Citations

Background— Hundreds of nonsynonymous single nucleotide variants (nsSNVs) have been identified in the 2 most common long-QT syndrome-susceptibility genes ( KCNQ1 and KCNH2 ). Unfortunately, an ≈3% background rate of rare KCNQ1 and KCNH2 nsSNVs amongst healthy individuals complicates the ability to distinguish rare pathogenic mutations from similarly rare yet presumably innocuous variants. Methods and Results— In this study, 4 tools [(1) conservation across species, (2) Grantham values, (3) sorting intolerant from tolerant, and (4) polymorphism phenotyping] were used to predict pathogenic or benign status for nsSNVs identified across 388 clinically definite long-QT syndrome cases and 1344 ostensibly healthy controls. From these data, estimated predictive values were determined for each tool independently, in concert with previously published protein topology–derived estimated predictive values, and synergistically when ≥3 tools were in agreement. Overall, all 4 tools displayed a statistically significant ability to distinguish between case-derived and control-derived nsSNVs in KCNQ1 , whereas each tool, except Grantham values, displayed a similar ability to differentiate KCNH2 nsSNVs. Collectively, when at least 3 of the 4 tools agreed on the pathogenic status of C-terminal nsSNVs located outside the KCNH2/Kv11.1 cyclic nucleotide−binding domain, the topology-specific estimated predictive value improved from 56% to 91%. Conclusions— Although in silico prediction tools should not be used to predict independently the pathogenicity of a novel, rare nSNV, our results support the potential clinical use of the synergistic utility of these tools to enhance the classification of nsSNVs, particularly for Kv11.1’s difficult to interpret C-terminal region.

Background— Coronary stents, drug-eluting stents in particular, have been linked to coronary epicardial endothelial dysfunction after implantation. However, less is known about their impact on coronary microvascular function and their long-term effects on the vasculature. Methods and Results— We evaluated 71 patients (mean age, 53.0±10.1 years) with chest pain and angiographically nonsignificant coronary artery disease 17.1±17.1 months after left anterior descending coronary artery stenting. Seventy-one age- and sex-matched patients (mean age, 53.0±10.3 years) with chest pain but no prior coronary intervention served as controls. Coronary blood flow in response to the endothelium-dependent vasodilator acetylcholine as well as the microvascular (endothelium-independent) coronary flow reserve in response to intracoronary adenosine were evaluated. Quantitative coronary angiography was used to study epicardial diameter changes to acetylcholine. Microcirculatory function was not significantly different between the stenting and control groups (median [interquartile range] coronary flow reserve, 2.9 [2.5–3.4] versus 3.0 [2.4–3.4] mL/min, P =0.24; change of coronary blood flow, 34.9% [−34.4% to 90.0%] versus 54.7% [−5.6% to 104.6%], P =0.18). Both groups exhibited epicardial endothelial dysfunction (−23.0% [−47.4% to −7.6%] versus −20.0% [−40.0% to 0.0%], P =0.4). Results did not differ between patients with drug-eluting stents (n=46) and patients with bare-metal stents (n=24). Conclusions— This study demonstrates that in patients with coronary arteries in which a stent has been placed, coronary microcirculatory and epicardial vascular function are not significantly different from that of an age- and sex-matched population with similar symptoms but nonsignificant coronary artery disease.

Background— Treatment options for patients with recurrent ventricular arrhythmias refractory to pharmacotherapy and ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long-QT syndrome, its role in non–long-QT syndrome arrhythmogenic channelopathies and cardiomyopathies is less clear. Here, we report our single-center experience in performing LCSD in this setting. Methods and Results— In this institutional review board–approved study, we retrospectively reviewed the electronic medical records of all patients (N=91) who had videoscopic LCSD at our institution from 2005 to 2011. Data were analyzed for the subset (n=27) who were denervated for an underlying diagnosis other than autosomal dominant or sporadic long-QT syndrome. The spectrum of arrhythmogenic disease included catecholaminergic polymorphic ventricular tachycardia (n=13), Jervell and Lange-Nielsen syndrome (n=5), idiopathic ventricular fibrillation (n=4), left ventricular noncompaction (n=2), hypertrophic cardiomyopathy (n=1), ischemic cardiomyopathy (n=1), and arrhythmogenic right ventricular cardiomyopathy (n=1). Five patients had LCSD because of high-risk assessment and β-blocker intolerance, none of whom had a sentinel breakthrough cardiac event at early follow-up. Among the remaining 22 previously symptomatic patients who had LCSD as secondary prevention, all had an attenuation in cardiac events, with 18 having no breakthrough cardiac events so far and 4 having experienced ≥1 post-LCSD breakthrough cardiac event. Conclusions— LCSD may represent a substrate-independent antifibrillatory treatment option for patients with life-threatening ventricular arrhythmia syndromes other than long-QT syndrome. The early follow-up seems promising, with a marked reduction in the frequency of cardiac events postdenervation.