Thomas Shook

Paradoxical Vasoconstriction Induced by Acetylcholine in Atherosclerotic Coronary Arteries

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.

Clopidogrel with or without Omeprazole in Coronary Artery Disease

BACKGROUND Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).

Previous Angina Alters In-Hospital Outcome in TIMI 4 A Clinical Correlate to Preconditioning?

BACKGROUND Ischemic preconditioning has been shown to reduce myocardial infarct size in experimental models, but its role in patients remains unclear. Angina before myocardial infarction reflects brief episodes of ischemia and may be a marker of preconditioning. As part of the Thrombolysis in Myocardial Infarction (TIMI) 4 study, we performed an analysis on the effect of a history of previous angina on in-hospital outcomes for patients with acute myocardial infarction. METHODS AND RESULTS Patients eligible for thrombolytic therapy were enrolled into the study. Data were collected from case report forms regarding previous history of angina, in-hospital outcome and 6-week follow-up. Two hundred eighteen patients had a history of previous angina at any time before acute myocardial infarction, and 198 patients did not have previous angina. Patients with any previous history of angina were less likely than with those without angina to experience in-hospital death (3% versus 8%) (P = .03), severe congestive heart failure (CHF) or shock (1% versus 7%, P = .006), or the combined end point of in-hospital death, severe CHF, or shock (4% versus 12%, P = .004). Moreover, patients with any history of angina were more likely to have a smaller creatine kinase (CK)-determined infarct size (119 versus 154 CK integrated units; P = .01) and were less likely to have Q waves on their ECG (57% versus 69%; P = .01). In the subset of patients who experienced angina within the 48 hours before infarction (compared with those who did not), there was a trend toward less likely in-hospital death (3% versus 6%; P = .09), a lower incidence of severe CHF or shock (1% versus 6% P = .008), a lower combined end point of death, CHF, or shock (3% versus 10%; P = .006), smaller infarct size assessed by CK (115 versus 151 CK units; P = .03), and a trend toward fewer Q-wave infarcts. However, patients with a history of previous angina did have a trend toward more recurrent ischemic pain. Of importance is that the beneficial in-hospital effects of previous angina were not dependent on angiographically visible coronary collaterals. CONCLUSIONS Previous angina confers a beneficial effect on in-hospital outcome after acute myocardial infarction. The reasons for this benefit are uncertain, but one potential mechanism for this observation may be ischemic preconditioning.

Inappropriate Use of Bivariable Analysis to Screen Risk Factors for Use in Multivariable Analysis

The use of bivariable selection (BVS) for selecting variables to be used in multivariable analysis is inappropriate despite its common usage in medical sciences. In BVS, if the statistical p value of a risk factor in bivariable analysis is greater than an arbitrary value (often p = 0.05), then this factor will not be allowed to compete for inclusion in multivariable analysis. This type of variable selection is inappropriate because the BVS method wrongly rejects potentially important variables when the relationship between an outcome and a risk factor is confounded by any confounder and when this confounder is not properly controlled. This article uses both hypothetical and actual data to show how a nonsignificant risk factor in bivariable analysis may actually be a significant risk factor in multivariable analysis if confounding is properly controlled. Furthermore, problems resulting from the automated forward and stepwise modeling with or without the presence of confounding are also addressed. To avoid these improper procedures and deficiencies, alternatives in performing multivariable analysis, including advantages and disadvantages of the BVS method and automated stepwise modeling, are reviewed and discussed.

Prospective Temporal Analysis of the Onset of Preinfarction Angina Versus Outcome: An Ancillary Study in TIMI-9B

BACKGROUND The timing of onset of angina before myocardial infarction in relation to outcome is unknown. METHODS AND RESULTS We prospectively determined the importance of the time of onset of preinfarction angina in relation to 30-day outcomes in the TIMI-9B study from standardized forms. Of the 3002 patients entered into the study, 425 reported angina before their myocardial infarction. Patients with angina onset within 24 hours of infarction had a lower 30-day cardiac event rate (mortality, recurrent myocardial infarction, heart failure, or shock) at 4% than those with onset of angina >24 hours (17%; P=.030). A history of any angina alone was not associated with reduced event rate. Peak creatine kinase levels tended to be lower in the group with angina within 24 hours. These benefits were not due to higher rates of use of antianginal medicines or aspirin and were not a consequence of differences in baseline characteristics or disease states (hypertension, hypercholesterolemia) among subgroups. CONCLUSIONS These temporal observations are consistent with the concept of preconditioning by preinfarction angina but do not rule out other mechanisms.

Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution and response to anti-ischemic medication. The Angina and Silent Ischemia Study Group (ASIS)

BACKGROUND Identification of whether episodes of ambulatory ischemia are caused by increases in myocardial oxygen demand or to episodic coronary vasoconstriction in patients with stable coronary disease may be important to guide selection of optimal anti-ischemic therapy and to gain insight into mechanisms responsible for adverse cardiac events. METHODS AND RESULTS Mean minute heart rate activity during ambulatory ECG (AECG) monitoring was determined for 50 patients treated with propranolol, diltiazem, nifedipine, or placebo in a randomized, double-blind, crossover trial. Periods of heart rate increases of various magnitudes and durations and starting at various baseline heart rates on each therapy were identified throughout each 48-hour AECG recording, and the proportion of these periods associated with an ischemic episode was determined. The circadian variation of ischemic episodes categorized by the presence or absence of an increase in heart rate was analyzed. Eighty-one percent of ischemic episodes were preceded by an increase in heart rate > or = 5 beats per minute. The likelihood of developing ischemia associated with a heart rate increase was proportional to the magnitude and duration of the heart rate increase and the baseline heart rate before the increases in heart rate: likelihood ranged from 4% when the heart rate increased 5-9 beats per minute and lasted < 10 minutes to 60% when the heart rate increased > or = 20 beats per minute and lasted > or = 40 minutes. The likelihoods of developing ischemia based on changes in the heart rate variables were similar for each of the therapies. Propranolol therapy significantly reduced the magnitude and duration of heart rate increase and the baseline heart rate compared with therapy with placebo, diltiazem, or nifedipine (P < .001). Ischemic episodes associated with a heart rate increase displayed a daytime peak, whereas ischemia occurring without a heart rate increase occurred evenly throughout the day. Propranolol reduced the proportion of heart rate-related ischemic episodes and increased the proportion of non-heart rate-related episodes compared with placebo (P < .02), and nifedipine exerted the opposite effect (P = .005). Multivariate analysis indicated that the probability of developing ischemia was strongly associated with heart rate variables and was unaffected by time of day. CONCLUSIONS Most episodes of ambulatory ischemia are associated with a preceding period of increased heart rate. The likelihood of developing ischemia is predicted by heart rate variables and unaffected by time of day. Anti-ischemic efficacy is generally a result of the medications efficacy in reducing heart rate variables. A minority of ischemic episodes are not associated with preceding periods of increased heart rate, may be caused by episodic coronary vasoconstriction, and are more effectively reduced by nifedipine than propranolol.

Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group.

Episodes of transient myocardial ischemia during ambulatory activities are common in patients with stable coronary artery disease and who are often asymptomatic. Selection of therapy for episodes of asymptomatic ischemia is limited by a lack of direct comparative studies. To determine the most effective monotherapy for patients with stable angina and a high frequency of asymptomatic ischemic episodes, propranolol-LA (mean daily dose, 293 mg), diltiazem-SR (mean daily dose, 350 mg), nifedipine (mean daily dose, 79 mg) were each compared with placebo, each for 2 weeks, in a randomized, double-blinded, crossover trial. Entry criteria were a positive exercise treadmill test during placebo therapy characterized by 1.0 mm or more ST segment depression and angina pectoris, and six or more episodes of transient ST segment depression of 1.0 mm or more on a 48-hour ambulatory electrocardiogram. One hundred ninety-four patients were screened, 63 were eligible and received randomized therapy, of which 56 patients completed at least two of the four treatment periods and were included in an intent-to-treat analysis. Fifty patients completed all four treatment phases and were included in the protocol-completed analysis. Anti-ischemia efficacy was assessed by 48-hour ambulatory electrocardiographic monitoring, exercise treadmill tests, and anginal diaries. Ninety-four percent of all episodes of ambulatory ischemia were asymptomatic. Compared with placebo, only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory electrocardiographic monitoring (2.3 versus 1.0 episodes/24 hr; mean duration of ischemia per 24 hours, 43.6 versus 5.7 minutes; both p less than 0.0001). Diltiazems reduction of the frequency of episodes compared with placebo (2.3 versus 1.9 episodes/24 hr) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03). Nifedipine had no significant effect on any measured variable of ambulatory ischemia. The dosages of medication used may have been excessive for some patients, and a more beneficial effect may have been evident at a lower dose. In contrast to the marked effects of the active agents on ambulatory asymptomatic ischemia, the effects on exercise performance and angina pectoris were slight. The active agents modestly improved treadmill exercise duration time until 1 mm ST segment depression (3%), and only propranolol and diltiazem had significant effects. Only diltiazem significantly prolonged the total exercise time. Anginal frequency was significantly decreased by both propranolol and diltiazem.(ABSTRACT TRUNCATED AT 400 WORDS)

Value of the intracoronary electrocardiogram to monitor myocardial ischemia during percutaneous transluminal coronary angioplasty.

To enhance detection of ischemia during percutaneous transluminal coronary angioplasty (PTCA), unipolar intracoronary electrocardiograms (ECGs) were recorded during PTCA in 25 patients from the tips of guidewires positioned distal to stenoses being dilated. Surface electrocardiographic leads chosen to reflect likely areas of reversible ischemia during PTCA were recorded simultaneously. In 21 of 29 stenoses dilated (72%), ST segment elevation and/or T wave peaking in intracoronary ECG appeared during balloon inflation and disappeared after deflation, accompanied by transient angina on 19 occasions. Two patients had transient ST segment elevation in intracoronary ECGs during PTCA without associated angina. ST changes in the surface ECG during PTCA were seen on only nine occasions (31%), always accompanied by ST segment elevation in the intracoronary ECG that appeared earlier and was of much greater magnitude. Five patients with prior myocardial infarction and aneurysm formation had fixed ST segment elevation in the intracoronary ECG unrelated to balloon inflation. Myocardial ischemia during PTCA can be detected easily with intracoronary ECGs and with greater sensitivity than that of the surface ECG. Furthermore, intracoronary ECGs may help to clarify the nature of chest pain during balloon inflation or during suspected complications.

Suppression of silent ischemia by metoprolol without alteration of morning increase of platelet aggregability in patients with stable coronary artery disease.

To determine the effect of metoprolol on silent ischemia and platelet aggregability, 10 patients with coronary artery disease were studied with a randomized, double-blind, placebo-controlled, crossover trial. Patients were treated with metoprolol (200 mg b.i.d.) or placebo for 1 week and then received the alternate therapy. Two days before the end of each treatment period, platelet aggregability was studied for 24 hours, and a 48-hour ambulatory electrocardiogram was obtained. Compared with placebo, metoprolol significantly decreased the total number (from 26 to 4, p less than 0.1) and duration (from 735 to 84 minutes, p less than 0.01) of silent ischemic episodes. This decrease was accompanied by a decrease in the mean blood pressure (from 127/81 to 118/71 mm Hg, p less than 0.01) and the mean heart rate (from 70 to 54 beats/min, p less than 0.01). The incidence of silent ischemic episodes in the morning was significantly higher in untreated patients than in treated patients. The few episodes observed during metoprolol treatment occurred at the same time as the peak incidence observed during placebo treatment. During placebo treatment, platelet aggregability increased from 6:00 to 9:00 AM as reflected by a decrease in the threshold concentrations of ADP and epinephrine required to induce biphasic platelet aggregation (from 4.8 +/- 0.8 to 2.6 +/- 0.4 microM, p less than 0.02; and from 7.3 +/- 2.3 to 1.8 +/- 0.9 microM, respectively, p less than 0.02). Metoprolol did not alter the basal level nor blunt the morning increase of platelet aggregability.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection Conferred by Preinfarct Angina is Manifest in the Aged Heart: Evidence from the TIMI 4 Trial

There has been debate regarding the issue of whether ischemic preconditioning is effective in the aging and diseased heart. Therefore, we retrospectively analyzed the effect of preinfarction angina in patients less than versus greater than 60 years of age in the TIMI 4 study. Preinfarction angina was defined as an episode of typical angina pectoris that occurs prior to the time of index chest pain associated with the myocardial infarction itself. Patients who were 60 years and older had a higher rate of death and the combined endpoints of death, heart failure/shock, and/or reinfarction compared with younger patients. However, patients 60 years or older who had preinfarction angina had lower rates of the combined endpoints of death, heart failure/shock, and/or reinfarction (11%) compared with patients without angina (23%; P = 0.04). They also had lower creatine kinase (CK) values. Therefore, preinfarction angina was protective in patients 60 years or older in the TIMI 4 study.