Disease progression rate is a strong predictor of ventricular arrhythmias in patients with cardiac laminopathies: a primary prevention cohort study.

AIMS: Cardiac disease progression prior to first ventricular arrhythmia (VA) in LMNA genotype-positive patients is not described. METHODS AND RESULTS: We performed a primary prevention cohort study, including consecutive LMNA genotype-positive patients from our centre. Patients underwent repeated clinical, electrocardiographic, and echocardiographic examinations. Electrocardiographic and echocardiographic disease progression as a predictor of first-time VA was evaluated by generalized estimation equation analyses. Threshold values at transition to an arrhythmic phenotype were assessed by threshold regression analyses. We included 94 LMNA genotype-positive patients without previous VA (age 38 ± 15 years, 32% probands, 53% females). Nineteen (20%) patients experienced VA during 4.6 (interquartile range 2.1-7.3) years follow up, at mean age 50 ± 11 years. We analysed 536 echocardiographic and 261 electrocardiogram examinations. Individual patient disease progression was associated with VA [left ventricular ejection fraction (LVEF) odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2-1.6 per 5% reduction, left ventricular end-diastolic volume index (LVEDVi) OR 1.2 (95% CI 1.1-1.3) per 5 mL/m2 increase, PR interval OR 1.2 (95% CI 1.1-1.4) per 10 ms increase]. Threshold values for transition to an arrhythmic phenotype were LVEF 44%, LVEDVi 77 mL/m2, and PR interval 280 ms. CONCLUSIONS: Incidence of first-time VA was 20% during 4.6 years follow up in LMNA genotype-positive patients. Individual patient disease progression by ECG and echocardiography were strong predictors of VA, indicating that disease progression rate may have additional value to absolute measurements when considering primary preventive ICD. Threshold values of LVEF <44%, LVEDVi >77 mL/m2, and PR interval >280 ms indicated transition to a more arrhythmogenic phenotype.

Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator.

BACKGROUND: LMNA genotype-positive patients have high risk of experiencing life-threatening ventricular tachyarrhythmias (VTAs). The LMNA-risk VTA calculator published in 2019 has not been externally validated. OBJECTIVE: The purpose of this study was to validate the LMNA-risk VTA calculator. METHODS: We included LMNA genotype-positive patients without previous VTAs from 2 large Scandinavian centers. Patients underwent electrocardiography, 24-hour Holter monitoring, and echocardiographic examinations at baseline and repeatedly during follow-up. Validation of the LMNA-risk VTA calculator was performed using Harrell's C-statistic derived from multivariable Cox regression analysis. RESULTS: We included 118 patients (age 37 years [IQR 27-49 years]; 39 [33%] probands; 65 [55%] women; 100 [85%] with non-missense LMNA variants). Twenty-three patients (19%) experienced VTA during 6.1 years (interquartile range 3.0-9.1 years) follow-up, resulting in 3.0% (95% confidence interval 2.0%-4.5%) yearly incidence rate. Atrioventricular block and reduced left ventricular ejection fraction were independent predictors of VTAs, while nonsustained ventricular tachycardia, male sex, and non-missense LMNA variants were not. The LMNA-risk VTA calculator showed 83% sensitivity and 26% specificity for identifying patients with VTAs during the coming 5 years, and a Harrell's C-statistic of 0.85, when applying ≥7% predicted 5-year VTA risk as threshold. The sensitivity increased to 100% when reevaluating risk at the time of last consultation before VTA. The calculator overestimated arrhythmic risk in patients with mild and moderate phenotype, particularly in men. CONCLUSION: Validation of the LMNA-risk VTA calculator showed high sensitivity for subsequent VTAs, but overestimated arrhythmic risk when using ≥7% predicted 5-year risk as threshold. Frequent reevaluation of risk was necessary to maintain the sensitivity of the model.

Progression of cardiac disease in patients with lamin A/C mutations.

AIMS: We aimed to study the progression of cardiac dysfunction in patients with lamin A/C mutations and explore markers of adverse cardiac outcome. METHODS AND RESULTS: We followed consecutive lamin A/C genotype-positive patients divided into tertiles according to age. Patients underwent repeated clinical examinations, electrocardiograms (ECGs), and echocardiograms. We followed left ventricular (LV) and right ventricular (RV) size and function, and the severity atrioventricular-valve regurgitations. Outcome was death, LVAD implant, or cardiac transplantation. We included 101 patients [age 44 (29-54) years, 39% probands, 50% female]. We analysed 576 echocardiograms and 258 ECGs during a follow-up of 4.9 (interquartile range 2.5-8.2) years. The PR-interval increased at young age from 204 ± 73 to 212 ± 69 ms (P < 0.001), LV ejection fraction (LVEF) declined from middle age from 50 ± 12% to 47 ± 13% (P < 0.001), while LV volumes remained unchanged. RV function and tricuspid regurgitation worsened from middle age with accelerating rates. Progression of RV dysfunction [odds ratio (OR) 1.3, 95% confidence interval (CI) (1.03-1.65), P = 0.03] and tricuspid regurgitation [OR 4.9, 95% CI (1.64-14.9), P = 0.004] were associated with outcome when adjusted for age, sex, comorbidities, LVEF, and New York Heart Association functional class. CONCLUSION: In patients with lamin A/C genotype, electrical disease started at young age. From middle age, LV function deteriorated progressively, while LV size remained unchanged. Worsening of RV function and tricuspid regurgitation accelerated in older age and were associated with outcome. Our systematic map on cardiac deterioration may help optimal monitoring and prognostication in lamin A/C disease.

Mitral annulus disjunction is associated with adverse outcome in Marfan and Loeys-Dietz syndromes.

AIMS: We aimed to assess the prevalence of mitral annulus disjunction (MAD) and to explore the association with aortic disease and mitral valve surgery in patients with Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). METHODS AND RESULTS: We included consecutive MFS patients fulfilling Revised Ghent Criteria and LDS patients fulfilling Loeys-Dietz Revised Nosology. MAD was identified by echocardiography and was quantified as the longitudinal distance from the ventricular myocardium to the hinge point of the posterior mitral leaflet. Aortic events were defined as aortic dissection or prophylactic aortic surgery. We recorded the need of mitral valve surgery including mitral valve repair or replacement. We included 168 patients (103 with MFS and 65 with LDS). The prevalence of MAD was 41%. MAD was present in all age groups. Aortic events occurred in 112 (67%) patients (27 with dissections and 85 with prophylactic surgical interventions). Patients with MAD were younger at aortic event than those without MAD (log rank = 0.02) Patients with aortic events had greater MAD distance in posterolateral wall [8 (7-10) mm vs. 7 (6-8) mm, P = 0.04]. Mitral events occurred more frequently in patients with MAD (P < 0.001). CONCLUSION: MAD was highly prevalent in patients with MFS and LDS. MAD was a marker of severe disease including aortic events at younger age and need of mitral valve surgery. Screening patients with MFS an LDS for MAD may provide prognostic information and may be relevant in planning surgical intervention. Detection of MAD in patients with MFS and LDS may infer closer clinical follow-up from younger age.

Cardiac Phenotypes and Markers of Adverse Outcome in Elite Athletes With Ventricular Arrhythmias.

OBJECTIVES: This study describes the cardiac phenotypes and markers of adverse outcome in athletes with ventricular arrhythmias with no other discernable etiology than high exercise doses. BACKGROUND: Little is known about phenotypes and risk markers of life-threatening arrhythmic events in athletes with ventricular arrhythmia. METHODS: We compared high-performance athletes who have ventricular arrhythmia with healthy controls using clinical data and cardiac imaging. None of the patients had family history of arrhythmogenic cardiomyopathy or any other discernable etiology of ventricular arrhythmia. Right (RV) and left ventricular (LV) function was assessed by echocardiographic longitudinal strain (right ventricular free wall strain longitudinal [RVFWSL] and left ventricular global longitudinal strain [LVGLS]). Mechanical dispersion was defined as the standard deviation of time to peak strain in 16 LV segments. RV ejection fraction and presence of late gadolinium enhancement was assessed by cardiac magnetic resonance. RESULTS: We included 43 athletes (45 ± 14 years of age, 16% female) with ventricular arrhythmias and 30 healthy athletes (41 ± 9 years of age, 7% female). Athletes with ventricular arrhythmias had worse RV function than healthy athletes by echocardiography (RVFWSL: -22.9 ± 4.8% vs. -26.6 ± 3.3%; p < 0.001) and by cardiac magnetic resonance (RV ejection fraction 48 ± 7% vs. 52 ± 6%; p = 0.04), and had more late gadolinium enhancement (24% vs. 3%; p = 0.03). Life-threatening arrhythmic events (aborted cardiac arrest, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator therapy) had occurred in 23 (53%) athletes with ventricular arrhythmias. These had impaired LV function compared to those with less severe ventricular arrhythmias (LVGLS: -17.1 ± 3.0% vs. -18.8 ± 2.0%; p = 0.04). LV mechanical dispersion was an independent marker of life-threatening events (adjusted odds ratio: 2.2 [1.1 to 4.8] by 10 ms increments; p = 0.03). CONCLUSIONS: Athletes with ventricular arrhythmias had impaired RV function and more myocardial fibrosis compared to healthy athletes. Athletes with life-threatening arrhythmic events had additional LV contraction abnormalities. These phenotypes mimic arrhythmogenic cardiomyopathy and may potentially be induced by high doses of exercise in susceptible individuals.

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.

The Mitral Annulus Disjunction Arrhythmic Syndrome.

BACKGROUND: Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the mitral valve leaflet hinge point. MAD has been associated with mitral valve prolapse (MVP) and sudden cardiac death. OBJECTIVES: The purpose of this study was to describe the clinical presentation, MAD morphology, association with MVP, and ventricular arrhythmias in patients with MAD. METHODS: The authors clinically examined patients with MAD. By echocardiography, the authors assessed the presence of MVP and measured MAD distance in parasternal long axis. Using cardiac magnetic resonance (CMR), the authors assessed circumferential MAD in the annular plane, longitudinal MAD distance, and myocardial fibrosis. Aborted cardiac arrest and sustained ventricular tachycardia were defined as severe arrhythmic events. RESULTS: The authors included 116 patients with MAD (age 49 ± 15 years; 60% female). Palpitations were the most common symptom (71%). Severe arrhythmic events occurred in 14 (12%) patients. Longitudinal MAD distance measured by CMR was 3.0 mm (interquartile range [IQR]: 0 to 7.0 mm) and circumferential MAD was 150° (IQR: 90° to 210°). Patients with severe arrhythmic events were younger (age 37 ± 13 years vs. 51 ± 14 years; p = 0.001), had lower ejection fraction (51 ± 5% vs. 57 ± 7%; p = 0.002) and had more frequently papillary muscle fibrosis (4 [36%] vs. 6 [9%]; p = 0.03). MVP was evident in 90 (78%) patients and was not associated with ventricular arrhythmia. CONCLUSIONS: Ventricular arrhythmias were frequent in patients with MAD. A total of 26 (22%) patients with MAD did not have MVP, and MVP was not associated with arrhythmic events, indicating MAD itself as an arrhythmogenic entity. MAD was detected around a large part of the mitral annulus circumference and was interspersed with normal tissue.