A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.

BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

Long-Term Arrhythmic Follow-Up and Risk Stratification of Patients With Desmoplakin-Associated Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Patients with likely pathogenic/pathogenic desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives: The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+). Methods: DSP-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics. Results: Among 252 DSP-TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank P = 0.0239). History of nonsustained VT (aHR 2.097; P = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age (P = 0.723) nor male sex (P = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]). Conclusions: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-TFC+ patients with nonsustained VT should be considered as high-risk.

Magnetic Resonance Imaging Characterization and Clinical Outcomes of Dilated and Arrhythmogenic Left Ventricular Cardiomyopathies.

BACKGROUND: Nondilated left ventricular cardiomyopathy (NDLVC) has been recently differentiated from dilated cardiomyopathy (DCM). A comprehensive characterization of these 2 entities using cardiac magnetic resonance (CMR) and genetic testing has never been performed. OBJECTIVES: This study sought to provide a thorough characterization and assess clinical outcomes in a large multicenter cohort of patients with DCM and NDLVC. METHODS: A total of 462 patients with DCM (227) or NDLVC (235) with CMR data from 4 different referral centers were retrospectively analyzed. The study endpoint was a composite of sudden cardiac death or major ventricular arrhythmias. RESULTS: In comparison to DCM, NDLVC had a higher prevalence of pathogenic or likely pathogenic variants of arrhythmogenic genes (40% vs 23%; P < 0.001), higher left ventricular (LV) systolic function (LV ejection fraction: 51% ± 12% vs 36% ± 15%; P < 0.001) and higher prevalence of free-wall late gadolinium enhancement (LGE) (27% vs 14%; P < 0.001). Conversely, DCM showed higher prevalence of pathogenic or likely pathogenic variants of nonarrhythmogenic genes (23% vs 12%; P = 0.002) and septal LGE (45% vs 32%; P = 0.004). Over a median follow-up of 81 months (Q1-Q3: 40-132 months), the study outcome occurred in 98 (21%) patients. LGE with septal location (HR: 1.929; 95% CI: 1.033-3.601; P = 0.039) was independently associated with the risk of sudden cardiac death or major ventricular arrhythmias together with LV dilatation, older age, advanced NYHA functional class, frequent ventricular ectopic activity, and nonsustained ventricular tachycardia. CONCLUSIONS: In a multicenter cohort of patients with DCM and NDLVC, septal LGE together with LV dilatation, age, advanced disease, and frequent and repetitive ventricular arrhythmias were powerful predictors of major arrhythmic events.

Role of arrhythmic phenotype in prognostic stratification and management of dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. METHODS AND RESULTS: In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF] <35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. CONCLUSION: In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. METHODS: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies.

BACKGROUND: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. OBJECTIVES: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. METHODS: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD). RESULTS: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. CONCLUSIONS: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing.

Sex differences in natural history of cardiovascular magnetic resonance- and biopsy-proven lymphocytic myocarditis.

AIMS: The role of sex in determining the profile and the outcomes of patients with myocarditis is largely unexplored. We evaluated the impact of sex as a modifier factor in the clinical characterization and natural history of patients with definite diagnosis of myocarditis. METHODS AND RESULTS: We retrospectively analysed a single-centre cohort of consecutive patients with definite diagnosis of myocarditis (i.e. endomyocardial biopsy or cardiac magnetic resonance proven). Specific sub-analyses were performed in cohorts of patients with chest pain, ventricular arrhythmias, and heart failure as different main symptoms at presentation. The primary outcome measure was a composite of all-cause mortality or heart transplantation (HTx). We included 312 patients, of which 211, 68% of the whole population, were males. Despite no clinically relevant differences found at baseline presentation, males had a higher indexed left ventricular end-diastolic volume (62 ± 23 mL/m2 vs. 52 ± 20 mL/m2, P = 0.011 in males vs. females, respectively) at follow-up evaluation. At a median follow-up of 72 months, 36 (17%) males vs. 8 (8%) females experienced death or HTx (P = 0.033). Male sex emerged as predictors of all-cause mortality or HTx in every combination of covariates (HR 2.600; 1.163-5.809; P = 0.020). Results were agreeable regardless of the main symptom of presentation. CONCLUSIONS: In a large cohort of patients with definite diagnosis of myocarditis, females experienced a more favourable long-term prognosis than males, despite a similar clinical profile at presentation.

Lyme Carditis: From Pathophysiology to Clinical Management.

Cardiac involvement is a rare but relevant manifestation of Lyme disease that frequently presents as atrioventricular block (AVB). Immune-mediated injury has been implicated in the pathogenesis of Lyme carditis due to possible cross-reaction between Borrelia burgdorferi antigens and cardiac epitopes. The degree of the AVB can fluctuate rapidly, with two-thirds of patients progressing to complete AVB. Thus, continuous heart rhythm monitoring is essential, and a temporary pacemaker may be necessary. Routinely permanent pacemaker implantation, however, is contraindicated because of the frequent transient nature of the condition. Antibiotic therapy should be initiated as soon as the clinical suspicion of Lyme carditis arises to reduce the duration of the disease and minimize the risk of complications. Diagnosis is challenging and is based on geographical epidemiology, clinical history, signs and symptoms, serological testing, ECG and echocardiographic findings, and exclusion of other pathologies. This paper aims to explain the pathophysiological basis of Lyme carditis, describe its clinical features, and delineate the treatment principles.