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.

Ventricular arrhythmias in arrhythmic mitral valve syndrome-a prospective continuous long-term cardiac monitoring study.

AIMS: Arrhythmic mitral valve syndrome is linked to life-threatening ventricular arrhythmias. The incidence, morphology and methods for risk stratification are not well known. This prospective study aimed to describe the incidence and the morphology of ventricular arrhythmia and propose risk stratification in patients with arrhythmic mitral valve syndrome. METHODS: Arrhythmic mitral valve syndrome patients were monitored for ventricular tachyarrhythmias by implantable loop recorders (ILR) and secondary preventive implantable cardioverter-defibrillators (ICD). Severe ventricular arrhythmias included ventricular fibrillation, appropriate or aborted ICD therapy, sustained ventricular tachycardia and non-sustained ventricular tachycardia with symptoms of hemodynamic instability. RESULTS: During 3.1 years of follow-up, severe ventricular arrhythmia was recorded in seven (12%) of 60 patients implanted with ILR [first event incidence rate 4% per person-year, 95% confidence interval (CI) 2-9] and in four (20%) of 20 patients with ICD (re-event incidence rate 8% per person-year, 95% CI 3-21). In the ILR group, severe ventricular arrhythmia was associated with frequent premature ventricular complexes, more non-sustained ventricular tachycardias, greater left ventricular diameter and greater posterolateral mitral annular disjunction distance (all P < 0.02). CONCLUSIONS: The yearly incidence of ventricular arrhythmia was high in arrhythmic mitral valve syndrome patients without previous severe arrhythmias using continuous heart rhythm monitoring. The incidence was even higher in patients with secondary preventive ICD. Frequent premature ventricular complexes, non-sustained ventricular tachycardias, greater left ventricular diameter and greater posterolateral mitral annular disjunction distance were predictors of first severe arrhythmic event.

Stretch of the papillary insertion triggers reentrant arrhythmia: an in silico patient study.

Background: The electrophysiological mechanism connecting mitral valve prolapse (MVP), premature ventricular complexes and life-threatening ventricular arrhythmia is unknown. A common hypothesis is that stretch activated channels (SACs) play a significant role. SACs can trigger depolarizations or shorten repolarization times in response to myocardial stretch. Through these mechanisms, pathological traction of the papillary muscle (PM), as has been observed in patients with MVP, may induce irregular electrical activity and result in reentrant arrhythmia. Methods: Based on a patient with MVP and mitral annulus disjunction, we modeled the effect of excessive PM traction in a detailed medical image-derived ventricular model by activating SACs in the PM insertion region. By systematically varying the onset of SAC activation following sinus pacing, we identified vulnerability windows for reentry with 1 ms resolution. We explored how reentry was affected by the SAC reversal potential ( E SAC ) and the size of the region with simulated stretch (SAC region). Finally, the effect of global or focal fibrosis, modeled as reduction in tissue conductivity or mesh splitting (fibrotic microstructure), was investigated. Results: In models with healthy tissue or fibrosis modeled solely as CV slowing, we observed two vulnerable periods of reentry: For E SAC of -10 and -30 mV, SAC activated during the T-wave could cause depolarization of the SAC region which lead to reentry. For E SAC of -40 and -70 mV, SAC activated during the QRS complex could result in early repolarization of the SAC region and subsequent reentry. In models with fibrotic microstructure in the SAC region, we observed micro-reentries and a larger variability in which times of SAC activation triggered reentry. In these models, 86% of reentries were triggered during the QRS complex or T-wave. We only observed reentry for sufficiently large SAC regions ( > = 8 mm radius in models with healthy tissue). Conclusion: Stretch of the PM insertion region following sinus activation may initiate ventricular reentry in patients with MVP, with or without fibrosis. Depending on the SAC reversal potential and timing of stretch, reentry may be triggered by ectopy due to SAC-induced depolarizations or by early repolarization within the SAC region.

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.

Left Ventricular Dysfunction in Arrhythmogenic Cardiomyopathy: Association With Exercise Exposure, Genetic Basis, and Prognosis.

Background Arrhythmogenic cardiomyopathy (AC) is characterized by biventricular dysfunction, exercise intolerance, and high risk of ventricular tachyarrhythmias and sudden death. Predisposing factors for left ventricular (LV) disease manifestation and its prognostic implication in AC are poorly described. We aimed to assess the associations of exercise exposure and genotype with LV dysfunction in AC, and to explore the impact of LV disease progression on adverse arrhythmic outcome. Methods and Results We included 168 patients with AC (50% probands, 45% women, 40±16 years old) with 715 echocardiographic exams (4.1±1.7 exams/patient, follow-up 7.6 [interquartile range (IQR), 5.4-10.9] years) and complete exercise and genetic data in a longitudinal study. LV function by global longitudinal strain was -18.8% [IQR, -19.2% to -18.3%] at presentation and was worse in patients with greater exercise exposure (global longitudinal strain worsening, 0.09% [IQR, 0.01%-0.17%] per 5 MET-hours/week, P=0.02). LV function by global longitudinal strain worsened, with 0.08% [IQR, 0.05%-0.12%] per year; (P<0.001), and progression was most evident in patients with desmoplakin genotype (P for interaction <0.001). Deterioration of LV function predicted incident ventricular tachyarrhythmia (aborted cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter defibrillator shock) (adjusted odds ratio, 1.1 [IQR, 1.0-1.3] per 1% worsening by global longitudinal strain; P=0.02, adjusted for time and previous arrhythmic events). Conclusions Greater exercise exposure was associated with worse LV function at first visit of patients with AC but did not significantly affect the rate of LV progression during follow-up. Progression of LV dysfunction was most pronounced in patients with desmoplakin genotypes. Deterioration of LV function during follow-up predicted subsequent ventricular tachyarrhythmia and should be considered in risk stratification.

Tricuspid Annulus Disjunction: Novel Findings by Cardiac Magnetic Resonance in Patients With Mitral Annulus Disjunction.

OBJECTIVES: This study aimed to assess whether patients with MAD also have disjunction of the tricuspid annulus. BACKGROUND: Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the mitral annulus. Whether the disjunction extends to the right side of the heart is not known. METHODS: In a cohort of patients with MAD, we assessed the presence of tricuspid annulus disjunction (TAD) with the use of cardiac magnetic resonance. We explored the associations between TAD and MAD characteristics and the relationship to ventricular arrhythmias (nonsustained/sustained ventricular tachycardias and aborted cardiac arrest). RESULTS: We included 84 patients (mean age: 48 ± 16 years; 63% female). We observed TAD in 42 (50%). Patients with TAD were older (age 52 ± 16 years vs. 43 ± 15 years; p = 0.02), had greater circumferential extent of MAD (164 ± 57° vs. 115 ± 58°; p = 0.002), greater maximum longitudinal MAD distance (9.4 ± 2.9 mm vs. 6.2 ± 2.8 mm; p < 0.001), and more frequent mitral valve prolapse (n = 39 [92%] vs. n = 24 [57%]; p < 0.001). Ventricular arrhythmias had occurred in 34 patients (41%), who were younger (age 39 ± 14 years vs. 54 ± 14 years; p < 0.001) and had lower prevalence of TAD (n = 22 [29%] vs. n = 12 [52%]; p = 0.03). TAD was not associated with ventricular arrhythmias when adjusted for age (odds ratio adjusted for age: 0.54; 95% confidence interval: 0.20 to 1.45; p = 0.22). CONCLUSIONS: We report for the first time the existence of right-sided annulus disjunction as a common finding in patients with MAD. TAD was associated with more severe left-sided annulus disjunction and mitral valve prolapse, but not with ventricular arrhythmias.

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-ß1 (TGFß1) 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 TGFß1 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 TGFß1 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.

Vigorous exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: We aimed to investigate if history of vigorous exercise was associated with changes in left ventricular morphology, left ventricular function and ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy genotype positive, phenotype negative (Genotype+ LVH-) and in phenotype positive (HCM LVH+). METHODS: In this cross sectional study we included 187 subjects (age 49±16years, 89(48%) female, 121(65%) HCM LVH+ and 66 (35%) Genotype+ LVH-) who answered a questionnaire on physical activity history. Exercise ≥6 metabolic equivalents was defined as vigorous. Subjects with a history of vigorous exercise ≥4h/week during ≥6years were defined as athletes. All underwent echocardiography and Holter monitoring. VAs were defined as aborted cardiac arrest, sustained or non-sustained ventricular tachycardia. RESULTS: In both Genotype+ LVH- and HCM LVH+, lifetime vigorous exercise correlated with larger left ventricular end-diastolic volume (rho 0.44 and 0.38 respectively, both p<0.001). Lifetime vigorous exercise correlated with increased left ventricular mass in Genotype+ LVH- (rho 0.28, p=0.03), but not in HCM LVH+ (p=0.53). Left ventricular systolic function was similar between athletes and non-athletes in Genotype+ LVH- and HCM LVH+. HCM LVH+ athletes had lower E/e' (p=0.03) and higher e' (p=0.02) compared to non-athletes, while this difference was not observed in Genotype+ LVH-. Lifetime vigorous exercise was similar among HCM LVH+ with and without VAs (p=0.89). CONCLUSIONS: Increased lifetime vigorous exercise was associated with larger left ventricular volumes in hypertrophic cardiomyopathy, but correlated to left ventricular mass only in Genotype+ LVH-. Vigorous exercise was associated with favorable diastolic function in HCM LVH+, and was not associated with VAs.

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.

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

Data presented in this paper are supplementary material to our study "Vigorous exercise in patients with hypertrophic cardiomyopathy" [1]. The current article presents supplementary data on collection and analyses of exercise parameters and genetic data in the original research article.

Left ventricular markers of mortality and ventricular arrhythmias in heart failure patients with cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure. However, prediction of the outcome remains difficult. We aimed to investigate for echocardiographic predictors of ventricular arrhythmias and fatal outcome and to explore how myocardial function is changed by biventricular pacing in heart failure. METHODS AND RESULTS: We prospectively included 170 heart failure patients (66 ± 10 years, New York Heart Association class 2.8 ± 0.5, 48% ischaemic cardiomyopathy) and recorded ventricular arrhythmias and fatal end point defined as death, heart transplantation, or left ventricular assist device implantation during 2 years. Two-dimensional echocardiography was performed before and 6 months after CRT implantation. CRT response was defined as ≥15% reduction in end-systolic volume at 6 months. Speckle-tracking technique was performed to assess longitudinal and circumferential left ventricular function, defined as global longitudinal (GLS) and circumferential strain (GCS), and to assess mechanical dyssynchrony, defined as mechanical dispersion. GLS before CRT was a predictor of fatal end point independently of CRT response [hazard ratio, HR 1.14 (1.02-1.27), P = 0.02]. Patients with GLS better than -8.3% showed event-free survival benefit (log rank, P < 0.001). Mechanical dispersion at 6 months was an independent predictor of ventricular arrhythmias [HR 1.20 (1.06-1.35), P = 0.005]. CRT responders (59%) had improvement of both GLS and GCS. CONCLUSION: In heart failure patients with CRT, worse longitudinal function before CRT was an important predictor of fatal outcome during 2 years, independently of CRT response. Mechanical dispersion at 6 months was a strong predictor of ventricular arrhythmias. CRT response by reverse remodelling was dependent on improvement of both longitudinal and circumferential function.

QT Adaptation and Intrinsic QT Variability in Congenital Long QT Syndrome.

BACKGROUND: Increased variability of QT interval (QTV) has been linked to arrhythmias in animal experiments and multiple clinical situations. Congenital long QT syndrome (LQTS), a pure repolarization disease, may provide important information on the relationship between delayed repolarization and QTV. METHODS AND RESULTS: Twenty-four-hour Holter monitor tracings from 78 genotyped congenital LQTS patients (52 females; 51 LQT1, 23 LQT2, 2 LQT5, 2 JLN, 27 symptomatic; age, 35.2±12.3 years) were evaluated with computer-assisted annotation of RR and QT intervals. Several models of RR-QT relationship were tested in all patients. A model assuming exponential decrease of past RR interval contributions to QT duration with 60-second time constant provided the best data fit. This model was used to calculate QTc and residual "intrinsic" QTV, which cannot be explained by heart rate change. The intrinsic QTV was higher in patients with long QTc (r=0.68; P<10(-4)), and in LQT2 than in LQT1/5 patients (5.65±1.28 vs 4.46±0.82; P<0.0002). Both QTc and intrinsic QTV were similar in symptomatic and asymptomatic patients (467±52 vs 459±53 ms and 5.10±1.19 vs 4.74±1.09, respectively). CONCLUSIONS: In LQTS patients, QT interval adaptation to heart rate changes occurs with time constant ≈60 seconds, similar to results reported in control subjects. Intrinsic QTV correlates with the degree of repolarization delay and might reflect action potential instability observed in animal models of LQTS.

Vigorous physical activity impairs myocardial function in patients with arrhythmogenic right ventricular cardiomyopathy and in mutation positive family members.

AIMS: Exercise increases risk of ventricular arrhythmia in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed to investigate the impact of exercise on myocardial function in ARVC subjects. METHODS AND RESULTS: We included 110 subjects (age 42 ± 17 years), 65 ARVC patients and 45 mutation-positive family members. Athletes were defined as subjects with ≥4 h vigorous exercise/week [≥1440 metabolic equivalents (METs × minutes/week)] during a minimum of 6 years. Athlete definition was fulfilled in 37/110 (34%) subjects. We assessed right ventricular (RV) and left ventricular (LV) myocardial function by echocardiography, and by magnetic resonance imaging (MRI). The RV function by RV fractional area change (FAC), RV global longitudinal strain (GLS) by echocardiography, and RV ejection fraction (EF) by MRI was reduced in athletes compared with non-athletes (FAC 34 ± 9% vs. 40 ± 11%, RVGLS -18.3 ± 6.1% vs. -22.0 ± 4.8%, RVEF 32 ± 8% vs. 43 ± 10%, all P < 0.01). LV function by LVEF and LVGLS was reduced in athletes compared with non-athletes (LVEF by echocardiography 50 ± 10% vs. 57 ± 5%, LVEF by MRI 46 ± 6% vs. 53 ± 8%, and LVGLS -16.7 ± 4.2% vs. -19.4 ± 2.9%, all P < 0.01). The METs × minutes/week correlated with reduced RV and LV function by echocardiography and MRI (all P < 0.01). The LVEF by MRI was also reduced in subgroups of athlete index patients (46 ± 7% vs. 54 ± 10%, P = 0.02) and in athlete family members (47 ± 3% vs. 52 ± 6%, P < 0.05). CONCLUSION: Athletes showed reduced biventricular function compared with non-athletes in ARVC patients and in mutation-positive family members. The amount and intensity of exercise activity was associated with impaired LV and RV function. Exercise may aggravate and accelerate myocardial dysfunction in ARVC.