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.

Right ventricular size and function evaluated by various echocardiographic indices in dogs with pulmonary hypertension.

BACKGROUND: Three-dimensional (3D) echocardiography and 2-dimensional (2D) strain measurements of the right ventricle (RV) are important indices in humans with pulmonary hypertension (PH) and need further evaluation in dogs with PH. OBJECTIVES: To evaluate various RV size and function indices in dogs with PH and to examine differences between pre- and postcapillary PH. ANIMALS: A total of 311 client-owned dogs: 100 dogs with PH, 31 with postcapillary and 69 with precapillary PH, and 211 healthy control dogs. METHODS: Retro- and prospective, multicenter study. Size and function of the RV was determined using several indices, derived using dedicated RV software, including 3D RV end-diastolic volume (EDVn), end-systolic volume (ESVn), ejection fraction, 2D global and free wall RV longitudinal strain (RVLS), end-diastolic area, end-systolic area, fractional area change, tricuspid annular plane systolic excursion, and tissue Doppler imaging-derived systolic myocardial velocity of the lateral tricuspid annulus (S'n). RESULTS: The EDVn (1.8 vs 2.5 mL/kg0.942 , P < .01) and ESVn (0.8 vs 1.2 mL/kg0.962 , P < .001) were significantly larger in the PH group compared to healthy controls. Free wall RVLS was decreased in dogs with severe PH compared to controls (-24% vs -29.6%, P < .001). Dogs with precapillary PH had worse RV systolic function than dogs with postcapillary PH. CONCLUSION: Three-dimensional echocardiography of the RV is a promising tool to detect RV changes in dogs with PH. Also, 2D strain measurements are able to detect decreased RV function and offer several advantages compared to conventional indices.

Echocardiographic reference intervals for right ventricular indices, including 3-dimensional volume and 2-dimensional strain measurements in healthy dogs.

BACKGROUND: There is currently a lack of reference intervals (RIs) for the novel measures like 3-dimensional (3D) echocardiography or speckle-tracking strain for assessment of right ventricular (RV) structure and function. OBJECTIVES: To generate RIs and to determine the influence of age, heart rate, and body weight (BW) on various RV function indices using a dedicated RV software for 3D RV end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), global and free wall RV longitudinal strain (RVLS), end-diastolic area (RVEDA), end-systolic area (RVESA), fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), and tissue Doppler imaging (TVI)-derived systolic myocardial velocity of the lateral tricuspid annulus (S'). ANIMALS: Healthy adult client-owned dogs (n = 211) of various breeds and ages. METHODS: Prospective study. Reference intervals were estimated as statistical prediction intervals using allometric scaling for BW-dependent variables. Right-sided (upper limit) or left-sided (lower limit) 95% RIs were calculated for every variable. Inter- and intraobserver variability was determined. RESULTS: Most variables showed clinically acceptable repeatability with coefficient of variation less than 10. Upper or respectively lower RI after allometric scaling to normalize for different BWs were: EDVn ≤ 2.5 mL/kg0.942 , ESVn ≤ 1.2 mL/kg0.962 , TAPSEn ≥ 4.5 mm0.285 , RVEDAn ≤ 1.4 cm2 /kg0.665 , RVESAn ≤ 0.8 cm2 /kg0.695 , and TVI S'n ≥ 5.6 cm/s/kg0.186 . The calculated limits for indices without allometric normalization were: EF > 42.1%, FAC > 30.0%, free wall RVLS < -20.8%, and global RVLS < -18.3%. CONCLUSIONS: Echocardiographic RIs for RV structure and function are provided.