Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3.

PURPOSE: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. METHODS: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. RESULTS: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood-onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. CONCLUSIONS: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function.

Spectrum of MYBPC3 Gene Mutations in Patients with Hypertrophic Cardiomyopathy, Reporting Two Novel Mutations from North-West of Iran.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death (SCD) in children and young adults and is the most frequent genetically determined cardiovascular disease following autosomal dominant pattern of inheritance. A number of genes have been shown to be responsible for HCM including MYBPC3. Cmybc, the protein encoded by MYBPC3 is a sarcomeric thick filament protein that interacts with titin, myosin, and actin to control sarcomeric gathering. Mutations in the MYBPC3 gene have been found to be associated with a history of sudden cardiac death in HCM patients. The main objective of the present study was to investigate the type and frequency of mutations in the MYBPC3 gene in HCM patients from the North-West of Iran. METHODS: All the exons and exon-intron flanking regions of the MYBPC3 gene were assessed by PCR-SSCP, and the PCR products with divergent pattern of bands on polyacrylamide gel were sent for bi-directional sequencing. RESULTS: Mutational screening of a cohort of 42 HCM cases led to the identification of 14 MYBPC3 variations. Three cases out of those variations were frameshift, 1 case was splice site, 3 cases were missense, 2 cases were synonymous, and 5 cases were intronic variants. MYBPC3 mutations (28.5%) represent the most prevalent cause of inherited HCM. The age of onset was 39.3 in MYBPC3 carrier patients. Multiple gene mutations were recognized in 1 case (2.3%). CONCLUSIONS: The results obtained from the present study indicate a significant role of MYBPC3 gene mutations in HCM disease and can be used for pre-symptomatic diagnosis of at risk family members of affected individuals.

In Situ Transesophageal Echocardiography During Electrical Cardioversion in Patients With Atrial Fibrillation-Safety and Echocardiographic Findings.

BACKGROUND: Transesophageal echocardiography (TEE) can reliably detect left atrial (LA) and LA appendage (LAA) thrombus in patients with atrial fibrillation (AF) before electrical cardioversion (ECV). However, evaluating cardiac and valve function pre-ECV can be challenging due to the increased and irregular heart rate. Additionally, post-ECV atrial stunning increases the risk of LAA thrombosis. Therefore, post-ECV TEE may allow for useful appendage, ventricular, and valve function assessment. However, the safety and usefulness of leaving the TEE probe in situ during ECV for post-ECV cardiac evaluation in clinical practice have not been previously evaluated. METHODS: We analyzed 37 out of 86 consecutive patients who had the TEE probe left in situ, for clinical reasons, during ECV by a single operator between February 20, 2019, and January 3, 2023. We examined changes in left ventricular (LV) function, dynamic changes in valvular regurgitation, electromechanical coupling of the left atrium, and qualitative spontaneous echo contrast. We also assessed the presence of any complications related to the periprocedural TEE exam. RESULTS: The mean age of the patients was 74 ± 9.65 years, and 29 (78%) were male. The periprocedural TEE time ranged from 7 to 55 minutes, with an average of 20.78 minutes. Immediately after ECV and restoration of normal sinus rhythm, there was an improvement in LV ejection fraction (47% ± 11.9% vs 40% ± 15.8%; P = .035). There was also a reduction in baseline mitral regurgitation of greater than moderate degree. However, spontaneous echo contrast worsened in the LAA in 11 (31.4%) patients. Additionally, 1 patient developed a new LAA thrombus, and 24 patients (72%) had evidence of electromechanical coupling with Doppler evidence of LA contraction. Clinically significant degenerative aortic and mitral stenosis were identified in 8% and mild or greater aortic regurgitation in 8% of patients post-ECV. No procedural complications were observed. CONCLUSIONS: In situ TEE before, during, and after ECV is safe and provides useful clinical information regarding immediate cardiac changes after ECV, with diagnostic and therapeutic implications.