肥大型心筋症

We aimed to develop and assess the performance of a Machine learning (ML) model integrating common clinical features to predict arrhythmic events in patients with Hypertrophic Cardiomyopathy (HCM). Post-hoc analysis of an international multicenter registry of 531 HCM patients (49 years (IQR 35-61), 57% male) who underwent cardiac magnetic resonance (CMR). The dataset comprised clinical, echocardiographic, and CMR variables, including quantification of late gadolinium enhancement (LGE) using the + 6 SD method. The endpoint was a composite of sudden cardiac death (SCD), aborted SCD, and sustained ventricular tachycardia (VT). A total of 28 events occurred over a median follow-up of 4.1 (IQR 1.8-7.3) years. Several ML models were developed and the predictive performance of the best model was compared to the ESC HCM risk score and to the amount of LGE. The Random Forest (RF) was the most effective method showing a good performance for predicting arrhythmic events [AUC of 0.78 (95% CI: 0.76-0.82, p < 0.001)], substantially outperforming the ESC HCM risk score [AUC of 0.64 (95% CI 0.62-0.67; p < 0.001), p < 0.001 for comparison]. However, when compared to LGE alone [AUC of 0.76 (95% CI: 0.73-0.84, p < 0.001)], the RF model did not provide significant improvement in predicting the endpoint (p = 0.817 for comparison). A ML model using available clinical variables significantly outperformed the ESC HCM risk score in predicting arrhythmic events in HCM. However, its incremental value over LGE alone was weak, underscoring the strong predictive value of this imaging marker. This findings should be interpreted as exploratory and hypothesis-generating.

BACKGROUND AND OBJECTIVES: Hypertrophic cardiomyopathy is a life-threatening disease with limited studies in Middle Eastern populations. This pilot study (n = 8) aimed to identify rare genetic variants to enable future presymptomatic diagnosis and primary prevention. While the sample size precludes establishing population-level prevalence, our findings provide a springboard for generating testable hypotheses for future multicenter trials. METHODS: Whole-exome sequencing was performed on eight unrelated Egyptian patients. We prioritised variants using stringent criteria: allele frequency < 0.01 in gnomAD, combined annotation dependent depletion (CADD) score > 10, and focused analysis of 29 genes with definitive or moderate evidence for hypertrophic cardiomyopathy causation according to Clinical Genome Resource (ClinGen). Variants were ACMG/AMP-classified and correlated with detailed clinical phenotypes. RESULTS: We identified 21 rare variants across 10 hypertrophic cardiomyopathy-associated genes. Core sarcomeric genes accounted for seven variants: MYBPC3 (n = 2; one likely pathogenic, p.Gly1206Asp), MYH7 (n = 2; one pathogenic, p.Phe252Ser), and TNNT2 (n = 3; all variants of uncertain significance). Additionally, likely pathogenic variants were found in PLN (p.Arg25Cys) and KLHL24 (p.Arg103*). Patients with pathogenic or likely pathogenic sarcomeric variants exhibited severe phenotypes, including septal thickness up to 30 mm, left ventricular outflow tract gradients up to 60 mmHg, and a high arrhythmic burden, influencing decisions like implantable cardioverter-defibrillator implantation and myectomy. Notably, all three TNNT2 carriers manifested atrial fibrillation or non-sustained ventricular tachycardia, reinforcing its arrhythmic risk. Four novel or likely pathogenic variants were submitted to ClinVar. CONCLUSION: As the first genetic study of hypertrophic cardiomyopathy in an Egyptian population, this work expands the global mutational spectrum, demonstrates the utility of genetic testing for risk stratification and personalised management, and underscores the need to diversify genomic datasets for equitable precision medicine.

BACKGROUND AND AIMS: Atrial cardiomyopathy (AtCM) is associated with atrial fibrillation (AF). While histological studies describe underlying mechanisms of AtCM, these insights remain disconnected from clinical AtCM. This study determines the histological basis of non-invasive AtCM markers and assess their prognostic value in patients undergoing cardiac surgery. METHODS AND RESULTS: Left and right (LA/RA) atrial tissue samples were obtained in patients undergoing cardiac surgery (n = 136) in the RACE V Tissue Bank study. Pre-operative rhythm history, digital ECG, transthoracic echocardiography (TTE) and biomarker levels were used to group patients in AtCM stages: AF: history of paroxysmal, persistent or permanent AF, Severe (LAVi>50 mL/m2 or LAEF<35%), Moderate (LAVi 34-50 mL/m2, or LAEF 35-50% AND NT-proBNP >250 pg/mL), Mild (no AF, LAVi≤34 mL/m2 AND P-terminal Force V1 > 5 mV*ms OR P wave duration > 120 ms), and no AtCM. Tissue was stained (WGA/CD31/Vimentin) to quantify fibrosis, fibroblast density, myocyte diameter and vascularization. Post-operative rhythm was monitored continuously (2.5 years) using implantable loop recorders. Patients with severe AtCM had extended endomysial fibrosis (LA: +0.82µm, pFDR,LA < 0.001; RA: +0.64µm, pFDR,RA = 0.010) and larger left atrial cardiomyocytes (LA: +0.92µm, pFDR,LA = 0.026). Moderate AtCM patients showed LA myocyte hypertrophy (LA: +1.35µm, pFDR,LA = 0.007). Mild AtCM patients had similar histological features to patients without AtCM. Moderate (β = 3.56, pFDR = 0.045) and severe (β = 3.74, pFDR = 0.034) AtCM patients had a higher AF burden late after cardiac surgery. CONCLUSION: Clinical AtCM markers reflect pro-fibrotic and pro-hypertrophic remodelling in the moderate to severe AtCM stages and are associated with a higher AF burden late after surgery.

TOP3A-related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss-of-function of the mitochondrial-specific isoform of topoisomerase 3α, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome-like disorder. Adult-onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS-like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A-related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A-related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A-related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke-like episodes, and Leigh-like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom-like syndrome and the adult-onset form.

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.