Glycoprotein IIb/IIIa receptor blockade improves outcomes in diabetic patients presenting with unstable angina/non-ST-elevation myocardial infarction: results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study.

BACKGROUND: Diabetic patients who present with unstable angina or non-ST-elevation myocardial infarction suffer a substantially greater incidence of subsequent infarction or death compared with nondiabetic patients. The present study was undertaken to examine whether diabetic patients in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study appeared to benefit from platelet glycoprotein IIb/IIIa receptor-mediated inhibition of platelet aggregation by tirofiban. METHODS AND RESULTS: Of the 1570 PRISM-PLUS patients treated with either tirofiban plus heparin (n=773) or heparin alone (n=797), approximately 23% in each treatment group were diabetic. A comparison of treatment outcomes in the diabetic subgroup revealed that the combination therapy compared with heparin alone was associated with reductions in the incidence of the composite primary end point of death, myocardial infarction (MI), or refractory ischemia at 2, 7, 30, and 180 days (7.7% versus 8.3%, 14. 8% versus 21.8%, 20.1% versus 29.0%, and 32.0% versus 39.9%, respectively; P=NS) and in the incidence of MI or death (0.0% versus 3.1%, P:=0.03; 1.2% versus 9.3%, P:=0.005; 4.7% versus 15.5%, P:=0. 002; and 11.2% versus 19.2%, P:=0.03). Tests for quantitative interaction between tirofiban therapy and diabetic status were significant. CONCLUSIONS: The addition of tirofiban to heparin and aspirin appears effective in the prevention of major ischemic events, particularly MI or death, in diabetic patients presenting with unstable angina and non-ST-elevation MI.

Wavelet time entropy, T wave morphology and myocardial ischemia.

Using wavelets, we computed the entropy of the signal at various frequency levels (wavelet time entropy) and, thus, find an optimal measure to differentiate normal states from ischemic ones. This new indicator is independent from the ST segment and yet provide a conclusive detection of the ischemic states.

Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry.

OBJECTIVE: Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated the hypotheses that: (1) the activation patterns of the initial PVT beats would be consistent with an origin in the ventricular conduction system; and (2) the inhomogeneous prolongation of repolarisation intervals can provide refractory barriers for re-entrant activity. METHODS: Unipolar electrograms were recorded from 127 epicardial (EPI) sites with a sock electrode array as well as from intramural and endocardial sites during PVTs. Electrograms were analysed to generate isochronal maps and measure the spatial distribution of activation-recovery intervals (ARI). RESULTS: Under S (9.9-14.5 mg.l-1), spontaneously terminating PVTs (cycle length of 270 +/- 43 ms, n = 45) (mean +/- s.d.) occurred when a PE bolus (10-50 micrograms.kg-1) was injected. The first beat of the PVTs occurred with a coupling interval of several hundred ms to the preceding idioventricular beat (IDV) without any bridging activity and its earliest EPI breakthrough occurred in areas overlying the terminations of the right or left bundle branch. ARI values measured in IDV (295 +/- 47 ms) were significantly prolonged prior to PVT (462 +/- 92 ms). Prolongation was greater in apical than in basal epicardial areas, and at endocardial than epicardial sites (to > 500 ms). Maximum delays > 200 ms developed in the regions of marked ARI prolongation and, in later beats, circus movement re-entry occurred around refractory barriers, shifting between various regions of the ventricles. CONCLUSION: Thus, PVTs occurring spontaneously under conditions of delayed repolarisation originate from shifting sites in the ventricular conduction system and re-entrant activity shifting between various regions of the ventricle may occur in later beats of the more sustained arrhythmias.

Statins in the prevention of coronary heart disease.

Although epidemiologic studies proved that a causal relationship exists between elevated serum cholesterol levels and coronary heart disease, it is only recently that cholesterol-lowering strategies have shown significant reductions in total mortality. In the last few years, three landmark coronary artery disease-reduction trials with HMG-coenzyme A reductase inhibitors (statins) showed significant reductions in coronary heart disease and mortality. Statins have beneficial effects on coronary heart disease and overall mortality in primary and secondary prevention, including in women and the elderly. Angiographic studies reveal the potential mechanisms through which statins exert their clinical benefits.

Effect of chronic oral moricizine and intravenous epinephrine on ventricular fibrillation and defibrillation thresholds.

The purpose of this study was to determine the effects of chronic oral moricizine therapy and physiological doses of epinephrine on ventricular fibrillation and defibrillation thresholds using an implantable transvenous/subcutaneous defibrillation system in a pig model. Thirteen pigs completed the three phases of the study. After a baseline study on day 1, the animals were randomized to receive moricizine 10-15 mg/kg tid or placebo for seven doses, at which time the protocol was repeated on day 4. The same protocol was again repeated on the same day after infusion of physiological doses of epinephrine. Multiple ventricular fibrillation and defibrillation thresholds were measured during each study. Moricizine did not alter ventricular fibrillation nor defibrillation thresholds, whereas epinephrine increased the ventricular defibrillation threshold from 20.8 J to 23.7 J (P < 0.05). In addition, we observed an increase in both ventricular fibrillation (19.7 J vs 12.6 J; P < 0.05) and defibrillation (20.8 J vs 17.8 J; P 0.05) thresholds over the 4 days of the study. These findings suggest that moricizine may be a safe antiarrhythmic agent to use in patients with implantable cardioverter defibrillators, and that elevated endogenous epinephrine may render defibrillation more difficult.

Lidocaine prophylaxis for fatal ventricular arrhythmias after acute myocardial infarction.

OBJECTIVE: To compare the efficacy and safety of a 40-hour lidocaine infusion after completion of a 8-hour open-label infusion for prophylaxis of primary ventricular fibrillation in patients with uncomplicated acute myocardial infarction. METHODS: This was a double-blind, randomized placebo-controlled trial held in the coronary care unit of a large nonprofit hospital. We studied 200 patients with uncomplicated acute myocardial infarction in Killip class I or II who came to the hospital within 6 hours of onset of symptoms and 22 patients who had ventricular fibrillation before the start of the study. Intervention consisted of an 8-hour lidocaine infusion followed by placebo or lidocaine for an additional 40 hours. The infusion rate was adjusted in patients > or = 70 years old and in those < 50 kg or > or = 90 kg. Measurements recorded were baseline demographic characteristics, incidence of ventricular arrhythmias, adverse reactions, and death. RESULTS: New congestive heart failure developed during the randomized phase in 9% of patients receiving lidocaine and in 2% of patients receiving placebo (p = 0.03). Ventricular fibrillation did not occur during the treatment period, and sustained ventricular tachycardia developed in one patient receiving placebo. The in-hospital mortality rate was comparable in both groups (4% versus 2%; p = 0.68) but was much higher (13.6%) in patients with initial ventricular fibrillation not included in the randomized study. CONCLUSIONS: A 40-hour age- and weight-adjusted lidocaine infusion administered after an initial 8-hour infusion provoked more congestive heart failure than placebo. In view of the absence of ventricular fibrillation episodes with both infusions, caution should be used when lidocaine is administered for longer than 8 hours in patients with uncomplicated myocardial infarction.

The pharmacokinetic and pharmacodynamic interaction between propafenone and lidocaine.

Although propafenone is a known substrate and inhibitor of the cytochrome P450 4-hydroxylation pathway of debrisoquin (CYP2D6 isozyme), its effects on other hepatic mixed- function oxidative isozymes have not been extensively evaluated. We studied the influence of propafenone on the disposition of continuously infused lidocaine in 12 healthy male volunteers. Placebo or propafenone (225 mg every 8 hours) was orally administered for 4 days before and during lidocaine administration (2 mg/kg/hr for 22 hours). In the 11 (92%) subjects phenotyped as extensive metabolizers, propafenone significantly increased the lidocaine area under the plasma concentration time curve (81.7 +/- 16.2 versus 76.3 +/- 15.6 micrograms.hr/ml; p < or = 0.05) and reduced systemic lidocaine clearance (9.53 +/- 1.77 versus 10.27 +/- 2.24 ml/min/kg; p < or = 0.05), but did not significantly affect volume of distribution at steady state (2.48 +/- 0.33 versus 2.64 +/- 0.45 L/kg; p = 0.10) or mean residence time (4.37 +/- 0.92 versus 4.47 +/- 0.87 hours; difference not significant) compared with placebo, respectively. Adverse central nervous system effects were significantly worse in severity and duration during the propafenone phase (p < or = 0.05). Propafenone minimally inhibits the metabolism of lidocaine. This suggests that the ability of propafenone to inhibit metabolic pathways exclusive of the CYP2D6 isozyme may be limited. In addition, potentiation of disturbing central nervous system adverse effects may occur during combination therapy of propafenone and lidocaine.