Brugada syndrome: 12 years of progression.

Brugada syndrome is increasingly being recognized in clinical medicine. What started as an electrocardiographic curiosity has become an important focus of attention for individuals working in the different disciplines related to sudden cardiac death, from basic scientists to clinical cardiac electrophysiologists. In just 12 years, since the description of the disease, clinically relevant information is continuously being provided to physicians to help protect the individuals with Brugada syndrome to the best of our ability. And this information has been gathered thanks to the effort of hundreds of basic scientists, physicians and patients who continue to give their time, effort and data to help understand how the electrocardiographic pattern may cause sudden cardiac death. There are still many unanswered questions, both at the clinical and basic field. However, with the further collection of data, the longer follow-up and the continued interest from the basic science world we will have the necessary tools to the successful unraveling of the disease.</p

Interplay between R513 methylation and S516 phosphorylation of the cardiac voltage-gated sodium channel

Arginine methylation is a novel post-translational modification within the voltage-gated ion channel superfamily, including the cardiac sodium channel, Naᵥ1.5. We show that Naᵥ1.5 R513 methylation decreases S516 phosphorylation rate by 4 orders of magnitude, the first evidence of protein kinase A inhibition by arginine methylation. Reciprocally, S516 phosphorylation blocks R513 methylation. Naᵥ1.5 p.G514C, associated to cardiac conduction disease, abrogates R513 methylation, while leaving S516 phosphorylation rate unchanged. This is the first report of methylation–phosphorylation cross-talk of a cardiac ion channel

Phase 2 Re-Entry Without Ito: Role of Sodium Channel Kinetics in Brugada Syndrome&nbsp;Arrhythmias.

BACKGROUND: In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (Ito) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations. OBJECTIVES: The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of Ito. METHODS: Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models. RESULTS: In the presence of Ito sufficient to generate robust P2R, reducing sodium current (INa) peak amplitude alone only slightly potentiated P2R. When INa inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of Ito. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. INa-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients. CONCLUSIONS: Altered INa kinetics synergize powerfully with reduced INa amplitude to promote P2R-induced arrhythmias in BrS in the absence of Ito, establishing a robust mechanistic link between altered INa kinetics and the P2R-mediated arrhythmia mechanism

Transient entrainment and interruption of atrioventricular node tachycardia

The possibility of transiently entraining and interrupting the common type of atrioventricular (AV) node tachycardia (anterograde slow, retrograde fast AV node pathway) was studied using atrial and ventricular pacing in 18 patients with paroxysmal AV node tachycardia. Transient entrainment occurred in all patients. During atrial pacing, localized block in the AV node for one beat followed by anterograde conduction over the fast pathway was observed in three patients. During ventricular pacing, localized block for one beat followed by retrograde conduction over the slow pathway was not observed in any patient. Neither atrial nor ventricular fusion beats were observed during entrainment.These observations indicate in a way not previously shown that reentry involving two functionally dissociated pathways in the AV node is the underlying mechanism of paroxysmal AV node tachycardia. The inability to demonstrate atrial or ventricular fusion beats during entrainment suggests a true intranodal location of the reentrant circuit. Finally, the ability to transiently entrain intranodal tachycardia demonstrates that this electrophysiologic phenomenon is not exclusively limited to macroreentrant circuits

Ventricular arrhythmias initiated by programmed stimulation in four groups of patients with healed myocardial infarction

Programmed electrical stimulation of the heart was prospectively used in 160 patients with healed myocardial infarction to study the incidence and characteristics of ventricular arrhythmias induced. Thirty-five patients had neither documented nor suspected ventricular arrhythmias (Group A); 37 patients had documented nonsus-tained ventricular tachycardia (Group B); 31 patients had been resuscitated from ventricular fibrillation (Group C); and 57 patients had documented sustained mono-morphic ventricular tachycardia (Group D). No electrophysiologic differences were found between patients in Group A and Group B, but patients in both groups differed significantly from patients in Group C and Group D. In the last two groups, sustained monomorphic ventricular tachycardia was more frequently induced, the cycle length of the induced ventricular tachycardia was slower and a lesser number of premature stimuli was required for induction. No differences were found in the incidence, rate or mode of induction of nonsustained monomorphic ventricular tachycardia, but nonsustained polymorphic ventricular tachycardia and ventricular fibrillation were more frequently induced in Groups A and B.It is concluded that the substrate for sustained ventricular arrhythmia is present in at least 42% of patients after myocardial infarction. The electrophysiologic characteristics of the substrate for ventricular tachycardia seem to be the major determinant of the clinical occurrence of sustained ventricular arrhythmia. Changes in the electrophysiologic properties of the substrate of ventricular tachycardia, either spontaneously with time or induced by ischemia or antiarrhythmic drugs, can contribute to the clinical occurrence of sustained ventricular arrhythmias in patients with an old myocardial infarction

Ventricular fibrillation in six adults without overt heart disease

AbstractFindings are described in six patients with no clinical evidence of heart disease who had documented ventricular fibrillation (five patients) or ventricular flutter (one patient). The mean age of the six patients, all men, was 34 years (range 26 to 43). Cardiovascular collapse occurred in all and was followed by successful cardioversion. No patient had electrolyte or QT abnormalities. One patient had slight right ventricular enlargement on M-mode echocardiography, and another had a left ventricular pressure gradient at rest of 30 mm Hg with a normal two-dimensional echocardiogram. Holter electrocardiographic monitoring revealed incessant ventricular tachycardia in one patient and nonsustained ventricular tachycardia in three others. Exercise testing revealed nonsustained ventricular tachycardia in one patient.Ventricular fibrillation was induced at the time of programmed electrical stimulation in four of the six patients. Documented recurrence of ventricular fibrillation or ventricular flutter occurred in three patients, but in only one patient receiving antiarrhythmic drugs. Four patients were treated with amiodarone and one received an automatic implantable cardioverter-defibrillator. All patients are alive after a mean follow-up period of 78 months after the first documentation of their arrhythmia and 37 months after programmed electrical stimulation.Ventricular fibrillation can occur in the apparently structurally normal human heart. Antiarrhythmic treatment can provide effective control of this malignant arrhythmia

Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation

Infective Endocarditis: Inflammatory Response, Genetic Susceptibility, Oxidative Stress, and Multiple Organ Failure

Infective endocarditis is defined by a focus of infection within the heart. Despite the optimal care, the mortality approaches 30% at 1 year, so the care for this type of patients represents a challenge to improve the result in your care. The challenges in this clinical entity have several aspects such as the diversity of germs that cause endocarditis, and the most important epidemiologically has generated resistance to antimicrobial treatment along with the possibility of apoptosis in their host-germ interaction. The immunogenetic susceptibility to host infection is discussed, which represents a deep area of research. Inflammation, local and systemic, is complex, with the genesis of reactive oxygen species, which are harmful when the antioxidant defenses are exceeded, causing the break in the mitochondrial electron transport chain with the fall in energy genesis, multiple organ failure, and death. Both at the cellular level and in the mitochondria, possible therapeutic targets are also commented

Identification of N-terminal protein acetylation and arginine methylation of the voltage-gated sodium channel in end-stage heart failure human heart

The α subunit of the cardiac voltage-gated sodium channel, Naᵥ1.5, provides the rapid sodium inward current that initiates cardiomyocyte action potentials. Here, we analyzed for the first time the post-translational modifications of Naᵥ1.5 purified from end-stage heart failure human cardiac tissue. We identified R526 methylation as the major post-translational modification of any Naᵥ1.5 arginine or lysine residue. Unexpectedly, we found that the N terminus of Naᵥ1.5 was: 1) devoid of the initiation methionine, and 2) acetylated at the resulting initial alanine residue. This is the first evidence for N-terminal acetylation in any member of the voltage-gated ion channel superfamily. Our results open the door to explore Naᵥ1.5 N-terminal acetylation and arginine methylation levels as drivers or markers of end-stage heart failure