The experience as a cardiovascular pathologist on sudden cardiac death (SCD) in the young and the impact that the findings had on in vivo diagnosis, treatment, and prevention are herein reported. The ...story dates back in the late 70s, when a series of juvenile sudden deaths occurred in the Veneto Region, North East of Italy. A successful application for a prospective study on young people dying suddenly (<35 years old, sudden infant death syndrome excluded) was submitted to the regional health authorities, thus implementing a network of collaboration with anatomic and forensic pathologists, to collect all such events and to gather epidemiological data. The project is still in progress, and since then we studied >650 hundreds consecutive juvenile SCD cases, allowing to identify the culprit diseases with abnormalities in the various cardiac structures (aorta, coronary arteries, myocardium, valves, and conduction system). The long standing Veneto Region experience clearly shows that autopsy still plays a pivotal role in the study and prevention of SCD and should be carried out regularly in the young. With time, the investigation of SCD necessarily moved from the classic postmortem study to molecular autopsy. In conclusion, SCD prevention in the young has to be faced by an interdisciplinary team, including pathologists, cardiologists, sport physicians, and geneticists, with a translational approach; the clinicopathologic correlation method still being the polar-star. In other words, the game in the fight against SCD is still played in the anatomical theater, the place where “death enjoys to save lives.”
In 1982 a nationwide program of pre-participation screening including 12-lead electrocardiography (ECG) was launched in Italy. The aim of this article is to examine whether this 25-year screening ...program should be considered a valid and advisable public health strategy. The analysis of data coming from the long-running Italian experience indicates that ECG screening has provided adequate sensitivity and specificity for detection of potentially lethal cardiomyopathy or arrhythmias and has led to substantial reduction of mortality of young competitive athletes by approximately 90%. Screening was feasible thanks to the Italian Health System, which is developed in terms of health care and prevention services, and because of the limited costs of cardiovascular evaluation in the setting of a mass program. On the basis of current scientific evidence the implementation of a mass-screening program aimed to prevent athletic-field sudden cardiac death should be at least carefully considered by public health administrators worldwide.
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).
To evaluate the impact of the presence and amount of myocardial fibrosis on arrhythmogenic risk prediction in NIDC.
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.
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).
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.
The aims of the present study were to investigate the incidence and characteristics of conduction disorders (CDs) after transcatheter aortic valve implantation (TAVI), to analyze the predictors of ...permanent pacemaker (PPM) implantation, and to evaluate the outcomes of CDs over time. In particular, we sought to investigate whether the depth of deployment and other technical aspects of valve implantation might predict the need for PPM implantation after TAVI. TAVI has been reported to favor the onset or worsening of CDs often requiring PPM implantation. A total of 70 patients with aortic stenosis due to dystrophic calcification underwent TAVI with third-generation CoreValve Revalving System from May 2007 to April 2009. We collected electrocardiograms at baseline, during TAVI, during hospitalization and at the 1-, 3-, 6-, and 12-month follow-up visits thereafter. The clinical, anatomic, and procedural variables were tested to identify the predictors of PPM implantation. The PPM dependency at follow-up was analyzed. Six patients were excluded from the analysis because of a pre-existing PPM. Of the 64 patients, 32 (50%) had one or more atrioventricular-intraventricular CDs at baseline. TAVI induced a worsening in the CDs in 49 (77%) of the 64 patients, with 25 (39%) requiring in-hospital PPM implantation. On multivariate analysis, the independent predictors of PPM implantation were the depth of the prosthesis implantation (p = 0.039) and the pre-existing right bundle branch block (p = 0.046). A trend in the recovery of the CDs over time was recorded, although 2 patients required PPM implantation 1 month after discharge for late complete atrioventricular block. In conclusion, TAVI often induces or worsens CDs, requiring PPM in more than one third of patients, although a trend in the recovery of CDs during the midterm was recorded. The independent predictors of PPM implantation were the depth of prosthesis implantation and pre-existing right bundle branch block.
Objective To describe the anatomy of the PV in tetralogy of Fallot (TOF) and to define the influence of PV anatomy on the development of surgical techniques for PV preservation during early repair. ...Methods The PV was evaluated in 79 anatomic specimens of patients with TOF who had not undergone surgery for repair, and in 82 patients who underwent early TOF repair at our institution. New surgical techniques for PV preservation during early repair are described. Results The PV in TOF was predominantly bicuspid (n = 118 of 160; 73.7%), less frequently tricuspid (n = 28 of 160; 17.5%), and seldom unicuspid (n = 14 of 160; 8.8%). In 82 cases (51.3%), the PV cusps were normal; in 78 cases (48.7%), they were thickened and dysplastic. Preservation of the PV was possible in 46 of 82 (56%) consecutive patients during TOF repair in our more recent experience, either using balloon dilation alone (18 of 46; 39%) or in association with other PV plasty procedures (28 of 46; 61%). Most bicuspid and tricuspid valves were salvageable, but unicuspid valves were not suitable. After a median follow-up time of 2.8 years (range, 0.5-6.8 years), the degree of PV regurgitation continued to be zero or mild in 40 patients (86%), and moderate in 6 (14%). Conclusions The majority of patients with TOF (>90%) have a bicuspid or tricuspid PV, which is the most favorable surgical anatomy for preserving the PV, independent of the degree of leaflet dysplasia. The recent introduction of more-complex PV plasty techniques, such as delamination plasty, allowed us to further extend the applicability of PV-preservation techniques.
Three-Dimensional Electroanatomical Voltage Mapping and Histologic Evaluation of Myocardial Substrate in Right Ventricular Outflow Tract Tachycardia Domenico Corrado, Cristina Basso, Loira Leoni, ...Barbara Tokajuk, Pietro Turrini, Barbara Bauce, Federico Migliore, Andrea Pavei, Giuseppe Tarantini, Massimo Napodano, Angelo Ramondo, Gianfranco Buja, Sabino Iliceto, Gaetano Thiene Twenty-seven patients (15 men and 12 women, age 33.9 ± 8 years) with right ventricular outflow tract (RVOT) tachycardia and no right ventricular (RV) dilation/dysfunction were studied by electroanatomical voltage mapping (EVM) and endomyocardial biopsy (EMB) before catheter ablation. Right ventricular EVM was normal in 20 of 27 patients (74%, group A), whereas the other 7 patients (26%, group B) showed RVOT electroanatomical scars that correlated with fibrofatty myocardial replacement at EMB (p < 0.001). Three of 7 patients (43%) from group B received an implantable defibrillator during the follow-up, compared with no patients from group A (p = 0.012). Electroanatomical voltage mapping is able to identify RVOT tachycardia due to concealed arrhythmogenic RV cardiomyopathy/dysplasia.
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses.
This study sought ...to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers.
Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing.
Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers.
Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias, associated with ...mutations in the desmosomal genes. Only a missense mutation in the DES gene coding for desmin, the intermediate filament protein expressed by cardiac and skeletal muscle cells, has been recently associated with ARVC. We screened 91 ARVC index cases (53 negative for mutations in desmosomal genes and an additional 38 carrying desmosomal gene mutations) for DES mutations. Two rare missense variants were identified. The heterozygous p.K241E substitution was detected in 1 patient affected with a severe form of ARVC who also carried the p.T816RfsX10 mutation in plakophilin-2 gene. This DES substitution, showing an allele frequency of <0.01 in the control population, is predicted to cause an intolerant amino acid change in a highly conserved protein domain. Thus, it can be considered a rare variant with a possible modifier effect on the phenotypic expression of the concomitant mutation. The previously known p.A213V substitution was identified in 1 patient with ARVC who was negative for mutations in the desmosomal genes. Because a greater prevalence of p.A213V has been reported in patients with heart dilation than in control subjects, the hypothesis that this rare variant could have an unfavorable effect on cardiac remodeling cannot be ruled out. In conclusion, our data help to establish that, in the absence of skeletal muscle involvement suggestive of a desminopathy, the probability of DES mutations in ARVC is very low. These findings have important implications in the mutation screening strategy for patients with ARVC.
The Wellens' electrocardiogram (ECG) pattern of dynamic T-wave inversion in the anterior leads is observed in clinical conditions characterized by reversible left ventricular (LV) dysfunction ...(stunned myocardium), either ischemic or nonischemic. The pathophysiologic basis of this ECG pattern remains to be elucidated.
The purpose of this study was to report the contrast-enhanced cardiac magnetic resonance (CE-CMR) findings in 4 cases of Wellens' ECG pattern associated with transient LV dysfunction from a variety of clinical conditions such as myocardial bridge, coronary artery dissection, cholecystitis, and takotsubo syndrome.
All patients underwent CE-CMR at the time of acute clinical manifestations and after 6 to 8 weeks of follow-up to assess the presence and dynamics of LV myocardial changes.
In all patients, the Wellens' ECG abnormalities were associated with increased signal intensity of the LV myocardium on T2-weighted sequences suggesting myocardial edema, in the absence of late enhancement on postcontrast sequences. Repolarization abnormalities and myocardial edema had a parallel time course with persistence beyond recovery of mechanical abnormalities. T-wave inversion was associated with transient prolongation of the QTc interval in all cases.
The study results suggest that myocardial edema rather than systolic dysfunction underlies the Wellens' ECG pattern, regardless of the causative mechanism.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease carrying a risk of sudden death. Information about the clinical features during childhood and the age at ...disease onset is scanty.
The aim of the study was to describe the ARVC phenotype as its initial clinical manifestation in a pediatric population (<18 years) with desmosomal gene mutations.
Fifty-three ARVC desmosomal gene mutation carriers (mean age 12.3 ± 3.9 years) were investigated by electrocardiogram (ECG), signal-averaged ECG, 24-hour Holter, echocardiogram, and contrast-enhanced cardiac magnetic resonance (CMR).
None of the children ≤10 years old fulfilled the 1994 criteria, as opposed to six (33%) aged 11–14 years and eight aged >14 years (42%). At the end of follow-up (9 ± 7 years), 21 (40%) fulfilled the 1994 diagnostic criteria (mean age 16 ± 4 years). By using the 2010 criteria in subjects aged ≤18 years, 53% were unaffected, versus 62% by using the traditional criteria. More than two-thirds of affected subjects had moderate-severe forms of the disease. Contrast-enhanced CMR was performed in 21 (40%); of 13 unaffected gene mutation carriers, six showed ARVC morphological and/or tissue abnormalities.
In pediatric ARVC mutation carriers, a diagnosis was achieved in 40% of cases, confirming that the disease usually develops during adolescence and young adulthood. The 2010 modified criteria seem to be more sensitive than the 1994 ones in identifying familial pediatric cases. Contrast-enhanced CMR can provide diagnostic information on gene mutation carriers not fulfilling either traditional or modified criteria. Management of asymptomatic gene mutation carriers remains the main clinical challenge.
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