Functional polymorphism of the renalase gene is associated with cardiac hypertrophy in female patients with aortic stenosis

Abstract

Renalase decreases circulating catecholamines concentration and is important in maintaining primary cellular metabolism. Renalase acts through the plasma membrane calcium ATPase 4b in the heart, which affects pressure overload but not exercise induced heart hypertrophy. The aim of this study was to test the association between a functional polymorphism Glu37Asp (rs2296545) of the renalase gene and left ventricular hypertrophy in a large cohort of patients with aortic stenosis. The study group consisted of 657 patients with aortic stenosis referred for aortic valve replacement. Preoperative echocardiographic assessment was performed to obtain cardiac phenotypes. Generalized-linear models were implemented to analyze data using crude or full model adjusted for selected clinical factors. In females, the Asp37 variant of the Glu37Asp polymorphism was associated with higher left ventricular mass (p = 0.0021 and p = 0.055 crude and full model respectively), intraventricular septal thickness (p = 0.0003 and p = 0.0143) and posterior wall thickness (p = 0.0005 and p = 0.0219) all indexed to body surface area, as well as relative wall thickness (p = 0.001 and p = 0.0097). No significant associations were found among the male patients. In conclusion, we have found the association of the renalase Glu37Asp polymorphism with left ventricle hypertrophy in large group of females with aortic stenosis. The Glu37Asp polymorphism causes not only amino-acid substitution in FAD binding domain but may also change binding affinity of the hypoxia- and hypertrophy-related transcription factors and influence renalase gene expression. Our data suggest that renalase might play a role in hypertrophic response to pressure overload, but the exact mechanism requires further investigation.

Association of Plasma Renalase and Left Ventricle Mass Index in Heart Failure Patients Stratified to the Category of the Ejection Fraction: A Pilot Study

“…Some investigators recently also confirmed the association of renalase gene polymorphism with cardiac hypertrophy in female patients with aortic stenosis [31], again suggesting a causal relationship between renalase and cardiac hypertrophy. The authors postulated the potential link knowing that in hypoxia, glycolysis is increased and that renalase is secreted in the manner of preserving primary metabolism [31].…”

“…The most recent genetic testing on the GG genotype of rs2576178 polymorphism concluded that this particular genotype increases renalase levels and thereby contributes to increased risk of coronary artery disease [30]. Some investigators recently also confirmed the association of renalase gene polymorphism with cardiac hypertrophy in female patients with aortic stenosis [31], again suggesting a causal relationship between renalase and cardiac hypertrophy. The authors postulated the potential link knowing that in hypoxia, glycolysis is increased and that renalase is secreted in the manner of preserving primary metabolism [31].…”

The Discriminatory Ability of Renalase and Biomarkers of Cardiac Remodeling for the Prediction of Ischemia in Chronic Heart Failure Patients With the Regard to the Ejection Fraction

“…In addition to cardioprotection, renalase was validated to inhibit the profibrotic gene expression and phosphorylation of the extracellular signal–regulated kinase 1/2 pathway, therefore preventing adverse cardiac remodeling ( 5 ). Furthermore, a hypoxic environment moves the mitochondrial oxidative metabolism toward glucose uptake, resulting in increased glycolysis; therefore, renalase may be secreted in the process of preserving the primary metabolism ( 8 ). Coupled with this, higher levels of renalase were previously confirmed in unstable angina pectoris patients, presuming that renalase rises in such conditions, owing to the body's metabolic changes, postponing its elevation grants mitigation of emergency cardiovascular conditions, including CAD ( 12 ).…”

“…Plasma renalase concentration is most likely up-regulated by circulating catecholamine levels, aiming to metabolize them (3)(4)(5) and significantly improving impaired hemodynamic in vivo (3). The most recent research has implicated renalase in numerous cardiovascular pathologies: HF (6, 7), coronary artery disease (CAD), hypertension, diabetes mellitus, and aortic stenosis (8)(9)(10)(11)(12)(13)(14)(15). Moreover, substantial evidence showed that functional polymorphisms of the renalase gene were associated with cardiac hypertrophy in patients with aortic stenosis (8) and an increased risk of CAD in the general population (9) and in hemodialyzed patients (10), patients with hypertension and associated CAD (11), patients with unstable angina pectoris and concomitant metabolic syndrome (12), and in patients with stable CAD, presenting with cardiac hypertrophy, ventricular dysfunction, and inducible ischemia (13).…”

“…The most recent research has implicated renalase in numerous cardiovascular pathologies: HF (6, 7), coronary artery disease (CAD), hypertension, diabetes mellitus, and aortic stenosis (8)(9)(10)(11)(12)(13)(14)(15). Moreover, substantial evidence showed that functional polymorphisms of the renalase gene were associated with cardiac hypertrophy in patients with aortic stenosis (8) and an increased risk of CAD in the general population (9) and in hemodialyzed patients (10), patients with hypertension and associated CAD (11), patients with unstable angina pectoris and concomitant metabolic syndrome (12), and in patients with stable CAD, presenting with cardiac hypertrophy, ventricular dysfunction, and inducible ischemia (13). Moreover, renalase has been suggested as a prognostic biomarker for ischemia in patients with acute coronary microvascular dysfunction (14) and as a predictor for all-cause mortality in chronic kidney disease (15).…”