Hypertrophic cardiomyopathy (HCM) represents the most common genetic heart disease, inherited with an autosomal dominant pattern, incomplete penetrance and variable expressivity. Due to the high HCM heteogeneity with respect instrumental, clinical spectra and course, many researchers focused their attemption on this aspect looking for possible HCM genotype-phenotypes correlations and, even, for a possible genotype-based risk stratification. However, the increasing use of genetic testing in the HCM patients as well as in their relatives (i.e. screening) resulted in a subset of subjects with genotype positive-phenotype negative disease that is individals carrying the mutation for HCM but lacking any pathologic evidence of disease. This particular category raises enourmous doubt about its clinical management (i.e. psichological counselling, sports activities, timing of follow up, early medical treatment, etc).
In recent years, we highlighted the possibility to achieve an optimal clinical characterization of HCM patients throughout an accurate multidimensional analysis of their functional capacity (by means of cardiopulmonary exercise test), their autonomic balance as well as their myocardial repolarization lability (heart rate and QT variability both in temporal and spatial domain). Supporting our approach, most recently (2020) we published a research paper dealing with the importance of a full clinical assessment over the genetic testing analysis in this setting of patients.
Therefore, following our research track, we plan to challenge our non-invasive multidimensional approach with a group of subjects HCM genotype positive-phenotype negative disease in order to disclose (if any) possible pre-clinical signs of the disease.
The setting of HCM genotype positive-phenotype negative represents an emerging and challenging topic in the cardiomyopathies' scenario.
Although patients with phenotypically silent HCM may not display outward indications of disease, few studies argues in favour of an altered cardiac function preceding clinical disease (i.e. impaired relaxation of the myocardium, reduced strain rate of the myocardium or, even, impaired energy metabolism). Notwithstanding, the impact of these early preclinical changes on clinical course, onset of symptoms, severity of disease, and cardiovascular risk are far to be determined. Due to this knowledge gap, there are still enourmous doubts with respect their clinical management in terms of timing of follow up (long-term follow up might be necessary), of possible early medical treatment (some drugs might be beneficial in reducing the disease's manifestation) and, even, of psichological counselling (the awareness of being a carrier of a LP/P variants might lead the subject to a depression state and/or to decide for deleterious lifestyle). Furthermore there are growing concerns also within the sports' medicine field. Indeed, although governing bodies all agree that sports restriction is necessary for HCM patients, there are discordance with respect their approach to athletes with genetic predisposition to HCM without evidence of disease. For instance, while the European Society for Cardiology position is restrictive, stating that individuals with genotype positive-phenotype negative HCM are barred from competitive athletics, the American Bethesda Guidelines are slightly more accommodating, stipulating that there is insufficient evidence to exclude this subset of athlets from competition.
The proponed multidimensional (mainly functional) analysis in a large cohort of subjects HCM genotype positive-phenotype negative is absolutely original with respect most of the techniques included in our research protocol. Indeed, to disclose (or not) early signs of cardiac disease might be insighful in such a debated scenario.