• genotype-phenotype correlation
• Hypertrophic cardiomyopathy
• MRI

Background: Hypertrophic cardiomyopathy is a primitive myocardium pathology characterized by left ventricle walls hypertrophy not related to secondary causes. It is the most common genetic cardiomyopathy. Indeed, it is an autosomal dominant transmitted pathology with incomplete penetrance. A known genetic basis can be find in 60% of cases and the genes more commonly involved are thick filaments’ sarcomeric genes, especially MYH7 and MYBPC3. Other genes involed less frequently are thin filaments sarcomeric genes, like ACTC1, TPMI1 or others like Z-disc or ionic channels proteins coding genes. This study aims to retrospectively analyze morphologic, functional, clinical and the outcome of a group of patients referred to Fondazione Monasterio of Pisa and Massa for cardiac CMR, all of whom were tested for genetic analysis. In order to achieve this objective, we compared CMR, echocadiography, holter ECG and provocative stress tests parmeters of patients with negative, VUS, pathogenetic and likely pathogenetic mutations. Moreover, we compared patients for every genetic mutation and we group them in the subcategories of thin and thick filaments genetic for sarcomeric mutations.
Methods: The study population included consecutive patients with HCM referred to FTGM of Pisa and Massa from 2012 to 2024 with positive genetic test (LP/P or VUS) and negative genetic test. We excluded patients with LV hypertrophy attributable to other conditions. CMR examinations were conducted on a 1.5 T (Signa Artist, GE) or 3 T (Ingenia, Philips) scanners. Genetic test was performed on a whole blood sample by next-generation sequencing (using the Illumina’s NextSeq™ 500 instrument) with a panel containing 202 genes. Statistical analysis was performed using Jamovi Statistics version (The jamovi project, 2021, version 2.3.6). Normal distribution was assessed through the Shapiro-Wilk test. All variables with normal distribution were presented as mean±standard deviation, and those with non-normal distribution as median and interquartile range. Categorical variables were compared using Chi-square test and continuous variables were compared through the Mann-Whitney’s U test for independent samples. Kaplan-Meier curves with log-rank calculation were derived.
Results: The whole cohort included 300 patients with HCM with P/PL mutation, VUS or negative (30,8% women, median age 68 years. Fifty-nine (20,3%) had family history of HCM. The typical symptom was dyspnea for moderate effort (NYHA II, 46,8 % of patients) and less frequently palpitation (97, 33,3%), angina (73, 25,2%) and syncope (31, 10,7 %). Compared with patients with VUS/negative result, those with P/LP mutations presented a lower age at diagnosis, a higher prevalence of a positive family history for SCD and female sex, higher HCM risk score, higher number of ventricular arrhythmias and NSVT, as well as greater maximal wall thickness and atrial size (both at echocardiogram and MRI), EF > 70% (hyperkinetic) and the evidence of more myocardial crypts. Although there was not a significant difference in number of segments and number of patients with LGE, there was a significant higher percentage and a greater mass of LGE in patients with P/LP mutations.