Mayosi, Bongani M.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. Methods: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2 -positive probands, and clinical evaluation was performed. Results: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2 -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). Conclusions: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2 -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

Objective The prevalence, predictors and outcome of myopericarditis in patients with tuberculous (TB) pericarditis are unknown. Methods Eighty-one patients (mean age±SD, 36.1±13.3 years; 54 (66.7%) men; 58 (71.6%) HIV seropositive) with TB pericarditis were recruited between January 2006 and September 2008. Myopericarditis was defined as echocardiographic LV systolic dysfunction (immediately after pericardiocentesis), elevated peripheral blood troponin T (>0.03 ng/mL), or elevated peripheral blood creatine kinase (CK >174 IU/L) with a CK:CK-myocardial band (MB) mass ratio of >6%. The outcome measure was case fatality rate at 6 months of follow-up. Results Myopericarditis was present in 43 (53.1%) patients. Patients with myopericarditis, as compared with those without, were more likely to be HIV seropositive (35 (81.4%) vs 23 (60.5%) respectively, p=0.038) and have lower peripheral CD4 count (median (IQR) 98 (54–290) vs 177 (104–429), p=0.026). Electrocardiographic ST segment elevation was more common in myopericarditis (15 (36.6%) vs 4 (10.8%), p=0.008) and predicted myopericarditis independently of CD4 count on multiple logistic regression analysis (OR 4.36, 95% CI 1.34 to 17.34, p=0.0132). At 6 months, 14 (18%) patients had died with no significant difference between those with or without myopericarditis (6/42 (14%) vs 8/36 (22%), respectively (p=0.363)). Conclusions Myopericarditis is common in TB pericardial effusion and associated with HIV-related immunosuppression. It can be identified by electrocardiographic ST-elevation, particularly when peripheral CD4 count is low. There was no significant difference in case fatality rate in those with or without myopericarditis.