Cardiac diseases with risk of severe ventricular arrhythmias; risk stratification and impact of exercise

Mitral annulus disjunction is a gap between the mitral ring and the ventricular myocardium and is associated with mitral valve prolapse. Previous life-threatening arrhythmias were prevalent (12%) in the study population of 116 patients with mitral annulus disjunction. Markers of severe ventricular arrhythmias were lower age, subtle left ventricular dysfunction, papillary muscle fibrosis and absence of concomitant mitral valve prolapse. Mitral annulus disjunction should be considered in the clinical evaluation of patients with malignant cardiac arrhythmias. The hereditary cardiac diseases arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy are frequent causes of sudden death in the young. High intensity exercise was a strong marker of life-threatening arrhythmias and worse cardiac function in arrhythmogenic cardiomyopathy. Contrarily, in hypertrophic cardiomyopathy, increased exercise was neither associated with ventricular arrhythmias nor increased myocardial hypertrophy and correlated to better diastolic left ventricular function. The results support exercise restriction in arrhythmogenic cardiomyopathy and encourage exercise execution in hypertrophic cardiomyopathy

Exercise is Associated With Impaired Left Ventricular Systolic Function in Patients With Lamin A/C Genotype

Background Lamin A/C cardiomyopathy is a malignant and highly penetrant inheritable cardiomyopathy. Competitive sports have been associated with adverse events in these patients, but data on recreational exercise are lacking. We aimed to explore associations between exercise exposure and disease severity in patients with lamin A/C genotype. Methods and Results Lamin A/C genotype positive patients answered a questionnaire on exercise habits from age 7 years until genetic diagnosis. We recorded exercise hours >3 metabolic equivalents and calculated cumulative lifetime exercise. Patients were grouped in active or sedate based on lifetime exercise hours above or below median. We performed echocardiography, 12‐lead ECG, Holter monitoring, and biomarkers including NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide). We defined left ventricular ejection fraction <45% as a clinically significant impairment of left ventricular function. We included 69 patients (age 42±14 years, 41% probands, 46% women) with median lifetime exercise 4160 (interquartile range 1041–6924) hours. Active patients were more frequently probands (53% versus 29%, P=0.04), had lower left ventricular ejection fraction (43±13% versus 51±11%, P=0.006), and higher NT‐proBNP (78 [interquartile range 32–219] pmol/L versus 30 [interquartile range 13–64] pmol/L, P=0.03) compared with sedate, while age did not differ (45±13 years versus 40±16 years, P=0.16). The decrease in left ventricular ejection fraction per tertile increment in lifetime exercise was 4% (95% CI −7% to −0.4%, P=0.03), adjusted for age and sex and accounting for dependence within families. Left ventricular ejection fraction <45% was observed at a younger age in active patients (log rank P=0.007). Conclusions Active lamin A/C patients had worse systolic function compared with sedate which occurred at younger age. Our findings may improve exercise recommendations in patients with lamin A/C

Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy

Data presented in this paper are supplementary material to our study âVigorous exercise in patients with hypertrophic cardiomyopathyâ [1]. The current article presents supplementary data on collection and analyses of exercise parameters and genetic data in the original research article. Keywords: Hypertrophic cardiomyopathy, Exercise, Genetics, Arrhythmi

Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers

INTRODUCTION: Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2). METHODS: CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed. RESULTS: In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731). CONCLUSION: No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.Funding agencies: This work was supported by Region Östergötland (ALF) undergrant LIO-609681 and by FORSS (Medical Research Council ofSoutheast Sweden) under grant FORSS/572421 and FORSS/307961.Pyotr G. Platonov is supported by The Swedish Heart-Lung Foundation and governmental funding of clinical research (ALF). Henrik K. Jensen is supported by the Novo Nordisk Foundation (NNF18OC0031258). Wojciech Zareba is supported by NIH Grant(1R01HL116906) (Mechanisms, Genotypes and Clinical Phenotypes of Arrhythmogenic Cardiomyopathy).</p

Increased levels of sST2 in patients with mitral annulus disjunction and ventricular arrhythmias

Objective Displacement of the mitral valve, mitral annulus disjunction (MAD), is described as a possible aetiology of sudden cardiac death. Stress-induced fibrosis in the mitral valve apparatus has been suggested as the underlying mechanism. We aimed to explore the association between stretch-related and fibrosis-related biomarkers and ventricular arrhythmias in MAD. We hypothesised that soluble suppression of tumourigenicity-2 (sST2) and transforming growth factor-β1 (TGFβ1) are markers of ventricular arrhythmias in patients with MAD. Methods We included patients with ≥1 mm MAD on cardiac MRI. We assessed left ventricular ejection fraction (LVEF) and fibrosis by late gadolinium enhancement (LGE). The occurrence of ventricular arrhythmia, defined as aborted cardiac arrest, sustained or non-sustained ventricular tachycardia, was retrospectively assessed. We assessed circulating sST2 and TGFβ1 levels. Results We included 72 patients with MAD, of which 22 (31%) had ventricular arrhythmias. Patients with ventricular arrhythmias had lower LVEF (60 % (±6) vs 63% (±6), p = 0.04), more frequently papillary muscle fibrosis (14 (64%) vs 10 (20%), p < 0.001) and higher sST2 levels (31.6 ± 10.1 ng/mL vs 25.3 ± 9.2 ng/mL, p = 0.01) compared with those without, while TGFβ1 levels did not differ (p = 0.29). Combining sST2 level, LVEF and papillary muscle fibrosis optimally detected individuals with arrhythmia (area under the curve 0.82, 95% CI 0.73 to 0.92) and improved the risk model (p < 0.05) compared with single parameters. Conclusion Circulating sST2 levels were higher in patients with MAD and ventricular arrhythmias compared with arrhythmia-free patients. Combining sST2, LVEF and LGE assessment improved risk stratification in patients with MAD