Although fast sodium current (INa) plays a major role in the generation and conduction of the cardiac impulse, the electrophysiological characteristics of INa in isolated human ventricular myocytes have not yet been fully described. We characterized the human ventricular INa of enzymatically isolated myocytes using whole cell voltage-clamp techniques. Sixty myocytes were isolated from ventricular specimens obtained from 22 patients undergoing open-heart surgery. A low temperature (17 degrees C) and Na+ concentration in the external solution (5 or 10 mM) allowed good voltage control and facilitated the measurement of INa. Cs+ was substituted for K+ in both internal and external solutions to block K+ currents, and F- was added to the internal solution to block Ca2+ current. INa was activated at a voltage threshold of approximately -70 mV, and maximal inward current was obtained at approximately -30 mV (holding potential = -140 mV). The voltage dependence of steady-state INa availability (h infinity) was sigmoidal with half inactivation occurring at -97.3 +/- 1.1 mV and a slope factor of 5.77 +/- 0.10 mV (n = 60). We did not detect any significant differences in these parameters in cells from patients with a variety of disease states, with or without congestive heart failure. The overlap in voltage dependence of h infinity and Na+ conductance suggested the presence of a Na+ "window" current. An inactivation time course was voltage dependent and was fitted best by the sum of two exponentials. The rate of recovery from inactivation also was voltage dependent and fitted by the sum of two exponentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Patch-clamp recording techniques have permitted measurement of the fast Na+ current (INa) [Na+]., and the current was completely blocked by 100 ,uM tetrodotoxin, findings typical of the fast cardiac Na+ current. The tetrodotoxin dose-response curve was best fitted by an equation describing binding to high-and low-affinity sites. INa was activated at a voltage threshold of -70 to -60 mV, and peak inward current was obtained at =-30 mV (holding potential, -140 mV). The inactivation time course was voltage dependent and was fitted best by the sum of two exponentials. The relation between voltage and steady-state availability (h.,) was sigmoidal with the half-inactivation at -95.8±0.9 mV and a slope factor of 5.3+0.1 mV (n=46), and we did not observe a significant difference with disease and age.

BackgroundThe usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known.Methods and ResultsWe measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed.ConclusionsIn patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification.Clinical Trial Registration URL: http://www.umin.ac.jp. Unique identifier: UMIN000012950.

Interactions of G-protein ␣ (G␣) and ␤␥ subunits (G␤␥) with N-(␣ 1B ) and P/Q-type (␣ 1A ) Ca 2؉ channels were investigated using the Xenopus oocyte expression system. G i3 ␣ was found to inhibit both N-and P/Q-type channels by receptor agonists, whereas G␤ 1 ␥ 2 was responsible for prepulse facilitation of N-type channels. L-type channels (␣ 1C ) were not regulated by G␣ or G␤␥. For N-type, prepulse facilitation mediated via G␤␥ was impaired when the cytoplasmic I-II loop (loop 1) was deleted or replaced with the ␣ 1C loop 1. G␣-mediated inhibitions were also impaired by substitution of the ␣ 1C loop 1, but only when the C terminus was deleted. For P/Q-type, by contrast, deletion of the C terminus alone diminished G␣-mediated inhibition. Moreover, a chimera of L-type with the ␣ 1B loop 1 gained G␤␥-dependent facilitation, whereas an L-type chimera with the Nor P/Q-type C terminus gained G␣-mediated inhibition. These findings provide evidence that loop 1 of N-type channels is a regulatory site for G␤␥ and the C termini of P/Q-and N-types for G␣.

When the analysis was limited to cases with clear sFMD recordings, the reliability of the sFMD assessment (scan and its analysis) conducted in individual institutions appeared to be acceptable. Reference sFMD values (lower cuff occlusion) for the Japanese population are proposed based on reliable data derived from multiple institutions, and the reference values may identify patients without advanced vascular damage.