Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart

AIM: Hypokalaemia is associated with a lethal form of ventricular tachycardia (VT), torsade de pointes, through pathophysiological mechanisms requiring clarification. METHODS: Left ventricular endocardial and epicardial monophasic action potentials were compared in isolated mouse hearts paced from the right ventricular epicardium perfused with hypokalaemic (3 and 4 mm [K(+)](o)) solutions. Corresponding K(+) currents were compared in whole-cell patch-clamped epicardial and endocardial myocytes. RESULTS: Hypokalaemia prolonged epicardial action potential durations (APD) from mean APD(90)s of 37.2 ± 1.7 ms (n = 7) to 58.4 ± 4.1 ms (n =7) and 66.7 ± 2.1 ms (n = 11) at 5.2, 4 and 3 mm [K(+)](o) respectively. Endocardial APD(90)s correspondingly increased from 51.6 ± 1.9 ms (n = 7) to 62.8 ± 2.8 ms (n = 7) and 62.9 ± 5.9 ms (n = 11) giving reductions in endocardial–epicardial differences, ΔAPD(90), from 14.4 ± 2.6 to 4.4 ± 5.0 and −3.4 ± 6.0 ms respectively. Early afterdepolarizations (EADs) occurred in epicardia in three of seven spontaneously beating hearts at 4 mm [K(+)](o) with triggered beats followed by episodes of non-sustained VT in nine of 11 preparations at 3 mm. Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K(+)](o) respectively. Early outward K(+) current correspondingly fell from 73.46 ± 8.45 to 61.16±6.14 pA/pF in isolated epicardial but not endocardial myocytes (n = 9) (3 mm [K(+)](o)). CONCLUSIONS: Hypokalaemic mouse hearts recapitulate the clinical arrhythmogenic phenotype, demonstrating EADs and triggered beats that might initiate VT on the one hand and reduced transmural dispersion of repolarization reflected in ΔAPD(90) suggesting arrhythmogenic substrate on the other

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)