👤 Mahnaz Tajik

We present multimodality imaging of ventricular septal calcification. A 38-year-old man with asymptomatic gene-positive hypertrophic cardiomyopathy was found to have extensive dystrophic calcification of the ventricular septum. We hypothesized that the extensive ventricular septal calcification would represent an area of severe myocardial fibrosis, resulting in calcification secondary to postsurgical (septal myectomy) changes. Calcification of the ventricular septum is a rare finding, not previously described following septal myectomy, that should prompt a comprehensive evaluation and follow-up with multimodality imaging and testing. Show less

Owing to the recognition of previously unknown pathogenic gene variants and reclassification of longer-known variants, gene distribution in patients with hypertrophic cardiomyopathy (HCM) is ever-changing. Conflicting data make the role of genotype in risk stratification unclear. We evaluated genotype distribution and genotype-phenotype correlations in all adult patients with HCM seen at our HCM Center of Excellence from March 31, 2010, to April 30, 2023. We also evaluated a composite outcome, including all-cause mortality, stroke, implantable cardioverter-defibrillator placement, heart failure hospitalization, left ventricular assist device implantation, heart transplantation, septal myectomy, and alcohol septal ablation, based on genotype status. All-cause mortality was separately analyzed. Of 827 patients with HCM, genotyping was completed in 754 (91.2 %). We identified 202 (27 %) genotype-positive (Gen-P), 163 (22 %) variant of unknown significance (VUS), and 389 (51 %) genotype-negative (Gen-N) patients. Mean ages were 47, 57, and 58 years, respectively. The most common gene implicated was MYBPC3 (63 %). More patients were on optimal medical treatment after following up with our HCM center. Electrocardiographic, Holter, echocardiographic, and cardiac magnetic resonance imaging characteristics differed based on genotype status. The composite outcome was worse in Gen-P than Gen-N (HR 1.84, p<0.001). Although analysis of all-cause mortality showed survival was different for Gen-P and VUS patients than for Gen-N patients, this difference was not statistically significant. MYBPC3 was the most common gene implicated. Outcomes were worse in Gen-P patients. Centers of Excellence play an important role in the optimal medical management of patients with HCM. Show less

Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations. Show less

To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes. Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness). The French study population harbored the highest frequency of mutations (61%), followed by the Mayo Clinic (38%), Harvard Medical School (36%), and Swedish (30%) study populations. For every study population, mutations in myosin binding protein C (MYBPC3) were the most common cause of HCM. Patients with a family history of HCM had mutations more frequently than those without. This pooled analysis revealed no statistically significant differences in left ventricular wall thickness or in mean age at diagnosis across all genotypes. Differentiation of sarcomeric genotypes, such as MYBPC3-HCM and MYH7-HCM, is not possible on the basis of currently reported phenotypic data. A myriad of genetic and/or environmental modifiers in addition to the primary disease-causing genetic substrate must play an important role in determining a patient's particular phenotype. Show less

We sought to determine the frequency and phenotype of mutations in myosin binding protein C (MYBPC3) in a large outpatient cohort of patients with hypertrophic cardiomyopathy (HCM) seen at our tertiary referral center. Mutations in MYBPC3 are one of the most frequent genetic causes of HCM and have been associated with variable onset of disease and prognosis. However, the frequency of mutations and associated clinical presentation have not been established in a large, unrelated cohort of patients. Using deoxyribonucleic acid from 389 unrelated patients with HCM, each protein coding exon of MYBPC3 was analyzed for mutations by polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. Clinical data were extracted from patient records blinded to patient genotype. Of 389 patients with HCM, 71 (18%) had mutations in MYBPC3. In all, 46 mutations were identified, 33 of which were novel (72%). Patients with MYBPC3 mutations did not differ significantly from patients with thick filament-HCM, thin filament-HCM, or genotype-negative HCM with respect to age at diagnosis, degree of hypertrophy, incidence of myectomy, or family history of HCM or sudden death. Patients with multiple mutations (n = 10, 2.6%) had the most severe disease presentation. This study defines the frequency and associated phenotype for MYBPC3 and/or multiple mutations in HCM in the largest cohort to date. In this cohort, unrelated patients with MYBPC3-HCM virtually mimicked the phenotype of those with mutations in the beta-myosin heavy chain. Patients with multiple mutations had the most severe phenotype. Show less