Organelle network dysfunction in primary cardiomyopathy: An integrated perspective on pathogenesis and therapeutics.

Pediatric dilated cardiomyopathy and the progression to heart failure: mechanisms and interventions focusing on the “gene-inflammation-metabolism” axis

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy in children and a leading indication for heart transplantation. Despite considerable progress in understanding its genetic architecture, translating these insights into improved outcomes for children remains challenging. The pathophysiology of pediatric dilated cardiomyopathy is highly complex, extending beyond a simple monogenic model to encompass intricate interactions between genetic predisposition, inflammatory triggers, and metabolic dysregulation. This review systematically synthesizes current evidence on the mechanisms driving heart failure progression in pediatric dilated cardiomyopathy, focusing on the integrated framework of the “gene-inflammation-metabolism” axis. We begin by outlining the genetic landscape of pediatric dilated cardiomyopathy, highlighting key pathogenic genes and their associated phenotypes, with particular emphasis on features distinct from adult disease. We then explore how environmental “second hits” (such as viral infection and autoimmune responses) trigger excessive inflammatory reactions, and discuss the significance of special clinical phenomena such as “hot phase” myocarditis in genetically susceptible children. Concurrently, we systematically examine the metabolic reprogramming of the failing heart, including mitochondrial dysfunction, substrate utilization shifts, insulin resistance, and iron metabolism disturbances, analyzing how these processes further compromise energy-starved cardiomyocytes. By integrating these three interconnected domains, this review presents a pediatric-specific triaxial framework that unifies known DCM pathways into a single actionable model for precision risk stratification and targeted therapy. This framework supports the development of novel biomarkers, multi-dimensional risk stratification strategies, and targeted interventions—ranging from anti-inflammatory agents and metabolic modulators to gene therapy, psychological support, and AI-assisted risk prediction. This review aims to provide a novel theoretical framework and practical roadmap for the clinical management and future research of pediatric dilated cardiomyopathy.

The role of IL-6 in hypertrophic and dilated cardiomyopathy: clinical and therapeutic implications

Targeted Therapies in Hypertrophic Cardiomyopathy: A Practical Review of Evidence, Implementation, and Innovation.

Hypertrophic cardiomyopathy (HCM) is a common inherited disorder characterized by sarcomere dysfunction leading to myocardial hypertrophy, diastolic impairment, and, in many patients can result in dynamic left ventricular outflow tract obstruction (LVOTO). Traditional pharmacologic management of HCM has relied on β-blockers and nondihydropyridine calcium channel blockers, which provide symptomatic relief but do not directly target underlying molecular pathology of the disease. Advances in mechanistic understanding of HCM, particularly the role of hyperactive actin-myosin cross-bridge cycling, have led to the development of cardiac myosin inhibitors (CMIs), a novel class of targeted therapeutics. This review systematically summarizes the pharmacology, clinical trial evidence, dosing strategies, and safety considerations surrounding CMIs. While CMIs have transformed the management of obstructive HCM, their role in non-obstructive HCM disease remains uncertain, highlighting ongoing unmet needs. Emerging therapies, including next-generation myosin modulators, metabolic agents, sodium-glucose cotransporter inhibitors, and RNA-targeted approaches, offer promise for broader disease modification across all HCM phenotypes. As therapeutic options expand, combining pharmacology and clinical assessment endpoints in the treatment of HCM patients will be essential to define long-term benefit.

Chronic Kidney Disease-Associated Cardiomyopathy: Mechanisms and Therapeutic Strategies.

Chronic kidney disease-associated cardiomyopathy (CKD-CM) is a term that captures the spectrum of myocardial disease that begins early in chronic kidney disease (CKD) and progresses as kidney function declines. Historically described as uremic cardiomyopathy, the condition was associated with severe left ventricular hypertrophy and fibrosis in patients with kidney failure. However, functional abnormalities and myocardial injury have been shown to begin much earlier, with diffuse interstitial fibrosis preceding overt hypertrophy or reduced ejection fraction. Fibrosis drives heart failure with preserved ejection fraction (HFpEF)-like physiology and atrial fibrillation and increases arrhythmic risk. In this review, we describe the multiple interacting mechanisms, including abnormal loading, neurohormonal activation, metabolic and inflammatory stress, mineral bone disorder, and microvascular dysfunction. We summarize imaging findings across CKD stages and describe established and emerging therapeutic strategies. A better understanding of CKD-CM pathogenesis is likely to enable early intervention and prevention, with successful outcomes measured by reduced progression to severe cardiomyopathy and lower cardiovascular mortality in CKD.

ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?

Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.

Acox2 deficiency induces cardiac dysfunction via cross-organ metabolic reprogramming in mice

Secondary cardiomyopathies are a major cause of heart failure (HF) with diverse etiologies and high mortality rates. For example, over 50% of patients with end-stage liver disease develop cardiac dysfunction, clinically termed cirrhotic cardiomyopathy (CCM). While serum metabolites mediating cross-organ communication are known to play a critical role in CCM development, the underlying pathogenic mechanisms remain poorly understood due to a lack of optimal experimental models. We generated Acox2 knockout (KO) mice using CRISPR/Cas9 technology to investigate the role of ACOX2, a rate-limiting peroxisomal enzyme. Cardiac function was assessed via echocardiography. We performed RNA sequencing and quantitative proteomic analyses to evaluate cardiac gene expression. Furthermore, global succinylome profiling was conducted to determine changes in protein succinylation, and global metabolomics analysis was used to identify significantly differentially expressed metabolites (SDMs). Acox2 KO mice successfully recapitulated the hepatic phenotypes observed in patients with ACOX2 homozygous mutations, including liver fibrosis and lymphocytic infiltration. Given that ACOX2 is not expressed in the mouse heart throughout its lifespan, we initially hypothesized that Acox2 deficiency would have no direct impact on cardiac function. However, by 6 months of age, Acox2 KO mice exhibited significantly compromised cardiac parameters via echocardiography, alongside elevated biomarkers of cardiomyopathy and heart failure. While Acox2 deficiency had limited impact on the cardiac proteome, global succinylome profiling revealed a pervasive decrease in protein succinylation in Acox2 KO hearts. Notably, approximately 60% of these hypo-succinylated sites were located on mitochondrial and myofibrillar proteins, including SUCLA2 (K94), CS (K321), FH (K470), MDH1 (K110), OGDH (K999), TNNC1 (K86), VCL (K453), MYH7 (K83), and MYL3 (K9)—a profile tightly associated with cardiomyopathy. Seahorse assays and scanning electron microscopy further indicated impaired mitochondrial function in Acox2 KO mice. Metabolomic analysis revealed a dramatic accumulation of plasma C27 bile acid intermediates and a concomitant decrease in cardiac succinyl-CoA levels. Our findings underscore the critical role of the succinylation landscape in maintaining cardiac function. The cardiac pathology observed in Acox2 KO mice originates from cross-organ metabolic signaling, providing new insights into the pathogenesis of secondary cardiomyopathies, such as cirrhotic cardiomyopathy.