BACKGROUND: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. METHODS AND RESULTS: We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. CONCLUSIONS: In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.

• Keywords
• genotype, hypertrophic cardiomyopathy, mortality, outcomes, sudden death,
• MeSH
• Time Factors MeSH
• Adult MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Testing methods   MeSH
• Genotype * MeSH
• Cardiomyopathy, Hypertrophic * genetics   mortality   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Death, Sudden, Cardiac etiology   epidemiology   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Risk Factors MeSH
• Aged MeSH
• Heart Failure genetics   mortality   MeSH
• Heart Transplantation MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.

• Keywords
• genetics, hypertrophic cardiomyopathy, molecular genetic testing, next-generation sequencing, pathogenic mutations, variants of uncertain significance,
• MeSH
• Genetic Testing * MeSH
• Cardiomyopathy, Hypertrophic diagnosis   genetics   MeSH
• Humans MeSH
• Mutation * MeSH
• Sarcomeres genetics   MeSH
• Muscle Proteins genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Muscle Proteins MeSH

BACKGROUND: The genetic background of patients with hypertrophic cardiomyopathy (HCM) treated with alcohol septal ablation (ASA) and its relationship to the outcomes are not known. We aimed to investigate whether the outcome of genotype positive (G+) patients differs from genotype negative (G-) patients treated with ASA. METHODS: We included 129 HCM patients (mean age 54±13 years) treated with ASA in a tertiary cardiovascular center and performed next generation sequencing (NGS) based genomic testing. All patients were followed-up three months after the procedure and yearly thereafter. RESULTS: A total of 30 (23%) HCM patients were G+ patients. At the 3-months follow-up, both groups of patients had similar left ventricular outflow tract PG (16.9±15.7 mmHg in G+ vs. 16.3±18.8 mmHg in G-, P=0.73) and symptoms (follow-up NYHA class 1.40±0.62 vs. 1.37±0.53, P=0.99, follow-up CCS class 0.23±0.52 vs. 0.36±0.65, P=0.36). The independent predictors of all-cause mortality were baseline interventricular septum (IVS) thickness (HR 1.12, 95% CI: 1.00-1.26, P=0.049) and age at the time of ASA (HR 1.11, 95% CI: 1.06-1.17, P<0.01). The adjusted all-cause mortality rate did not differ significantly between G+ and G- patients (P=0.52). The adjusted combined mortality event rate did not differ between both groups (P=0.78). CONCLUSIONS: Despite more severe phenotype in G+ HCM patients, ASA is an equally effective treatment for LVOTO in G+ patients as it is for treating LVOTO in G- patients. The long-term outcome after ASA is similar in G+ and G- patients.

• Keywords
• Cardiomyopathy, alcohol septal ablation (ASA), genetics, hypertrophic cardiomyopathy (HCM), hypertrophic obstructive cardiomyopathy,
• Publication type
• Journal Article MeSH

Conflicting results have been published considering the role of head-up tilt test (HUTT) positivity as a prognostic factor in patients with hypertrophic cardiomyopathy (HCM). The relationship between HCM patients' genotype and their HUTT results has not been previously reported. The aim of this study was to evaluate patients with HCM and their HUTT results in regard to its value for outcome prediction and to investigate the relation of patients' genotype and their HUTT results. Seventy-four (51 ± 15 years; 42% women; median follow-up 72 months) HCM patients were divided into two groups based on their HUTT results and were retrospectively analyzed. In 67 (90.5%) subjects included in the analysis, next-generation sequencing-based genomic testing was performed. A composite end point of unexplained syncope, heart failure hospitalization, and death was defined. A total of 14 patients (18.9%) had positive HUTT (HUTT+), whereas 60 (81.1%) had negative HUTT (HUTT-). Except for the New York Heart Association functional class ( p = 0.01), both groups had similar characteristics. Positive genotype was evenly distributed between the two groups. Composite end point occurred in 5 patients (35.7%) in HUTT+ group versus 14 (23.3%) patients in HUTT- group ( p = 0.33). We did not find a relationship between HUTT results and long-term outcome. We found no association between HUTT results and genotype.

• Keywords
• HCM, HOCM, abnormal baroreflex, genotype, head-up tilt test, hypertrophic cardiomyopathy, hypertrophic obstructive cardiomyopathy,
• Publication type
• Journal Article MeSH