Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome.

BACKGROUND: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene. METHODS AND RESULTS: We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband. CONCLUSIONS: The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.

Intravenous three-dimensional coronary angiography using contrast enhanced electron beam computed tomography.

Coronary angiography remains the diagnostic standard for establishing the presence, site, and severity of coronary artery disease (CAD). Electron beam computed tomography (EBCT), with its 3-dimensional capabilities, is an emerging technology with the potential for obtaining essentially noninvasive coronary arteriograms. The purpose of this study was to (1) test the accuracy of intravenous coronary arteriography using the EBCT to conventional coronary arteriographic images; (2) establish the inter-reader variability of this procedure; (3) determine the limitations due to location within the coronary tree; and (4) identify factors that contributed to improved image quality of the 3-dimensional EBCT angiograms. Fifty-two patients underwent both EBCT angiography and coronary angiography within 2 weeks. The coronary angiogram and the EBCT 3-dimensional images were analyzed by 2 observers blinded to the results of the other techniques. EBCT correctly identified 43 of 55 significantly stenosed arteries (sensitivity 78%), and correctly identified 118 of 130 of the nonobstructed arteries, yielding a specificity of 91% (p <0.001, chi-square analysis). The overall accuracy for EBCT angiography was 87%. Significantly more left main and anterior descending coronary arteries were adequately visualized than the circumflex and right coronary vessels (p = 0.003). Overall, 23 of 208 (11%) major epicardial vessels were noninterpretable by the blinded EBCT readers, primarily due to motion artifacts caused by cardiac and respiratory motion and poor electrocardiographic gating. The inter-reader variability was similar to that of angiography, and its high accuracy makes this a clinically useful test. This study demonstrates, by using intravenous contrast enhancement, that EBCT can clearly depict the coronary artery anatomy and can permit identification of coronary artery stenosis.