High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing.     

Utility of implantable cardioverter defibrillator electrograms to estimate repolarization alternans preceding a tachyarrhythmic event

Electrical alternans is a pattern of variation in the shape of the ECG waveform that appears on an every-other-beat basis. In humans, alternation in ventricular repolarization, namely, repolarization alternans, has been associated with increased vulnerability to ventricular tachycardia/ventricular fibrillation and sudden cardiac death. This study investigates the utility of implantable cardioverter defibrillator electrograms to estimate repolarization alternans preceding a tachyarrhythmic event. It is demonstrated that microvolt-level repolarization alternans is present prior to an arrhythmic event, and one can record low-amplitude-noise signals that can be used to obtain reliable estimates of repolarization alternans. This study eventually may lead to new methods that would prevent the onset of malignant tachyarrhythmias.     

参仙升脉口服液辅助治疗缓慢性心律失常疗效观察

摘 要 目的: 观察参仙升脉口服液辅助治疗缓慢性心律失常的疗效和安全性。方法：缓慢性心律失常患者80例按就诊顺序分为两组。对照组患者采用常规治疗,观察组患者在对照组基础上加用参仙升脉口服液20 ml,po bid。两组均治疗4周。比较两组治疗前后24 h动态心电图变化、临床疗效及药品不良反应。结果：观察组临床总有效率为92.5%,明显高于对照组的70.0%（P＜0.05）。观察组患者治疗后24 h动态心电图检查结果明显优于对照组（P＜0.05）。治疗中两组患者均未出现明显不良反应。结论：常规治疗基础上加服参仙升脉口服液可有效提高缓慢性心律失常的临床疗效,安全性好,具有推广应用价值。     

Lead I R‐wave amplitude to distinguish ventricular arrhythmias with lead V3 transition originating from the left versus right ventricular outflow tract

BackgroundThe electrophysiology algorithm for localizing left or right origins of outflow tract ventricular arrhythmias (OT‐VAs) with lead V₃ transition still needs further investigation in clinical practice.HypothesisLead I R‐wave amplitude is effective in distinguishing the left or right origin of OT‐VAs with lead V₃ transition.MethodsWe measured lead I R‐wave amplitude in 82 OT‐VA patients with lead V₃ transition and a positive complex in lead I who underwent successful catheter ablation from the right ventricular outflow tract (RVOT) and left ventricular outflow tract (LVOT). The optimal R‐wave threshold was identified, compared with the V₂S/V₃R index, transitional zone (TZ) index, and V₂ transition ratio, and validated in a prospective cohort study.ResultsLead I R‐wave amplitude for LVOT origins was significantly higher than that for RVOT origins (0.55 ± 0.13 vs. 0.32 ± 0.15 mV; p < .001). The area under the curve (AUC) for lead I R‐wave amplitude as assessed by receiver operating characteristic (ROC) analysis was 0.926, with a cutoff value of ≥0.45 predicting LVOT origin with 92.9% sensitivity and 88.2% specificity, superior to the V₂S/V₃R index, TZ index, and V₂ transition ratio. VAs in the LVOT group mainly originated from the right coronary cusp (RCC) and left and right coronary cusp junction (L‐RCC). In the prospective study, lead I R‐wave amplitude identified the LVOT origin with 92.3% accuracy.ConclusionLead I R‐wave amplitude provides a useful and simple criterion to identify RCC or L‐RCC origin in OT‐VAs with lead V₃ transition.     

Cardiac injury with damped sine and trapezoidal defibrillator waveforms

To assess defibrillator-induced cardiac damage, 49 anaesthetized greyhounds received either no shocks (control group) or five shocks from a defibrillator delivering one of five waveforms (Lown, Edmark, Belfast damped sine waveforms: 5 and 20 ms trapezoidal waveforms). At 3 days the hearts of the 36 surviving dogs were examined for macroscopic damage. The Belfast and Edmark waveforms caused significantly more damage (mean 21.1 +/- SEM 2.9 g and 16.0 +/- 3.7 g) respectively than the Lown waveform (3.5 +/- 1.3 g) P less than 0.01. The 20 ms trapezoid caused significantly more damage (8.1 +/- 3.1 g) than the 5 ms pulse (0.7 +/- 1.3 g) P less than 0.05). The ventricular ectopic counts per minute were not significantly different in the three sine wave and 20 ms trapezoidal groups at 24 and 48 h (P greater than 0.05), but at 2 and 72 h were significantly greater in the Belfast and Edmark groups than in the Lown group (2 h, Belfast P less than 0.01, Edmark P less than 0.05: 72 h P less than 0.05). At 15 min there was more right chest ST-segment elevation in the Belfast than in the Lown, Edmark and 20 ms trapezoid groups (P less than 0.01), while left chest ST elevation was greater in the Belfast and Edmark than in the Lown (P less than 0.05) and 20 ms trapezoid groups (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Is extensive atrial fibrosis in the setting of heart failure associated with a reduced atrial fibrillation burden?

Atrial fibrillation (AF) affects 10–50% of patients with chronic heart failure (HF) and is associated with poor long‐term prognosis. AF is commonly associated with atrial structural remodeling (ASR), principally characterized by atrial dilatation and fibrosis. However, the occurrence of AF in the full spectrum of ASR encountered in patients with HF is poorly defined. Experimental studies have presented evidence that extensive ASR can be accompanied with a reduced burden of AF, secondary to a prominent depression of atrial excitability. This reduction in AF burden is associated with severe atrial fibrosis rather than with dilatation. Clinical studies of patients with HF point to the possibility that advanced ASR is associated with a less frequent AF occurrence than moderate ASR. Our goal in this review is to introduce the hypothesis that AF is less likely to occur in severe versus moderate atrial ASR in the setting of HF and that it is severe atrial fibrosis‐associated depression of atrial excitability that reduces AF burden.