Journal of Cardiovascular Pharmacology and Therapeutics

Platelets are key mediators in the pathophysiology of atherothrombotic disease. Inappropriate platelet activation can lead to thrombosis and ischemic events. Platelet function testing has been used to monitor patient response to antiplatelet therapy. Variability in response to antiplatelet therapy may be due in part to incomplete inhibition of targeted pathways (thromboxane A₂ and adenosine diphosphate [ADP]) by currently available agents (aspirin and P2Y₁₂ ADP receptor antagonists). Low responsiveness to antiplatelet therapy (as measured in various platelet function assays) correlates with a high rate of ischemic events. However, tailoring treatment based on platelet response remains to be definitively proven in clinical trials, correlations between assays are modest, and concordance in defining suboptimal response is poor. Additional studies are needed to determine whether changes in therapy based on results of platelet function testing improve clinical outcomes, and thus will determine whether broader use of platelet function testing in clinical practice is warranted.

Tegaserod is a first-in class selective serotonin 4 receptor agonist approved for the treatment of irritable bowel syndrome. In March 2007, the US Food and Drug Administration (FDA) suspended its use citing increased cardiovascular (CV) events in clinical trials. However, there is no known mechanistic basis for an adverse CV effect. To reassess the CV safety of tegaserod, teagaserod-treated patients (pts) in the Intermountain Healthcare database were identified (n = 2603), matched 1:6 with untreated (n = 15,618) patients by age, sex, and date of tegaserod initiation, and followed for an average of 2.5 years. Age averaged 38.6 ± 13.5 years, and 94% were female. Cardiovascular event rates were low and similar in patients treated with tegaserod and matched untreated patients. For the primary composite CV endpoint, 54 (0.35%) untreated and 12 (0.46%) treated pts had an event (treated OR = 1.27, 95% CI: 0.68-2.38, P =.46), with 7 and 0 events, respectively, occurring within 3 months. A total of 12 (0.1%) untreated and 1 (<0.1%) treated pts were hospitalized for a myocardial infarction (MI). 36 (0.2%) untreated and 10 (0.4%) treated pts for a cardiovascular accident, and 1 pt in each group for unstable angina. A total of 6 (<0.1%) untreated and no treated pts died from cardiac causes. Event rates were comparable to expected rates in this population of mostly premenopausal women. This large epidemiologic study failed to confirm a reported large event differential for tegaserod that was noted incidentally in a clinical trials database, suggesting that the prior observation may have been due to chance.

Of 209 patients with heart failure treated with combined cardiac resynchronization therapy and implantable cardioverter-defibrillator therapy, appropriate cardioverter-defibrillator shocks occurred at 34-month follow-up in 22 of 121 patients (18%) on statins and in 30 of 88 patients (34%) not on statins (P = .009). Deaths occurred in 3 of 121 patients (2%) on statins and in 9 of 88 patients (10%) not on statins (P = .017). Stepwise Cox regression analysis showed that significant independent prognostic factors for appropriate shocks were use of statins (risk ratio = 0.46), smoking (risk ratio = 3.5), and diabetes (risk ratio = 0.34). Significant independent prognostic factors for the time to mortality were use of statins (risk ratio = 0.05), use of digoxin (risk ratio = 4.2), systemic hypertension (risk ratio = 14.2), diabetes (risk ratio = 4.3), and left ventricular ejection fraction (risk ratio = 1.1).

Medical treatments of coronary myocardial bridging (CMB) generally include β-blockers and calcium channel blockers. Nitrates are avoided because symptoms may worsen. Nicorandil is a hybrid of a nitrate and a potassium channel opener. However, the effect of nicorandil on CMB is unknown. We analyzed nicorandil reactivity at the site with CMB in 51 patients. Maximal and minimal diameters of CMB were measured by quantitative angiography at baseline and at 60 seconds after intracoronary administration of 200 mg nicorandil. The maximal diameter during diastole increased from 2.15 + 0.42 mm to 2.34 + 0.44 mm after administration of nicorandil (P < .001), and the minimal diameter during systole increased from 1.24 + 0.63 mm to 1.67 + 0.64 mm (P < .001). Thus, nicorandil reduced the percentage vessel narrowing from 44.0 + 26.1% to 30.3 + 21.2% (P < .001). In 22 patients, we also evaluated the effect of nitroglycerin. The maximal diameter during diastole increased from 2.25 + 0.47 mm to 2.51 + 0.44 mm after administration of nitroglycerin (P < .019), and the minimal diameter during systole decreased from 1.28 + 0.64 mm to 1.14 + 0.60 mm (P = .276). Thus, nitroglycerin augmented the percentage vessel narrowing from 44.9% + 25.0% to 56.0% + 23.5% (P = .023). These results indicate that intracoronary administration of nicorandil could dilate coronary arteries during diastole as well as systole in patients with CMB during coronary angiography.

Background: Recently, hemodynamic instability including hypotension and its effect on the clinical outcome in patients treated with angiotensin-converting enzyme inhibitors (ACEIs) during coronary artery bypass graft (CABG) has been described. However, no analysis has examined the dose of ACEIs and its risk of hypotension. In this study, we tested the hypothesis that a higher dose of ACEIs could lead to increased episodes of hypotension.

Methods: A total of 300 patients scheduled for CABG were studied prospectively. They were divided into 3 groups according to their preoperative use of different doses of ACEIs. The demographic and medical characteristics were compared between these 3 groups. During CABG and throughout the intensive care unit (ICU), vasoconstrictors were infused in patients undergoing hypotension (mean arterial pressure [MAP] < 65 mm Hg or >30% below baseline). The predictive factors responsible for hypotension were investigated separately using univariate and multivariate logistic regression models.

Results: The 3 groups were similar with regard to the patients’ demographic and medical characteristics. The patients treated with ACEIs were more likely to develop hypotension (73% of high dose and 47% of low dose) in the operating room than those without ACEIs (30%). However, in the ICU, there was no significant association between hemodynamic changes and ACEIstreated patients. Other independent risk factors identified for hypotension were ejection fraction, history of myocardial infarction, coronary grafting count, and pump time during surgery and/or ICU admission. Conclusions: Hemodynamic changes during CABG were observed to be directly proportional to the dosage of ACEIs prescribed preoperatively.

Background: Smoking has been shown to influence the tone of the autonomic nervous system as reflected by heart rate variability (HRV). To date, no information is available as to whether 24-hour HRV might differentiate users of different tobacco products. Objective: To assess the differences in HRV derived from the 24-hour electrocardiogram (ECG) following the use of 2 tobacco products of potentially different exposures. Methods: Thirty adult Caucasian male smokers (mean age: 42.8 + 5.7 years) smoking 20 to 40 cigarettes/ day were randomized in a 3-way crossover study design to either smoke a conventional cigarette (CC, tar: 11 mg, Nic: 0.8 mg), to use the Electrically Heated Cigarette Smoking System (EHCSS: tar: 5 mg, Nic: 0.3 mg, according to the Federal Trade Commission [FTC]), or to stop smoking (NS) for 3 days each. The 24 hours ECGs were recorded during the last 24 hours of each exposure period. Results: A 24-hour ECG showed highest mean values for standard deviation of all normal-to-normal heart beat (NN) intervals (SDNN), standard deviation of all 5-minute averaged NN intervals in a 24-hour period (SDANN), mean of the standard deviations of the NN intervals calculated from all 5-minute segments in a 24-hour period (SDNNI), percentage (P) of all NN intervals that differ by 50 milliseconds of all NN (PNN50%), the square root of the mean of all squared differences between adjacent NN intervals in 24-hour period (RMSSD), and total number of all NN intervals divided by the height of the histogram of all NN intervals measured on a discrete scale with bins of 7 × 8125 ms (1/128 seconds; HRVTI) when participants stopped smoking followed by the use of the reduced exposure product and CC. Conclusion: Heart rate variability tended to increase with reduced smoke exposure.

Remote conditioning induced by ischemia in distant organs protects the heart from ischemia/reperfusion injury; however, its effect on ischemia-induced ventricular arrhythmias is unknown. Therefore, we tested the hypothesis that partial hindlimb occlusion during coronary artery occlusion increases the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion. Rats (n = 7) were instrumented with a radio-telemetry device for recording arterial pressure, electrocardiogram (ECG), and body temperature. A Doppler ultrasonic flow probe and vascular occluder were placed around the terminal aorta. Finally, a snare was placed around the left main coronary artery. The VAT was determined without and, on an alternate day, during partial hindlimb occlusion (remote conditioning) in conscious rats. Without remote conditioning, the VAT was 4.56 + 0.15 minutes. Importantly, remote conditioning significantly increased the VAT (6.29 + 0.49 minutes), suggesting that ischemia in a distant organ may delay the development of ischemia-induced ventricular arrhythmias.

The antiarrhythmic dipeptide, GAP-134, ([2S,4R]-1[2-aminoacetyl]-4-benzamido-pyrrolidine-2-carboxylic acid) was evaluated in canine ischemia/reperfusion model. In dogs subjected to 60-minute ischemia and 4-hour reperfusion, GAP-134 was administered 10 minutes before reperfusion as a bolus + intravenous (IV) infusion. The doses administered were 0.25 µg/kg bolus + 0.19 µg/kg per hour infusion; 2.5 µg/kg + 1.9 µg/kg per hour; 25 mg/kg + 19 mg/kg per hour; 75 mg/kg + 57 mg/kg per hour. Ventricular ectopy was quantified during reperfusion, including premature ventricular contractions (PVC) and ventricular tachycardia (VT). Total incidence of VT was reduced significantly with the 2 highest doses of GAP-134 (1.7 + 0.8; 2.2 + 1.4 events; P < .05) compared to controls (23.0 + 6.1). Total PVCs were reduced significantly from 11.1 + 1.6% in control animals to 2.0% + 0.7% and 1.8% + 0.8% after the 2 highest doses of GAP-134. Infarct size, expressed as percentage of left ventricle, was reduced significantly from 19.0% + 3.5% in controls to 7.9% + 1.5% and 7.1% + 0.8% (P < .05) at the 2 highest doses of GAP-134. GAP-134 is an effective antiarrhythmic agent with potential to reduce ischemia/reperfusion injury.

Background: Early studies in different stress models have shown potential beneficial effects of exogenous zinc application with reduction in the rate of apoptotic cell death. This has not been shown in models of myocardial infarction. Methods: Rats were exposed to either brief episodes of acute ischemia followed by reperfusion (phase 1) or chronic coronary occlusion (phase 2). Animals were either treated with zinc or vehicle. Groups 1 and 3 received zinc-bis-(DL-hydrogenaspartate) 10 mg/kg body weight as a single 5-mL bolus administered intraperitoneally 24 hours prior to coronary occlusion, groups 2 and 4 received saline. The infarct sizes were determined by triphenyltetrazolium chloride staining and expressed at relative areas to areas of ischemia. Histological slices of the rat’s myocardium at the border zones of the infarcts were stained with the TUNEL method to assess for apoptosis. Animals in groups 5, 7, and 9 received zinc, given once before and then repeated every 4 days after coronary occlusion, whereas groups 6, 8, and 10 received saline. Animals were observed for observation periods of 13 (groups 9 and 10), 16 (groups 7 and 8), or 19 weeks (groups 5 and 6), respectively. Two-dimensional echocardiography was performed to measure ejection fraction (EF) at baseline and at the end of the observation periods. TUNEL staining was used to detect and quantify apoptosis rate in the border zones of infarcts after the hearts were excised. Results: Infarct sizes were 49% + 22% in group 1 (zinc + 30 minutes ischemia + 30 minutes reperfusion); 48% + 10% in group 2 (vehicle + 30 minutes ischemia + 30 minutes reperfusion); 42% + 11% in group 3 (zinc + 60 minutes ischemia + 30 minutes reperfusion); and 41% + 23% in group 4 (vehicle + 60 minutes ischemia + 60 minutes reperfusion). In group 1, 11% + 6% of cells were apoptotic compared to 12% + 4% in group 2, 16% + 9% in group 3, and 17% + 7% in group 4 (P > .05). In phase 2, echocardiography revealed a significant reduction in EF in all groups after coronary occlusion. There were no significant differences in EF between the 5 groups at baseline and at follow-up. TUNEL staining did not reveal any significant apoptosis after 13 to 19 weeks. Conclusion: Application of zinc failed to result in reduction of infarct size after temporary coronary occlusion followed by reperfusion and did not demonstrate any reduction in apoptotic cell death. In chronic coronary occlusion, zinc also did not improve EF compared to controls in the presented model in rats. The mechanisms involved in antiapoptotic effects seem to be more complex and might not be inducible by simple zinc injections.

Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of K _ATP channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P <. 01), and 47% (P < .001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness.

Background: Suppression of hypercholesterolemic atherosclerosis with vitamin E is associated with reductions in oxidative stress without reductions in serum lipids. The objectives of this study were to determine if (1) vitamin E regresses hypercholesterolemic atherosclerosis; and (2) regression is associated with reductions in serum lipids and aortic oxidative stress. Methods and Results: The studies were conducted in 4 groups of rabbits: group I, control, regular diet (2 months); group II, 0.25% cholesterol diet (2 months); group III, 0.25% cholesterol diet (2 months) followed by regular diet (2 months); and group IV, 0.25% cholesterol diet (2 months) followed by regular diet with vitamin E (40 mg/kg body weight/day) (2 months). Blood samples were collected monthly for the measurement of serum lipids and oxidative stress (chemiluminescent activity of white blood cells [WBC-CL]). Aortas were removed at the end of the protocol for assessment of atherosclerotic lesions, and oxidative stress (malondialdehyde [MDA] and CL). Increases in serum lipids in group II were associated with an increase in oxidative stress and development of atherosclerosis. Serum lipids decreased to a similar extent in groups III and IV but the atherosclerotic lesions increased by 63% and 141% compared to group II. Acceleration of atherosclerosis in the rabbits on regular diet with or without vitamin E was associated with practically no change in the oxidative stress. Conclusion: These results suggest that (1) regular diet following a high-cholesterol diet decreased oxidative stress but did not induce regression of atherosclerosis; (2) vitamin E did not produce regression; and (3) regular diet with vitamin E following a high-cholesterol diet was not associated with an increase in oxidative stress but produced acceleration of atherosclerosis.

This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca²⁺]_i) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca²⁺]_i overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M₃-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M₃-mAChR. The mechanism may be related to the improvement of Ca²⁺ handling.