Risk Stratification in Hypertrophic Cardiomyopathy. Insights from Genetic Analysis and Cardiopulmonary Exercise Testing

Abstract

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification.

Insights from Cardiopulmonary Exercise Testing in Pediatric Patients with Hypertrophic Cardiomyopathy

“…Indeed, besides the occurrence of the well-known disease-related complications (i.e., atrial fibrillation or end-stage phase), myocardial fiber disarray, interstitial fibrosis, microvascular ischemia, chronotropic incompetence, as well as LVOT obstruction, are all factors able to impact negatively on diastolic and systolic left ventricular function at rest and, particularly, during exercise [ 17 ]. Although each of the abovementioned clinical features might concur theoretically to an exercise impairment also in pediatric HCM patients, it might be conceivable that, particularly in this setting, the genetic burden might play the greatest role through a direct impact on the cardiomyocytes’ efficiency [ 15 , 34 ].…”

“…Last, most recently, in nearly 400 pediatric HCM patients (median age 14 years and median follow-up 5.9 years), Alashi et al found the presence of symptoms as an important feature associated with the primary composite outcome of SCD-related events, septal reduction procedure due to HF worsening and cardiac transplantation [ 37 ]. Accordingly, it is highly reasonable that a more reliable functional classification in pediatric HCM patients might further improve also their risk stratification as it has been proven yet in adult HCM patients [ 10 , 11 , 12 , 13 , 14 , 15 ]. Our data support the abovementioned hypothesis given that the most important CPET-derived variable, namely, the pVO 2 , was greatly impaired in those HCM patients who experienced a cardiac event during the follow-up and univariately associated to the tested end-point.…”

“…Last, we showed VE/VCO 2 slope values significantly higher in the HCM group than in the healthy control group and even worse in those HCM patients who suffered from a cardiac event. Indeed, in HCM patients, the ventilatory efficiency is thought to mirror the diastolic dysfunction degree as well as the exercise-induced ventilation/perfusion mismatch derangement [ 41 ], and it has been demonstrated as the CPET-derived variable with the strongest association with the SCD risk in an adulthood HCM cohort [ 15 ]. However, most likely due to the small sample and the low number of arrhythmic events collected, this fashion parameter failed to achieve a statistical significance at the univariate analysis.…”

“…The predicted peak VO 2 (pVO 2 ) was determined using the gender-, age-, and weight-adjusted Hansen/Wasserman equations [ 27 ]. Circulatory power (CP = pVO 2 , mL/kg/min * SBP, mmHg) was obtained also considering pVO 2 value as percentage of predicted (CP%) [ 13 , 15 , 17 , 28 ]. Anaerobic threshold (AT) was measured by V-slope analysis of VO 2 and carbon dioxide production (VCO 2 ), and it was confirmed by ventilator equivalents and end-tidal pressures of CO 2 and O 2 .…”

“…Accordingly, besides the historical markers of disease severity [ 8 , 9 ], it is conceivable that, properly in young HCM patients, an adjunctive analysis of the exercise capacity by means of a cardiopulmonary exercise test (CPET) could be extremely useful with respect to their clinical management. Indeed, growing evidence suggests that a full CPET assessment, in combination with other clinical and instrumental variables, is able to stratify both the SCD and the HF risk in adult cohort of HCM patients [ 10 , 11 , 12 , 13 , 14 , 15 ]. Furthermore, regardless its potential prognostic value in pediatric HCM patients, it is likely that a systematic CPET assessment might be helpful in this setting to disclose an unsuspected functional limitation [ 16 , 17 ], to develop individualized exercise training programs to prevent deconditioning [ 18 , 19 ], and, last but not least, to instill confidence in young HCM patients and their relatives through a maximal exercise test performed without side effects [ 20 , 21 ].…”