JACC: Basic to Translational Science最新文献

The phospholamban (PLN) pathogenic gene variant, p.Arg14del (PLN-R14del), can lead to dilated and arrhythmogenic cardiomyopathy, resulting in heart failure. PLN-R14del cardiomyopathy has been conceptualized as a disease caused by sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) superinhibition. However, recent studies raised controversy regarding the effect of PLN-R14del on SERCA activity and revealed a prominent role for abnormal PLN protein distribution and sarco/endoplasmic reticulum disorganization as underlying disease mechanism. Strategies targeting sarco/endoplasmic reticulum malformation may, therefore, prove more effective than SERCA activity modulation. This review reassesses the disease mechanisms of PLN-R14del cardiomyopathy and emphasizes the importance of dissecting the underlying molecular mechanisms to uncover targets for innovative treatments.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). β-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac β-adrenoceptors (βARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local βAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different βAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by β₁AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)–dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca²⁺) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced β₁AR–nitric oxide synthetase 3 (NOS3)–dependent cyclic guanosine monophosphate signaling, drawing a parallel to the β₁AR–cyclic adenosine monophosphate–protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with β₁AR were observed. Stimulating β₁AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament β₁AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca²⁺ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

In this study, we investigated the feasibility, safety, and efficiency of using a novel device system to perform percutaneous left atrial appendage occlusion concomitant with left atrial appendage electrical isolation (LAAEI) via pulsed field ablation. In the acute phase, LAAEI was successful in 10 of 10 canines. At follow-up, full endothelialization was observed in 5 of 5 (100%) cases at 6 months. LAAEI was durable in 8 of 10 (80.00%) canines. Histologic examination in 4 of 6 LAAs with durable isolation showed transmural scars comprising fibrosis and fat. No pericardial effusion or phrenic paralysis was observed at follow-up. This preliminary study provides the scientific basis for first-in-human studies.