Marwan Refaat

Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes

This international consensus statement is the collaborative effort of three medical societies representing electrophysiology in North America, Europe, and Asian-Pacific area: the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asia Pacific Heart Rhythm Society. The objective of the consensus document is to provide clinical guidance for diagnosis, risk stratification, and management of patients affected by inherited primary arrhythmia syndromes. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the clinical data on patients affected by channelopathies. This document does not address the indications of genetic testing in patients affected by inherited arrhythmias and their family members. Diagnostic, prognostic, and therapeutic implications of the results of genetic testing are also not included in this document because this topic has been covered by a recent publication1 coauthored by some of the contributors of this consensus document, and it remains the reference text on this topic. Guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden arrhythmic death …

2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing

Implantable cardioverter-defibrillator (ICD) therapy is clearly an effective therapy for selected patients in definable populations. The benefits and risks of ICD therapy are directly impacted by programming and surgical decisions. This flexibility is both a great strength and a weakness, for which there has been no prior official discussion or guidance. It is the consensus of the four continental electrophysiology societies that there are four important clinical issues for which there are sufficient ICD clinical and trial data to provide evidence-based expert guidance. This document systematically describes the >80% (83–100%, mean: 96%) required consensus achieved for each recommendation by official balloting in regard to the programming of (i) bradycardia mode and rate, (ii) tachycardia detection, (iii) tachycardia therapy, and (iv) the intraprocedural testing of defibrillation efficacy. Representatives nominated by the Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA), Asian Pacific Heart Rhythm Society (APHRS), and the Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLAECE)-Latin American Society of Cardiac Pacing and Electrophysiology participated in the project definition, the literature review, the recommendation development, the writing of the document, and its approval. The 32 recommendations were balloted by the 35 writing committee members and were approved by an …

Three‐Dimensional Anatomy of the Left Atrium by Magnetic Resonance Angiography: Implications for Catheter Ablation for Atrial Fibrillation

Background: Pulmonary vein isolation (PVI) has become one of the primary treatments for symptomatic drug‐refractory atrial fibrillation (AF). During this procedure, delivery of ablation lesions to certain regions of the left atrium can be technically challenging. Among the most challenging regions are the ridges separating the left pulmonary veins (LPV) from the left atrial appendage (LAA), and the right middle pulmonary vein (RMPV) from the right superior (RSPV) and right inferior (RIPV) pulmonary veins. A detailed anatomical characterization of these regions has not been previously reported.

Ventricular arrhythmias after left ventricular assist device implantation.

Background: Left ventricular assist devices (LVADs) have been used as a bridge to cardiac transplantation and as destination therapy in patients with advanced heart failure. The period after LVAD support is associated with ventricular arrhythmias (VAs) despite ventricular unloading and such VAs can have a detrimental effect on survival. Despite the increasing use of LVAD, little is known regarding post‐LVAD VAs at the molecular level and in vivo.

Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy

BACKGROUND Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous. OBJECTIVES We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes. METHODS Subjects included in the Genetic Risk Assessment of Defibrillator Events (GRADE) study were aged at least 18 years, had an ejection fraction of ≤30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in subjects with DCM; 2 common polymorphisms in RBM20, rs942077 and rs35141404, were genotyped in all GRADE subjects. RESULTS A total of 1465 subjects were enrolled in the GRADE study, and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 ± 13 years, 64% were males, and the mean follow-up time was 24.2 ± 17.1 months after ICD placement. RBM20 mutations were identified in 8 subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared with nonmutation carriers. Three of 8 subjects with RBM20 mutations (37.5%) had atrial fibrillation (AF), whereas 19 subjects without mutations (7.4%) had AF (P = .02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele odds ratio = 0.62; 95% confidence interval = 0.44-0.86; P = .006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele odds ratio = 0.58; P = .047). CONCLUSIONS Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers.

Neoplastic Pericardial Effusion

Neoplastic pericardial effusion is a serious and common clinical disorder encountered by cardiologists, cardiothoracic surgeons, oncologists, and radiation oncologists. It may develop from direct extension or metastatic spread of the underlying malignancy, from an opportunistic infection, or from a complication of radiation therapy or chemotherapeutic toxicity. The clinical presentation varies, and the patient may be hemodynamically unstable in the setting of constrictive pericarditis and cardiac tamponade. The management depends on the patients prognosis and varies from pericardiocentesis, sclerotherapy, and balloon pericardiotomy to cardiothoracic surgery. Patients with neoplastic pericardial effusion face a grave prognosis, as their malignancy is usually more advanced. This review article discusses the epidemiology and etiology, pathophysiology, clinical presentation, diagnosis, management, and prognosis of neoplastic pericardial effusion.

A Novel Ryanodine Receptor Mutation Linked to Sudden Death Increases Sensitivity to Cytosolic Calcium

Rationale: Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during &bgr;-adrenergic stimulation. Objective: This study sought to determine the effects of a novel RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca2+). Methods and Results: Functional characterizations of recombinant human RyR2-G230C channels were performed under conditions mimicking stress. Human RyR2 mutant channels were generated by site-directed mutagenesis and heterologously expressed in HEK293 cells together with calstabin2. RyR2 channels were measured to examine the regulation of the channels by cytosolic versus luminal sarcoplasmic reticulum Ca2+. A 50-year-old white man with repeated syncopal episodes after exercise had a cardiac arrest and harbored the mutation RyR2-G230C. cAMP-dependent protein kinase–phosphorylated RyR2-G230C channels exhibited a significantly higher open probability at diastolic Ca2+ concentrations, associated with a depletion of calstabin2. The luminal Ca2+ sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like. Conclusions: The RyR2-G230C mutant exhibits similar biophysical defects compared with previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca2+ dependence for activation under conditions that simulate exercise, consistent with a “leaky” channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca2+ activation. Thus, diastolic sarcoplasmic reticulum Ca2+ leak caused by reduced calstabin2 binding and a leftward shift in the Ca2+ dependence for activation by diastolic levels of cytosolic Ca2+ is a common mechanism underlying CPVT.

Late Perforation by Cardiac Implantable Electronic Device Leads: Clinical Presentation, Diagnostic Clues, and Management

Late intracardiac lead perforation is defined as migration and perforation of an implanted lead after 1 month of cardiac electronic device implantation. It is an under‐recognized complication with significant morbidity and mortality, particularly if not recognized early. Two patients with late perforation caused by passive‐fixation leads are reported and the clinical features of their presentation and management are reviewed. We conducted a thorough review of the available English language literature pertaining to this complication to draw relevant conclusions regarding presentation, diagnosis, and management. Early recognition of this complication is important as the indications for and numbers of patients who receive cardiac implantable electronic devices continue to expand. Copyright

Syrian refugees in Lebanon: facts and solutions

R i c h a r d H o r t o n ’s C o m m e n t (July 13, p 112) suggests that recent international commitments on development cooperation have done more harm than good for healthcare in Africa. I disagree. But his conclusion that our “global health panjandrums” need better feedback from beneficiaries on the ground is sound. We now have a window of opportunity to get things right. As the international community designs successors to the Millennium Development Goals, it needs to listen to those on the receiving end of the existing international development machinery, and to draw lessons from a decade-long international drive for more eff ective aid. The Global Partnership for Eff ective Development Co-operation allows us to do just that. Founded after the 2011 Busan High-Level Forum on Aid Effectiveness, it offers a global platform for leaders to listen to the concerns of developing countries and—crucially—to take action. Busan saw donors and benefi ciaries reaffirming their 2005 Paris Declaration commitments on aid quality—not stepping away from them as Horton suggests. A major independent evaluation showed that the Paris principles remain highly relevant, and that Paris-style aid reforms have contributed to results in the health sector. But it also reminded us that these reforms need to be put in to perspective and viewed alongside other resources, actors, and eff orts. Busan was in places messy, dealing with complexities that previous international summits on development had yet to address. It was a necessary step towards a global model fi t for our times. That model must see leaders meeting their aid commitments alongside a broader set of enablers: cooperation on taxation, illicit fi nancial fl ows, climate change, and South-South partnerships, to name a few. Without a fresh and far-reaching partnership for implementation, even the most ambitious of global goals will do little to address Africa’s health challenges.

Characterization and Mechanisms of Action of Novel NaV1.5 Channel Mutations Associated With Brugada Syndrome

Background—Brugada syndrome is a heterogeneous heart rhythm disorder characterized by an atypical right bundle block pattern with ST-segment elevation and T-wave inversion in the right precordial leads. Loss-of-function mutations in SCN5A encoding the cardiac sodium channel NaV1.5 are associated with Brugada syndrome. We found novel mutations in SCN5A in 2 different families diagnosed with Brugada syndrome and investigated how those affected NaV1.5 channel function. Methods and Results—We performed genetic testing of the probands’ genomic DNA. After site-directed mutagenesis and transfection, whole-cell currents were recorded for NaV1.5 wild type and mutants heterologously expressed in Chinese hamster ovary-K1 cells. Proband 1 had two novel NaV1.5 mutations: NaV1.5-R811H and NaV1.5-R620H. The NaV1.5-R811H mutation showed a significant loss of function in peak Na+ current density and alteration of biophysical kinetic parameters (inactivation and recovery from inactivation), whereas NaV1.5-R620H had no significant effect on the current. Proband 2 had a novel NaV1.5-S1218I mutation. NaV1.5-S1218I had complete loss of function, and 1:1 expression of NaV1.5-wild type and NaV1.5-S1218I mimicking the heterozygous state revealed a 50% reduction in current compared with wild type, suggesting a functional haploinsufficiency in the patient. Conclusions—NaV1.5-S1218I and R811H are novel loss-of-function mutations in the SCN5A gene causing Brugada syndrome.