Endocardial repolarization dispersion in BrS: A novel automatic algorithm for mapping activation recovery interval.

INTRODUCTION: Repolarization dispersion in the right ventricular outflow tract (RVOT) contributes to the type-1 electrocardiographic (ECG) phenotype of Brugada syndrome (BrS), while data on the significance and feasibility of mapping repolarization dispersion in BrS patients are scarce. Moreover, the role of endocardial repolarization dispersion in BrS is poorly investigated. We aimed to assess endocardial repolarization patterns through an automated calculation of activation recovery interval (ARI) estimated on unipolar electrograms (UEGs) in spontaneous type-1 BrS patients and controls; we also investigated the relation between ARI and right ventricle activation time (RVAT), and T-wave peak-to-end interval (Tpe) in BrS patients. METHODS: Patients underwent endocardial high-density electroanatomical mapping (HDEAM); BrS showing an overt type-1 ECG were defined as OType1, while those without (latent type-1 ECG and LType1) received ajmaline infusion. BrS patients only underwent programmed ventricular stimulation (PVS). Data were elaborated to obtain ARI corrected with the Bazett formula (ARIc), while RVAT was derived from activation maps. RESULTS: 39 BrS subjects (24 OType1 and 15 LTtype1) and 4 controls were enrolled. OType1 and post-ajmaline LType1 showed longer mean ARIc than controls (306 ± 27.3 ms and 333.3 ± 16.3 ms vs. 281.7 ± 10.3 ms, p = .05 and p < .001, respectively). Ajmaline induced a significant prolongation of ARIc compared to pre-ajmaline LTtype1 (333.3 ± 16.3 vs. 303.4 ± 20.7 ms, p < .001) and OType1 (306 ± 27.3 ms, p < .001). In patients with type-1 ECG (OTtype1 and post-ajmaline LType1) ARIc correlated with RVAT (r = .34, p = .04) and Tpec (r = .60, p < .001), especially in OType1 subjects (r = .55, p = .008 and r = .65 p < .001, respectively). CONCLUSION: ARIc mapping demonstrates increased endocardial repolarization dispersion in RVOT in BrS. Endocardial ARIc positively correlates with RVAT and Tpec, especially in OType1.

Blebbistatin protects iPSC-CMs from hypercontraction and facilitates automated patch-clamp based electrophysiological study.

Recently, there have been great advances in cardiovascular channelopathy modeling and drug safety pharmacology using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The automated patch-clamp (APC) technique overcomes the disadvantages of the manual patch-clamp (MPC) technique, which is labor intensive and gives low output. However, the application of the APC platform is still limited in iPSC-CM based research, due to the difficulty in maintaining the high quality of single iPSC-CMs during dissociation and recording. In this study, we improved the method for single iPSC-CM preparation by applying 2.5 µM blebbistatin (BB, an excitation-contraction coupling uncoupler) throughout APC procedures (dissociation, filtration, storage, and recording). Under non-BB buffered condition, iPSC-CMs in suspension showed a severe bleb-like morphology. However, BB-supplement led to significant improvements in morphology and INa recording, and we even obtained several CMs that showed spontaneous action potentials with typical morphology. Furthermore, APC faithfully recapitulated the single-cell electrophysiological phenotypes of iPSC-CMs derived from Brugada syndrome patients, as detected with MPC. Our study indicates that APC is capable of replacing MPC in the modeling of cardiac channelopathies using human iPSC-CMs by providing high-quality data with higher throughput.

Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome.

A healthy regime is fundamental for the prevention of cardiovascular diseases (CVD). In inherited channelopathies, such as Brugada syndrome (BrS) and Long QT syndrome (LQTS), unfortunately, sudden cardiac death could be the first sign for patients affected by these syndromes. Several known factors are used to stratify the risk of developing cardiac arrhythmias, although none are determinative. The risk factors can be affected by adjusting lifestyle habits, such as a particular diet, impacting the risk of arrhythmogenic events and mortality. To date, the importance of understanding the relationship between diet and inherited channelopathies has been underrated. Therefore, we describe herein the effects of dietary factors on the development of arrhythmia in patients affected by BrS and LQTS. Modifying the diet might not be enough to fully prevent arrhythmias, but it can help lower the risk.

Local peribulbar anesthesia before glaucoma filtering surgery in a patient with Brugada syndrome.

We report anesthetic management in a patient with Brugada syndrome, an inherited syndrome characterized by normal QT interval, typical ST-segment-elevation in the right precordial leads, and increased risk of sudden cardiac death in the absence of myocardial ischemia or structural heart disease. A 69-year-old man scheduled for glaucoma filtering surgery underwent local peribulbar anesthesia using 5 mL of lidocaine 20 mg/mL solution that was slowly injected into two different sites approximately 10 min prior to the surgical procedure. The surgery proceeded uneventful and data of patient's blood pressure, heart rate, oxygen saturation were collected. Continuous electrocardiography monitoring before, during, and up to 6 h after surgery did not reveal any arrhythmia or tachycardia. A certain number of drugs should be avoided in patients with Brugada syndrome because of their potential risk to trigger an arrhythmia. Among them there are some anesthetics and in particular those that are sodium channel blockers. Ropivacaine and bupivacaine, commonly used for peribulbar block, have been associated with onset of severe arrhythmias. Contrarily, the use of class IB drugs mexiletine and lidocaine is generally considered safe. Local anesthetic agent should be carefully chosen, and anesthesia should be obtained using the minimal necessary drug dose.

Electrocardiographic imaging of the arrhythmogenic substrate of Brugada syndrome: Current evidence and future perspectives.

Brugada syndrome is responsible for about 20% of sudden cardiac deaths in patients with apparently normal hearts. Basic and clinical research has elucidated some of the mechanisms that are responsible for life-threatening ventricular arrhythmias in this syndrome. Delays in activation and repolarization over the right ventricular outflow tract are the most likely cause of the ECG typical pattern and arrhythmogenesis. Invasive epicardial and endocardial mapping has identified the epicardium as the principal region of interest for these anomalies, and areas of fragmented potentials at invasive mapping are a target for epicardial ablation. Noninvasive mapping systems have been developed to study the epicardial depolarization and repolarization and may be particularly useful in assessing the epicardial arrhythmogenic substrate of Brugada syndrome for both clinical and research purpose. This review focuses on recent advances in this field.

PNA-Based Graphene Oxide/Porous Silicon Hybrid Biosensor: Towards a Label-Free Optical Assay for Brugada Syndrome.

Peptide nucleic acid (PNA) is a synthetic DNA mimic that outperforms the properties of traditional oligonucleotides (ONs). On account of its outstanding features, such as remarkable binding affinity towards complementary DNA or RNA as well as high thermal and chemical stability, PNA has been proposed as a valuable alternative to the ON probe in gene-sensor design. In this study, a hybrid transducer made-up of graphene oxide (GO) nano-sheets covalently grafted onto a porous silicon (PSi) matrix has been investigated for the early detection of a genetic cardiac disorder, the Brugada syndrome (BS). A functionalization strategy towards the realization of a potential PNA-based device is described. A PNA, able to detect the SCN5A gene associated with the BS, has been properly synthesized and used as a bioprobe for the realization of a proof-of-concept label-free optical PNA-biosensor. PSi reflectance and GO photoluminescence signals were simultaneously exploited for the monitoring of the device functionalization and response.

Restitution metrics in Brugada syndrome: a systematic review and meta-analysis.

BACKGROUND: Brugada syndrome (BrS) is an ion channelopathy that predisposes affected subjects to ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death. Restitution analysis has been examined in BrS patients but not all studies have reported significant differences between BrS patients and controls. Therefore, we conducted a systematic review and meta-analysis to investigate the different restitution indices used in BrS. METHODS: PubMed and Embase were searched until April 7, 2019, identifying 20 and 27 studies. RESULTS: A total of ten studies involving 178 BrS (mean age 38 years old, 63% male) and 102 controls (mean age 31 years old, 42% male) were included in this systematic review. Pacing was carried out at the right ventricular outflow tract (RVOT)/right ventricular apex (RPA) (n = 4), RPA (n = 4), or right atrium (RA) (n = 1). Basic cycle lengths of 400 (n = 4), 500 (n = 2), 600 (n = 6) and 750 ms (n = 1) were used. Recording methods include electrograms (n = 4), monophasic action potentials (n = 5), and electrocardiograms (n = 1). Signals were obtained from the RVOT (n = 8), RVA (n = 3), RA (n = 1), or the body surface (n = 1). The maximum restitution slope for endocardial repolarization at the RVOT was 0.87 for BrS patients (n = 5; 95% confidence interval [CI] 0.68-1.07) compared with 0.74 in control subjects (n = 4; 95% CI 0.42-1.06), with a significant mean difference of 0.40 (n = 4; 95% CI 0.11-0.69; P = 0.007). CONCLUSIONS: Steeper endocardial repolarization restitution slopes are found in BrS patients compared with controls at baseline. Restitution analysis can provide important information for risk stratification in BrS.

Clinical characteristics and long-term clinical course of patients with Brugada syndrome without previous cardiac arrest: a multiparametric risk stratification approach.

AIMS: Risk stratification in Brugada syndrome (BrS) still represents an unsettled issue. In this multicentre study, we aimed to evaluate the clinical characteristics and the long-term clinical course of patients with BrS. METHODS AND RESULTS: A total of 111 consecutive patients (86 males; aged 45.3 ± 13.3 years) diagnosed with BrS were included and followed-up in a prospective fashion. Thirty-seven patients (33.3%) were symptomatic at enrolment (arrhythmic syncope). An electrophysiological study (EPS) was performed in 59 patients (53.2%), and ventricular arrhythmias were induced in 32 (54.2%). A cardioverter defibrillator was implanted in 34 cases (30.6%). During a mean follow-up period of 4.6 ± 3.5 years, appropriate device therapies occurred in seven patients. Event-free survival analysis (log-rank test) showed that spontaneous type-1 electrocardiogram pattern (P = 0.008), symptoms at presentation (syncope) (P = 0.012), family history of sudden cardiac death (P < 0.001), positive EPS (P = 0.024), fragmented QRS (P = 0.004), and QRS duration in lead V2 > 113 ms (P < 0.001) are predictors of future arrhythmic events. Event rates were 0%, 4%, and 60% among patients with 0-1 risk factor, 2-3 risk factors, and 4-5 risk factors, respectively (P < 0.001). Current multiparametric score models exhibit an excellent negative predictive value and perform well in risk stratification of BrS patients. CONCLUSIONS: Multiparametric models including common risk factors appear to provide better risk stratification of BrS patients than single factors alone.

Beyond the One Gene-One Disease Paradigm: Complex Genetics and Pleiotropy in Inheritable Cardiac Disorders

Inheritable cardiac disorders, which may be associated with cardiomyopathic changes, are often associated with increased risk of sudden death in the young. Early linkage analysis studies in Mendelian forms of these diseases, such as hypertrophic cardiomyopathy and long-QT syndrome, uncovered large-effect genetic variants that contribute to the phenotype. In more recent years, through genotype-phenotype studies and methodological advances in genetics, it has become evident that most inheritable cardiac disorders are not monogenic but, rather, have a complex genetic basis wherein multiple genetic variants contribute (oligogenic or polygenic inheritance). Conversely, studies on genes underlying these disorders uncovered pleiotropic effects, with a single gene affecting multiple and apparently unrelated phenotypes. In this review, we explore these 2 phenomena: on the one hand, the evidence that variants in multiple genes converge to generate one clinical phenotype, and, on the other, the evidence that variants in one gene can lead to apparently unrelated phenotypes. Although multiple conditions are addressed to illustrate these concepts, the experience obtained in the study of long-QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, and in the study of functions related to SCN5A (the gene coding for the α-subunit of the most abundant sodium channel in the heart) and PKP2 (the gene coding for the desmosomal protein plakophilin-2), as well, is discussed in more detail.

Supranormal heart rate during peak exercise stress test triggering type-1 Brugada ECG pattern.

We present a remarkable maximal capacity exercise test of a 52-year-old patient diagnosed with Brugada syndrome (BrS). As the patient reaches a supranormal sinus heart rate, the type-1 electrocardiogram pattern of BrS appeared and then disappeared immediately after cessation of exercise.

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome.

BACKGROUND: Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited. OBJECTIVES: The purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence. METHODS: A total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31). RESULTS: Patients' median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents. CONCLUSIONS: Young BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered.

Pulseless Electric Activity with Pre-Excitation.

A 41-year-old man developed cardiac arrest. A resting 12-lead electrocardiogram showed a delta wave, suggestive of preexcitation syndrome. An electrophysiological test revealed the existence of inducible atrial fibrillation and a fasciculoventricular accessory pathway (FVAP). After these examinations, idiopathic ventricular arrhythmia was suspected. For evaluating concealed Brugada syndrome, pilsicainide was administered, which diminished the delta wave and no Brugada-like electrocardiogram was observed. Ventricular double extra-stimulation from the RV apex easily induced VF, which could not be defibrillated by an external defibrillator, and later stopped spontaneously. These results established the diagnosis of FVAP and idiopathic VF, and not pre-excited atrial fibrillation or Brugada syndrome.

Hybrid thoracoscopic epicardial ablation of right ventricular outflow tract in patients with Brugada syndrome.

BACKGROUND: Abnormal delayed electrograms (EGMs) from the anterior wall of the right ventricular outflow tract (RVOT) epicardium have become the ablation target in Brugada syndrome (BrS). OBJECTIVE: The aim of this study was to analyze the safety, feasibility, and efficacy of a novel hybrid thoracoscopic approach to perform epicardial RVOT radiofrequency ablation in BrS. METHODS: Thirty-six patients with BrS (26 men (72.2%); mean age 36.6±15.8 years; range 3-63 years) who underwent hybrid thoracoscopic epicardial ablation of RVOT from January 2016 to April 2018 were included in this study. Two expert electrophysiologists analyzed the EGMs during ajmaline challenge and guided the surgeon to perform ablation. Ajmaline challenge was repeated after 1 month to assess the absence of the BrS electrocardiographic pattern. Patients were followed by remote monitoring and outpatient visits every 6 months. RESULTS: The elimination of all abnormal EGMs was achieved in 94.4% of patients. After a mean follow-up of 16 ± 8 months (range 6-30 months), freedom from ventricular arrhythmias was obtained in 7 (77.8%) patients in secondary prevention 9/36 (25%) and in 24 (100%) patients in primary prevention 24/36 (75%). Major complications were observed in 1 patient (2.8%), who experienced late cardiac tamponade. CONCLUSION: Hybrid thoracoscopic epicardial RVOT ablation in BrS is a safe and feasible approach, allowing direct visualization of ablation during radiofrequency delivery. Because of ventricular arrhythmia recurrences, implantable cardioverter-defibrillator implantation is still mandatory in patients treated in secondary prevention and with high risk.

The Fever Tree: from Malaria to Neurological Diseases.

This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in the 17th century, it played a role in treating emperors and peasants and was central to colonialism and wars. Over those 400 years, the medical use of cinchona alkaloids has evolved from bark extracts to chemical synthesis and controlled clinical trials. At the present time, the use of quinine and quinidine has declined, to a large extent due to their toxicity. However, quinine is still being prescribed in resource-limited settings, in severe malaria, and in pregnant women, and quinidine made a limited comeback in the treatment of several cardiac and neurological syndromes. In addition, the article presents more recent studies which improved our understanding of cinchona alkaloids' pharmacology. The knowledge gained through these studies will hopefully lead to a wider use of these drugs in precision medicine and to design of new generation, safer quinine and quinidine derivatives.

Pharmacological Modulation of Right Ventricular Endocardial-Epicardial Gradients in Brugada Syndrome.

Background We explored the hypothesis that increased cholinergic tone exerts its proarrhythmic effects in Brugada syndrome (BrS) through increasing dispersion of transmural repolarization in patients with spontaneous and drug-induced BrS. Methods BrS and supraventricular tachycardia patients were studied after deploying an Ensite Array in the right ventricular outflow tract and a Cardima catheter in the great cardiac vein to record endo and epicardial signals, respectively. S1-S2 restitution curves from the right ventricular apex were conducted at baseline and after edrophonium challenge to promote increased cholinergic tone. The local unipolar electrograms were then analyzed to study transmural conduction and repolarization dynamics. Results The study included 8 BrS patients (5 men:3 women; mean age, 56 years) and 8 controls patients with supraventricular tachycardia (5 men:3 women; mean age, 48 years). Electrophysiological studies in controls demonstrated shorter endocardial than epicardial right ventricular activation times (mean difference: 26 ms; P<0.001). In contrast, patients with BrS showed longer endocardial than epicardial activation time (mean difference: -15 ms; P=0.001). BrS hearts, compared with controls, showed significantly larger transmural gradients in their activation recovery intervals (mean intervals, 20.5 versus 3.5 ms; P<0.01), with longer endocardial than epicardial activation recovery intervals. Edrophonium challenge increased such gradients in both controls (to a mean of 16 ms [ P<0.001]) and BrS (to 29.7 ms; P<0.001). However, these were attributable to epicardial and endocardial activation recovery interval prolongations in control and BrS hearts, respectively. Dynamic changes in repolarization gradients were also observed across the BrS right ventricular wall in BrS. Conclusions Differential contributions of conduction and repolarization were identified in BrS which critically modulated transmural dispersion of repolarization with significant cholinergic effects only identified in the patients with BrS. This has important implications for explaining the proarrhythmic effects of increased vagal tone in BrS, as well as evaluating autonomic modulation and epicardial ablation as therapeutic strategies.

Efficacy of Endocardial Ablation of Drug-Resistant Ventricular Fibrillation in Brugada Syndrome: Long-Term Outcome.

Background Both endocardial trigger elimination and epicardial substrate modification are effective in treating ventricular fibrillation (VF) in Brugada syndrome. However, the primary approach and the characteristics of patients who respond to endocardial ablation remain unknown. Methods Among 123 symptomatic Brugada syndrome patients (VF, 63%; syncope, 37%), ablation was performed in 21 VF/electrical storm patients, the majority of whom were resistant to antiarrhythmic drugs. Results Careful endocardial mapping revealed that 81% of the patients had no specific findings, whereas 19% of the patients, who experienced the most frequent VF episodes with notching of the QRS in lead V1, had delayed low-voltage fractionated endocardial electrograms. Ablation of VF triggers followed by endocardial substrate modification was performed in the right ventricular outflow tract in 85% of the cases and in the right ventricle in 15%. VF triggers could not be completely eliminated in 1 patient and VF became noninducible in 14 (88%) patients among 16 patients who underwent VF induction with normalization of Brugada-type ECG in 3. During follow-up (56.14±36.95 months), VF recurrence was observed in 7 patients. Importantly, all patients who had nothing of QRS in lead V1 did not respond to endocardial ablation despite presence of VF-triggering ectopic beats during ablation. Conclusions With careful documentation of VF-triggering ectopic beats and detailed endocardial mapping, endocardial VF trigger elimination followed by endocardial substrate modification has an excellent long-term outcome, whereas presence of QRS notching in lead V1 was associated with high VF recurrence suggesting epicardial substrate ablation as effective initial approach.

Coexistence of atrioventricular accessory pathways and drug-induced type 1 Brugada pattern.

BACKGROUND: Atrial arrhythmias, particularly atrioventricular nodal reentrant tachycardia, can coexist with drug-induced type 1 Brugada electrocardiogram (ECG) pattern (DI-Type1-BrP). The present study was designed to determine the prevalence of DI-Type1-BrP in patients with atrioventricular accessory pathways (AV-APs) and to investigate the clinical, electrocardiographic, electrophysiologic, and genetic characteristics of these patients. METHODS: One-hundred twenty-four consecutive cases of AV-APs and 84 controls underwent an ajmaline challenge test to unmask DI-Type1-BrP. Genetic screening and analysis was performed in 55 of the cases (19 with and 36 without DI-Type1-BrP). RESULTS: Patients with AV-APs were significantly more likely than controls to have a Type1-BrP unmasked (16.1 vs 4.8%, P = 0.012). At baseline, patients with DI-Type1-BrP had higher prevalence of chest pain, QR/rSr' pattern in V1 and QRS notching/slurring in V2 and aVL during preexcitation, rSr' pattern in V1 -V2 , and QRS notching/slurring in aVL during orthodromic atrioventricular reentrant tachycardia (AVRT) compared to patients without DI-Type1-BrP. Abnormal QRS configuration (QRS notching/slurring and/or fragmentation) in V2 during preexcitation was present in all patients with DI-Type1 BrP. The prevalence of spontaneous preexcited atrial fibrillation (AF) and history of AF were similar (15% vs 18.3%, P = 0.726) in patients with and without DI-Type1-BrP, respectively. The prevalence of mutations in Brugada-susceptibility genes was higher (36.8% vs 8.3%, P = 0.02) in patients with DI-Type1-BrP compared to patients without DI-Type1-BrP. CONCLUSIONS: DI-Type1-BrP is relatively common in patients with AV-APs. We identify 12-lead ECG characteristics during preexcitation and orthodromic AVRT that point to an underlying type1-BrP, portending an increased probability for development of malignant arrhythmias.

Yellow phosphorus-induced Brugada phenocopy.

BACKGROUND: Metallic phosphides (of aluminum and phosphide) and yellow phosphorus are commonly used rodenticide compounds in developing countries. Toxicity of yellow phosphorus mostly pertains to the liver, kidney, heart, pancreas and the brain. Cardiotoxicity with associated Brugada ECG pattern has been reported only in poisoning with metallic phosphides. METHODS AND RESULTS: Brugada phenocopy and hepatic dysfunction were observed in a 29-year-old male following yellow phosphorus consumption. He had both type 1 (day1) and type 2 (day2) Brugada patterns in the electrocardiogram, which resolved spontaneously by the third day without hemodynamic compromise. CONCLUSION: Toxins such as aluminum and zinc phosphide have been reported to induce Brugada ECG patterns due to the generation of phosphine. We report the first case of yellow phosphorus-related Brugada phenocopy, without hemodynamic compromise or malignant arrhythmia.

Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. AIM: Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. METHODS: Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. RESULTS: Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63-8.66; P=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67-0.83; P<0.001). Ten studies were identified that evaluated ICD use in patients with various comorbidities including renal disease, chronic obstructive pulmonary disease, atrial fibrillation, heart disease, and others. A random effects model demonstrated that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.72; 95% confidence interval: 0.65-0.79; P<0.0001), and a second "minimal overlap" analysis also found that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.61-0.82; P<0.0001). In 5 studies that included data on renal dysfunction, ICD implantation was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.60-0.85; P<0.001).