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Background: Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.Objectives: To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.Methods: A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10 mg, simvastatin (10-80 mg), and atorvastatin (10-80 mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipo protein [LDL-C] = 145-250 mg/dL; triglycerides < or = 350 mg/dL; N = 975) but without a recent (< or = 6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.Results: Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p < 0.001), whereas statins significantly lowered desmo sterol and lathosterol levels (p < 0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p < 0.001).Conclusions: The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe-statin) doses and circulating non-cholesterol levels. [ABSTRACT FROM AUTHOR]

Aims To evaluate the efficacy and safety of ezetimibe 10mg administered with pravastatin in patients with primary hypercholesterolemia.Methods and results After dietary stabilization, 2–12 week screening/washout period, and 4-week, single-blind, placebo lead-in period, 538 patients with baseline LDL-C ≥3.8 to ≤6.5mmol/l and TG ≤4.0mmol/l were randomized to one of eight possible treatments administered daily for 12 weeks: ezetimibe 10mg; pravastatin 10, 20, or 40mg; ezetimibe 10mg plus pravastatin 10, 20, or 40mg; or placebo. The primary efficacy endpoint was percent reduction in LDL-C from baseline to study endpoint for ezetimibe 10mg plus pravastatin (pooled doses) compared to pravastatin alone (pooled doses) and ezetimibe alone. The combined use of ezetimibe and pravastatin resulted in significant incremental reductions in LDL-C and TG compared to pooled pravastatin alone \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((p{<}0.01)\) \end{document}. Coadministration therapy reduced LDL-C by 34–41%, TG by 21–23%, and increased HDL-C by 7.8–8.4%, depending on the dose of pravastatin. The combined regimen was well tolerated, with a safety profile similar to pravastatin alone and placebo.Conclusions When coadministered with pravastatin, ezetimibe provided significant incremental reductions in LDL-C and TG and was well tolerated with a safety profile similar to pravastatin alone. [ABSTRACT FROM PUBLISHER]

During a 6-year cumulative experience, 163 patients with drug-refractory ventricular tachycardia/fibrillation (VT/VF) underwent automatic implantable defibrillator (AID) and/or automatic implantable cardioverter defibrillator (AICD) implantation at our institutions. Baseline preimplantation programmed electrical stimulation was performed in 160 patients revealing induction of sustained arrhythmias in 115 patients (71%), nonsustained arrhythmia in 20 patients (13%), and noninducible arrhythmia in 25 patients (16%). Operative mortality was 4.9%. At 22 ± 15 (mean ± standard deviation) months follow-up 77 patients (50%) had experienced at least one appropriate AID/AICD discharge. The actuarial incidence of sudden cardiac death (VT/VF death within 1 hour of symptoms or during sleep) in the AICD population was 1.8% and 4.1% at 1 and 2 years, respectively. Excluding patients with operative death and those responding to concomitant subendocardial resection (no longer inducible arrhythmias), the incidence of clinical arrhythmic event (AICD discharge and/or VT/VF death) in patients with sustained, nonsustained, and noninducible arrhythmias were not significantly different. We conclude that the AICD appears to reduce the expected incidence of sudden cardiac death in patients with drug-refractory VT/VF and that selection for AICD therapy should not be based on results of baseline programmed electrical stimulation alone. [ABSTRACT FROM AUTHOR]

Holiday heart syndrome is defined as the occurrence of cardiac arrhythmia in alcohol users without overt heart disease after the ingestion of alcohol. Additionally, alcohol has been implicated as a potential etiology of sudden cardiac death in susceptible individuals. We report on a 53-year-old black woman with mild nonischemic dilated congestive cardiomyopathy and alcohol-provoked ventricular tachyarrhythmias who received an automatic implantable cardioverter defibrillator (AICD). She subsequently had recurrent cardiac arrest during bouts of alcohol intoxication and with out-of-hospital AICD rescue. Electrophysiological study using alcohol infusion confirmed alcohol as the etiology of arrhythmogenicity. We propose that holiday heart be expanded to include people with overt heart disease. These individuals have a high risk of sudden cardiac death after alcohol ingestion, irrespective of underlying cardiac substrate; the AICD is an effective back-up modality of therapy. [ABSTRACT FROM AUTHOR]

Investigates the effects of amiodarone, a benzofuran derivative, on defibrillation. Impact of ventricular fibrillation (VF) duration on defibrillation threshold (DFT); Serum and tissue amiodarone and desethylamiodarone levels after one to three weeks of oral amiodarone therapy; Comparison between DFT control and amiodarone dogs DFT; Increase in DFT in amiodarone-treated dogs.

The article informs that current antitachycardia systems such as the automatic implantable cardioverter/defibrillator (AlCD) detect tachyarrhythmias primarily by sensing rate and thereby perform inadequately in differentiating hemodynamically stable from unstable arrhythmias. Hemodynamic parameters have been previously proposed for incorporation into a rate responsive pacing system. Such parameters may also be important in improving the function of current antitachycardia devices. The antitachycardia systems presently in use detect arrhythmias primarily by sensing rate and, thus, are inadequate to differentiate a hemodynamically stable from an unstable rhythm.

Presents a letter to the editor about sudden cardiac death, published in the journal "Pace."

The elective replacement indicator (ERI) of an automatic implantable cardioverter-defibrillator (AICD) is intended to be utilized as strict criteria for the appropriate timing of pulse generator replacement. The manufacturer's newest recommendations suggest replacement within 3 months post-ERI attainment and this applies to both AID-B units and the latest Ventak models currently being implanted with expectations for increased battery longevity. Twelve patients with the AID-B model were prospectively evaluated in regard to (a) time from attainment of ERI to generator exchange and (b) total battery life with respect to the presence or absence of spontaneous discharges. In the overall group, the ERI was reached at 18.9 ± 3.9 months (mean ± standard deviation). The time from ERI attainment to generator exchange due to battery' depletion was 8.1 ± 5.1 months, and total battery life was 27.3 ± 3.1 months. ln the group with spontaneous discharges, the duration of time (months) post-ERI to generator exchange was 5.7 ± 2.6 but was 11.4 ± 6.1 in the others (P = 0.052): battery life was 25.7 ± 2.4 and 29.4 ± 2.7, respectively (P = 0.03). We conclude that the current ERI recommendation seems overly conservative in planning generator exchange for patients without the occurrence of spontaneous discharges and appropriate for patients with such discharges. [ABSTRACT FROM AUTHOR]

The AICD uses an automatic gain control amplifier for detecting the small electrograms during ventricular fibrillation. The latest generation of the AICD appears to have a more sensitive lock on gain amplifier, as 6 of 76 patients implanted with the new AICD had double counting of the QRS-T wave complex resulting in asymptomatic discharges. Solutions to the problem of limiting these asymptomatic discharges are difficult and include slowing of the heart rate with beta blockers, changing the lead system, or replacement of the device. One of the six patients was treated with beta blockers. Three patients had their device changed, two patients requested the inactivation of their device until a rate programmable unit was available. The potential for T wave sensing in a lock on gain amplifier represents the unique dilemma between detecting small electrograms of ventricular fibrillation, and detecting diastolic events which occur shortly after the QRS complex. [ABSTRACT FROM AUTHOR]

The hemodynamic responses to rapid atrial and ventricular pacing were examined in 10 closed-chest anesthetized dogs in an attempt to distinguish hemodynamically stable from unstable tachycardias. Pressure monitoring catheters were placed in the femoral artery, right atrium, and right ventricle to measure mean arterial pressure, mean right atrial pressure, and mean right ventricular pressure at baseline heart rate and after rapid high right atria! and right ventricular apex pacing. Pressures recorded during rapid pacing (average of the pressures at 30 and 60 seconds of pacing) at pacing rates of 180, 250, and 280/minute were compared to those recorded initially at baseline heart rates. Rapid right ventricular apex pacing resulted in significant increases in mean right atrial pressure (from 6 ± 1 mmHg (mean ± standard error) to 12 ± 1 mmHg, a 100% increase, P < 0.001) and mean right ventricular pressure (from 11 ± 1 mmHg to 16 ± 1 mmHg, a 45% increase, p < 0.02) with marked hemodynamic compromise (mean arterial pressure decreased from 85 ± 6 mmHg to 50 ± 6 mmHg, a 41% decrease, P < 0.01). These parameters remained stable (no statistically significant difference from baseline) during high right atrial pacing. In half of the dogs high right atrial pacing at rates ≥ 250 resulted in atrioventricular Wenckebach. Thus, it is concluded that mean right atrial pressure and mean right ventricular pressure may be useful in distinguishing hemodynamically significant tachycardias, and in the future design of antitachycardia devices. [ABSTRACT FROM AUTHOR]

Presents an overview of the ambulatory management of patients of the automatic implantable cardioverter–defibrillator before and following their discharge from the hospital. Information included on the discharge summary of the patients; List of specific tests recommended prior the to the discharge of the patients; Recommendations for out&#x2013ofȓhospital follow–up.

Twiddler's syndrome, characterized by dislodgment of pacemaker leads due to twisting of pulse generators within the subcutaneous pocket with subsequent retraction of leads and loss of pacing function, has been well described in patients with permanent pacemakers implanted for bradyarrhythmias. The case presented here is the first report of a patient with an internal automatic cardioverter-defibrillator with lead dislodgment due to pulse generator rotation. This case exemplifies a new subset of patients prone to the Twiddler's syndrome. [ABSTRACT FROM AUTHOR]

The article focuses on thrombin receptor antagonist as an approach for the treatment of atherothrombosis. It outlines the efforts of Schering-Plough in the discovery and early clinical development of thrombin receptor antagonists in treating atherothrombosis. It highlights the development of a human platelet membrane-binding assay by scientists at Schering-Plough. It states the ability of the scientists to advance SCH 530348 to two large phase III clinical trials in order to evaluate its efficacy and safety in patients with acrute coronary syndromes.

The purpose of this study was to examine the efficacy and safety of ezetimibe (EZE) coadministered with simvastatin (SIMVA) in a large cohort of African Americans with primary hypercholesterolemia. In a multicenter, randomized, double-blind study, patients were considered eligible for enrollment if after a washout/placebo run-in period, low-density-lipoprotein (LDL) cholesterol level was > or = 145 and < or = 250 mg/dl and triglyceride level was < or = 350 mg/dl. Eligible patients were randomized to SIMVA 20 mg coadministered with either EZE 10 mg (n = 124) or placebo (n = 123) for 12 weeks. At study endpoint, EZE/SIMVA 10/20 mg resulted in a significant mean percent reduction in LDL cholesterol from baseline of 45.6% compared with 28.3% for SIMVA 20 mg alone (p < or = 0.01). There were significantly greater mean reductions in total cholesterol (33% vs. 21%), triglycerides (median 22% vs. 15%), nonhigh-density-lipoprotein (non-HDL) cholesterol (42% vs. 26%), and apolipoprotein B (38% vs. 25%) with EZE/SIMVA 10/20 mg compared with SIMVA 20 mg alone, respectively (p < or = 0.01). There was no difference in HDL cholesterol between the EZE/SIMVA 10/20-mg and SIMVA 20-mg alone groups (+1% vs. +2%, respectively). Coadministration of EZE/SIMVA 10/20 mg demonstrated a safety profile similar to that of SIMVA 20 mg. In conclusion, EZE/SIMVA 10/20 mg provided significantly greater improvement in atherogenic lipid profiles and was well tolerated compared with SIMVA 20-mg monotherapy in a large cohort of African Americans with primary hypercholesterolemia.

Objective: The cholesterol absorption inhibitor, ezetimibe, significantly decreases low-density lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia. The pharmacodynamic, pharmacokinetic, and safety profiles of ezetimibe and fenofibrate were evaluated alone and after co-administration in 32 subjects with primary hypercholesterolemia., Research Design and Methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study. Subjects with untreated LDL-C > or = 130 mg/dL (3.37 mmol/L) were randomized to receive one of four oral treatments each morning for 14 days: fenofibrate 200 mg + ezetimibe 10 mg, fenofibrate 200 mg, ezetimibe 10 mg, or placebo. Serum lipids were assessed before drug administration on day 1, day 7, and day 14. Pharmacokinetic parameters were assessed on day 14., Main Outcome Measures: The primary pharmacodynamic parameter was percentage change from baseline in LDL-C concentration following co-administration of ezetimibe and fenofibrate vs either drug alone, or placebo. A secondary outcome was the potential for a pharmacokinetic interaction between ezetimibe and fenofibrate., Results: Ezetimibe and fenofibrate co-administration was well tolerated and produced statistically significant mean percentage reductions from baseline in LDL-C (p < or = 0.05 vs either drug alone or placebo), total cholesterol and triglycerides (p < or = 0.05 vs either fenofibrate or placebo), apolipoprotein C-III (p < or = 0.05 vs placebo), and LDL-III (p < or = 0.05 vs either drug alone or placebo). Ezetimibe did not significantly affect the pharmacokinetics of fenofibrate. Concomitant fenofibrate administration significantly increased the mean C(max) and AUC of total ezetimibe approximately 64% and 48%, respectively. However, based on the established safety profile and flat dose-response of ezetimibe, this effect is not considered to be clinically significant., Conclusion: Co-administration of ezetimibe and fenofibrate produced significantly greater reductions in LDL-C than either drug alone and greater reductions in triglycerides than fenofibrate. These effects were accompanied by improvements in the lipid/lipoprotein profile, suggesting that co-administration therapy with ezetimibe and fenofibrate may be an effective therapeutic option for patients with mixed dyslipidemia.