Genetic variations in hypoxia response genes influence hypertrophic cardiomyopathy phenotype

Abstract

Background: Risk factors for diastolic dysfunction in hypertrophic cardiomyopathy (hcM) are poorly understood. We investigated the association of variants in hypoxia-response genes with phenotype severity in pediatric hcM. Methods: a total of 80 unrelated patients <21 y and 14 related members from eight families with hcM were genotyped for six variants associated with vascular endothelial growth factor a (VEGFA) downregulation, or hypoxia-inducible factor a (HIF1A) upregulation. associations between risk genotypes and leftventricular (LV) hypertrophy, LV dysfunction, and freedom from myectomy were assessed. Tissue expression was measured in myocardial samples from 17 patients with hcM and 20 patients without hcM. results: age at enrollment was 9 ± 5 y (follow-up, 3.1 ± 3.6 y). Risk allele frequency was 67% VEGFA and 92% HIF1A. Risk genotypes were associated with younger age at diagnosis (P < 0.001), septal hypertrophy (P < 0.01), prolonged e-wave deceleration time (eWDT) (P < 0.0001) and isovolumic relaxation time (IVRT) (P < 0.0001), and lower freedom from myectomy (P < 0.05). These associations were seen in sporadic and familial hcM independent of the disease-causing mutation. Risk genotypes were associated with higher myocardial hIF1a and transforming growth factor B1 (TGFB1) expression and increased endothelialfibroblast transformation (P < 0.05). conclusion: HIF1A-upregulation and/or VEGFA-downregulation genotypes were associated with more severe septal hypertrophy and diastolic dysfunction and may provide genetic markers to improve risk prediction in hcM.

Serum Biomarkers of Myocardial Remodeling and Coronary Dysfunction in Early Stages of Hypertrophic Cardiomyopathy in the Young

“…Myocardial ischemia is previously suggested as an important complication in HCM [38] and supported by a previous mouse model of HCM [40] where sarcomere mutation-positive animals were found to upregulate genes involved in extracellular matrix remodeling in early stage of the disease, prior to the onset of histological changes characteristic for LVH and fibrosis. A human study [41] recently showed genetic variations in angiogenic and hypoxia-responsive genes with the association to younger age at diagnosis, diastolic dysfunction, and greater septal hypertrophy [41]. Although ICTP showed no correlation with any of the above CMR indices, there was an inverse relationship of myocardial perfusion during adenosine hyperemia with both LVM and mitral E/e′, a finding that strengthens the concept that myocardial perfusion abnormalities occur in parallel with the progression of myocardial hypertrophy and diastolic dysfunction.…”

Killing Many Birds With Two Stones: Hypoxia and Fibrosis Can Generate Ectopic Beats in a Human Ventricular Model

“…Approximately 70% of all patients with HCM die suddenly (Maron et al, 1995 ; Ho et al, 2010 ; Namboodiri and Francis, 2010 ; Alkon et al, 2012 ). The high arrhythmic propensity in HCM is due to the combination of the abnormal substrate, like fibrosis, and ischemia or hypoxia (Alkon et al, 2012 ), in general associated with intense physical exercise. Extreme physical exercise may induce, in HCM patients, diastolic pressure and volume overload of the ventricles, and hypoxemia, i.e., low oxygen saturation in the blood.…”

Vascular Endothelial Growth Factor Is Associated with the Morphologic and Functional Parameters in Patients with Hypertrophic Cardiomyopathy

“…It has been shown that VEGF is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in in vivo models [ 15 ] and plays an important role in myocardial hypertrophy [ 16 ]. In our study, we confirmed increased serum VEGF level in patients with nonobstructive HCM when compared to normal population.…”