Cardiomyopathy classification remains challenging due to their extraordinary clinical, morphological, and genetic heterogeneity. As diagnostic technologies evolve, so too must the frameworks by which we conceptualize and communicate these diseases. Since the 2008 ESC morphofunctional classification and the genotype-phenotype integrated MOGE(S) system proposed in 2013, substantial advances in imaging and genetics have prompted a revised 2023 ESC phenotype-first model. The five current phenotypes-dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and non-dilated left ventricular cardiomyopathy (NDLVC)-capture major morphological expressions but display extensive overlap, especially among DCM, ARVC, and NDLVC. This overlap underscores the need for dynamic, multiparametric diagnostic pathways and individualized interpretation.

Fatty acid oxidation (FAO) provides the healthy heart with 60%-90% of its ATP, with the remainder coming from metabolism of glucose. Metabolic flexibility is key to heart function, ensuring an uninterrupted source of fuel. In heart failure, a shift from FAO to glucose-dependent metabolism occurs as disease progresses, supporting the widely held notion that fat is the optimal substrate in the heart. In this issue of the JCI, Kim et al. challenge this assumption. In studies of acetyl-CoA carboxylase-deficient (ACC-deficient) mice, they found that unregulated use of fat as a substrate led to cardiac damage. ACC-deficient mice developed cardiolipin deficiency as a result of excessive FAO depleting stores of linoleic acid, which is used as a substrate for cardiolipin maturation. The resulting mitochondrial dysfunction was associated with dilated cardiomyopathy and heart failure in these mice. The findings highlight potential for development of therapeutic strategies that balance energy sources and replenish cardiolipin levels.

Dilated cardiomyopathy (DCM) is a primary myocardial disorder characterized by progressive ventricular dilatation and impaired myocardial systolic contractility, and it represents the most common form of cardiomyopathy globally. DCM drives a substantial worldwide disease burden, thus presenting a formidable and persistent challenge to global public health systems. The pathogenesis of DCM is marked by extreme etiological heterogeneity: 30%-50% of cases have a familial origin, with genetic determinants serving as the core driver of disease onset and progression. With the rapid advancement and widespread application of next-generation sequencing (NGS) technologies, a growing repertoire of DCM-causative genes has been successfully identified. These genes encode key functional proteins that regulate multiple core physiological processes in cardiomyocytes, including sarcomeric structure maintenance, intracellular signal transduction, and myocardial energy homeostasis. DCM-causing genes can be classified into multiple categories according to their functions. Sarcomeric protein genes (such as TTN, MYH7, and TNNT2) disrupt sarcomere assembly and contractile function through mechanisms such as haploinsufficiency and the toxic peptide hypothesis; mutations in nuclear membrane protein genes (such as LMNA and EMD) cause abnormal nuclear structure and disordered mechanotransduction signals; ion channel genes (such as SCN5A, CACNA1C, and RYR2) affect electrophysiological balance and calcium handling; desmosome-related genes (such as DSC2 and DSP) are associated with abnormal cell junctions and dysregulation of the Wnt/β-catenin pathway; KLF13, ETS1, and BMP10 are possible candidate genes for DCM with limited research; loss of function of RBM20 leads to abnormal splicing of TTN, CamkIIδ, RyR2, etc. and causes nuclear import defects as well as cytoplasmic RBM20-RNP granule toxicity, thereby driving ventricular dilation. These genes drive myocardial remodeling through common signaling pathways (such as ERK and TGF-β). Potential treatment strategies include gene-level interventions, targeted pathway inhibitors, and myosin activators. However, genetic heterogeneity results in a narrow applicable population for single-gene therapies. Future research needs to shift from targeting individual genes to improving the common pathological environment to achieve broad-spectrum treatment. Exploring upstream prevention of mutations or activation of endogenous repair mechanisms provides new directions for the treatment of DCM.

Although Doxorubicin (Dox) is an effective anticancer drug, it can cause severe cardiotoxicity. While several mechanisms have been proposed to explain Dox-induced cardiomyopathy (DIC), strategies to prevent it remain limited. In previous research on isolated cardiomyocytes, we identified that Empagliflozin (EMPA), an antidiabetic drug, mitigated Dox-induced ER stress and apoptosis. In this in vivo study using rats, we further investigated EMPA's potential in preventing and treating DIC. Rats administered a cumulative dose of 15 mg/kg Dox exhibited significant cardiovascular damage, including left ventricular cavity dilation, decreased left ventricular ejection fraction (LVEF), ER dilation, mitochondrial defects and vacuole formation. These structural changes were linked to the activation of ER-stress pathways (PERK, IRE1 and ATF6) and upregulation of apoptotic proteins initiated by ER stress. When EMPA (10 mg/kg/day) was administered either prophylactically or concurrently with Dox, it significantly attenuated adverse LV remodelling and preserved LVEF. Additionally, EMPA prevented ER stress and subsequent apoptosis in the myocardium of the Dox + EMPA-treated group. These findings suggest that EMPA offers cardioprotective benefits in DIC, likely through the inhibition of ER-stress-induced myocardial injury.

Genetic mutations in myosin, the motor protein that powers the heartbeat, are linked to inherited hypertrophic and dilated cardiomyopathies. Mavacamten and omecamtiv mecarbil are therapeutic, myosin-targeted drugs designed to treat these myopathies, but their mechanism of action has remained unclear. Using single-particle cryo-EM, we determined near-atomic resolution structures of wild-type, mavacamten-bound, and omecamtiv mecarbil-bound myosin molecules. Across all conditions, we observe two distinct, alternate conformations of myosin, not previously reported. We show how mavacamten stabilizes one conformation by reinforcing key electrostatic interfaces in the molecule, whereas omecamtiv mecarbil weakens these interfaces, favoring the second structure. This remodeling elucidates previously unclear allosteric mechanisms through which these drugs either inhibit or enhance myosin activity, countering the deleterious impacts of disease. These findings reveal how drugs modulate myosin structure to control cardiac contractility.

Developing cardiomyocytes grow by proliferative and hypertrophic pathways and can be mediated by the RAF/MEK/ERK (MAPK) pathway. Dysregulation of Raf-1 in late development causes murine myocardial hypertrophy, however, less is known about B-Raf. We hypothesized the loss of B-Raf (conditional knockout) would lead to reduced neonatal cardiomyocyte proliferation and accelerate maturation, resulting in impaired function in adulthood. We also determined sex differences to ensure complete interrogation of the model. Murine neonatal hearts undergo a proliferative to terminal differentiation switch that is complete by 2 weeks of age and thus studied hearts at four timepoints in that period (Days 1, 3, 8, 14). Primary cultures of knockout (KO) hearts revealed reduced B-Raf and phosphorylated ERK1/2 by postnatal day 3, even when stimulated with insulin growth factor 1. Histology revealed increased cardiomyocyte volume in KO hearts by 3d and elevated markers of hypertrophy and maturation by 8d (mTOR and SERC2A). There was also elevated cell cycle inhibitors p21, p27 and p53, accompanied with increased cyclin levels. Heart weight to body weight ratio was greater in 8d KO compared to age matched wildtype (WT) animals as well as other KO ages, whereas there was no difference among WT ages. Earliest signs of altered myocardium via echocardiographs were detected by 3 months. KO mice exhibited dilated cardiomyopathy, thinned myocardial walls, and enlarged left chamber volume. Deletion of B-Raf led to adaptive remodeling of male KO hearts. This adaptation maintains cardiac function however future studies will interrogate changes in the face of physiological stress.

In 2018, the FDA issued an alert about a potential link between dilated cardiomyopathy (DCM) in pet dogs and cats and diets high in pulses (peas, lentils, chickpeas, and beans). Given reported myocardial ultrastructural abnormalities in this disease, the objective was to compare myocardial mitochondria, autophagic structures, and other subcellular organelles in cats with DCM eating high- versus low-pulse diets. Left ventricular tissue from cats with DCM eating high- (n = 4) or low-pulse (n = 3) diets was evaluated using transmission electron microscopy. Myofibrils, mitochondria, T-tubules, nuclei, z-lines, autophagic structures, and intercalated discs were evaluated qualitatively. Diet groups were compared for qualitative findings, as well as mitochondrial number, area, and perimeter; sarcomere length; lipid droplet number and area, and mitochondrial stage in the perinuclear, interfibrillar, and subsarcolemmal regions. Cats with DCM eating high-pulse diets had more unknown vacuoles and fewer Stage B mitochondria, with more Stage BC mitochondria compared to cats with DCM eating low-pulse diets. These results suggest that cats with DCM eating high-pulse diets have mitochondria in more advanced stages of degeneration. The higher number of unknown vacuoles could represent more mitochondrial degeneration or increased autophagy. Further ultrastructural investigation is warranted to help identify the cause of this diet-associated disease.