Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans.

BACKGROUND: Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress. METHODS AND RESULTS: Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia ( approximately 25 micromol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477+/-82%; placebo, 673+/-110%; P=0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3+/-2.7%) compared with placebo (8. 2+/-1.6%, P=0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (P=0.03). CONCLUSIONS: Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

Continuously updated 12-lead ST-segment recovery analysis for myocardial infarct artery patency assessment and its correlation with multiple simultaneous early angiographic observations.

Early angiography may not adequately subgroup patients with myocardial infarction if cyclic changes in coronary flow occur frequently. From a pilot experience using a new 12-lead ST-segment monitor, a continuously updated, self-referenced ST-recovery analysis method was developed to quantify both instantaneous recovery, as a noninvasive marker of patency, and cumulative ST recovery over time, as a marker of the speed, stability and duration of reperfusion. In 22 patients with acute infarction in whom 44 observations of unique angiographic patency were noted within 6 hours of presentation, serial patency assessments simultaneous with all angiographic observations predicted coronary occlusion with 90% sensitivity and 92% specificity. Of the 22 patients, 11 (50%) had multiple ST trend transitions suggesting cyclic changes in coronary flow before catheterization. Speed, stability and duration of ST-segment recovery were defined by the time to first 50% ST recovery, total number of ST-trend transitions and patent physiology index (percentage of monitoring period showing ST recovery), respectively. Subgrouped angiographically, the median (interquartile range) for cumulative ST parameters with patent (n = 8) versus occluded (n = 14) arteries were, respectively--time to 50% recovery, 1.57 (1.16, 1.70) versus 0.17 (-0.47, 0.32) hours; number of reelevation/recovery events, 1.5 (1, 3) versus 3 (1, 3); and patent physiology index, 52 (47, 59) versus 50 (5, 73). Thus, continuous ST-segment recovery analysis appears to predict simultaneous angiographic patency over serial assessments, whereas cumulative parameters appear to contain independent information, probably because of patency changes before or after angiography.

The impact of autoperfusion on quantitative electrocardiographic parameters of ischemia severity, extent, and "burden" during salvage of elective coronary angioplasty.

Long angioplasty inflations have been reported using an autoperfusion system that delivers oxygenated blood distal to the balloon segment. The safety and efficacy of this system has been demonstrated in anatomically selected patients. The clinical use, however, is frequently to stabilize intimal dissection in unselected patients. We reviewed 12-lead continuous electrocardiographic (ECG) recordings in 40 patients in whom prolonged salvage with autoperfusion was attempted. Sub-optimal results were stabilized in 36 of 40, while 4 patients had urgent bypass. The presence of ischemia, as > or = 100 uV ST elevation over the 12 lead ECG, and the total ST deviation over all leads over the entire inflation period (total ischemic "burden") were compared within each patient between the longest standard balloon and autoperfusion inflations. Median duration of inflation was 3.03 min. with balloon vs. 15.6 min. with autoperfusion (p < 0.00002). Of the 40 patients, 35 (87%) had ECG ischemia with balloon vs. 18 (45%) with autoperfusion (p < .00002). Median severity of peak ST deviation was 321 uV with balloon vs. 132 uV with autoperfusion (p = 0.0001). Median extent of ST elevation was 3 leads with balloon vs. 0 leads with autoperfusion (p = 0.0001). Median total ischemic burden was similar with balloon (1173 uVmin) and autoperfusion (1083 uVmin, NS) despite the fivefold longer inflation duration with autoperfusion. Thus, in patients selected by clinical necessity rather than optimal anatomy, severity and extent of ST elevation were significantly reduced, although not entirely eliminated, by autoperfusion.

Acute deleterious effects of cocaine on cardiac conduction, hemodynamics, and ventricular fibrillation threshold: effects of interaction with a selective dopamine D1 antagonist SCH 39166.

Cocaine has demonstrated cardiotoxicity that has led to sudden death by unknown mechanisms. SCH 39166, a selective dopaminergic D1-receptor antagonist, suppresses the compulsive drug-intake actions of cocaine in primates. This study examined the cumulative toxic effects of cocaine after the long-term administration of SCH 39166. After pretreatment with oral placebo/SCH 39166 for 5 days, an i.v. infusion of 0.25 mg/kg/min of cocaine HCl was delivered to 14 anesthetized dogs, and cardiac conduction, arterial blood pressure, ventricular refractoriness, and arrhythmogenesis were examined. The cocaine infusion was stopped when QRS width increased by 20% from baseline (QRS20). In Coc + Placebo regimen, the QRS and His-Ventricular (HV) intervals showed a dose-dependent lengthening. Initially, the mean blood pressure (MBP) increased followed by a precipitate decrease at a mean dose of 2.03 +/- 0.5 mg/kg of cocaine. At QRS20, the ventricular effective refractory period (ERP) increased significantly, whereas the ventricular fibrillation threshold (VFT) showed a significant reduction from the baseline. In Coc + SCH, the QRS, HV intervals, and ERP increased similarly, but the decrease in MBP was attenuated, and the VFT was increased. A relatively small infusion of cocaine causes a hemodynamic compromise. The His-ventricular conduction delay and lengthened ERP suggest a predominant direct local anesthetic effect. Cocaine additionally decreased the VFT, suggesting an increased susceptibility to VF. SCH 39166 did not potentiate the cardiotoxic effects of cocaine. It displayed a protective trend by suppressing the arrhythmogenic effects and the hemodynamic compromise caused by cocaine.

Growth of the aorta in children with Williams syndrome: does surgery make a difference?

Supravalve aortic stenosis (SAS) and arch hypoplasia are features of Williams syndrome. The effect of aortoplasty on growth of the aorta is not established. We hypothesize that growth of the aorta remains deficient whether or not aortoplasty has been performed. Review of the Children's Hospital of Pittsburgh database revealed 18 patients with Williams syndrome and SAS. Fourteen had sufficient data for inclusion. Patients were divided into two groups based on whether or not they had undergone aortoplasty (groups 1 and 2, respectively). Echocardiographic velocity estimates of the aorta were made at two time points in all patients and one additional time point postoperatively for group 1. Measurements were converted to zeta scores and compared. Peak pulsed echo Doppler velocity (m/sec) in the ascending aorta was higher in patients who underwent aortoplasty. This decreased significantly after surgery. Preoperatively, there was no difference between the groups' annulus, ascending aorta, transverse aorta, and isthmus measurements. At a mean of 43 months postoperatively, there was no significant change in size of the ascending aorta, transverse aorta, and isthmus. Children with Williams syndrome have hypoplasia of the aortic arch that remains constant. Aortoplasty decreases the aortic gradient but has no effect on the size of the ascending aorta, transverse aorta, and aortic isthmus over the short-term.