In CAD, P2Y12 inhibitor vs. aspirin monotherapy reduces a composite CV outcome without increasing major bleeding.

SOURCE CITATION: Gragnano F, Cao D, Pirondini L, et al; PANTHER Collaboration. P2Y12 inhibitor or aspirin monotherapy for secondary prevention of coronary events. J Am Coll Cardiol. 2023;82:89-105. 37407118.

Preventing new-onset heart failure: Intervening at stage A.

Heart failure (HF) prevention is an urgent public health need with national and global implications. Stage A HF patients do not show HF symptoms or structural heart disease but are at risk of HF development. There are no unique recommendations on detecting Stage A patients. Patients in Stage A are heterogeneous; many patients have different combinations of risk factors and, therefore, have markedly different absolute risks for HF. Comprehensive strategies to prevent HF at Stage A include intensive blood pressure lowering, adequate glycemic and lipid management, and heart-healthy behaviors (adopting Life's Essential 8). First and foremost, it is imperative to improve public awareness of HF risk factors and implement healthy lifestyle choices very early. In addition, recognize the HF risk-enhancing factors, which are nontraditional cardiovascular (CV) risk factors that identify individuals at high risk for HF (genetic susceptibility for HF, atrial fibrillation, chronic kidney disease, chronic liver disease, chronic inflammatory disease, sleep-disordered breathing, adverse pregnancy outcomes, radiation therapy, a history of cardiotoxic chemotherapy exposure, and COVID-19). Early use of biomarkers, imaging markers, and echocardiography (noninvasive measures of subclinical systolic and diastolic dysfunction) may enhance risk prediction among individuals without established CV disease and prevent chemotherapy-induced cardiomyopathy. Efforts are needed to address social determinants of HF risk for primordial HF prevention.Central illustrationPolicies developed by organizations such as the American Heart Association, American College of Cardiology, and the American Diabetes Association to reduce CV disease events must go beyond secondary prevention and encompass primordial and primary prevention.

The Evolution of Pulmonary Artery Denervation for Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive, life-limiting disease. Despite significant medical progress over the last three decades, the prognosis of PAH remains poor. PAH is associated with sympathetic nervous system over-stimulation and baroreceptor-mediated vasoconstriction, leading to pathologic pulmonary artery (PA) and right ventricular remodeling. PA denervation is a minimally-invasive intervention that ablates local sympathetic nerve fibers and baroreceptors to modulate pathologic vasoconstriction. Preliminary animal and clinical studies have shown improvements in short-term pulmonary hemodynamics and PA remodeling. However, future studies are needed to elucidate appropriate patient selection, timing of intervention, and long-term efficacy before integration into standard of care.

Slow on the Uptake, Progression to Heartbreak.

The prevalence of serotonin syndrome increases over the past several years as more serotonergic medications are being used in clinical practice. It is a potentially lethal condition caused by excessive serotonergic activity. Common causes of serotonin syndrome are the use of prescription medications, illicit drugs, or a combination of substances, leading to an increase in the activity of serotonin in the central and peripheral nervous system. The clinical symptoms range from mild to severe. We report a case of a 25-year-old woman with polysubstance abuse, including cocaine, who presented with confusion, rigidity, high-grade fever, and reduced biventricular function on echocardiogram. Based on the combination of substance used history, clinical presentation, and echocardiogram findings, she was diagnosed with serotonin syndrome complicated by takotsubo cardiomyopathy. She improved after being treated in the intensive care unit and was discharged from the hospital. This patient demonstrates the importance of recognizing and promptly initiating management of serotonin syndrome in order to improve morbidity and mortality.

Statin-Induced Necrotizing Autoimmune Myopathy.

Statin-induced necrotizing autoimmune myopathy (SINAM) is an exceptionally rare yet devastating complication of statin therapy that can occur at any time after initiation. It should be considered in patients who develop proximal muscle weakness and marked elevated creatine phosphokinase while taking statin therapy. (Level of Difficulty: Beginner.).

BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility.

RATIONALE: The contractile dysfunction that underlies heart failure involves perturbations in multiple biological processes ranging from metabolism to electrophysiology. Yet the epigenetic mechanisms that are altered in this disease state have not been elucidated. SWI/SNF chromatin-remodeling complexes are plausible candidates based on mouse knockout studies demonstrating a combined requirement for the BRG1 and BRM catalytic subunits in adult cardiomyocytes. Brg1/Brm double mutants exhibit metabolic and mitochondrial defects and are not viable although their cause of death has not been ascertained. OBJECTIVE: To determine the cause of death of Brg1/Brm double-mutant mice, to test the hypothesis that BRG1 and BRM are required for cardiac contractility, and to identify relevant downstream target genes. METHODS AND RESULTS: A tamoxifen-inducible gene-targeting strategy utilizing αMHC-Cre-ERT was implemented to delete both SWI/SNF catalytic subunits in adult cardiomyocytes. Brg1/Brm double-mutant mice were monitored by echocardiography and electrocardiography, and they underwent rapidly progressive ventricular dysfunction including conduction defects and arrhythmias that culminated in heart failure and death within 3weeks. Mechanistically, BRG1/BRM repressed c-Myc expression, and enforced expression of a DOX-inducible c-MYC trangene in mouse cardiomyocytes phenocopied the ventricular conduction defects observed in Brg1/Brm double mutants. BRG1/BRM and c-MYC had opposite effects on the expression of cardiac conduction genes, and the directionality was consistent with their respective loss- and gain-of-function phenotypes. To support the clinical relevance of this mechanism, BRG1/BRM occupancy was diminished at the same target genes in human heart failure cases compared to controls, and this correlated with increased c-MYC expression and decreased CX43 and SCN5A expression. CONCLUSION: BRG1/BRM and c-MYC have an antagonistic relationship regulating the expression of cardiac conduction genes that maintain contractility, which is reminiscent of their antagonistic roles as a tumor suppressor and oncogene in cancer.

BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo.

There has been an increasing recognition that mitochondrial perturbations play a central role in human heart failure. Mitochondrial networks, whose function is to maintain the regulation of mitochondrial biogenesis, autophagy ('mitophagy') and mitochondrial fusion/fission, are new potential therapeutic targets. Yet our understanding of the molecular underpinning of these processes is just emerging. We recently identified a role of the SWI/SNF ATP-dependent chromatin remodeling complexes in the metabolic homeostasis of the adult cardiomyocyte using cardiomyocyte-specific and inducible deletion of the SWI/SNF ATPases BRG1 and BRM in adult mice (Brg1/Brm double mutant mice). To build upon these observations in early altered metabolism, the present study looks at the subsequent alterations in mitochondrial quality control mechanisms in the impaired adult cardiomyocyte. We identified that Brg1/Brm double-mutant mice exhibited increased mitochondrial biogenesis, increases in 'mitophagy', and alterations in mitochondrial fission and fusion that led to small, fragmented mitochondria. Mechanistically, increases in the autophagy and mitophagy-regulated proteins Beclin1 and Bnip3 were identified, paralleling changes seen in human heart failure. Evidence for perturbed cardiac mitochondrial dynamics included decreased mitochondria size, reduced numbers of mitochondria, and an altered expression of genes regulating fusion (Mfn1, Opa1) and fission (Drp1). We also identified cardiac protein amyloid accumulation (aggregated fibrils) during disease progression along with an increase in pre-amyloid oligomers and an upregulated unfolded protein response including increased GRP78, CHOP, and IRE-1 signaling. Together, these findings described a role for BRG1 and BRM in mitochondrial quality control, by regulating mitochondrial number, mitophagy, and mitochondrial dynamics not previously recognized in the adult cardiomyocyte. As critical to the pathogenesis of heart failure, epigenetic mechanisms like SWI/SNF chromatin remodeling seem more intimately linked to cardiac function and mitochondrial quality control mechanisms than previously realized.

The role of ubiquitin ligases in cardiac disease.

Rigorous surveillance of protein quality control is essential for the maintenance of normal cardiac function, while the dysregulation of protein turnover is present in a diverse array of common cardiac diseases. Central to the protein quality control found in all cells is the ubiquitin proteasome system (UPS). The UPS plays a critical role in protein trafficking, cellular signaling, and most prominently, protein degradation. As ubiquitin ligases (E3s) control the specificity of the UPS, their description in the cardiomyocyte has highlighted how ubiquitin ligases are critical to the turnover and function of the sarcomere complex, responsible for the heart's required continuous contraction. In this review, we provide an overview of the UPS, highlighting a comprehensive overview of the cardiac ubiquitin ligases identified to date. We then focus on recent studies of new cardiac ubiquitin ligases outlining their novel roles in protein turnover, cellular signaling, and the regulation of mitochondrial dynamics and receptor turnover in the pathophysiology of cardiac hypertrophy, cardiac atrophy, myocardial infarction, and heart failure. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".