Left Ventricular Dysfunction in Arrhythmogenic Cardiomyopathy: Association With Exercise Exposure, Genetic Basis, and Prognosis

Abstract

Background Arrhythmogenic cardiomyopathy (AC) is characterized by biventricular dysfunction, exercise intolerance, and high risk of ventricular tachyarrhythmias and sudden death. Predisposing factors for left ventricular (LV) disease manifestation and its prognostic implication in AC are poorly described. We aimed to assess the associations of exercise exposure and genotype with LV dysfunction in AC, and to explore the impact of LV disease progression on adverse arrhythmic outcome. Methods and Results We included 168 patients with AC (50% probands, 45% women, 40±16 years old) with 715 echocardiographic exams (4.1±1.7 exams/patient, follow-up 7.6 [interquartile range (IQR), 5.4-10.9] years) and complete exercise and genetic data in a longitudinal study. LV function by global longitudinal strain was -18.8% [IQR, -19.2% to -18.3%] at presentation and was worse in patients with greater exercise exposure (global longitudinal strain worsening, 0.09% [IQR, 0.01%-0.17%] per 5 MET-hours/week, P=0.02). LV function by global longitudinal strain worsened, with 0.08% [IQR, 0.05%-0.12%] per year; (P<0.001), and progression was most evident in patients with desmoplakin genotype (P for interaction <0.001). Deterioration of LV function predicted incident ventricular tachyarrhythmia (aborted cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter defibrillator shock) (adjusted odds ratio, 1.1 [IQR, 1.0-1.3] per 1% worsening by global longitudinal strain; P=0.02, adjusted for time and previous arrhythmic events). Conclusions Greater exercise exposure was associated with worse LV function at first visit of patients with AC but did not significantly affect the rate of LV progression during follow-up. Progression of LV dysfunction was most pronounced in patients with desmoplakin genotypes. Deterioration of LV function during follow-up predicted subsequent ventricular tachyarrhythmia and should be considered in risk stratification.

Keywords: arrhythmogenic cardiomyopathy; arrhythmogenic right ventricular cardiomyopathy; left ventricular dysfunction; ventricular arrhythmia.

Figure 1. Left ventricular function in 146 patients with arrhythmogenic cardiomyopathy and known exercise habits at presentation.

Slopes are fitted mean linear response with 95% CIs for patients with and without desmoplakin mutations. P values for progression and interaction by linear mixed‐model regression with random effects for families and individuals and exchangeable covariance structure. Exercise during 3 immediate years before presentation expressed as average MET‐hours per week, with dichotomization at median exercise exposure. Patients with exercise exposure above median had GLS 1.0% (interquartile range, 0.1%–1.9%; P=0.02) worse than patients with exercise exposure below median. There was no difference in the progression of left ventricular dysfunction in patients with greater or lesser exercise exposure (illustrated by P for interaction=0.87). See Table 2 for coefficients and continuous exercise variable. GLS indicates global longitudinal strain; and LV, left ventricular.

Figure 2. Left ventricular functional deterioration during follow‐up of 168 patients with arrhythmogenic cardiomyopathy with desmoplakin genotypes (blue curves) and with other genotypes or gene elusive patients (green curves).

Slopes are fitted mean linear response with 95% CIs for patients with and without desmoplakin mutations. P values for progression and interaction by linear mixed‐model regression with random effects for families and individuals and exchangeable covariance structure. Patients with desmoplakin genotypes had worse progression of left ventricular dysfunction than patients with other genotypes or gene‐elusive patients (illustrated by P for interaction<0.001 for both EF and GLS). See text for regression coefficients. DSP indicates desmoplakin; EF, ejection fraction; and GLS, global longitudinal strain.

Figure 3. Left ventricular functional deterioration during follow‐up of 168 patients with arrhythmogenic cardiomyopathy predicted subsequent ventricular tachyarrhythmias.

Odds ratios for impending ventricular tachyarrhythmias with 1% decline in GLS presented in the lower left panel were calculated by generalized estimating equations of the repeated left ventricular functional assessments with binomial family, logit link, and independent correlation structure, adjusting for the effect of patient relatedness, elapsed time (primary prevention subgroup) and previous ventricular arrhythmia (all patients). GLS indicates global longitudinal strain; ICD, implantable cardioverter defibrillator; OR, odds ratio; and VT, ventricular tachycardia.