Cardiomyopathies constitute a heterogeneous group of myocardial disorders representing leading causes of heart failure and cardiovascular mortality worldwide. While genetic mutations have been extensively characterized across different cardiomyopathy subtypes, the mechanistic links between genotype and phenotype remain incompletely understood. This review synthesizes current knowledge regarding chromatin remodeling complexes and their roles in cardiac gene regulation under physiological and pathological conditions. Moreover, disease-specific chromatin remodeling patterns were examined across dilated, hypertrophic, arrhythmogenic, and restrictive cardiomyopathies, highlighting both conserved mechanisms and subtype-specific alterations. Chromatin remodeling alterations contribute significantly to cardiomyopathy pathogenesis across multiple subtypes. The reversibility of epigenetic modifications presents therapeutic opportunities not available with genetic interventions. Selective HDAC inhibitors and EZH2 antagonists show promise in preclinical models, though clinical translation requires development of cardiac-specific delivery systems. CRISPR-based epigenetic editing technologies offer future potential for precise genomic locus-specific interventions to reverse pathological transcriptional programs. Chromatin remodeling complexes including SWI/SNF (BAF), NuRD, Polycomb, ISWI, CHD, and INO80 families- modulate disease expression, progression, and phenotypic variability through epigenetic modifications and ATP-dependent chromatin remodeling. Emerging evidence demonstrates that chromatin remodelers interact dynamically with DNA methylation machinery, histone-modifying enzymes, and cardiac transcription factors to orchestrate pathological gene expression programs. Understanding these epigenetic mechanisms offers unprecedented opportunities for developing novel therapeutic strategies targeting the chromatin regulatory apparatus, potentially reversing maladaptive transcriptional programs that drive disease progression.

Background: Iron overload cardiomyopathy (IOC) is a major determinant of outcomes in hemochromatosis, and conventional echocardiography may miss early myocardial toxicity. Comparative data on primary (PH) versus secondary hemochromatosis (SH) using myocardial work (MW) indices are limited. Methods: We performed a retrospective cross-sectional study of 34 adults (16 PH and 18 SH patients) at a tertiary center. They all underwent echocardiography with speckle-tracking to obtain LV global longitudinal strain (GLS) and non-invasive MW indices from pressure-strain loops: global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). Echocardiographic phenotypes were classified as a Normal, Dilated, Restrictive, or right ventricular/pulmonary hypertension (RVPH) phenotype. Results: SH patients showed higher iron burden and neurohormonal activation than PH patients (maximum ferritin 2954 vs. 444 ng/mL; BNP 93 vs. 13.5 pg/mL; both p < 0.001) and accounted for all deaths (33% vs. 0%) despite similar 3D LVEFs and GLSs. PH patients predominantly exhibited Normal phenotypes (81%), whereas SH patients more often showed advanced phenotypes, mainly RVPH and Dilated. GWI correlated inversely with ferritin (ρ ≈ -0.40), particularly ferritin at echocardiography in SH patients, while PH patients showed no significant correlations. GWW was higher in Dilated/RVPH compared to Normal phenotypes, and in SH patients, higher maximum ferritin was associated with impaired right ventricular free-wall strain. Conclusions: PH and SH patients exhibit distinct IOC phenotypes, with SH patients showing more advanced remodeling and worse outcomes. In this exploratory analysis, MW indices showed modest associations with iron burden markers, suggesting they may provide complementary information beyond LVEF and GLS. These preliminary findings require validation in larger, prospective studies.

Troponin T (TnT), the tropomyosin (Tm)-binding subunit of troponin, plays a central role in regulating striated muscle contractility. The recently identified Tm-binding site 3 in the highly conserved C-terminal end segment of TnT has a troponin I (TnI)-like inhibitory function. A restrictive proteolytic removal of the N-terminal hypervariable region (amino acids 1-71) of cardiac TnT (cTnT-ND) in vivo in adaptation to inotropy-afterload mismatch slows down ventricular end-systolic velocity to increase ejection time and stroke volume through a conformational modulation that enhances the function of Tm-binding site 3. Mutations in this segment of cTnT cause hyperactivation of cardiac muscle and hypertrophic cardiomyopathy (HCM). Here we characterized isolated C-terminal end 14 amino acids (275-288) peptide of cTnT (cTnT-C14) for interactions with Tm, F-actin, and F-actin-Tm thin filament using localized surface plasmon resonance (LSPR). Wild-type cTnT-C14 peptide showed saturable strong binding to Tm and F-actin in LSPR, which is significantly weakened by HCM mutation R278C, K280N or R286C. Contractility studies of permeabilized mouse cardiac muscle strips found that the HCM mutant peptides all lost the known Ca[2+]-desensitization function of wild-type cTnT-C14 peptide, correlating to the pathogenesis and pathophysiology of HCM. Treatment of cTnT-ND transgenic mouse cardiac muscle with the phenotype of lower than wild-type maximum force production with wild-type cTnT-C14 peptide did not produce additive effect, implicating that cTnT-C14 peptide and cTnT-ND both utilize the Tm-binding site 3 mechanism to reduce maximum activation while free cTnT-C14 peptide does not diminish the effect of cTnT-ND in native thin filament on increasing the overall sensitivity to Ca[2+]-activation. The functionality of cTnT-C14 in the form of free peptide presents a novel reagent for adjusting contractile kinetics of cardiac muscle and alleviating myofilament hyperactivation.

Restrictive cardiomyopathy (RCM) is a rare cause of cardiomyopathy, the etiology of which remains poorly understood and may result from inherited or acquired predispositions to disease, or a combination thereof. Familial RCM 5 (OMIM 617047) usually has autosomal dominant inheritance with most of the identified genes encoding sarcomere or Z-disk proteins. The aim of this study was to determine the disease-causing variant in a South African family diagnosed with RCM. A South African family was screened at Groote Schuur Hospital, and the DNA of the affected individuals were investigated using next-generating sequencing methods with a custom cardiomyopathy panel of 38 genes. Possible RCM-causing variants were selected according to the ACMG/AMP guidelines. Primers were designed, and the Sanger sequencing method was used for variant validation. Segregation analysis was performed after the RCM-causing variant was identified. The family was initially diagnosed with Noonan syndrome-associated cardiomyopathy based on suggestive clinical findings; however, panel screening for Noonan's found no causative gene. The diagnosis was revised, and an alternative cause of RCM was considered. A custom cardiomyopathy panel sequencing found a heterozygous missense NM_001458.5 (FLNC): c.6031G > A (p.Gly2011Arg) variant in all affected individuals. The variant is located in the FLNC protein R18 Ig-loop of the rod 2 domain and has been associated with severe RCM. This case highlights the importance of considering a broader genetic differential diagnosis in patients presenting with Noonan syndrome-like features, particularly when cardiac abnormalities are present and initial genetic testing for common Noonan syndrome genes is negative. Mutations in genes like FLNC, while not typically associated with classic Noonan syndrome, can cause overlapping clinical presentations. Whole exome sequencing can be a valuable tool for identifying these alternative genetic etiologies and guiding appropriate clinical management and genetic counseling for families.

Mulibrey nanism is a rare autosomal recessive multisystem disorder caused by biallelic loss of function variants in TRIM37 encoding a peroxisomal E3 ubiquitin ligase. Initially described in Finland, where it remains most prevalent due to a founder mutation, the condition is now recognized worldwide and is characterized by severe prenatal-onset growth failure, distinctive craniofacial features, radiological abnormalities, ocular findings, and hepatopathy. Although its clinical spectrum extends far beyond these core manifestations, the major determinant of morbidity and mortality is progressive cardiovascular disease, including constrictive pericarditis and restrictive cardiomyopathy. Additional features include metabolic dysfunction such as insulin resistance and type 2 diabetes, gonadal insufficiency, skeletal abnormalities including fibrous dysplasia, and an increased risk of benign and malignant tumours. The clinical course evolves across the lifespan from early growth and developmental abnormalities to progressive multisystem disease in adolescence and adulthood. Recent advances have expanded understanding of TRIM37 function, linking it to mTORC1 TFEB signalling autophagy, centrosome integrity, extracellular matrix regulation, and immune cell function, providing mechanistic insights into tumour predisposition, skeletal pathology, and immune dysregulation. Management remains supportive and requires multidisciplinary care with emphasis on early recognition and treatment of cardiac disease, metabolic complications, and malignancy risk. Prognosis is variable but improves with early diagnosis and appropriate surveillance. This review summarises the clinical spectrum molecular mechanisms and current management of Mulibrey nanism and highlights priorities for future research.

Constrictive pericarditis (CP) is an uncommon but potentially reversible cause of heart failure, characterized by pericardial thickening, fibrosis, and loss of elasticity. Early recognition is essential because timely intervention can be curative. We report the case of a 64-year-old man with multiple comorbidities and recurrent heart failure admissions who was ultimately diagnosed with CP. Echocardiography suggested constrictive physiology (including annulus reversus), and hemodynamic catheterization demonstrated elevated right atrial pressure with rapid "y" descent, equalization of diastolic pressures across chambers, and a classic square root sign. He underwent pericardiectomy with an uneventful recovery and marked symptomatic improvement. This case highlights the diagnostic complexity of CP and underscores the central role of invasive hemodynamics in distinguishing it from other causes of heart failure, including restrictive cardiomyopathy and diastolic heart failure.