Objective: The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and Results: Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas ( P =0.005) but not AS-aortas ( P =0.23). This pathological remodeling included mucoid extracellular matrix accumulation ( P =0.005), elastin loss ( P =0.003), elastin fragmentation ( P =0.008), and decreased expression of fibrillin ( P =0.003) and collagen ( P =0.008). Furthermore, eNOS (endothelial nitric oxide synthase) expression was decreased in the intima ( P =0.0008) and in vasa vasorum ( P =0.004) of AR-aortas but not AS-aortas (all P >0.05). Likewise, subendothelial apoptosis was increased in AR-aortas ( P =0.03) but not AS-aortas ( P =0.50). Conclusions: AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR. Graphic A graphic abstract is available for this article.

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.

Purpose of Review: Preservation or repair of the aortic valve has evolved dynamically in the past 20 years. It leads to a high freedom from valve-related complications if an adequate valve durability can be achieved; it may possibly also improve survival. To date, little structured information is available about which valves can be repaired and which should better be replaced. Recent Findings: For surgical decision-making, the size of the aortic root is important and the anatomy of the aortic valve must be considered. In the presence of root aneurysm, most tricuspid and bicuspid aortic valves can be preserved. In aortic regurgitation and normal aortic dimensions, the majority of tricuspid and bicuspid aortic valves can be repaired with good long-term durability. In bicuspid aortic valves, the morphologic characteristics must be taken into consideration. Unicuspid and quadricuspid aortic valves can be repaired in selected cases. Generally, cusp calcification is a sign of a poor substrate for repair; the same is true for cusp retraction and cusp destruction due to active endocarditis. They are associated with limited valve durability. Summary: Using current concepts, many non-calcified aortic valves can be repaired. Modern imaging, in particular three-dimensional transesophageal echocardiography (TEE), should be able to define repairable aortic valves with a high probability.