Baseline characteristics of the AGNES case-control set.

<p>CK-MB, creatine kinase-MB; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery. *In case of missing values, the sample sizes of the total, case and control sets (total, case, control) for which information was available are given. ^† Normally distributed continuous variables are presented as mean ± SD or as Median [interquartile range] otherwise. Categorical variables data are presented as number (%). ‡ <i>P</i> value for comparison of cases and controls using independent t-test, Mann-Whitney test, or chi-square test where appropriate.</p

ECG characteristics of AGNES cases and controls according to the artery harbouring the stenotic lesion.

<p>LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery</p>*<p><i>P</i> value of comparison between cases and controls using a logistic regression model adjusted for age and sex. (All patients with AV block or PR≥200 ms or QRS≥120 ms & AF are excluded)</p

Association analysis of SNPs with ECG indices of conduction and repolarization during myocardial ischemia.

<p>SE, Standard Error * Direction of effect estimate per copy coded allele; Inc, Increasing effect; Dec, Decreasing effect; data from previous GWA studies † Effect estimate is given per copy of the coded allele adjusted for age, sex and culprit artery (all patients with AV block or PR ≥ 200 ms or QRS ≥ 120 ms are excluded).</p

Association analysis of SNPs with VF in AGNES cases versus AGNES controls.

*<p>effect estimate is given per copy of the coded allele adjusted for age, sex and culprit artery. † <i>P</i> values for interaction between SNPs and culprit artery on risk of VF</p

1493delK mutant and wild-type (WT) human cardiac sodium channel current expressed in HEK293 cells.

<p>(A) Whole-cell sodium current traces in response to increasing step depolarizations in WT (left) and 1493delK (right). (B) Voltage protocols for activation and steady-state inactivation. (C) Averaged sodium current– voltage relation for WT and 1493delK sodium channels. (D) Bar histogram showing averaged WT and 1493delK sodium peak currents at −20 mV. (E) Average voltage-dependence of activation and steady-state inactivation for wild-type (WT) and 1493delK sodium channels. For the activation curve, normalized peak conductance was plotted as a function of the membrane potential. For the inactivation curve, peak sodium currents were normalized to maximum values in each cell and plotted as a function of the voltage of the conditioning step.</p

Inactivation kinetics of 1493delK mutant and wild-type (WT) human cardiac sodium channels.

<p>(A) Time course of current decay. (A-i) Fast and slow time constants of current decay for WT and 1493delK sodium channels are plotted as a function of membrane potential. Asterisks indicate statistical significance (p<0.05). (A-ii) Ratio of the amplitudes of fast and slow inactivation time constants plotted as a function of voltage for WT and 1493delK sodium channels. (B) Time course of recovery from inactivation for WT and 1493delK sodium channels. Peak sodium currents elicited by P2 were normalized (P2/P1) and plotted as a function of the recovery interval. Inset: 2-pulse protocol. (C) Development of slow inactivation for WT and 1493delK sodium channels. Peak sodium currents elicited by P2 were normalized (P2/P1) and plotted as a function of the duration of the conditioning step (P1). Inset: 2-pulse protocol.</p

Clinical and Genetic Characteristics of <i>SCN5A</i> 1493delK Carriers.

<p>ECG, electrocardiogram; ICD, implantable cardioverter defibrillator; PM, Pacemaker; m, male; f, female; y, years; +, mutation carrier or ICD implanted; (+),obligate mutation carrier; SCD, sudden cardiac death; RV, right ventricle; CAD, coronary artery disease; #, by transthoracic echocardiographic; §, by magnetic resonance imaging; $, by ventriculography; n.p., not performed; n.a., not avalible; PWD, P-wave duration; AVB I°, atrioventricular block first-degree; CCD, cardiac conduction delay; RFB, right fascicular block; LAFB, left anterior fascicular block. Propositus (10021_149) printed in italics.</p

Topological model of the cardiac sodium channel (Na_V1.5).

<p>Location of the mutations in the linker region between domains DIII and DIV that is responsible for the inactivation of the channel.</p

Sodium channel membrane expression in wild-type and mutant 1493delK <i>SCN5A</i>-transfected HEK293 cells.

<p>Confocal immunofluorescence of the a-subunit of cardiac sodium channel (Na_V1.5) and the endoplasmic reticulum transmembrane protein calnexin in HEK293 expressing WT (left) and mutant 1493delK (right) sodium channels. Top and middle panels show staining with anti-Na_V1.5 (green) and anti-calnexin (red) respectively. Bottom panels show overlay of red and green channels of double staining with anti-Na_V1.5 (green) and anti-calnexin (red) antibodies. Membrane labeling for Na_V1.5 is observed as a clearly distinguishable green rim surrounding the intracellularly located calnexin (red) in WT <i>SCN5A</i> transfected HEK293 cells, whereas mutant 1493delK <i>SCN5A</i> transfected HEK293 cells do not show clear cell-surface labeling, but mostly cytoplasmic Na_V1.5 staining. Scale bars indicate 25 µm.</p

Electrophysiological characteristics of WT and 1493delK mutant sodium channels in HEK293 cells.

<p>V_1/2, voltage of half-maximal (in)activation; k, slope factor of voltage- dependence of (in)activation; A, fraction of channels that enter the slow inactivated state at t = 1 s; <i>τ</i>, time constant for development of slow inactivation; <i>τ</i>_f, fast time constant of recovery from inactivation; <i>τ</i>_s, slow time constant of recovery from inactivation.</p>*<p>p<0.05 vs WT (Student’s t-test).</p