Background A dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2/rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2/rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes. Methods Two-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway. Results The TT genotype at NDUFC2/rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height2.7(p = 0.010) after adjustment for covariates. In-vitro, the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway. Conclusions We demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.

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Introduction: Whether increased left atrial (LA) volume (V) is an indicator of LV filling pattern in mild chronic heart failure (CHF) is unclear. Methods: The AREA-IN-CHF (AntiRemodeling Effect of Aldosterone receptors blockade with canrenone IN mild Chronic Heart Failure) is a prospective, randomized, double blind study on antialdosterone treatment in patients with Class 2 NYHA chronic heart failure (CHF) and ejection fraction. Among 505 participants undergoing Doppler echocardiography, we evaluated 303 subjects (mean age 63± 10 yrs, 49 women) with available LAV and without valvular or rhythm abnormalities. Orthogonal LA diameters were measured in parasternal short-axis and apical 4-chamber view. LAV was calculated using biplane linear dimensions by the ellipsoidal model. LA was considered dilated when >53mL for women or >59mL for men, as recommended. LV end-diastolic pressure (LVEDP) was computed from pulmonary and mitral A velocity signal durations, applying an invasively-validated equation. Results: LAV correlated positively to male gender (r=0.14), LV mass (r=0.31), mitral E/A ratio (r=0.36), and LVEDP (r=0.34) and negatively to ejection fraction it (r=-0.20) and isovolumic relaxation time (IVRT; r=-0.29) (all p age, heart rate, blood pressure or mitral peak E deceleration time. Among participants, 110 had dilated LA (36.3% of population). Patients with dilated atria had similar mean age, heart rate and blood pressure compared to patients with normal atrial volume, but higher body mass index, LV mass, mitral peak E/A ratio, lower ejection fraction, relative wall thickness and shorter IVRT (all p ejection fraction, left ventricular mass and relative wall thickness, patients with dilated atria confirmed higher mitral E/A ratio (1.38±1.15 vs 0.98±0.57) higher LVEDP (16.8±7.8 vs 13.9±9.6 mmHg) and shorter IVRT (75.1±21.1 vs 85.9±21.2 msec; p for all<0.01). Conclusions: In class 2 NYHA CHF patients with systolic dysfunction, in sinus rhythm, dilated LA is frequent (36.3%) and associated with restrictive LV physiology independently of demographics, LV geometry and pump function.

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