Monitoring of Myocardial Involvement in Early Arrhythmogenic Right Ventricular Cardiomyopathy Across the Age Spectrum

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of primarily the right ventricular myocardium, a substrate for life-threatening ventricular arrhythmias (VAs). Repeated cardiac imaging of at-risk relatives is important for early disease detection. However, it is not known whether screening should be age-tailored. Objectives: The goal of this study was to assess the need for age-tailoring of follow-up protocols in early ARVC by evaluating myocardial disease progression in different age groups. Methods: We divided patients with early-stage ARVC and genotype-positive relatives without overt structural disease and VA at first evaluation into 3 groups: age 50 years without overt ARVC phenotype at first evaluation. Unlike recommended by current guidelines, our study suggests that follow-up of ARVC patients and relatives should not stop at older age

The added value of abnormal regional myocardial function for risk prediction in arrhythmogenic right ventricular cardiomyopathy

Aims A risk calculator for individualized prediction of first-time sustained ventricular arrhythmia (VA) in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients has recently been developed and validated (www.ARVCrisk.com). This study aimed to investigate whether regional functional abnormalities, measured by echocardiographic deformation imaging, can provide additional prognostic value. Methods From two referral centres, 150 consecutive patients with a definite ARVC diagnosis, no prior sustained VA, and an echo- and results cardiogram suitable for deformation analysis were included (aged 41 ± 17 years, 50% female). During a median follow-up of 6.3 (interquartile range 3.1–9.8) years, 37 (25%) experienced a first-time sustained VA. All tested left and right ventricular (LV and RV) deformation parameters were univariate predictors for first-time VA. While LV function did not add predictive value in multivariate analysis, two RV deformation parameters did; RV free wall longitudinal strain and regional RV deformation patterns remained independent predictors after adjusting for the calculator-predicted risk [hazard ratio 1.07 (95% CI 1.02–1.11); P = 0.004 and 4.45 (95% CI 1.07–18.57); P = 0.040, respectively] and improved its discriminative value (from C-statistic 0.78 to 0.82 in both; Akaike information criterion change > 2). Importantly, all patients who experienced VA within 5 years from the echocardiographic assessment had abnormal regional RV deformation patterns at baseline. Conclusions This study showed that regional functional abnormalities measured by echocardiographic deformation imaging can further refine personalized arrhythmic risk prediction when added to the ARVC risk calculator. The excellent negative predictive value of normal RV deformation could support clinicians considering the timing of implantable cardioverter defibrillator implantation in patients with intermediate arrhythmic risk

Left ventricular dysfunction in arrhythmogenic cardiomyopathy: Association with exercise exposure, genetic basis, and prognosis

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

Right Ventricular Functional Abnormalities in Arrhythmogenic Cardiomyopathy: Association With Life-Threatening Ventricular Arrhythmias

Objectives This study aimed to perform an external validation of the value of right ventricular (RV) deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). Secondly, this study assessed the association of these parameters with life-threatening ventricular arrhythmia (VA). Background Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared. Methods We analyzed AC probands and mutation-positive family members, matched from 2 large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, or aborted cardiac arrest. Results We included 160 subjects, 80 from each center (43% proband, 55% women, age 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms; p < 0.001 for the total cohort). Both parameters were independently associated to VA (adjusted odds ratio: 2.71 [95% confidence interval: 1.47 to 5.00] per class step-up, and 1.26 [95% confidence interval: 1.07 to 1.49]/10 ms, respectively). The association with VA significantly improved when adding RV mechanical dispersion to pattern recognition (net reclassification improvement 0.42; p = 0.02 and integrated diagnostic improvement 0.06; p = 0.01). Conclusions We externally validated 2 RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value

Sex differences in disease progression and arrhythmic risk in patients with arrhythmogenic cardiomyopathy

Abstract Aims We aimed to assess sex-specific phenotypes and disease progression, and their relation to exercise, in arrhythmogenic cardiomyopathy (AC) patients. Methods and results In this longitudinal cohort study, we included consecutive patients with AC from a referral centre. We performed echocardiography at baseline and repeatedly during follow-up. Patients’ exercise dose at inclusion was expressed as metabolic equivalents of task (MET)-h/week. Ventricular arrhythmia (VA) was defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate therapy by implantable cardioverter-defibrillator. We included 190 AC patients (45% female, 51% probands, age 41 ± 17 years). Ventricular arrhythmia had occurred at inclusion or occurred during follow-up in 85 patients (33% of females vs. 55% of males, P = 0.002). Exercise doses were higher in males compared with females [25 (interquartile range, IQR 14–51) vs. 12 (IQR 7–22) MET-h/week, P &amp;lt; 0.001]. Male sex was a marker of proband status [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4–5.0, P = 0.003] and a marker of VA (OR 2.6, 95% CI 1.4–5.0, P = 0.003), but not when adjusted for exercise dose and age (adjusted OR 1.8, 95% CI 0.9–3.6, P = 0.12 and 1.5, 95% CI 0.7–3.1, P = 0.30, by 5 MET-h/week increments). In all, 167 (88%) patients had ≥2 echocardiographic examinations during 6.9 (IQR 4.7–9.8) years of follow-up. We observed no sex differences in deterioration of right or left ventricular dimensions and functions. Conclusion Male AC patients were more often probands and had higher prevalence of VA than female patients, but not when adjusting for exercise dose. Importantly, disease progression was similar between male and female patients

Complications of implantable cardioverter-defibrillator treatment in arrhythmogenic right ventricular cardiomyopathy

Aims: Treatment with implantable cardioverter-defibrillators (ICD) is a cornerstone for prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at describing the complications associated with ICD treatment in a multinational cohort with long-term follow-up. Methods and results: The Nordic ARVC registry was established in 2010 and encompasses a large multinational cohort of ARVC patients, including their clinical characteristics, treatment, and events during follow-up. We included 299 patients (66% males, median age 41 years). During a median follow-up of 10.6 years, 124 (41%) patients experienced appropriate ICD shock therapy, 28 (9%) experienced inappropriate shocks, 82 (27%) had a complication requiring surgery (mainly lead-related, n = 75), and 99 (33%) patients experienced the combined endpoint of either an inappropriate shock or a surgical complication. The crude rate of first inappropriate shock was 3.4% during the first year after implantation but decreased after the first year and plateaued over time. Contrary, the risk of a complication requiring surgery was 5.5% the first year and remained high throughout the study period. The combined risk of any complication was 7.9% the first year. In multivariate cox regression, presence of atrial fibrillation/flutter was a risk factor for inappropriate shock (P 0.05). Conclusion: Forty-one percent of ARVC patients treated with ICD experienced potentially life-saving ICD therapy during long-term follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority

Monitoring of Myocardial Involvement in Early Arrhythmogenic Right Ventricular Cardiomyopathy Across the Age Spectrum

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of primarily the right ventricular myocardium, a substrate for life-threatening ventricular arrhythmias (VAs). Repeated cardiac imaging of at-risk relatives is important for early disease detection. However, it is not known whether screening should be age-tailored. Objectives: The goal of this study was to assess the need for age-tailoring of follow-up protocols in early ARVC by evaluating myocardial disease progression in different age groups. Methods: We divided patients with early-stage ARVC and genotype-positive relatives without overt structural disease and VA at first evaluation into 3 groups: age &lt;30 years, 30 to 50 years, and =50 years. Longitudinal biventricular deformation characteristics were used to monitor disease progression. To link deformation abnormalities to underlying myocardial disease substrates, Digital Twins were created using an imaging-based computational modeling framework. Results: We included 313 echocardiographic assessments from 82 subjects (57% female, age 39 ± 17 years, 10% probands) during 6.7 ± 3.3 years of follow-up. Left ventricular global longitudinal strain slightly deteriorated similarly in all age groups (0.1%-point per year [95% CI: 0.05-0.15]). Disease progression in all age groups was more pronounced in the right ventricular lateral wall, expressed by worsening in longitudinal strain (0.6%-point per year [95% CI: 0.46-0.70]) and local differences in myocardial contractility, compliance, and activation delay in the Digital Twin. Six patients experienced VA during follow-up. Conclusions: Disease progression was similar in all age groups, and sustained VA also occurred in patients aged &gt;50 years without overt ARVC phenotype at first evaluation. Unlike recommended by current guidelines, our study suggests that follow-up of ARVC patients and relatives should not stop at older age

Integrating Exercise Into Personalized Ventricular Arrhythmia Risk Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy

BACKGROUND: Exercise is associated with sustained ventricular arrhythmias (VA) in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) but is not included in the ARVC risk calculator (arvcrisk.com). The objective of this study is to quantify the influence of exercise at diagnosis on incident VA risk and evaluate whether the risk calculator needs adjustment for exercise. METHODS: We interviewed ARVC patients without sustained VA at diagnosis about their exercise history. The relationship between exercise dose 3 years preceding diagnosis (average METh/wk) and incident VA during follow-up was analyzed with time-to-event analysis. The incremental prognostic value of exercise to the risk calculator was evaluated by Cox models. RESULTS: We included 176 patients (male, 43.2%; age, 37.6±16.1 years) from 3 ARVC centers, of whom 53 (30.1%) developed sustained VA during 5.4 (2.7-9.7) years of follow-up. Exercise at diagnosis showed a dose-dependent nonlinear relationship with VA, with no significant risk increase 18, >24, and >36 METh/wk), was significantly associated with VA (hazard ratios, 2.53-2.91) but was also correlated with risk factors currently in the risk calculator model. Thus, adding athlete status to the model did not change the C index of 0.77 (0.71-0.84) and showed no significant improvement (Akaike information criterion change, <2). CONCLUSIONS: Exercise at diagnosis was dose dependently associated with risk of sustained VA in ARVC patients but only above 15 to 30 METh/wk. Exercise does not appear to have incremental prognostic value over the risk calculator. The ARVC risk calculator can be used accurately in athletic patients without modification

The added value of abnormal regional myocardial function for risk prediction in arrhythmogenic right ventricular cardiomyopathy

BACKGROUND &amp; AIMS: A risk calculator for individualized prediction of first-time sustained ventricular arrhythmia (VA) in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients has recently been developed and validated (www.ARVCrisk.com). This study aimed to investigate whether regional functional abnormalities, measured by echocardiographic deformation imaging, can provide additional prognostic value. METHODS &amp; RESULTS: From two referral centres, 150 consecutive patients with a definite ARVC diagnosis, no prior sustained VA and an echocardiogram suitable for deformation analysis were included (aged 41±17 years, 50% female). During a median follow-up of 6.3 (IQR 3.1-9.8) years, 37 (25%) experienced a first-time sustained VA. All tested left and right ventricular (LV, RV) deformation parameters were univariate predictors for first-time VA. While LV function did not add predictive value in multivariate analysis, two RV deformation parameters did; RV free wall longitudinal strain and regional RV deformation patterns remained independent predictors after adjusting for the calculator-predicted risk (HR 1.07 [1.02-1.11]; p = 0.004 and 4.45 [1.07-18.57]; p = 0.040, respectively) and improved its discriminative value (from C-statistic 0.78 to 0.82 in both. Akaike information criterion change &gt;2). Importantly, all patients who experienced VA within 5 years from the echocardiographic assessment had abnormal regional RV deformation patterns at baseline. CONCLUSIONS: This study showed that regional functional abnormalities measured by echocardiographic deformation imaging can further refine personalized arrhythmic risk prediction when added to the ARVC risk calculator. The excellent negative predictive value of normal RV deformation could support clinicians considering timing of ICD implantation in patients with intermediate arrhythmic risk