Introduction The yield of genetic testing in hypertrophic cardiomyopathy (HCM) is variable. The Mayo HCM Genotype Predictor score (Mayo Score) provides the pre-test probability of a positive HCM genetic test. In the original cohort of Mayo Score patients, only 9 HCM-associated myofilament genes were evaluated. The aim of this study was to validate the Mayo Score in the national HCM cohort and assess the yield of genetic testing using next generation sequencing (NGS) evaluating up to 229 genes. Material and methods We included 336 consecutive unrelated HCM patients (41% women, mean age: 53 ±15 years). We performed NGS-based genomic testing with classification of identified variants according to American College of Medical Genetics and Genomics guidelines. NGS findings were compared with the Mayo Score (ranging from –1 to 5) based on clinical and echocardiographic variables. Results We identified 72 variants classified as pathogenic or likely pathogenic in 70 (21%) HCM patients. One patient with the highest Mayo Score of 5 had a pathogenic mutation (100% yield). Patients with a Mayo Score of 4 had a pathogenic mutation in 71% of cases. Patients with a Mayo Score of 3 or 2 had a pathogenic mutation in 50 and 35% of cases, respectively. The yield of genetic testing in patients with a Mayo Score of –1 to 1 was low (6–21%). Conclusions The overall yield of genetic testing using NGS evaluating up to 229 genes was low. The yield of genetic testing was consistently predicted with Mayo Score values.

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.

Article Dąbrowski et al., see p. 181 The first alcohol septal ablation (ASA) for hypertrophic obstructive cardiomyopathy (HOCM) was performed by Ulrich Sigwart, and the description of the procedure was published in The Lancet in 1995 [1]. Currently, based on the increasing body of evidence, it is known that severe and symptomatic left ventricular obstruction usually needs effective mechanical relief in the form of septal reduction therapy (ASA or myectomy) [2]. The technique of ASA involves an injection of a small amount (1-3 mL) of desiccated alcohol into an appropriate septal branch [3-6]. The rapid postprocedural pressure gradient decrease is caused mainly by stunning and myocardial necrosis. However, the main mechanism of the continuous pressure gradient relief is the widening of the left ventricular outflow tract developing secondarily to infarction and fibrosis of the basal septum. Subsequently, the basal septal shrinking is followed by a gradual reduction in the left ventricular mass, improvement of the diastolic function, and reduction in the degree of mitral regurgitation [3-7]. Also, successful procedures lead to an improvement in symptoms of angina pectoris and dyspnoea [3-7]. The first European multinational study focused on early outcomes of ASA undoubtedly demonstrated its clinical efficacy, but the safety of this interventional procedure was limited as complete heart blocks occurred in one-third of the procedures and one-tenth of the patients needed permanent pacing after ASA [7, 8]. It was also found that in the younger HOCM patients, characterised by a thicker basal septum, post-ASA haemodynamic improvement was slower, but the procedure was effective irrespective of the age of the treated patients [9]. Although encouraging results of single-centre or national ASA registries were published in the first two decades after the first procedure performed by Sigwart, the long-term safety and efficacy of ASA have been a matter of ongoing debate.

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Background: The aim of this study was to evaluate short-and long-term outcomes related to dose of alcohol administered during alcohol septal ablation (ASA) in patients with hypertrophic obstructive cardiomyopathy (HOCM). Current guidelines recommend using 1-3 mL of alcohol administered in the target septal perforator artery, but this recommendation is based more on practical experience of interventionalists rather than on systematic evidence. Methods: We included 1448 patients and used propensity score to match patients who received a low-dose (1.0-1.9 mL) versus a high-dose (2.0-3.8 mL) of alcohol during ASA. Results: The matched cohort analysis comprised 770 patients (n = 385 in both groups). There was a similar occurrence of 30-day post-procedural adverse events (13% vs. 12%; p = 0.59), and similar all-cause mortality rates (0.8% vs. 0.5%; p = 1) in the low-dose group and the high-dose group, respectively. In the long-term follow-up (5.4 ± 4.5 years), a total of 110 (14%) patients died representing 2.58 deaths and 2.64 deaths per 100 patientyears in the low dose and the high dose group (logrank, p = 0.92), respectively. There were no significant differences in the long-term dyspnea and left ventricular outflow gradient between the two groups. Patients treated with a low-dose of alcohol underwent more subsequent septal reduction procedures (logrank, p = 0.04). Conclusions: Matched HOCM patients undergoing ASA with a low-dose (1.0-1.9 mL) or a high-dose (2.0-3.8 mL) of alcohol had similar short-and long-term outcomes. A higher rate of repeated septal reduction procedures was observed in the group treated with a low-dose of alcohol.