Inappropriate Sinus Tachycardia (IST), a syndrome characterized by abnormally fast sinus rates and multisystem symptoms, is still poorly understood. Because of the relevance of HCN4 channels to pacemaker activity, we used a candidate-gene approach and screened IST patients for the presence of disease-causing HCN4 mutations. Methods and results Forty-eight IST patients, four of whom of known familial history, were enrolled in the study. We initially identified in one of the patients with familial history the R524Q mutation in HCN4. Investigation extended to the family members showed that the mutation co-segregated with IST-related symptoms. The R524Q mutation is located in the C-linker, a region known to couple cAMP binding to channel activation. The functional relevance of the mutation was investigated in heterologous expression systems by patch-clamp experiments. We found that mutant HCN4 channels were more sensitive to cAMP than wild-type channels, in agreement with increased sensitivity to basal and stimulated adrenergic input and with a faster than normal pacemaker rate. The properties of variant channels indicate therefore that R524Q is a gain-of-function mutation. Increased channel contribution to activity was confirmed by evidence that when spontaneously beating rat newborn myocytes were transfected with R524Q mutant HCN4 channels, they exhibited a faster rate than when transfected with wild-type HCN4 channels. Conclusion This is the first report of a gain-of-function HCN4 mutation associated with IST through increased sensitivity to cAMPdependent activation.

Background-QRS-ST changes in the inferior and lateral ECG leads are frequently observed in athletes. Recent studies have suggested a potential arrhythmogenic significance of these findings in the general population. The aim of our study was to investigate whether QRS-ST changes are markers of cardiac arrest (CA) of unexplained cause or sudden death in athletes. Methods and Results-In 21 athletes (mean age, 27 years; 5 women) with cardiac arrest or sudden death, the ECG recorded before or immediately after the clinical event was compared with the ECG of 365 healthy athletes eligible for competitive sport activity. We measured the height of the J wave and ST elevation and searched for the presence of QRS slurring in the terminal portion of QRS. QRS slurring in any lead was present in 28.6% of cases and in 7.6% of control athletes (Pϭ0.006). A J wave and/or QRS slurring without ST elevation in the inferior (II, III, and aVF) and lateral leads (V 4 to V 6 ) were more frequently recorded in cases than in control athletes (28.6% versus 7.9%, Pϭ0.007). Among those with cardiac arrest, arrhythmia recurrences did not differ between the subgroups with and without J wave or QRS slurring during a median 36-month follow-up of sport discontinuation. Conclusions-J wave and/or QRS slurring was found more frequently among athletes with cardiac arrest/sudden death than in control athletes. Nevertheless, the presence of this ECG pattern appears not to confer a higher risk for recurrent malignant ventricular arrhythmias. (Circ Arrhythm Electrophysiol. 2010;3:305-311.)

Endothelial dysfunction and underperfusion of exercising muscle contribute to exercise intolerance, hyperventilation, and breathlessness in atrial fibrillation (AF). Cardioversion (CV) improves endothelial function and exercise performance. We examined whether CV is equally beneficial in diabetes and hypertension, diseases that cause endothelial dysfunction and are often associated with AF. Cardiopulmonary exercise and pulmonary and endothelial (brachial artery flow-mediated dilation) function were tested before and after CV in patients with AF alone (n ϭ 18, group 1) or AF with hypertension (n ϭ 19, group 2) or diabetes (n ϭ 19, group 3). Compared with group 1, peak exercise workload, O2 consumption (V O2), O2 pulse, aerobic efficiency (⌬V O2/⌬WR), and ratio of brachial diameter changes to flow changes (⌬D/⌬F) were reduced in group 2 and, to a greater extent, in group 3; exercise ventilation efficiency (V E/V CO2 slope) and dead space-to-tidal volume ratio (VD/VT) were similar among groups. CV had less effect on peak workload (ϩ7% vs. ϩ18%), peak V O2 (ϩ12% vs. ϩ17%), O2 pulse (ϩ33% vs. ϩ50%), ⌬V O2/⌬WR (ϩ7% vs. ϩ12%), V E/V CO2 slope (Ϫ6% vs. Ϫ12%), ⌬D/⌬F (ϩ7% vs. ϩ10%), and breathlessness (Borg scale) in group 2 than in group 1 and was ineffective in group 3. The antioxidant vitamin C, tested in eight additional patients in each cohort, improved flow-mediated dilation in groups 1 and 2 before, but not after, CV and was ineffective in group 3, suggesting that the oxidative injury is least in lone AF, greater in hypertension with AF, and greater still in diabetes with AF. Comorbidities that impair endothelial activity worsen endothelial dysfunction and exercise intolerance in AF. The advantages of CV appear to be inversely related to the extent of the underlying oxidative injury.arrhythmias; endothelium; exercise ATRIAL FIBRILLATION (AF) impairs endothelial function and downregulates nitric oxide (NO) production (3, 10, 27). Exercise correlates of these dysfunctions are underperfusion of working muscle, hyperventilation, and breathlessness (10). These findings are consistent with the concept that, during exercise, an endothelium-mediated vasodilation modulates neurogenic vasoconstriction, increases arterial conductance, and upregulates muscle perfusion (6,12,16). Conversion to sinus rhythm [i.e., cardioversion (CV)] is beneficial in this respect (10). Irregular pulsatile blood flow in AF may impair the endothelial responsiveness to vascular shear stress, and loss of the cyclic stretch of atrial endocardial cells may decrease expression of NO synthase (3). Restoration of a regular flow regimen and atrial contactile activity with CV normalizes the endothelial physiology.Hypertension and diabetes cause endothelial dysfunction (13,20,23,26). Because AF is not uncommonly associated with high blood pressure and diabetes, we considered the pathophysiological and clinical significance of this association to investigate whether the improvement of endothelial function with CV, its exercise pathophysiological correlates, ...

In this cohort, ivabradine significantly improved symptoms associated with inappropriate sinus tachycardia and completely eliminated them in approximately half of the patients. These findings suggest that ivabradine may be an important agent for improving symptoms in patients with inappropriate sinus tachycardia.

High-energy radiation can cause different malfunctions on CIED, particularly ICD, even without direct exposure to ionizing radiation due to scattered radiation of neutrons produced by the linear accelerator.