Prediction of outcome in genetic cardiac diseases

Cardiac involvement is the main cause of decreased survival in patients with genetic cardiac diseases. Fatal arrhythmias at young age are a recognized cause of death in these patients. Better characterization of the outcome and identification of prognostic markers are necessary for early intervention and prevention of fatal events in these patients. The aim of this thesis was to describe disease outcome in patients with genetic cardiac diseases associated with risk of sudden cardiac death at young age: arrhythmogenic cardiomyopathy, Brugada syndrome and inherited connective tissue disorders. We found high disease penetrance in family members of patients with arrhythmogenic cardiomyopathy, similar structural disease progression between patients with arrhythmogenic cardiomypathy and their family members and higher arrhythmic risk in patients with structural disease progression. There was a considerable overlap between Brugada syndrome and arrhythmogenic cardiomyopathy: 24% of patients with Brugada syndrome had electrical features and 84% had structural features of arrhythmogenic cardiomyopathy. Brugada syndrome patients with arrhythmogenic cardiomyopathy features had worse prognosis. Presence of right ventricular outflow tract dilatation along with syncope and spontaneous type I ECG improved detection of arrhythmic events in patients with Brugada syndrome. Mitral annulus disjunction had a high prevalence in patients with inherited connective tissue disorders. Mitral annulus disjunction was associated with a more severe disease phenotype with aortic event (aortic dissection or prophylactic aortic surgery) at younger age and higher need for mitral valve surgery. Overall, these findings indicate that a close follow-up might be necessary even in individuals previously thought to be at low risk. Presence of markers of high arrhythmic risk or severe disease phenotype should lead to closer monitoring and appropriate interventions in order to prevent fatal events

High penetrance and similar disease progression in probands and in family members with arrhythmogenic cardiomyopathy

Aims We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study. Methods and results Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5–9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (−0.6%/year vs. −0.8%/year, P < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47–182.81, P < 0.01). Conclusion More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events

Life-threatening arrhythmic presentation in patients with arrhythmogenic cardiomyopathy before and after entering the genomic era; a two-decade experience from a large volume center

Background: Arrhythmogenic cardiomyopathy (AC) is an inheritable progressive heart disease with high risk of life-threatening ventricular arrhythmia (VA). We aimed to explore the prevalence of VA as presenting event in patients with AC over two decades, symptoms preceding VA and compare the clinical presentations and rate of AC-diagnosis over time. Methods: We included consecutive AC-patients from our tertiary referral center. We recorded clinical history, VA (aborted cardiac arrest, sustained ventricular tachycardia or appropriate implantable cardioverter-defibrillator therapy), cardiac symptoms preceding VA in AC, and compared the history of patients diagnosed before and after implementation of genetic testing. Results: We included 179 consecutive AC-patients and mutation-positive family members (95 [53%] probands, 84 [45%] female, 49 ± 17 years), 33 (18%) diagnosed before and 146 (82%) after genetic testing became available. VA led to the AC-diagnosis in 46 (26%), and was less prevalent after implementation of genetic testing (17[52%] vs. 29[20%], p < 0.001), also when adjusted for proband status (Adjusted OR 2.7, 95% CI 1.1–6.7, p = 0.03). Yearly rate of AC-diagnosis increased after implementation of genetic testing in probands (2.7 ± 1.3 vs. 6.8 ± 4.3, p = 0.01) and family members (0.7 ± 1.1 vs. 7.7 ± 5.9, p = 0.002). Most patients with VA (92%) reported cardiac symptoms prior to event, and exercise-induced syncope was the strongest marker of subsequent VA (Adjusted OR 5.3, 95% CI 1.7–16.4, p = 0.004). Conclusion: VA led to AC-diagnosis in 46% of probands and was preceded by cardiac symptoms in the majority of cases. Yearly rate of AC-diagnoses increased after the implementation of genetic testing and life-threatening presentation of AC-disease seemed to decrease

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

Right Ventricular Functional Abnormalities in Arrhythmogenic Cardiomyopathy: Association With Life-Threatening Ventricular Arrhythmias

Objectives This study aimed to perform an external validation of the value of right ventricular (RV) deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). Secondly, this study assessed the association of these parameters with life-threatening ventricular arrhythmia (VA). Background Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared. Methods We analyzed AC probands and mutation-positive family members, matched from 2 large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, or aborted cardiac arrest. Results We included 160 subjects, 80 from each center (43% proband, 55% women, age 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms; p < 0.001 for the total cohort). Both parameters were independently associated to VA (adjusted odds ratio: 2.71 [95% confidence interval: 1.47 to 5.00] per class step-up, and 1.26 [95% confidence interval: 1.07 to 1.49]/10 ms, respectively). The association with VA significantly improved when adding RV mechanical dispersion to pattern recognition (net reclassification improvement 0.42; p = 0.02 and integrated diagnostic improvement 0.06; p = 0.01). Conclusions We externally validated 2 RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value

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

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

Abstract 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 &amp;lt; 0.001), LV ejection fraction (LVEF) declined from middle age from 50 ± 12% to 47 ± 13% (P &amp;lt; 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

Sex differences in disease progression and arrhythmic risk in patients with arrhythmogenic cardiomyopathy

Abstract Aims We aimed to assess sex-specific phenotypes and disease progression, and their relation to exercise, in arrhythmogenic cardiomyopathy (AC) patients. Methods and results In this longitudinal cohort study, we included consecutive patients with AC from a referral centre. We performed echocardiography at baseline and repeatedly during follow-up. Patients’ exercise dose at inclusion was expressed as metabolic equivalents of task (MET)-h/week. Ventricular arrhythmia (VA) was defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate therapy by implantable cardioverter-defibrillator. We included 190 AC patients (45% female, 51% probands, age 41 ± 17 years). Ventricular arrhythmia had occurred at inclusion or occurred during follow-up in 85 patients (33% of females vs. 55% of males, P = 0.002). Exercise doses were higher in males compared with females [25 (interquartile range, IQR 14–51) vs. 12 (IQR 7–22) MET-h/week, P &amp;lt; 0.001]. Male sex was a marker of proband status [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4–5.0, P = 0.003] and a marker of VA (OR 2.6, 95% CI 1.4–5.0, P = 0.003), but not when adjusted for exercise dose and age (adjusted OR 1.8, 95% CI 0.9–3.6, P = 0.12 and 1.5, 95% CI 0.7–3.1, P = 0.30, by 5 MET-h/week increments). In all, 167 (88%) patients had ≥2 echocardiographic examinations during 6.9 (IQR 4.7–9.8) years of follow-up. We observed no sex differences in deterioration of right or left ventricular dimensions and functions. Conclusion Male AC patients were more often probands and had higher prevalence of VA than female patients, but not when adjusting for exercise dose. Importantly, disease progression was similar between male and female patients

Romanian Registry of Hypertrophic Cardiomyopathy – overview of general characteristics and therapeutic choices at a national level

Introduction. Hypertrophic cardiomyopathy (HCM) is a disease with increased left ventricular (LV) wall thickness not solely explained by abnormal loading conditions, with great heterogeneity regarding clinical expression and prognosis. The aim of the present study was to collect data on HCM patients from different centres across the country, in order to assess the general characteristics and therapeutic choices in this population

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

Abstract 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 &amp;lt; 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