Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy

Abstract

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.

Figure 1. Diagram summarizing clinical outcome of 1156 individual genotype‐negative (G−) patients with hypertrophic cardiomyopathy (HCM), tabulating the number and causes for death and nonfatal adverse HCM events.

*Includes unknown cause of death. Twenty‐three (17%) patients died from unknown causes at 69±14 years; with no significant difference (P=0.45) in proportion of unknown deaths between G− (n=20; 2%) and genotype‐positive patients (n=3; 1%). ^†More than 1 adverse event occurred over follow‐up, most commonly atrial fibrillation (AF) and heart failure (HF) in 122 patients, and HF with implantable cardioverter‐defibrillator (ICD) shocks in 17 patients, other combinations of adverse events were rare (<1%). ^‡Sixteen (6%) of 256 patients with AF experienced embolic stroke, 4 of them (0.3%) developed concomitant progressive HF. ASA indicates alcohol ablation; CAD, coronary artery disease; OHCA, out‐of‐hospital cardiac arrest; and SCD, sudden cardiac death.

Figure 2. Diagram summarizing clinical outcome of 312 individual genotype‐positive (G+) patients with hypertrophic cardiomyopathy (HCM), tabulating the number and causes for death and nonfatal adverse HCM events.

*Includes unknown cause of death in 3 patients. ^†More than 1 adverse event occurred over follow‐up, most commonly atrial fibrillation (AF) and heart failure (HF) in 39 patients, and HF with implantable cardioverter‐defibrillator (ICD) therapy in 5 patients, other combinations of adverse events were rare (<1%). ^‡Eight of 83 patients with AF experienced embolic stroke, including 2 who developed concomitant progressive HF. ASA indicates alcohol ablation; CAD, coronary artery disease; OHCA, out‐of‐hospital cardiac arrest; and SCD, sudden cardiac death.

Figure 3. Comparison of 10‐year incidence rates in genotype‐positive (G+) vs genotype‐negative (G−) patients with hypertrophic cardiomyopathy (HCM).

There were no significant differences in rates between G+ and G− patients adjusted for age at diagnosis, and for sudden cardiac death (SCD) adjusted for age and ≥1 established American Heart Association/American College of Cardiology risk markers. Shown for all‐cause and HCM‐related mortality, SCD events, heart failure (HF), atrial fibrillation, and embolic stroke. The rates were obtained from the cumulative incidence function.

Figure 4. Cumulative incidence (Kaplan‐Meier) curves adjusted for age at diagnosis, demonstrating no difference between genotype‐positive (G+) and genotype‐negative (G−) patients with hypertrophic cardiomyopathy (HCM).

A, All‐cause mortality. B, HCM‐related mortality. C, Sudden cardiac death (SCD) events. D, Heart failure (HF) events. HR indicates hazard ratio.

Figure 5. Forest plots demonstrate no significant difference in hazard ratios (HRs) between genotype‐positive (G+) and genotype‐negative (G−) patients adjusted for age at diagnosis, and for sudden cardiac death (SCD) adjusted for age and ≥1 established American Heart Assocation/American College of Cardiology risk markers.

Shown for all‐cause and HCM‐related mortality, SCD events, and heart failure (HF). Comparison are: A) G+ vs G−; B) variant of uncertain significance (VUS) vs no mutation; and C) G+ vs VUS. Numbers along the horizontal axis represent hazard ratios. HCM indicates hypertrophic cardiomyopathy.