Hydroxychloroquine reduces interleukin-6 levels after myocardial infarction: The randomized, double-blind, placebo-controlled OXI pilot trial.

OBJECTIVES: To determine the anti-inflammatory effect and safety of hydroxychloroquine after acute myocardial infarction. METHOD: In this multicenter, double-blind, placebo-controlled OXI trial, 125 myocardial infarction patients were randomized at a median of 43 h after hospitalization to receive hydroxychloroquine 300 mg (n = 64) or placebo (n = 61) once daily for 6 months and, followed for an average of 32 months. Laboratory values were measured at baseline, 1, 6, and 12 months. RESULTS: The levels of interleukin-6 (IL-6) were comparable at baseline between study groups (p = 0.18). At six months, the IL-6 levels were lower in the hydroxychloroquine group (p = 0.042, between groups), and in the on-treatment analysis, the difference at this time point was even more pronounced (p = 0.019, respectively). The high-sensitivity C-reactive protein levels did not differ significantly between study groups at any time points. Eleven patients in the hydroxychloroquine group and four in the placebo group had adverse events leading to interruption or withdrawal of study medication, none of which was serious (p = 0.10, between groups). CONCLUSIONS: In patients with myocardial infarction, hydroxychloroquine reduced IL-6 levels significantly more than did placebo without causing any clinically significant adverse events. A larger randomized clinical trial is warranted to prove the potential ability of hydroxychloroquine to reduce cardiovascular endpoints after myocardial infarction.

Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. CASE PRESENTATION: We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands' siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies. CONCLUSIONS: The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.

Prevalence and prognostic significance of T-wave inversions in right precordial leads of a 12-lead electrocardiogram in the middle-aged subjects.

BACKGROUND: T-wave inversion in right precordial leads V(1) to V(3) is a relatively common finding in a 12-lead ECG of children and adolescents and is infrequently found also in healthy adults. However, this ECG pattern can also be the first presentation of arrhythmogenic right ventricular cardiomyopathy. The prevalence and prognostic significance of T-wave inversions in the middle-aged general population are not well known. METHODS AND RESULTS: We evaluated 12-lead ECGs of 10 899 Finnish middle-aged subjects (52% men, mean age 44 ± 8.5 years) recorded between 1966 and 1972 for the presence of inverted T waves and followed the subjects for 30 ± 11 years. Primary end points were all-cause mortality, cardiac mortality, and arrhythmic death. T-wave inversions in right precordial leads V(1) to V(3) were present in 54 (0.5%) of the subjects. In addition, 76 (0.7%) of the subjects had inverted T waves present only in leads other than V(1) to V(3). Right precordial T-wave inversions did not predict increased mortality (not significant for all end points). However, inverted T waves in leads other than V(1) to V(3) were associated with an increased risk of cardiac and arrhythmic death (P<0.001 for both). CONCLUSIONS: T-wave inversions in right precordial leads are relatively rare in the general population, and are not associated with adverse outcome. Increased mortality risk associated with inverted T waves in other leads may reflect the presence of an underlying structural heart disease.

QRS-T angle as a predictor of sudden cardiac death in a middle-aged general population.

AIMS: Spatial QRS-T angle measured from a 12-lead electrocardiogram (ECG) has been shown to predict cardiac mortality. However, there is a paucity of studies on the prognostic significance of frontal QRS-T angle, which is more readily available from the standard 12-lead ECG. The purpose of the present study was to investigate the importance of wide frontal QRS-T angle, QRS-axis, and T-wave axis as cardiac risk predictors in general population. METHODS AND RESULTS: We evaluated the 12-lead ECGs of 10 957 Finnish middle-aged subjects from the general population recorded between 1966 and 1972, and followed them for 30 ± 11 years. QRS-T angle 0 to 90°, QRS-axis -30 to 90°, and T-wave axis 0 to 90° were considered normal. The primary endpoint was death from arrhythmia, and the secondary endpoints were all-cause mortality and non-arrhythmic cardiac mortality. QRS-T angle ≥ 100° was present in 2.0% of the subjects, and it was associated with an increased risk of sudden arrhythmic death [relative risk (RR) 2.26; 95% confidence interval (CI) 1.59-3.21; P< 0.001) and all-cause mortality (RR 1.57; CI 1.34-1.84; P< 0.001), but not with non-arrhythmic cardiac mortality (RR 1.34; CI 0.93-1.92; P= 0.13). The prognostic significance of wide QRS-T angle was mainly due to abnormal T-wave axis, which predicted death from arrhythmia (RR 2.13; CI 1.63-2.79; P< 0.001), all-cause mortality (RR 1.39; 1.24-1.55; P< 0.001), and non-arrhythmic cardiac death (RR 1.87; CI 1.50-2.34; P< 0.001). CONCLUSION: Frontal QRS-T angle ≥ 100° increases the risk of arrhythmic death, this being mainly the result of an altered T-wave axis.

Long-term follow-up of patients with short QT syndrome.

OBJECTIVES: The aim of this study was to investigate the clinical characteristics and the long-term course of a large cohort of patients with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy characterized by an increased risk of sudden death. Data on the long-term outcome of SQTS patients are not available. METHODS: Fifty-three patients from the European Short QT Registry (75% males; median age: 26 years) were followed up for 64 ± 27 months. RESULTS: A familial or personal history of cardiac arrest was present in 89%. Sudden death was the clinical presentation in 32%. The average QTc was 314 ± 23 ms. A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1). Twenty-four patients received an implantable cardioverter defibrillator, and 12 patients received long-term prophylaxis with hydroquinidine (HQ), which was effective in preventing the induction of ventricular arrhythmias. Patients with a HERG mutation had shorter QTc at baseline and a greater QTc prolongation after treatment with HQ. During follow-up, 2 already symptomatic patients received appropriate implantable cardioverter defibrillator shocks and 1 had syncope. Nonsustained polymorphic ventricular tachycardia was recorded in 3 patients. The event rate was 4.9% per year in the patients without antiarrhythmic therapy. No arrhythmic events occurred in patients receiving HQ. CONCLUSIONS: SQTS carries a high risk of sudden death in all age groups. Symptomatic patients have a high risk of recurrent arrhythmic events. HQ is effective in preventing ventricular tachyarrhythmia induction and arrhythmic events during long-term follow-up.

Ventricular tachyarrhythmia as a primary presentation of sarcoidosis.

AIMS: Sarcoidosis is a multisystem, granulomatous disease with occasional cardiac manifestations. The clinical course of patients with ventricular tachyarrhythmias as a primary presentation of sarcoidosis is mostly unknown. METHODS AND RESULTS: We describe nine patients (four males and five females) in whom sarcoidosis manifested as ventricular tachycardia (VT). The age of the patients was 53 +/- 10 years (range 33-68). The disease was diagnosed by endomyocardial biopsy in eight patients and by lymph node biopsy in one patient. The presenting arrhythmia varied from non-sustained VT to incessant VT and ventricular fibrillation. All patients received implantable cardioverter defibrillator (ICD) and anti-arrhythmic medication. High-dose steroid treatment was used in eight cases. During the follow-up (50 +/- 34 months), five patients underwent appropriate ICD therapies and non-sustained VT episodes were detected in four patients. Two patients developed incessant VT, which was treated by catheter ablation. One patient was referred for heart transplantation. CONCLUSION: Our data indicate that sarcoidosis can manifest as VT without any detectable systemic findings. This makes sarcoidosis an important diagnostic consideration in patients with VT of unknown origin. Arrhythmia control in cardiac sarcoidosis is difficult, and all modern treatments including high-dose steroids, anti-arrhythmic drugs, ICD, and catheter ablation are needed to suppress the arrhythmias.

Short QT syndrome: clinical findings and diagnostic-therapeutic implications.

AIMS: Clinical presentation, occurrence of sudden infant death, and results of the available therapies in the largest group of patients with short QT syndrome (SQTS), studied so far, are reported. METHODS AND RESULTS: Clinical history, physical examination, electrocardiogram (ECG), exercise stress testing, electrophysiological study, morphological evaluation, genetic analysis and therapy results in 29 patients with SQTS and personal and/or familial history of cardiac arrest are reported. The median age at diagnosis was 30 years (range 4-80). In all subjects, structural heart disease was excluded. Eighteen patients were symptomatic (62%): 10 had cardiac arrest (34%) and in 8 (28%) this was the first clinical presentation. Cardiac arrest had occurred in the first months of life in two patients. Seven patients had syncope (24%); 9 (31%) had palpitations with atrial fibrillation documented even in young subjects. At ECG, patients exhibited a QT interval < or = 320 ms and QTc < or = 340 ms. Fourteen patients received an implantable cardioverter-defibrillator (ICD) and 10 hydroquinidine prophylaxis. At a median follow-up of 23 months (range 9-49), one patient received an appropriate shock from the ICD; no patient on hydroquinidine had sudden death or syncope. CONCLUSION: SQTS carries a high risk of sudden death and may be a cause of death in early infancy. ICD is the first choice therapy; hydroquinidine may be proposed in children and in the patients who refuse the implant.