Matteo Anaclerio

SCN5A Polymorphism Restores Trafficking of a Brugada Syndrome Mutation on a Separate Gene

Background— Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation. Methods and Results— In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy transfer and protein fragments centered on H558R-SCN5A, we demonstrated that cardiac sodium channels preferentially interact when the polymorphism is expressed on one protein but not the other. Conclusions— This study suggests a mechanism whereby the Brugada syndrome has incomplete penetrance. More importantly, this study suggests that genetic polymorphisms may be a potential target for future therapies aimed at rescuing specific dysfunctional protein channels.

Rate, causes, and impact on patient outcome of implantable device complications requiring surgical revision: large population survey from two centres in Italy

AIMS The long-term impact of implantable device-related complications on the patient outcome has not been thoroughly evaluated. The aims of this retrospective, bi-centre study were to analyse the rate and nature of device-related complications requiring surgical revision in a large series of patients undergoing device implantation, elective generator replacement and pacing system upgrade and to systematically assess the impact of such complications on patient outcome and healthcare utilization. METHODS AND RESULTS Data from 2671 consecutive procedures (1511 device implantations, 1034 elective generator replacements, and 126 pacing system upgrades) performed between January 2006 and March 2011 were retrospectively analysed. The outcome measures recorded were complication-related mortality, number of re-operations, need for complex surgical procedures, number of re-hospitalizations, and additional hospital treatment days. Over a median follow-up of 27 months, the overall rate of complications was 2.8% per procedure-year [9.5% in cardiac resynchronisation therapy (CRT) device implantation, 6.1% in pacing system upgrade, 3.5% in implantable cardioverter defibrillator implantation, 1.7% in pacemaker implantation, and 1.7% in generator replacement). The procedure with the highest risk of complications was CRT device implantation (odds ratio: 6.6; P < 0.001); these complications primarily involved coronary sinus lead dislodgement and device infection. Patients with complications had a significantly higher number of device-related hospitalizations (2.3 ± 0.6 vs. 1.0 ± 0.1; P < 0.001) and hospital treatment days (15.7 ± 25.1 vs. 3.6 ± 1.1; P < 0.001) than those without complications. Device infection was the complication with the greatest negative impact on patient outcome. CONCLUSION Cardiac resynchronisation therapy implantation was the procedure with the highest risk of complications requiring surgical revision. Complications were associated with substantial clinical consequences and a significant increase in the number and length of hospitalizations.

Prognostic value of brain natriuretic peptide in the management of patients receiving cardiac resynchronization therapy

To evaluate the role of brain natriuretic peptide (BNP) in predicting the progression of heart failure (HF) after cardiac resynchronization therapy (CRT).

Altered two-dimensional strain measures of the right ventricle in patients with Brugada syndrome and arrhythmogenic right ventricular dysplasia/cardiomyopathy

AIMS Brugada syndrome (BrS) is an inherited channelopathy that can be characterized by mild right ventricular (RV) abnormalities that are not detectable with conventional echocardiography. The aim of this study was to evaluate the presence of RV abnormalities in BrS patients when compared with controls and a group of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using two-dimensional (2D) strain analysis. METHODS AND RESULTS We enrolled 25 BrS, 15 ARVD/C patients, and 25 controls. Right and left ventricular dimension and systo-diastolic function were evaluated by conventional echocardiography. Longitudinal systolic strain (sS) peak, systolic and early diastolic strain rate of lateral RV segments were evaluated by 2D speckle tracking analysis. Left ventricle global and segmental strain measures were also evaluated. A reduced basal or mid-RV lateral sS were the parameters mostly associated with both BrS and ARVD/C. In BrS patients the minimum sS observed in these segments was significantly lower than that of controls (-28.9±3.2% vs. -32.3±3.2%, P: 0.002) but significantly greater than that evaluated in ARVD/C patients (-24.6±6.7%, P<0.001 both vs. BrS and controls). No differences were found between the BrS and the control group when left ventricular strain measures were analysed. CONCLUSION By 2D strain technique it is possible to observe mild abnormalities in RV systolic and diastolic function of BrS patients that are less pronounced than those observed in ARVD/C patients. These results help to better define the phenotypic characteristics of BrS patients and represent the basis for future studies aimed at testing their clinical usefulness in BrS patients.

Predictive factors for pacemaker implantation in patients receiving an implantable loop recorder for syncope remained unexplained after an extensive cardiac and neurological workup

BACKGROUND Several previous implantable loop recorder (ILR) studies have shown bradyarrhythmic events requiring a pacemaker implantation in a significant proportion of patients with unexplained syncope (US). The aim of this observational, two-centre, study was to identify the predictive factors for pacemaker implantation in a population of patients receiving an ILR for US with suspected arrhythmic aetiology. METHODS Fifty-six patients (mean age 68 years, 61% male) with a history of US and negative cardiac and neurological workup, who underwent ILR implantation, were enrolled. After the implantation, a follow-up visit was undertaken after symptomatic events or every 3 months in asymptomatic subjects. The end-point of the study was the detection of a bradyarrhythmia (with or without a syncopal recurrence) requiring pacemaker implantation. RESULTS After a median ILR observation of 22 months, a clinically significant bradyarrhythmia was detected in 11 patients (20%), of which 9 cases related to syncopal relapses. In the multivariable analysis, three independent predictive factors for pacemaker implantation were identified: an age >75 years (odd ratio [OR]: 29.9; p=0.035); a history of trauma secondary to syncope (OR: 26.8; p=0.039); and the detection of periods of asymptomatic bradycardia, not sufficient to explain the mechanism of syncope, during conventional ECG monitoring (through 24 h Holter or in hospital telemetry), performed before ILR implantation (OR: 24.7; p=0.045). CONCLUSIONS An advanced age, a history of trauma secondary to syncope, and the detection of periods of asymptomatic bradycardia during conventional ECG monitoring were independent predictive factors for bradyarrhythmias requiring pacemaker implantation in patients receiving an ILR for US.

Access to magnetic resonance imaging of patients with magnetic resonance-conditional pacemaker and implantable cardioverter-defibrillator systems: results from the Really ProMRI study

Aims The Really ProMRI study evaluates magnetic resonance imaging (MRI) access for patients with cardiac implantable electronic devices (CIEDs) as well as the performance of magnetic resonance (MR)-conditional leads when undergoing MRI. Methods and results Patients either with an MR-conditional pacemaker or implantable defibrillator (ICD) system or with at least a component (device or one or more leads) from an MR-conditional system, were asked to fill in a questionnaire when they were referred to a MR scan. The rate of prescription, denial, or execution of MR examinations was evaluated in a 1-year follow-up visit. In total, 555 patients [median age (interquartile range) 72.2 (62.2-78.6); 72% male] were enrolled, 49% (270) with a pacemaker, 51% (285) with an ICD system. Five-hundred and ten patients completed the follow-up period. A total of 37 MRI referrals were reported in 35 patients, with a consequent event rate of 7.0/100 patient-years (CI, 4.9-9.7). Fourteen were denied, while 23 [66%; (CI, 48-81%)] were performed. The number of patients with MR referrals was not statistically different between pacemaker and ICD groups (21 vs. 14; P = 0.178). The rate of scans performed was higher in the pacemaker subjects (19/23 vs. 4/14, P = 0.003), while it was similar between patients with or without a complete MR-conditional system (19/30 vs. 4/7, P = 0.606). Conclusion In this study, we reported a 7.0/100 patient-years event rate of MR prescriptions in CIED patients. Many examinations were denied, despite MR-conditional systems, especially in ICD patients. Regulatory and cultural changes are needed to allow wider access to MR imaging in CIED patients with MR-conditional systems.

Methodical approach to collecting and preserving plasma samples containing B-type natriuretic peptide

We have read the comments raised by Hazukova and Colleagues on the method used for collecting and preserving the plasma samples containing B-type natriuretic peptide (BNP), which we described in a paper recently published in this Journal [1]. The method we used is not an original one, since the number of articles that have used it so far is not negligible [2–7]. BNP is a widely used tool for managing heart failure patients from the diagnostic, therapeutic and prognostic points of view. Therefore, we strongly agree on the need to have stringent methodological criteria in order to obtain reliable and applicable results. In the clinical setting, applicability of a measurement is important. This is, for example, the case for the time during which we and others, maintained the patients in a supine position before collecting the blood samples. Although at least 60–100 min could be considered ideal, from the practical point of view this time is so long that it would strongly limit the applicability of BNP evaluation in clinical practice. This is why, in our research we tried to minimize these problems by using a standard time of rest before sample collection. Data regarding stability of BNP and related peptides are sparse and conflicting. The usage of stabilizing agents has been suggested in several studies that have validated the diagnostic and prognostic values ofBNP andNT-proBNP [8] and has also been recently recommended by the IFCC Committee on standardization of markers of cardiac damage [7]. On the basis of these reports, our results and the interesting considerations made by Hazukova and Colleagues, we can only say that the blood sample storage used so far has not limited the prognostic information carried by BNP in our series. As far as the time to analysis is concerned, we are happy to providemore information on the protocolwe used. The baseline and the onemonth samples for each patient were analysed using the same kit. Since one kit was used for analysing more than two samples, the mean time to analysis was 10 months. We tested the hypothesis that time could influence the results butwe did not find any significant difference in the BNP plasma levels related to the time between collection and analysis.

Usefulness of handgrip to improve ibutilide efficacy in organizing atrial electrical activity during atrial fibrillation.

We analyzed the effect of handgrip on atrial electrical activity during atrial fibrillation (AF) by recording right and left atrial activity in 15 patients with persistent AF under baseline conditions and after saline and ibutilide infusions. The handgrip test for 15 seconds, which was always associated with a significant increase in mean atrial cycle length, was recorded in both atria (right atrium: saline vs saline + handgrip 141 +/- 29 vs 171 +/- 24 ms, p <0.001; ibutilide vs ibutilide + handgrip: 197 +/- 43 vs 221 +/- 39 ms, p <0.005). Handgrip favorably modifies atrial electrophysiologic properties during AF.