Gerardo Nigro

Dispersion of repolarization and beta-thalassemia major: the prognostic role of QT and JT dispersion for identifying the high-risk patients for sudden death

Background:  Patients with beta‐thalassemia major (β‐TM) are at increased risk for sudden cardiac death (SCD). Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QT dispersion (QTc‐D) and JT dispersion (JTc‐D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with beta‐thalassemia and to test the hypothesis that an abnormal QTc and JTc dispersion may predict SCD in this population.

Risk of arrhythmias in myotonic dystrophy: trial design of the RAMYD study.

Objective Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adults. DM1 is a multisystem disorder also affecting the heart with an increased incidence of sudden death, which has been explained with the common impairment of the conduction system often requiring pacemaker implantation; however, the occurrence of sudden death despite pacemaker implantation and the observation of major ventricular arrhythmias generated the hypothesis that ventricular arrhythmias may play a causal role as well. The aim of the study was to assess the 2-year cumulative incidence and the value of noninvasive and invasive findings as predictive factors for sudden death, resuscitated cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia and severe sinus dysfunction or high-degree atrioventricular block. Methods/design More than 500 DM1 patients will be evaluated at baseline with a clinical interview, 12-lead ECG, 24-h ECG and echocardiogram. Conventional and nonconventional indications to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implantation have been developed. In the case of an indication to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implant at baseline or at follow-up, the patient will be referred for the procedure. At the end of 2-year follow-up, all candidate prognostic factors will be tested for their association with the endpoints. Trial registration: ClinicalTrials.gov ID NCT00127582. Conclusion The available evidence supports the hypothesis that both bradyarrhythmias and tachyarrhythmias may cause sudden death in DM1, but the course of cardiac disease in DM1 is still unclear. We expect that this large, prospective, multicenter study will provide evidence to improve diagnostic and therapeutic strategies in DM1.

Autonomic nervous system imbalance and left ventricular systolic dysfunction as potential candidates for arrhythmogenesis in Becker muscular dystrophy

We evaluated the arrhythmic profile in a population of 20 Becker muscular dystrophy (BMD) patients searching for possible correlations between the severity of the arrhythmic events, the cardiac autonomic balance (assessed by heart rate variability analysis in the time domain) and the degree of left ventricular systolic impairment. A population of 14 male healthy individuals served as the control group. BMD subjects exhibited lower values of SDNN (P=0.013), SDANN index (P=0.008) and 24-h mean heart rate (P=0.002). The total number of premature ventricular beats (totPVB) and the number of PVB out of 1000 heartbeats (PVB/1000) appeared also higher in BMD subjects (P=0.05 and P=0.046, respectively). No difference was found in terms of 24-h mean QTc and 24-h longest QT among the two groups. TotPVB and PVB/1000 were inversely related to both the ejection fraction (r= -0.620, P=0.004 and r= -0.517, P=0.019) and to the shortening fraction (r= -0.568, P=0.009 and r= -0.469, P=0.037). Twenty-four-h mean QTc was also inversely related to both the ejection fraction (r= -0.520, P=0.019) and the fractional shortening (r= -0.491, P=0.028). These data suggest that in BMD there is cardiac autonomic imbalance characterized by sympathetic predominance and an increased susceptibility to ventricular arrhythmias, even in the absence of overt cardiomyopathy. Furthermore, the severity of the arrhythmic profile in BMD appears closely related to the degree of left ventricular systolic dysfunction.

Right ventricular myocardial function in patients with either idiopathic or ischemic dilated cardiomyopathy without clinical sign of right heart failure: effects of cardiac resynchronization therapy.

Objective: In dilated cardiomyopathy (DCM), right ventricular (RV) dysfunction has been reported and attributed both to altered loading conditions and to RV involvement in the myopathic process. The aim of the study was to detect RV myocardial function in DCM using two‐dimensional (2D) strain echocardiography and to assess the effects of cardiac resynchronization therapy (CRT) on RV myocardial strain during a 6‐month follow‐up.

Combined deficiency of alpha and epsilon sarcoglycan disrupts the cardiac dystrophin complex

Cardiomyopathy is a puzzling complication in addition to skeletal muscle pathology for patients with mutations in β-, γ- or δ-sarcoglycan (SG) genes. Patients with mutations in α-SG rarely have associated cardiomyopathy, or their cardiac pathology is very mild. We hypothesize that a fifth SG, ɛ-SG, may compensate for α-SG deficiency in the heart. To investigate the function of ɛ-SG in striated muscle, we generated an Sgce-null mouse and a Sgca-;Sgce-null mouse, which lacks both α- and ɛ-SGs. While Sgce-null mice showed a wild-type phenotype, with no signs of muscular dystrophy or heart disease, the Sgca-;Sgce-null mouse developed a progressive muscular dystrophy and a more anticipated and severe cardiomyopathy. It shows a complete loss of residual SGs and a strong reduction in both dystrophin and dystroglycan. Our data indicate that ɛ-SG is important in preventing cardiomyopathy in α-SG deficiency.

Disease rescue and increased lifespan in a model of cardiomyopathy and muscular dystrophy by combined AAV treatments.

Background The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure. Methodology/Principal Findings Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement. Conclusions/Significance Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders.

Early electrocardiographic evaluation of atrial fibrillation risk in beta-thalassemia major patients

Although previous studies have documented a variety of electrocardiogram abnormalities in beta-thalassemia major (β-TM), little is known about P-wave dispersion (PD), an independent risk factor for development of atrial fibrillation. The aim of our study was to evaluate PD in β-TM patients with conserved systolic and diastolic functions. The study involved 40 β-TM patients (age 37.5 ± 10.2; 33 M) and 40 healthy subjects used as controls, matched for age and gender. PD was carefully measured using a 12-lead electrocardiogram. Cardiac iron levels were measured by cardiac magnetic resonance T2 star (CMR T2*) imaging. Comparing to the healthy control group, β-TM group presented increased values of the PD (40.1 ± 12.9 vs. 24 ± 7 ms; P < 0.004) and decreased CMR T2* imaging (29 ± 15 vs. 55 ± 13 ms; P = 0.03). We found a significant correlation between PD and CMR T2* values. Our study showed a significant increase of PD in β-TM patients with conserved systolic and diastolic cardiac functions. Our results indicate that PD is correlated to myocardial iron deposit, as assessed by CMR T2* imaging.

Increased heterogenity of ventricular repolarization in obese nonhypertensive children.

Objective: Obese children, without arterial hypertension, may be a unique clinical opportunity to evaluate the effect of obesity, per se, on ventricular repolarization, excluding the influence of possible comorbidities. The QTc dispersion (QTc‐d), JTc dispersion (JTc‐d), and transmural dispersion of repolarization (TDR) have been suggested to be electrocardiographic indexes reflecting the physiological variability of regional ventricular repolarization. The aim of our study is to define the effects of obesity on the ventricular repolarization in obese children who have no other clinically appreciable cause of heart disease.

Does Bachmann's bundle pacing prevent atrial fibrillation in myotonic dystrophy type 1 patients? A 12 months follow-up study

AIMS Paroxysmal atrial arrhythmias occur in myotonic dystrophy type 1 (MD1) patients frequently. Pacemaker (PM) including detailed diagnostic functions may facilitate the diagnosis and management of frequent paroxysmal atrial tachyarrhythmias that may remain undetected during conventional clinical follow-up. Aim of our study was to evaluate the preventive effects of interatrial septum pacing in the Bachmanns Bundle region on atrial fibrillation (AF) in MD1 patients during 12 months follow up period. METHODS AND RESULTS Thirty MD1 patients (age 50.3 +/- 7.3; 11 F) who underwent dual chamber PM implantation were randomized at implantation to receive right atrial appendage pacing (16 patients) or Bachmanns bundle pacing (14 patients). No statistically significant difference in the electrical parameters (P wave amplitude, pacing threshold and lead impedance) was found between the two groups at implantation. Patients were followed at 1 month, 3 months, and every 6 months thereafter. They underwent clinical assessment, a standard 12-lead ECG and assessment of device performance at every visit. We counted the number of episodes of atrial arrhythmia occurred during the collection period and the duration of each episode. At 12 months of follow-up, no statistically significant differences in the number of AF episodes or in AF duration were found. Lead parameters remained stable over time and there were no displacements of the electrodes after implantation. CONCLUSION Implantation of an atrial-active fixation lead on the atrial septum is safe and feasible. However, this study showed no significant difference between septal pacing and high atrial pacing, using the endpoints of AF duration and number of AF episodes.

P-Wave Duration and Dispersion in Patients With Emery-Dreifuss Muscular Dystrophy

Background Paroxysmal episodes of atrial fibrillation frequently occur in Emery-Dreifuss muscular dystrophy (EDMD). Although previous studies have documented a variety of electrocardiographic abnormalities in EDMD, little is still known about P-wave dispersion (PD), an independent risk factor for the development of atrial fibrillation. The aim of our study was to evaluate the P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function. Methods The study involved 36 patients with EDMD (age, 20 [SD, 12] years; 26 men) and 36 healthy subjects used as controls, matched for age and sex. P-wave dispersion was carefully measured using 12-lead electrocardiogram. Compared with the healthy control group, patients with EDMD presented increased maximum P-wave duration (108.2 [SD, 22.2] vs 97.8 [SD, 11] milliseconds, P = 0.04) and PD (51.4 [SD, 12.8] vs 39.3 [SD, 9.7] milliseconds, P = 0.004) values. No statistically significant differences in left atrium diameter (37.1 [SD, 2.9] vs 34.1 [SD, 4.2] mm, P = 0.3) and maximum left atrium volume (15.2 [SD, 3.8] vs 14.1 [SD, 4.2] mL/m2, P = 0.4) were found between the 2 groups. We divided our study population into 2 subgroups, according to the different genetic diagnosis, patients with laminopathy EDMD (n = 17) or with emerinopathy EDMD (n = 19). No statistically significant differences were found in PD between the 2 subgroups (54.6 [SD, 15.6] vs 50.2 [SD, 11.5] milliseconds, P = 0.4). Conclusions Our study showed a significant increase of maximum P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function.