特発性拡張型心筋症

Left atrial (LA) strain parameters predict mortality in patients with ischaemic/non-ischaemic dilated cardiomyopathy (DCM). Left bundle branch block (LBBB) is a common conduction abnormality in those patients. To date, the impact of LBBB on LA strain parameters assessed by cardiovascular magnetic resonance imaging (cMRI) has not been studied systematically. In this retrospective single-centre study, we included 20 (10 female) controls without DCM or LBBB, 21 (11 female) patients with LBBB without DCM, 20 (7 female) patients with DCM without LBBB, and 20 (9 female) patients with DCM and LBBB. LA volumes and strain were assessed semi-automatically using the cvi42® and Segment® software. LA reservoir/conduit strain and corresponding strain rates were significantly impaired in patients with DCM (p = 0.003/0.022 respectively < 0.001/0.004) in comparison to controls. The presence of LBBB did not lead to significant changes of LA reservoir/conduit strain in controls (p = 0.919/0.391) nor in patients with DCM (p = 0.862/0.999), same was true for LA reservoir/conduit strain rate in patients with DCM (p = 0.999/0.812). LA conduit strain rate of patients with LBBB was significantly impaired in comparison to controls (p = 0.005). Left ventricular dilatation was associated with significantly impaired LA reservoir/conduit strain/strain rates. The presence of LBBB was not associated with additional impairment in LA strain/strain rate parameters in patients with ischaemic/non-ischaemic DCM, supporting the robustness of LA functional parameters in the presence of this common conduction abnormality. However, in patients with LBBB without dilatation LA conduit strain rate was significantly impaired in comparison to controls and further studies are needed to evaluate the impact of this finding.

Dilated cardiomyopathy (DCM) is a major cause of heart failure, but the organelle-level mechanisms linking cardiomyocyte stress to maladaptive remodeling remain incompletely defined. Transmembrane protein 87a (TMEM87a) is a Golgi-associated transmembrane protein implicated in organelle homeostasis and ion conductance. Here, we investigated whether TMEM87a regulates cardiomyocyte integrity and DCM pathogenesis. In a doxorubicin-induced mouse model of DCM, cardiac TMEM87a expression was increased, suggesting engagement of this pathway during myocardial stress. Cardiomyocyte-specific Tmem87a knockout mice developed spontaneous DCM-like disease, including impaired systolic function, ventricular dilation, elevated plasma brain natriuretic peptide, myocardial fibrosis, and cardiomyocyte hypertrophy. Quantitative proteomics of knockout hearts identified ferroptosis as the most significantly enriched pathway. Consistent with disrupted iron and redox homeostasis, Tmem87a-null hearts showed increased iron-handling proteins, myocardial iron deposition, elevated hydrogen peroxide and malondialdehyde levels, reduced GPX4, and increased PTGS2. Pharmacological inhibition of ferroptosis with ferrostatin-1 improved cardiac function and attenuated pathological remodeling in Tmem87a knockout mice. These findings identify TMEM87a as a previously unrecognized regulator of cardiomyocyte homeostasis and implicate ferroptosis as an important downstream effector of cardiac injury caused by Tmem87a knockout.

AIMS: Mutations in the LMNA gene, which encodes lamin A/C, cause a variety of diseases known as laminopathies. Some mutations are particularly associated with the occurrence of dilated cardiomyopathy and heart failure, but the genotype-phenotype relationship and underlying mechanisms are unclear. METHODS AND RESULTS: Induced pluripotent stem cells (hiPSCs) from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro) and a CRISPR/Cas9 corrected isogenic control hiPSCs clones were differentiated into cardiomyocytes (hiPSC-CMs), with no difference in the differentiation yield and in sarcomere organisation between the two cell lines. However, 3D cardiac organoids generated with LMNA p.H222P hiPSC-CMs showed an impaired contractility compared to control organoids. Calcium transient recordings in LMNA p.H222P mutant cardiomyocytes showed a significantly higher calcium transient amplitude with a significantly slower calcium re-uptake. Transcriptomic analyses suggested a global mitochondrial dysfunction and in particular an impaired mitochondrial calcium uptake with a significantly decreased expression of the mitochondrial calcium uniporter (MCU). This decrease in MCU expression was confirmed by western blot and was accompanied by an increased MICU1:MCU ratio, as well as an increased PDH Ser232 and PDH Ser300 phosphorylation, indicating an altered mitochondrial calcium uptake in the LMNA mutant hiPSC-CMs. Consistently, lower mitochondrial respiration and ATP levels were found in LMNA p.H222P hiPSC-CMs as compared to isogenic controls. Strikingly, treatment with the MCU activator amorolfine restored mitochondrial calcium uptake and improved contractility in LMNA mutant hiPSC-CMs. CONCLUSIONS: Our results establish a direct mechanistic link between nuclear envelope dysfunction and impaired mitochondrial function, and highlight the MCU complex as a potential therapeutic target in LMNA-related cardiomyopathy. More broadly, this work provides a paradigm for connecting gene-specific nuclear defects to mitochondrial dysfunction in inherited cardiomyopathies.

BACKGROUND: Infantile-onset cardiomyopathy due to mitochondrial dysfunction is a severe condition frequently associated with poor prognosis. Biallelic pathogenic variants in ELAC2, an essential mitochondrial tRNA processing gene, have been implicated in this phenotype. This study investigates the clinical and genetic spectrum of ELAC2-related disease in a national cohort from Kuwait. METHODS: We conducted a retrospective cohort study using data from the Kuwait Medical Genetics Center registry, including individuals with genetically confirmed or clinically suspected ELAC2-related cardiomyopathy. Clinical, metabolic, and molecular data were reviewed. Exome sequencing or targeted mutation testing was performed in affected individuals and at-risk family members. RESULTS: A total of 34 individuals from 23 consanguineous families were identified, of whom 30 were genetically confirmed to harbor the homozygous ELAC2 founder variant c.460T>C; p.(Phe154Leu). All individuals presented in infancy with severe cardiomyopathy and refractory lactic acidosis. Neurological involvement was observed in 39% of cases. The majority exhibited hypertrophic cardiomyopathy, with variable dilated features and pericardial effusion. The disease course was fatal in all, with most patients dying in infancy. CONCLUSION: This is the largest single-country cohort reported to date with ELAC2-related mitochondrial cardiomyopathy, raising the global case total to over 70. The uniform presence of the Phe154Leu variant across unrelated Bedouin families highlights a strong founder effect. Given the rapid disease progression and high mortality, we recommend targeted ELAC2 screening in infants with idiopathic cardiomyopathy and persistent lactic acidosis, particularly in consanguineous populations. Premarital carrier testing and early family counseling should be prioritized to support preventive strategies.

In non-muscle cells, actin filaments exhibit variable lengths and rapid turnover, with subunits adding primarily at the barbed end. The situation is strikingly different in striated muscle sarcomeres, where despite rapid turnover, actin thin filaments exhibit uniform length and exchange subunits primarily at the pointed end. This filament length uniformity is tightly regulated by several proteins, including the molecular ruler nebulin in skeletal muscle and the barbed- and pointed-end capping proteins CapZ and tropomodulin (Tmod) in both skeletal and cardiac muscles. Recent studies in cells and animal models have identified leiomodin-2 (Lmod2) as an additional regulator proposed to promote pointed-end elongation to maintain thin filament length. This activity would make leiomodin the only known eukaryotic factor to drive pointed-end elongation, yet its molecular mechanism remains unresolved. Here, we present a series of cryo-electron microscopy structures that support a stepwise elongation mechanism in which two Lmod2 molecules alternate at the pointed end while recruiting actin monomers. These findings establish the molecular basis of pointed-end elongation in muscle sarcomeres and provide a framework for understanding mutations in Lmod2 that cause dilated cardiomyopathy.