Circulation: Heart Failure最新文献

Background: Mitral regurgitation (MR) is a frequent comorbidity in patients with hypertrophic cardiomyopathy (HCM), which includes distinct subtypes with various characteristics. However, data on the long-term prognostic impact of MR and its progression or regression over time remain limited, particularly across individual HCM subtypes.

Methods: Patients with HCM were retrospectively included from a Japanese multicenter registry and compared by MR severity (moderate or greater versus mild or less) within each subtype: hypertrophic obstructive cardiomyopathy (HOCM), end-stage HCM (ES-HCM), and other HCM (including nonobstructive, midventricular obstruction, and apical HCM).

Results: Among 3602 patients (HOCM: n=837; ES-HCM: n=275; other HCM: n=2490), the prevalence of moderate or greater MR was highest in HOCM (36.3%), followed by ES-HCM (21.5%) and other HCM (8.5%). During a median follow-up of 5.3 (interquartile range, 2.1-9.3) years, the cumulative 5-year incidence of all-cause death or heart failure hospitalization was not significantly different between the moderate or greater MR and mild or less MR groups in HOCM (14.6% versus 12.4%; P=0.35) or ES-HCM (60.7% versus 54.7%; P=0.84). After adjustment for clinical covariates, no significant association was observed in either subtype (HOCM: hazard ratio, 1.13 [95% CI, 0.79-1.60], P=0.51; ES-HCM: hazard ratio, 0.84 [95% CI, 0.55-1.28], P=0.42). In contrast, in other HCM, moderate or greater MR was significantly associated with the higher 5-year cumulative incidence of all-cause death or heart failure hospitalization (34.2% versus 13.9%, P<0.001), which remained significant after adjustment, with a significant interaction (hazard ratio, 1.45 [95% CI, 1.09-1.91], P=0.01; P_interaction=0.02). MR severity improved over time in HOCM, showed no clear change in ES-HCM, and worsened in other HCM (P<0.001, 0.46, and <0.001, respectively; P_interaction <0.001).

Conclusions: In patients with HCM, moderate or greater MR was not associated with worse outcomes in HOCM or ES-HCM, but had significant prognostic implications in other HCM subtypes, suggesting the need for HCM subtype-specific MR management.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome affecting ≈32 million individuals worldwide. It accounts for at least half of all heart failure cases and is associated with substantial morbidity and mortality. Although the prevalence of HFpEF increases with age, a substantial proportion of the HFpEF subjects present with cardiometabolic alterations, marking a specific phenogroup of HFpEF. Obesity, diabetes, and hypertension are considered central features in the pathophysiology of HFpEF, driving its development and disease progression by a complex interplay of metabolic-, hemodynamic-, and neurohormonal impairments, resulting in systemic inflammation and immune system dysregulation. Cellular and systemic immunometabolic stress induces vascular endothelial microvascular dysfunction, infiltration of immune cells in the myocardium, and activation of innate and adaptive immune cells in cardiac tissue. The resulting bidirectional crosstalk between systemic and cardiac metabolism influences immune cell reprogramming, sustaining a vicious cycle of cardiac chronic inflammatory response, ultimately leading to adverse structural and functional cardiac remodeling. In this review, we discuss the role of cellular interactions and immunometabolic mechanisms of immune system dysregulation resulting in cardiometabolic HFpEF and elaborate on therapeutic strategies targeting cardiometabolic risk.

Background: MGP (matrix Gla-protein), a known inhibitor of vascular calcification, becomes biologically active by vitamin K-dependent carboxylation. Circulating levels of dpucMGP (dephospho-uncarboxylated matrix Gla-protein), the inactive form of MGP, have been associated with large artery stiffening and reduced skeletal muscle mass in heart failure (HF). Whether dpucMGP is related to adverse outcomes in patients with HF is unknown.

Methods: In this cohort study, we measured plasma dpucMGP among 2247 PHFS (Penn HF Study) participants. We examined the relationship between dpucMGP and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with dpucMGP. We assessed the association between dpucMGP levels and (1) death or HF-related hospital admission; (2) all-cause death.

Results: Participants' median age was 61 years (interquartile range, 53-70 years), 64% were male, and 71% were White. dpucMGP exhibited prominent proteomic associations with acute phase response, coagulation, complement system, fibrosis, cell signaling, and metabolic pathways. Greater dpucMGP was associated with older age, renal dysfunction, and warfarin use, whereas Black ethnicity was associated with lower dpucMGP. Increased dpucMGP levels were associated with an increased risk of death or HF-related hospital admission (standardized hazard ratio, 1.23 [95% CI, 1.17-1.28]; P<0.0001) and all-cause death (standardized hazard ratio, 1.32 [95% CI, 1.25-1.40]; P<0.0001), particularly among participants with nonischemic HF. Associations between dpucMGP and outcomes were dependent on warfarin use, and higher dpucMGP levels were found to mediate the association between warfarin use and adverse outcomes (death [total effect: P=0.005; indirect effect: P<0.001] and death or HF-related hospital admission [total effect: P<0.001; indirect effect: P=0.002]).

Conclusions: Higher dpucMGP is associated with multiple biological pathways and with an increased risk for adverse outcomes in HF. Greater dpucMGP levels mediated the relationship between warfarin use and adverse outcomes. Further studies are required to determine the role of therapeutic interventions to reduce dpucMGP levels in this patient population.

Background: Arrhythmogenic cardiomyopathy (ACM) is a fatal genetic heart disease primarily caused by mutations in desmosomal genes, leading to impaired cell-cell adhesion, ventricular arrhythmias, and progressive heart failure. Although gene therapy for specific ACM populations shows promise, it remains unclear whether mutation-agnostic pathways dysregulated across desmosomal mutations could be exploited for therapeutic intervention in this genetically broad and severe population. The reduction in expression of the ventricular gap junction protein Cx43 (connexin-43) is a common molecular alteration underlying desmosomal junctional deficits and arrhythmias, suggesting a potential common underlying mechanism and a therapeutic target for ACM. We hypothesized that restoration of Cx43 expression could be a mutation-agnostic intervention for ACM.

Methods: We exploited adeno-associated-viral-mediated gene therapy to restore the gap junction protein, Cx43, in genetic mouse models and human stem cell models of ACM, harboring loss or mutations in desmosomal genes, including desmoplakin (Dsp), plakophilin-2 (PKP2), and desmoglein-2 (DSG2).

Results: Administration of AAV-Cx43 (adeno-associated-viral-mediated connexin-43) gene therapy alleviated the severe biventricular dilatation, contractile dysfunction, and arrhythmias, while prolonging lifespan in 2 severe desmosomal ACM mouse models, either harboring Dsp loss and a prevalent human PKP2 mutation. Viral-mediated restoration of Cx43 could also alleviate physiological deficits in ACM human induced pluripotent stem cell-derived cardiomyocytes harboring PKP2 and DSG2 mutations. Mechanistically, Cx43 targets desmosomal protein expression and relocalization to the cell junction to support their mechanical stabilization and coupling.

Conclusions: By using mouse and human models of desmosomal ACM harboring different mutational backgrounds, we show the sufficiency of Cx43 gene therapy and its restoration to modify and alleviate ACM deficits. These data suggest that noncanonical functions of Cx43, including mechanical modulation and reassembly of the desmosome, are a therapeutic target with the potential to treat diverse ACM populations.