Mitochondrial abnormalities have long been described in the setting of cardiomyopathies and heart failure (HF), yet the mechanisms of mitochondrial dysfunction in cardiac pathophysiology remain poorly understood. Many studies have described HF as an energy-deprived state characterized by a decline in adenosine triphosphate production, largely driven by impaired oxidative phosphorylation. However, impairments in oxidative phosphorylation extend beyond a simple decline in adenosine triphosphate production and, in fact, reflect pervasive metabolic aberrations that cannot be fully appreciated from the isolated, often siloed, interrogation of individual aspects of mitochondrial function. With the application of broader and deeper examinations into mitochondrial and metabolic systems, recent data suggest that HF with preserved ejection fraction is likely metabolically disparate from HF with reduced ejection fraction. In our review, we introduce the concept of the mitochondrial ecosystem, comprising intricate systems of metabolic pathways and dynamic changes in mitochondrial networks and subcellular locations. The mitochondrial ecosystem exists in a delicate balance, and perturbations in one component often have a ripple effect, influencing both upstream and downstream cellular pathways with effects enhanced by mitochondrial genetic variation. Expanding and deepening our vantage of the mitochondrial ecosystem in HF is critical to identifying consistent metabolic perturbations to develop therapeutics aimed at preventing and improving outcomes in HF.

Hereditary dilated cardiomyopathy (DCM) is a primary disease of cardiac myocytes caused by mutations in genes encoding proteins with a diverse array of functions. Mutations in the LMNA gene, encoding the nuclear envelope protein lamin A/C, are the second most common causes of DCM. The phenotype is characterized by progressive cardiac dysfunction, leading to refractory heart failure, myocardial fibrosis, cardiac arrhythmias, and sudden cardiac death. The molecular pathogenesis of DCM caused by the LMNA mutations is not well known. The LMNA protein is involved in nuclear membrane stability. It is also a guardian of the genome involved in the processing of the topoisomerases at the transcriptionally active domain and the repair of double-stranded DNA breaks (DSBs). Deletion of the mouse Lmna gene in cardiac myocytes leads to premature death, DCM, myocardial fibrosis, and apoptosis. The phenotype is associated with increased expression of the cytosolic DNA sensor cyclic GMP-AMP synthase (CGAS) and activation of the DNA damage response (DDR) pathway. Genetic blockade of the DDR pathway, upon knockout of the Mb21d1 gene encoding CGAS, prolonged survival, improved cardiac function, partially restored levels of molecular markers of heart failure, and attenuated myocardial apoptosis and fibrosis in the LMNA-deficient mice. The findings indicate that targeting the CGAS/DDR pathway might be beneficial in the treatment of DCM caused by mutations in the LMNA gene.

Eosinophilic myocarditis (EM) is a cardiac manifestation of hypereosinophilic syndrome with a high mortality rate. EM shares imaging features similar to other restrictive cardiopathies, and include patchy intramural late gadolinium enhancement on cardiac magnetic resonance with or without presence of biventricular thrombus. Diagnosis is confirmed on histopathology, and is the current gold standard. Here we report clinical presentation and imaging findings of EM in a 70-year-old woman who presented with fever and chills.

A 72-year-old male with severe dilated cardiomyopathy, benefited of implantable cardiac defibrillator implementation. Device control shows high impedance. On X-ray, electrodes were completely twisted in the generator pocket, they were replaced and the generator was fixed to pectoralis-major fascia. Nurses report patient abnormal movements, scratching implantation area. This was identified as probably the trigger of the complication.

Remission of heart failure, defined by resolution of symptoms, normalization of left ventricular ejection fraction, and plasma concentrations of natriuretic peptides and by the ability to withdraw diuretic agents without recurrence of congestion is increasingly recognized among patients with dilated cardiomyopathy. Once remission has been achieved, it is unclear which treatments need to be continued long term. The durability of remission and likelihood of relapse are likely to be determined by intrinsic myocardial susceptibility, the persistence or recurrence of any acquired triggers, and current and future myocardial workload. Each of these should be addressed to enable personalized therapy to delay or prevent relapse. Management should be informed by evidence from randomized trials of targeted therapeutic strategies.

Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency plays a role in cardiomyopathy. Whether ECHS1 deficiency causes or is only associated with cardiomyopathy remains unclear. By using Echs1 heterogeneous knockout (Echs1 +/-) mice, we found that ECHS1 deficiency caused cardiac dysfunction, as evidenced by diffuse myocardial fibrosis and upregulated fibrosis-related genes. Mechanistically, ECHS1 interacts with the p300 nuclear localization sequence, preventing its nuclear translocation in fibroblasts. ECHS1 deficiency promotes p300 nuclear translocation, leading to increased H3K9 acetylation, a known risk factor for cardiomyopathy. Nicotinamide mononucleotide-mediated acetylation targeting suppressed ECHS1 deficiency-induced cardiomyopathy phenotypes in Echs1 +/- mice. Thus, enhancing p300-mediated H3K9ac is a potential interventional approach for preventing ECHS1 deficiency-induced cardiomyopathy.

SCN5A was considered an exclusively cardiac expressed ion channel but discovered to also act as a novel innate immune sensor. We report on a young SCN5A variant carrier with recurrent ventricular fibrillation and massive myocardial inflammation whose peculiar clinical course is highly suggestive of such a dual role of SCN5A. (Level of Difficulty: Advanced.).

The primary etiology of a diverse range of cardiomyopathies is now understood to be genetic, creating a new paradigm for targeting treatments on the basis of the underlying molecular cause. This review provides a genetic and etiologic context for the traditional clinical classifications of cardiomyopathy, including molecular subtypes that may exhibit differential responses to existing or emerging treatments. The authors describe several emerging cardiomyopathy treatments, including gene therapy, direct targeting of myofilament function, protein quality control, metabolism, and others. The authors discuss advantages and disadvantages of these approaches and indicate areas of high potential for short- and longer term efficacy.

We describe the successful retrieval of a novel large mitral clip, which embolized in a patient with severe secondary mitral regurgitation and left ventricular dysfunction, dilated left ventricle, and severely tethered mitral valve leaflets in the setting of a challenging anatomy for transcatheter edge-to-edge repair. The description highlights planning, technical issues, and possible adverse events of this bailout procedure. (Level of Difficulty: Intermediate.).

UNASSIGNED: Adriamycin-associated cardiomyopathy (ACM) can lead to end-stage heart failure requiring advanced heart failure therapies.
UNASSIGNED: This study sought to provide post-cardiac transplant survival data in patients with ACM in the contemporary era of mechanical circulatory support and cardiac transplantation.
UNASSIGNED: Adults (≥18 years of age) who underwent first-time, single-organ heart transplantation were identified from the United Network for Organ Sharing between October 18, 2008, and October 18, 2018. Cardiomyopathy subtypes that could have been supported with a left ventricular assist device (LVAD) including ACM, dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM) were included. A multivariable Cox regression analysis was performed to determine the association between cardiomyopathy subtype and post-cardiac transplant survival.
UNASSIGNED: This analysis included 18,270 patients (357 with ACM; 10,662 with DCM; and 7,251 with ICM). Heart transplant recipients with ACM were younger, included more women, and had higher pulmonary vascular resistance at the time of listing. Patients with ACM had a lower percentage of durable LVADs at the time of transplant across all years of the study period. Patients with ACM did not experience an increase in post-cardiac transplant mortality compared to those with DCM (adjusted hazard ratio: 0.96; 95% confidence interval: 0.79 to 1.40; p = 0.764) or ICM (adjusted hazard ratio: 0.85; 95% confidence interval: 0.6 to 1.2; p = 0.304).
UNASSIGNED: Patients with ACM who received heart transplants between 2008 and 2018 had similar post-cardiac transplant survival to those with dilated and ischemic cardiomyopathy. Bridge-to-transplant LVAD use remains lower compared to other cardiomyopathy subtypes.