Patients with hypertension and hyperaldosteronism show an increased risk of stroke compared with patients with essential hypertension. Aim of the study was to assess the effects of aldosterone on left atrial function in rats as a potential contributor to thromboembolism. Osmotic mini-pumps delivering 1.5 μg aldosterone/h were implanted in rats subcutaneously (Aldo, n = 39; controls, n = 38). After 8 wk, left ventricular pressure-volume analysis of isolated working hearts was performed, and left atrial systolic and diastolic function was also assessed by atrial pressure-diameter loops. Moreover, left atrial myocytes were isolated to investigate their global and local Ca²⁺ handling and contractility. At similar heart rates, pressure-volume analysis of isolated hearts and in vivo hemodynamic measurements revealed neither systolic nor diastolic left ventricular dysfunction in Aldo. In particular, atrial filling pressures and atrial size were not increased in Aldo. Aldo rats showed a significant reduction of atrial late diastolic A wave, atrial active work index, and increased V waves. Consistently, in Aldo rats, sarcomere shortening and the amplitude of electrically evoked global Ca²⁺ transients were substantially reduced. Sarcoplasmic reticulum-Ca²⁺ content and fractional Ca²⁺ release were decreased, substantiated by a reduced sarcoplasmic reticulum calcium ATPase activity, resulting from a reduced CAMKII-evoked phosphorylation of phospholamban. Hyperaldosteronism induced atrial systolic and diastolic dysfunction, while atrial size and left ventricular hemodynamics, including filling pressures, were unaffected in rats. The described model suggests a direct causal link between hyperaldosteronism and decreased atrial contractility and diastolic compliance.

BACKGROUND: 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 ₂ O ₂ disrupt CK function in HCM. METHODS: 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 Mybpc3 knock-in, and mito-roGFP2-Orp1 mouse models. We also tested the effects of the Ca ²⁺ sensitizer EMD-57033, the CK inhibitor 1-fluoro-2,4-dinitrobenzene (DNFB), and the myosin inhibitor MYK-581, a mavacamten derivative. RESULTS: 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 ₂ O ₂ , causing cellular arrhythmias and CK inactivation. Hypercontractility-induced oxidative stress, arrhythmias, and CK dysfunction were also observed in Mybpc3 knock-in cardiomyocytes. Mitochondrial-targeted catalase-overexpressing mice with enhanced H ₂ O ₂ scavenging were protected against H ₂ O ₂ -induced (EMD-57033-mediated) arrhythmias and CK dysfunction. MYK-581 treatment in Mybpc3 knock-in cardiomyocytes reduced hypercontractility, lowered H ₂ O ₂ production and arrhythmias, and preserved CK function. CK inhibition using DNFB in wild-type cardiomyocytes elevated mitochondrial H ₂ O ₂ levels and triggered cellular arrhythmias. This mitochondrial oxidation was independently confirmed in mito-roGFP2-Orp1 cardiomyocytes exposed to DNFB. Mitochondrial-targeted catalase-overexpressing mice were protected from DNFB–induced oxidative stress and arrhythmogenic events. CONCLUSIONS: 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.

Hypertrophic cardiomyopathy is the most common genetic cardiac disease and is characterized by left ventricular hypertrophy. Although this hypertrophy often associates with sarcomeric gene mutations, nongenetic factors also contribute to the disease, leading to diastolic dysfunction. Notably, this dysfunction manifests before hypertrophy and is linked to hypercontractility, as well as nonuniform contraction and relaxation (myofibril asynchrony) of the myocardium. Although the distribution of hypertrophy in hypertrophic cardiomyopathy can vary both between and within individuals, in most cases, it is primarily confined to the interventricular septum. The reasons for septal thickening remain largely unknown. In this article, we propose that alterations in muscle fiber geometry, present from birth, dictate the septal shape. When combined with hypercontractility and exacerbated by left ventricular outflow tract obstruction, these factors predispose the septum to an isometric type of contraction during systole, consequently constraining its mobility. This contraction, or more accurately, this focal increase in biomechanical stress, prompts the septum to adapt and undergo remodeling. Drawing a parallel, this is reminiscent of how earthquake-resistant buildings are retrofitted with vibration dampers to absorb the majority of the shock motion and load. Similarly, the heart adapts by synthesizing viscoelastic elements such as microtubules, titin, desmin, collagen, and intercalated disc components. This pronounced remodeling in the cytoskeletal structure leads to noticeable septal hypertrophy. This structural adaptation acts as a protective measure against damage by attenuating myofibril shortening while reducing cavity tension according to Laplace Law. By examining these events, we provide a coherent explanation for the septum’s predisposition toward hypertrophy.

The Anrep effect, an adaptation enhancing left ventricular (LV) contractility in response to raised afterload, is hypothesized to influence hypertrophic cardiomyopathy pathophysiology. This study investigated the activation and reversibility of the Anrep effect in obstructive hypertrophic cardiomyopathy (HOCM) patients undergoing percutaneous transluminal septal myocardial ablation (PTSMA) to relieve LV outflow tract obstruction. Invasive pressure-volume (PV) analysis was performed on 14 HOCM patients before and after PTSMA. The "Anrep Triad," defined by elevated afterload (higher LV end-systolic pressure and effective arterial elastance), augmented contractility (higher end-systolic elastance and maximum LV pressure rise [dP/dt_max]), and prolonged systolic duration (dTes), was assessed via direct hemodynamic comparison preprocedure and postprocedure. Stroke work (SW), potential energy, and total PV area (PVA) quantified mechanical work and efficiency (SW/PVA). Postprocedure reversal of the Anrep effect was confirmed (pre- vs post-PTSMA), with reductions in afterload (LV end-systolic pressure: 180 vs 138 mm Hg, P = 0.0001; effective arterial elastance: 2.5 vs 1.9 mm Hg/mL, P = 0.002), contractility (end-systolic elastance: 2.0 vs 1.5 mm Hg/mL, P = 0.0001; dP/dt_max: 1,775 vs 1,560 mm Hg/s, P = 0.017), and systolic duration (dTes: 371 vs 327 ms, P = 0.002). Preprocedure, HOCM patients exhibited higher mechanical workload (SW: 8,161 vs 7,495 mm Hg·mL, P = 0.004; potential energy: 7,837 vs 4,915 mm Hg·mL, P = 0.002; PVA: 16,135 vs 11,742 mm Hg·mL, P = 0.0002) and lower efficiency (SW/PVA: 50% vs 59%, P = 0.03). The Anrep effect is an energy-demanding compensatory mechanism that maintains stroke volume under elevated afterload by increasing contractility and prolonging systole. This study confirms its chronic activation in HOCM and its immediate reversal post-PTSMA.