👤 Nazha Hamdani

Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disorder marked by left ventricular hypertrophy and hypercontractility. This excessive mechanical workload creates an energetic mismatch in which consumption exceeds production, leading to myocardial energy depletion. Although CK (creatine kinase) plays a key role in cardiac energy homeostasis, its involvement in HCM remains unclear. This study investigates how hypercontractility-driven mitochondrial stress and the resulting increase in mitochondrial H CK function was analyzed using myocardial left ventricular tissue from 92 patients with HCM (with and without pathogenic sarcomere variants) and 30 non-failing human controls. Myofilament and mitochondrial CK isoforms were measured using mRNA analysis, protein immunoblotting, enzyme activity assays, mass spectrometry, and redox-sensitive proteomics. To explore links between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction, we used isolated cardiomyocytes from wild-type, mitochondrial-targeted catalase-overexpressing, CK knockout (myofilament and mitochondrial CK deletion), HCM-associated Our analysis revealed significant reductions in myofilament and mitochondrial CK protein levels, as well as CK activity, in myocardium of patients with HCM, primarily because of oxidative modifications of CK. In isolated mouse cardiomyocytes from wild-type and CK knockouts, hypercontractility induced by EMD-57033 elevated mitochondrial H This study reveals a mechanistic link between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction in HCM, perpetuating a cycle of energetic dysfunction. Targeting hypercontractility and oxidative stress through myosin inhibition offers a strategy to restore energy balance and reduce arrhythmic risk in HCM. Show less

Obesity and Type 2 diabetes mellitus (DM) induce left ventricular (LV) diastolic dysfunction, which contributes to an increasing prevalence of heart failure with a preserved LV ejection fraction. We investigated the effects of sitagliptin (SITA), an inhibitor of dipeptidylpeptidase-4 (DPP-4) and anti-diabetic drug, on LV structure and function of obese mice with Type 2 DM. Obese Type 2 diabetic mice (Lepr(db/db), BKS.Cg-Dock7(m)+/+ Lepr(db)/J), displaying increased cardiomyocyte and LV stiffness at the age of 16 weeks, were treated with SITA (300 mg/kg/day) or vehicle for 8 weeks. SITA severely impaired serum DPP-4 activity, but had no effect on glycaemia. Invasive haemodynamic recordings showed that SITA reduced LV passive stiffness and increased LV stroke volume; LV end-systolic elastance remained unchanged. In addition, SITA reduced resting tension of isolated single cardiomyocytes and intensified phosphorylation of the sarcomeric protein titin. SITA also increased LV concentrations of cGMP and increased activity of protein kinase G (PKG). In vitro activation of PKG decreased resting tension of cardiomyocytes from vehicle-treated mice, but had no effect on resting tension of cardiomyocytes from SITA-treated mice. In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus. Show less