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Background Cardiac involvement is a leading cause of death from sarcoidosis. Because the efficacy of corticosteroid treatment is limited in patients with cardiac manifestation, early diagnosis is important. However, cardiac involvement is difficult to identify at early stages and is often underdiagnosed. Therefore, this study aimed to identify electrocardiographic risk factors for cardiac events in patients with extracardiac sarcoidosis. Methods This prospective observational cohort study included 227 patients with extracardiac sarcoidosis who did not have any cardiac manifestation (age, 49±17years; women, 63%). We studied the association of electrocardiographic abnormalities with developing cardiac manifestations. Results During a follow-up of 6.3±3.7years, 11 patients developed cardiac events, including advanced atrioventricular block (4 patients), ventricular tachycardia (4 patients), and systolic dysfunction (3 patients). All patients had electrocardiographic abnormalities prior to the development of cardiac events. In multivariate analyses, the baseline heart rate and PR interval were associated with increased risk of developing cardiac events. The QRS duration and corrected QT interval were not associated with cardiac manifestations. The multivariate analyses also revealed that baseline conduction disorder, ST segment/T wave abnormalities, and fragmented QRS complexes were associated with cardiac events. Conclusions Electrocardiographic abnormalities occurred prior to cardiac events in extracardiac sarcoidosis. Patients with electrocardiographic abnormalities may require further evaluation for cardiac involvement and careful follow-up.

Background Genome‐wide association studies have implicated variants in SCN 10A , which encodes Nav1.8, as modulators of cardiac conduction. Follow‐up work has indicated the SCN 10A sequence includes an intronic enhancer for SCN 5A . Yet the role of the Nav1.8 protein in the myocardium itself is still unclear. To investigate this , we use homozygous knockout mice ( Scn10a −/− ) generated by disruption of exons 4 and 5, leaving the Scn5a enhancer intact. Methods and Results We previously reported that pharmacologic blockade of Nav1.8 in wild‐type animals blunts action potential prolongation by ATX ‐ II at slow drive rates (≤1 Hz). Here we present evidence of the same blunting in Scn10a −/− compared to wild‐type ventricular myocytes, supporting the conclusion that Nav1.8 contributes to late sodium current at slow rates. In contrast to earlier studies, we found no differences in electrocardiographic parameters between genotypes. Low‐dose ATX ‐ II exposure in lightly anesthetized animals and Langendorff‐perfused hearts prolonged QT c and generated arrhythmias to the same extent in wild‐type and Scn10a −/− . RNA sequencing failed to identify full‐length Scn10a transcripts in wild‐type or knockout isolated ventricular myocytes. However, loss of late current in Scn10a −/− myocytes was replicated independently in a blinded set of experiments. Conclusions While Scn10a transcripts are not detectible in ventricular cardiomyocytes, gene deletion results in reproducible loss of late sodium current under extreme experimental conditions. However, there are no identifiable consequences of this Scn10a deletion in the intact mouse heart at usual rates. These findings argue that common variants in SCN 10A that affect ventricular conduction do so by modulating SCN 5A .

We appreciated hearing from Casado-Arroyo et al regarding our recently published article, “Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated With Early Repolarization,” showing that SCN5A is a novel causative gene of early repolarization syndrome.1 In this study, we identified 3 SCN5A mutations in 3 unrelated patients with idiopathic ventricular fibrillation associated with early repolarization (or early repolarization syndrome). Because all of the patients had J-point elevation in the right precordial lead(s) in addition to J-point elevation in the inferior/lateral leads, Casado-Arroyo et al suggested that all of our patients have Brugada syndrome based on their recent findings that the risk of arrhythmia events is similar between patients with the Type 1 Brugada electrocardiographic pattern in 1 of the right precordial leads and patients with the Type 1 electrocardiographic pattern in >1 lead.2 However, we respectfully disagree because our patients never met the diagnostic criteria for Brugada syndrome.3 The diagnosis of Brugada syndrome is made when patients have a Type 1 Brugada electrocardiographic pattern, which is characterized by a prominent coved ST-segment elevation displaying a J-wave amplitude or ST-segment elevation ≥0.2 mV followed by a negative T-wave in ≥2 of the right precordial leads in the absence or presence of sodium channel blockers.3 Although the J-point elevation was ≥0.2 mV in 1 (Patients 2 and 3) or 2 (Patient 1) of the right …

Background— Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear. Methods and Results— This study included 50 patients (44 men; age, 45±17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels. Conclusions— We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.

It is not known if J waves of early repolarization can be affected by depolarization or not. We report 2 cases in whom J waves were unmasked by preexcitation. A 59-year-old woman with Wolff-Parkinson-White syndrome who had frequent episodes of tachycardia underwent radiofrequency catheter ablation. The 12-lead electrocardiogram on admission showed delta waves and a notch in leads II, III, and aVF (J waves), which disappeared after the elimination of preexcitation. A 56-year-old man with Wolff-Parkinson-White syndrome was admitted for catheter ablation for supraventricular tachycardia. His electrocardiogram showed delta waves in I, II, aVL, V 2 to V 6 , and J waves in the inferior leads and V 3 through V 6 with ST elevation and ST elevation in V 2 . After ablation, J waves disappeared and were replaced by S waves. However, ST elevation remained in the precordial leads. The 2 cases suggest that J waves may be affected by the depolarization process: preexcitation.

J wave or early repolarization has been associated with the risk of ventricular tachyarrhythmias, and its risk stratification is to be established. Case 1: A 51-year-old man without structural heart disease was admitted because of near syncope due to repeated episodes of very rapid non-sustained monomorphic VT (∼240 bpm). His ECG showed J waves in the inferior and lateral leads, and J waves persisted after the administration and were not affected by pilsicainide or epinephrine. VT was mapped to the free wall of right ventricular outflow tract. Case 2: A 74 year-old man developed ventricular fibrillation after successful coronary artery bypass graft surgery. His preoperative ECG showed small J waves in the inferior and lateral leads. During the stay in ICU, J waves were dramatically augmented and led to VF. After the restoration of sinus rhythm by a DC shock, they decreased. The dynamicity and relation of the influence to J wave on the ventricular arrhythmias may be different.