ARVD/C: The Triangle of Dysplasia Displaced
Introduction
The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates ...genetic testing and excludes biventricular phenotypes.
Methods and Results
We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation‐positive ARVD/C patients for regional abnormalities on a 5‐segment RV and 17‐segment LV model. The location of electroanatomic endo‐ and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (<0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation.
Conclusion
Mutation‐positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C.
We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers.
...Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs. 36 years; P < 0.001) than those presenting with sustained monomorphic ventricular tachycardia (VT). Among 541 subjects presenting alive, over a mean follow-up of 6 ± 7 years, 12 (2%) patients died, 162 (30%) had sustained VT/VF, 78 (14%) manifested left ventricular dysfunction (EF < 55%), 28 (5%) experienced heart failure (HF), and 10 (2%) required cardiac transplantation. Patients (n = 22; 4%) with >1 mutation had significantly earlier occurrence of sustained VT/VF (mean age 28 ± 12 years), lower VT-/VF-free survival (P = 0.037), more frequent left ventricular dysfunction (29%), HF (19%) and cardiac transplantation (9%) when compared with those with only one mutation. Desmoplakin mutation carriers experienced more than four-fold occurrence of left ventricular dysfunction (40%) and HF (13%) than PKP2 carriers. Missense mutation carriers had similar death-/transplant-free survival and VT/VF penetrance (P = 0.137) when compared with those with truncating or splice site mutations. Men are more likely to be probands (P < 0.001), symptomatic (P < 0.001) and have earlier and more severe arrhythmic expression.
Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.
Introduction
The benefit of implantable cardioverter‐defibrillator (ICD) implantation in patients with hemodynamically not tolerated ventricular tachycardia (VT) and midrange reduced to normal ...ejection fraction (LVEF >35%) is currently unclear. The purpose of this study was to investigate follow‐up after hemodynamically not tolerated VT in patients with LVEF >35%. In addition, we aimed to find possible predictive factors to identify who will benefit from ICD implantation.
Methods
In a retrospective single‐centre case series, all patients with hemodynamically not tolerated VT and LVEF >35% that underwent electrophysiological study (EPS) and/or radiofrequency VT ablation were included.
Results
Forty‐two patients (5 women, median age 68 years) with hemodynamically not tolerated VT and LVEF >35% underwent EPS. VT ablation was performed in thirty‐one patients, which was considered successful in twenty‐three patients. Nineteen patients had an ICD at discharge while 23 patients were discharged without an ICD. The severity of hemodynamic compromise, LVEF and ablation success played an important role in the decision‐making for ICD implantation. Six patients (14.3%) had recurrence of VT, all hemodynamically tolerated.
Conclusions
In this small case series, patients with hemodynamically not tolerated VT and LVEF >35% had a relatively low recurrence rate and all recurrences were nonfatal. Based on our results, we hypothesize that the severity of hemodynamic compromise, LVEF and ablation success might modify the risk for VA recurrence. A prospective study to determine the prognostic value of these factors in patients with hemodynamically not tolerated VT and LVEF >35% is necessary.
The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS).
Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of ...commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective.
Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented.
Patients (56% female, 27% symptomatic, heart rate 76 ± 16 beats/min, QTc 472 ± 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol.
Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients.
Abstract
Aims
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for ...individualized prediction of incident VA/SCD in ARVC patients.
Methods and results
Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44–9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 95% confidence interval (CI) 0.73–0.81 and minimal over-optimism calibration slope of 0.93 (95% CI 0.92–0.95). By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001).
Conclusion
Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).
Structural Atrial Involvement in ARVD/C
Introduction
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with desmosomal mutations. Although desmosomal disruption affects ...both ventricles and atria, little is known about atrial involvement in ARVD/C.
Objective
To describe the extent and clinical significance of structural atrial involvement and atrial arrhythmias (AA) in ARVD/C stratified by genotype.
Methods
We included 71 patients who met ARVD/C Task Force Criteria and underwent cardiac magnetic resonance (CMR) imaging and molecular genetic analysis. Indexed atrial end‐diastolic volume and area‐length‐ejection‐fraction (ALEF) were evaluated on CMR and compared to controls with idiopathic right ventricular outflow tract tachycardia (n = 40). The primary outcome was occurrence of AA (atrial fibrillation or atrial flutter) during follow‐up, recorded by 12‐lead ECG, Holter monitoring or implantable cardioverter defibrillator (ICD) interrogation.
Results
Patients harbored a desmosomal plakophilin‐2 (PKP2) (n = 37) or nondesmosomal phospholamban (PLN) (n = 14) mutation. In 20 subjects, no pathogenic mutation was identified. Compared to controls, right atrial (RA) volumes were reduced in PKP2 (P = 0.002) and comparable in PLN (P = 0.441) mutation carriers. In patients with no mutation identified, RA (P = 0.011) and left atrial (P = 0.034) volumes were increased. Bi‐atrial ALEF showed no significant difference between the groups. AA were experienced by 27% of patients and occurred equally among PKP2 (30%) and no mutation identified patients (30%), but less among PLN mutation carriers (14%).
Conclusion
Genotype influences atrial volume and occurrence of AA in ARVD/C. While the incidence of AA is similar in PKP2 mutation carriers and patients with no mutation identified, PKP2 mutation carriers have significantly smaller atria. This suggests a different arrhythmogenic mechanism.
Objectives The purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS). Background Beta-blockers are the mainstay in managing LQTS. Studies comparing ...the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective. Methods Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented. Results Patients (56% female, 27% symptomatic, heart rate 76 ± 16 beats/min, QTc 472 ± 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol. Conclusions Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients.
Abstract Background Previous studies suggested that electrical abnormalities precede overt structural disease in arrhythmogenic right ventricular cardiomyopathy (ARVC). Abnormal RV deformation has ...been reported in early ARVC without structural abnormalities. The pathophysiological mechanisms underlying these abnormalities remain unknown. Objectives The authors used imaging and computer simulation to differentiate electrical from mechanical tissue substrates among ARVC clinical stages. Methods ARVC desmosomal mutation carriers (n = 84) were evaluated by electrocardiography (ECG), Holter monitoring, late-enhancement cardiac magnetic resonance imaging, and echocardiographic RV deformation imaging. Subjects were categorized based on the presence of 2010 International Task Force criteria: 1) subclinical stage (n = 21); 2) electrical stage (n = 15); and 3) structural stage (n = 48). Late enhancement was not present in any subclinical or electrical stage subjects. Results Three distinctive characteristic RV longitudinal deformation patterns were identified: type I: normal deformation (n = 12); type II: delayed onset of shortening, reduced systolic peak strain, and mild post-systolic shortening (n = 35); and type III: systolic stretching with large post-systolic shortening (n = 37). A majority (69%) of structural staged mutation carriers were type III, whereas a large proportion of both electrical and subclinical stage subjects (67% and 48%, respectively) were type II. Computer simulations demonstrated that the type II pattern can be explained by a combination of reduced contractility and mildly increased passive myocardial stiffness. This evolved into type III by aggravating both mechanical substrates. Electrical activation delay alone explained none of the patterns. Conclusions Different ARVC stages were characterized by distinct RV deformation patterns, all of which could be reproduced by simulating different degrees of mechanical substrates. Subclinical and electrical staged ARVC subjects already showed signs of local mechanical abnormalities. Our novel approach could lead to earlier disease detection and, thereby, influence current definitions of electrical and subclinical ARVC stages.
OBJECTIVE
We investigated whether serum magnesium (Mg2+) was prospectively associated with macro- or microvascular complications and mediated by glycemic control (hemoglobin A1c HbA1c), in type 2 ...diabetes (T2D).
RESEARCH DESIGN AND METHODS
We analyzed in 4,348 participants the association of serum Mg2+ with macrovascular disease and mortality (acute myocardial infarction AMI, coronary heart disease CHD, heart failure HF, cerebrovascular accident CVA, and peripheral arterial disease PAD), atrial fibrillation (AF), and microvascular complications (chronic kidney disease CKD, diabetic retinopathy, and diabetic foot) using Cox regression, adjusted for confounders. Mediation analysis was performed to assess whether HbA1c mediated these associations.
RESULTS
The average baseline serum Mg2+ concentration was 0.80 ± 0.08 mmol/L. During 6.1 years of follow-up, serum Mg2+ was inversely associated with major macrovascular, 0.87 (95% CI 0.76; 1.00); HF, 0.76 (95% CI 0.62; 0.93); and AF, 0.59 (95% CI 0.49; 0.72). Serum Mg2+ was not associated with AMI, CHD, CVA, and PAD. During 5.1 years of follow-up, serum Mg2+ was inversely associated with overall microvascular events, 0.85 (95% CI 0.78; 0.91); 0.89 (95% CI 0.82; 0.96) for CKD, 0.77 (95% CI 0.61; 0.98) for diabetic retinopathy, and 0.85 (95% CI 0.78; 0.92) for diabetic foot. HbA1c mediated the associations of serum Mg2+ with HF, overall microvascular events, diabetic retinopathy, and diabetic foot.
CONCLUSIONS
Serum Mg2+ concentration is inversely associated with the risk to develop HF and AF and with the occurrence of CKD, diabetic retinopathy, and foot complications in T2D. Glycemic control partially mediated the association of serum Mg2+ with HF and microvascular complications.
A combination of variable expression, age-related penetrance, and unpredictable arrhythmic events complicates management of relatives of arrhythmogenic right ventricular dysplasia/cardiomyopathy ...(ARVD/C) patients. We aimed to (i) determine predictors of ARVD/C diagnosis and (ii) optimize arrhythmic risk stratification among first-degree relatives of ARVD/C patients.
Detailed phenotypic and outcome data of 274 first-degree relatives (46% male; 36.5 ± 18.9 years) of 138 ARVD/C probands were obtained. Ninety-six (35%) relatives were diagnosed with ARVD/C according to 2010 Task Force Criteria (TFC). Siblings had a three-fold-increased risk of ARVD/C diagnosis compared with parents and children (odds ratio 3.11, P < 0.001). Multivariable logistic regression identified symptoms (P < 0.001), being a sibling (P < 0.001), the presence of a pathogenic mutation (P < 0.001), and female sex (P = 0.010) as predictors of ARVD/C diagnosis. During 6.7 ± 3.8 years of follow-up, 21 (8%) relatives experienced a sustained ventricular arrhythmia (cycle length 271 ± 48 ms). While being a sibling was a predictor of ARVD/C diagnosis, neither relatedness to the proband (P = 0.185) nor malignant family history (P = 0.347) was significantly associated with arrhythmic events. Meeting TFC independent of family history criteria had higher prognostic value for arrhythmic events than conventional 2010 TFC, which include family history area under the receiver operating characteristic curve 0.95 (95% CI 0.93-0.97) vs. 0.85 (95% CI 0.82-0.88), P < 0.001.
One-third of first-degree relatives develop manifest ARVD/C. Siblings have highest risk of disease, even after correcting for age and sex. Fulfilment of TFC independent of family history is superior to conventional TFC for arrhythmic risk stratification of relatives.
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