Alessandro Zorzi

Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy.

Background—Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene–related ARVC. Methods and Results—The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years [22–52]) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22–52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54–8.92; P=0.003) and 2.76 (95% confidence interval, 1.19–6.41; P=0.02), respectively. Conclusions—Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.

Prevalence of Cardiomyopathy in Italian Asymptomatic Children With Electrocardiographic T-Wave Inversion at Preparticipation Screening

Background— T-wave inversion on a 12-lead ECG is usually dismissed in young people as normal persistence of the juvenile pattern of repolarization. However, T-wave inversion is a common ECG abnormality of cardiomyopathies such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, which are leading causes of sudden cardiac death in athletes. We prospectively assessed the prevalence, age relation, and underlying cardiomyopathy of T-wave inversion in children undergoing preparticipation screening. Methods and Results— The study population included 2765 consecutive Italian children (1914 male participants; mean age, 13.9±2.2 years; range 8–18 years) undergoing preparticipation screening including an ECG. Of 229 children (8%) who underwent further evaluation because of positive findings at initial preparticipation screening, 33 (1.2%) were diagnosed with cardiovascular disease. T-wave inversion was recorded in 158 children (5.7%) and was localized in the right precordial leads in 131 (4.7%). The prevalence of right precordial T-wave inversion decreased significantly with increasing age (8.4% in children <14 years of age versus 1.7% in those ≥14 years; P<0.001), pubertal development (9.5% of children with incomplete versus 1.6% with complete development; P<0.001), and body mass index below the 10th percentile (P<0.001). Incomplete pubertal development was the only independent predictor for right precordial T-wave inversion (odds ratio, 3.6; 95% confidence interval, 1.9–6.8; P<0.001). Of 158 children with T-wave inversion, 4 (2.5%) had a diagnosis of cardiomyopathy, including arrhythmogenic right ventricular cardiomyopathy (n=3) and hypertrophic cardiomyopathy (n=1). Conclusions— The prevalence of T-wave inversion decreases significantly after puberty. Echocardiographic investigation of children with postpubertal persistence of T-wave inversion at preparticipation screening is warranted because it may lead to presymptomatic diagnosis of a cardiomyopathy that could lead to sudden cardiac death during sports.

Imaging Study of Ventricular Scar in Arrhythmogenic Right Ventricular Cardiomyopathy Comparison of 3D Standard Electroanatomical Voltage Mapping and Contrast-Enhanced Cardiac Magnetic Resonance

Background— The hallmark lesion of arrhythmogenic right ventricular cardiomyopathy (ARVC) is fibrofatty scar replacement. We compared endocardial voltage mapping (EVM) and contrast-enhanced cardiac magnetic resonance (CE-CMR) for imaging scar lesions in ARVC patients. Methods and Results— We studied 23 consecutive ARVC patients (16 males; mean age, 38±12 years) who underwent RV EVM and CE-CMR and 37 control subjects. In 21 (91%) of 23 ARVC patients, RV EVM was abnormal, with a total of 45 electroanatomical scars (EAS): 17 (38%) in the inferobasal region, 12 (26.6%) in the anterolateral region, 8 (17.7%) in the RV outflow tract (RVOT), and 8 (17.7%) in the apex. RV delayed contrast enhancement (DCE) was found in 9 (39%) of 23 patients, with a total of 23 RV DCE scars: 4 (17.4%) in the inferobasal region, 9 (39.1%) in the anterolateral region, 4 (17.4%) in the RVOT, and 6 (26.1%) in the apex. There was a mismatch in 24 RV scars, with 22 EAS not confirmed by DCE and 2 DCE scars (both in the RVOT) undetected by EVM. In 9 (75%) of 12 patients with abnormal RV EVM/normal RV DCE, ≥1 DCEs were identified in the left ventricle (LV). Overall, ventricular DCE was detected in 78% of patients. No control subjects showed either EAS or DCE. Conclusions— EVM and CE-CMR allow identification of RV scar lesions in most ARVC patients. CE-CMR is less sensitive than EVM in identifying RV scar lesions. The high prevalence of LV DCE confirms the frequent biventricular involvement and indicates the diagnostic relevance of LV scar detection by CE-CMR.Background— The hallmark lesion of arrhythmogenic right ventricular cardiomyopathy (ARVC) is fibrofatty scar replacement. We compared endocardial voltage mapping (EVM) and contrast-enhanced cardiac magnetic resonance (CE-CMR) for imaging scar lesions in ARVC patients. Methods and Results— We studied 23 consecutive ARVC patients (16 males; mean age, 38±12 years) who underwent RV EVM and CE-CMR and 37 control subjects. In 21 (91%) of 23 ARVC patients, RV EVM was abnormal, with a total of 45 electroanatomical scars (EAS): 17 (38%) in the inferobasal region, 12 (26.6%) in the anterolateral region, 8 (17.7%) in the RV outflow tract (RVOT), and 8 (17.7%) in the apex. RV delayed contrast enhancement (DCE) was found in 9 (39%) of 23 patients, with a total of 23 RV DCE scars: 4 (17.4%) in the inferobasal region, 9 (39.1%) in the anterolateral region, 4 (17.4%) in the RVOT, and 6 (26.1%) in the apex. There was a mismatch in 24 RV scars, with 22 EAS not confirmed by DCE and 2 DCE scars (both in the RVOT) undetected by EVM. In 9 (75%) of 12 patients with abnormal RV EVM/normal RV DCE, ≥1 DCEs were identified in the left ventricle (LV). Overall, ventricular DCE was detected in 78% of patients. No control subjects showed either EAS or DCE. Conclusions— EVM and CE-CMR allow identification of RV scar lesions in most ARVC patients. CE-CMR is less sensitive than EVM in identifying RV scar lesions. The high prevalence of LV DCE confirms the frequent biventricular involvement and indicates the diagnostic relevance of LV scar detection by CE-CMR.

Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy

BACKGROUND Current risk stratification for sudden cardiac death (SCD) in nonischemic dilated cardiomyopathy (NIDC) relies on left ventricular (LV) dysfunction, a poor marker of ventricular electrical instability. Contrast-enhanced cardiac magnetic resonance has the ability to accurately identify and quantify ventricular myocardial fibrosis (late gadolinium enhancement [LGE]). OBJECTIVE To evaluate the impact of the presence and amount of myocardial fibrosis on arrhythmogenic risk prediction in NIDC. METHODS One hundred thirty-seven consecutive patients with angiographically proven NIDC were enrolled for this study. All patients were followed up for a combined arrhythmic end point including sustained ventricular tachycardia (VT), appropriate implantable cardioverter-defibrillator (ICD) intervention, ventricular fibrillation (VF), and SCD. RESULTS LV-LGE was identified in 76 (55.5%) patients. During a median follow-up of 3 years, the combined arrhythmic end point occurred in 22 (16.1%) patients: 8 (5.8%) sustained VT, 9 (6.6%) appropriate ICD intervention, either against VF (n = 5; 3.6%) or VT (n = 4; 2.9%), 3 (2.2%) aborted SCD, and 2 (1.5%) died suddenly. Kaplan-Meier analysis revealed a significant correlation between the LV-LGE presence (not the amount and distribution) and malignant arrhythmic events (P < .001). In univariate Cox regression analysis, LV-LGE (hazard ratio [HR] 4.17; 95% confidence interval [CI] 1.56-11.2; P = .005) and left bundle branch block (HR 2.43; 95% CI 1.01-5.41; P = .048) were found to be associated with arrhythmias. In multivariable analysis, the presence of LGE was the only independent predictor of arrhythmias (HR 3.8; 95% CI 1.3-10.4; P = .01). CONCLUSIONS LV-LGE is a powerful and independent predictor of malignant arrhythmic prognosis, while its amount and distribution do not provide additional prognostic value. Contrast-enhanced cardiac magnetic resonance may contribute to identify candidates for ICD therapy not fulfilling the current criteria based on left ventricular ejection fraction.

Programmed ventricular stimulation for risk stratification in the Brugada syndrome: A pooled analysis

Background— The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. Methods and Results— We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44–4.92, P<0.001), with the greatest risk observed among those induced with single or double extrastimuli. Annual event rates varied substantially by syncope history, presence of spontaneous type 1 ECG pattern, and arrhythmia induction. The lowest risk occurred in individuals without syncope and with drug-induced type 1 patterns (0.23%, 95% CI, 0.05–0.68 for no induced arrhythmia with up to double extrastimuli; 0.45%, 95% CI, 0.01–2.49 for induced arrhythmia), and the highest risk occurred in individuals with syncope and spontaneous type 1 patterns (2.55%, 95% CI, 1.58–3.89 for no induced arrhythmia; 5.60%, 95% CI, 2.98–9.58 for induced arrhythmia). Conclusions— In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.

LAD Coronary Artery Myocardial Bridging and Apical Ballooning Syndrome

OBJECTIVES This study sought to evaluate the prevalence and potential role of myocardial bridging in the pathogenesis of apical ballooning syndrome (ABS). BACKGROUND ABS is characterized by reversible left ventricular dysfunction, frequently precipitated by a stressful event, but the pathogenesis remains still unclear. METHODS Forty-two consecutive patients (40 female, mean age 66 ± 7 years) with ABS underwent echocardiography, cardiac magnetic resonance, coronary angiography (CA) with intravascular ultrasound, and computed tomography angiography (CTA). Myocardial bridging was diagnosed by CA when a dynamic compression phenomenon was observed in the coronary artery and by CTA when a segment of coronary artery was completely (full encasement) or incompletely (partial encasement) surrounded by the myocardium. The prevalence of myocardial bridging detected by CTA and CA in ABS patients was compared with 401 controls without ABS who underwent both CTA and CA. RESULTS Myocardial bridging by CTA was observed in 32 ABS patients (76%): 23 with partial encasement and 9 with full encasement. All myocardial bridging was located in the mid segment of the left anterior descending coronary artery (LAD) with a mean length of 17 ± 9 mm. CA revealed myocardial bridging in 17 subjects (40%) (9 with partial encasement and 8 with full encasement by CTA). All subjects in which dynamic compression was observed by CA showed myocardial bridging by CTA, while none of the subjects with negative findings for myocardial bridging by CTA revealed dynamic compression by CA. Compared with controls, ABS patients showed a significant higher prevalence of myocardial bridging in the LAD either by CA (40% vs. 8%; p < 0.001) or by CTA (76% vs. 31%; p < 0.001). CONCLUSIONS Our study showed that myocardial bridging of the LAD is a frequent finding in ABS patients as revealed both by CA and, mostly, by CTA, suggesting a role of myocardial bridging as potential substrate in the pathogenesis of ABS.

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable heart muscle disease characterized by fibrofatty replacement of the right ventricle (RV) and by ventricular arrhythmias potentially leading to sudden cardiac death, mostly in young people and athletes. Later in the disease history, the RV becomes more diffusely involved and left ventricular involvement may result in biventricular heart failure. However, clinical diagnosis of ARVC is often difficult to make in the early stage of the disease because of the broad spectrum of phenotypic manifestations and the nonspecific nature of the disease features. In 1994, an international task force proposed criteria for the clinical diagnosis of ARVC, which have been recently revised to improve their sensitivity. Causative mutations have been identified in approximately half of patients with ARVC. Advances in molecular genetics of ARVC have provided important insight into our understanding of the pathogenesis and pathophysiology of ARVC, which has contributed to the improvement of clinical management. Therapeutic strategies for the prevention of sudden death and disease progression include antiarrhythmic drugs, catheter ablation, and use of an implantable cardioverter defibrillator (ICD). ICD is the most effective tool against arrhythmic sudden death. The implantation of an ICD should be carefully evaluated because of the possibility of device/lead-related complications and inappropriate interventions. This review article focuses on the most current knowledge regarding clinical presentation, diagnosis, molecular genetics, and management strategies of ARVC.

Prognostic Value of Endocardial Voltage Mapping in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

Background—Endocardial voltage mapping (EVM) identifies low-voltage right ventricular (RV) areas, which may represent the electroanatomic scar substrate of life-threatening tachyarrhythmias. We prospectively assessed the prognostic value of EVM in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Methods and Results—We studied 69 consecutive ARVC/D patients (47 males; median age 35 years [28–45]) who underwent electrophysiological study and both bipolar and unipolar EVM. The extent of confluent bipolar (<1.5 mV) and unipolar (<6.0 mV) low-voltage electrograms was estimated using the CARTO-incorporated area calculation software. Fifty-three patients (77%) showed ≥1 RV electroanatomic scars with an estimated burden of bipolar versus unipolar low-voltage areas of 24.8% (7.2–31.5) and 64.8% (39.8–95.3), respectively (P=0.009). In the remaining patients with normal bipolar EVM (n=16; 23%), the use of unipolar EVM unmasked ≥1 region of low-voltage electrogram affecting 26.2% (11.6–38.2) of RV wall. During a median follow-up of 41 (28–56) months, 19 (27.5%) patients experienced arrhythmic events, such as sudden death (n=1), appropriate implantable cardioverter defibrillator interventions (n=7), or sustained ventricular tachycardia (n=11). Univariate predictors of arrhythmic outcome included previous cardiac arrest or syncope (hazard ratio=3.4; 95% confidence interval, 1.4–8.8; P=0.03) and extent of bipolar low-voltage areas (hazard ratio=1.7 per 5%; 95% confidence interval, 1.5–2; P<0.001), whereas the only independent predictor was the bipolar low-voltage electrogram burden (hazard ratio=1.6 per 5%; 95% confidence interval, 1.2–1.9; P<0.001). Patients with normal bipolar EVM had an uneventful clinical course. Conclusions—The extent of bipolar RV endocardial low-voltage area was a powerful predictor of arrhythmic outcome in ARVC/D, independently of history and RV dilatation/dysfunction. A normal bipolar EVM characterized a low-risk subgroup of ARVC/D patients.

Electrocardiographic predictors of electroanatomic scar size in arrhythmogenic right ventricular cardiomyopathy: implications for arrhythmic risk stratification.

The extent of right ventricular (RV) electroanatomic scar (EAS) detected by endocardial voltage mapping (EVM) is a powerful invasive predictor of arrhythmic outcome in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Electrocardiogram (ECG) and signal‐averaged ECG are noninvasive tools of established clinical value for the diagnosis of electrical abnormalities in ARVC. This study was designed to assess the role of ECG and SAECG abnormalities for noninvasive estimation of the extent and regional distribution of RV‐EAS and prediction of scar‐related arrhythmic risk.

Morphological and Functional Adaptation of Left and Right Atria Induced by Training in Highly Trained Female Athletes

Background—Exercise is able to induce atrial remodeling in top-level athletes. However, evidence is mainly limited to men and based on cross-sectional studies. The aim of this prospective, longitudinal study was to investigate whether exercise is able to influence left and right atrial morphology and function also in female athletes. Methods and Results—Two-dimensional echocardiography was performed before season and after 16 weeks of intensive training in 24 top-level female athletes. Left and right atrial myocardial deformation was assessed by two-dimensional speckle-tracking echocardiography. Left atrial volume index (24.0±3.6 versus 26.7±6.9 mL/m2; P<0.001) and right atrial volume index (15.66±3.09 versus 20.47±4.82 mL/m2; P<0.001) significantly increased after training in female athletes. Left atrial global peak atrial longitudinal strain and peak atrial contraction strain significantly decreased after training in female athletes (43.9±9.5% versus 39.8±6.5%; P<0.05 and 15.5±4.0% versus 13.9±4.0%; P<0.05, respectively). Right atrial peak atrial longitudinal strain and peak atrial contraction strain showed a similar, although non-significant decrease (42.8±10.6% versus 39.3±8.3%; 15.6±5.6% versus 13.1±6.1%, respectively). Neither biventricular E/e′ ratio nor biatrial stiffness changed after training, suggesting that biatrial remodeling occurs in a model of volume rather than pressure overload. Conclusions—Exercise is able to induce biatrial morphological and functional changes in female athletes. Biatrial enlargement, with normal filling pressures and low atrial stiffness, is a typical feature of the heart of female athletes. These findings should be interpreted as physiological adaptations to exercise and should be considered in the differential diagnosis with cardiomyopathies.