM guidelines for echocardiography. Doppler variables of the same region, measured from different views, were compared for agreement where appropriate. Descriptive statistics were provided for all measured variables. Statistical comparisons of selected M-mode and PW Doppler echocardiographic variables and correlations with weight or age were made, with significance set at P < 0.01. RESULTS: Most cats (42/51) had diastolic LV septal and posterior wall diastolic dimensions <4.5 mm (maximum = 5.7 mm). Only septal diastolic wall dimension correlated weakly with body weight (ρ = 0.36). Median peak transvalvular velocities (m/s) were: aorta 1.04 (range: 0.77-1.40); LV inflow 0.60 (range: 0.43-0.95) (E wave), 0.47 (range: 0.32-0.76) (A wave), RV inflow 0.56 (range: 0.37-0.85), pulmonic valve (right) 0.96 (range: 0.65-1.21). For mitral valve inflow, the E and A waves were usually separately measurable at heart rates ≈ <180/min, merging into a single diastolic wave (EA) at heart rates ≈ >190/min. Peak E wave velocity correlated with heart rate. No variables correlated with age. CONCLUSIONS: Our study provides comprehensive 2D-guided echocardiographic M-mode and PW Doppler reference data for apparently healthy cats.

Comparison of high definition oscillometric and Doppler ultrasonic devices for measuring blood pressure in anaesthetised cats.

Indirect blood pressure measurements using high definition oscillometric (HDO) and Doppler devices were compared in 50 anaesthetised client-owned cats presented for various surgical procedures. Sites of cuff placement for Doppler were identified as forelimb and hindlimb and for HDO as forelimb and tail. Oscillometric and Doppler readings were obtained in 90.05% and 100% of attempts, respectively. Both devices enabled precise measurement of systolic arterial pressure (SAP), although the Doppler device gave higher precision. In the low pressure group (SAP<100 mmHg; n=30), 66.7% biases were within 10 mmHg of discrepancy, but in groups of normal (100 mmHg ≤ SAP ≤ 150 mmHg; n=120) and high measurements (SAP>150 mmHg; n=62), 86.7% and 75.0% of discrepancy, respectively, were lower than 10 mmHg. Frequency of discrepancy at the range of 15 mmHg showed similar differences between pressure groups. There were significantly higher discrepancies when the cuff was positioned on the tail rather than on the leg. The SAP value obtained by HDO can be calculated from the Doppler measurement from SAP (HDO)=0.8515 × SAP (Doppler)+19.221 mmHg. Compared to Doppler, HDO overestimated low pressure and underestimated high pressure values.