Association between C-reactive protein, anti-Chlamydia pneumoniae antibodies, and vascular function in healthy adults.

Abnormalities of vascular function occur in patients with risk factors for atherosclerosis before the development of obstructive disease. Our pilot data suggest that elevated serum markers of infection and/or inflammation are associated with functional abnormalities of the vasculature in subjects at otherwise low risk for atherosclerosis.

Chlamydia pneumoniae and atherosclerosis.

Chlamydia pneumoniae (C. pneumoniae) is a common respiratory pathogen. Many reports have documented the presence of C. pneumoniae in atheromatous coronary arteries, aorta, carotid arteries, and peripheral arteries using a variety of techniques. There is clear experimental evidence that C. pneumoniae can infect macrophages, endothelial cells, smooth muscle cells, and induce the formation of foam cells. Evidence from basic research and epidemiologic studies suggest that C. pneumoniae can induce macrophage foam cell formation by dysregulating native LDL uptake or metabolism (or both). Relatively small, secondary prevention studies, have suggested that antibiotic therapy might reduce monocyte activation and C. pneumoniae antibody titers, reduce inflammatory markers and possibly reduce adverse cardiovascular events. It is possible that C. pneumoniae enhances atherogenesis by causing inflammation and eliciting immune responses and may be one of the factors contributing to this multifactorial disease process.

Systolic hypertension in older patients: are calcium channel antagonists safe?

The Editor and Associate Editors are pleased that our readership will have the opportunity to benefit from a series of contributions by Dr John Rutherford addressing current issues in pharmacology and therapeutics pertinent to coronary artery disease. We are pleased also that Dr Rutherford will provide authoritative perspectives on topics of immediate interest on a regular basis.

The clinical dilemma of anorectic drug use and valvular heart disease.

Recent attention has focused on reported valvular heart lesions in patients taking anorectic drugs. This editorial reviews published reports, comments on new findings from a study published in this issue of The American Journal of Cardiology, and makes clinical recommendations.

Place conditioning with the dopamine D1-like receptor agonist SKF 82958 but not SKF 81297 or SKF 77434.

While self-administration and place conditioning studies have shown that dopamine D2-like receptor agonists produce reward-related learning, the effects of dopamine D1-like receptor agonists remain equivocal. The present study tested three dopamine D1-like receptor agonists for their ability to induce a place preference. Like control rats treated with amphetamine (2.0 mg/kg i.p.), rats treated with SKF 82958 (+/- -6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1-phenyl-1H- 3-benzazepine hydrobromide; 0.05 but not 0.01, 0.025, 0.075, or 0.10 mg/kg s.c. and/or i.p.) during conditioning showed a significant increase in the amount of time spent on the drug-paired side during the drug free test. Neither SKF 81297 (+/- -6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; 0.25, 0.50, 1.0, 2.0, and 4.0 mg/kg i.p.) nor SKF 77434 (+/- -7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; 0.20, 1.0, 5.0, and 10.0 mg/kg i.p.) produced place conditioning. Significant increases in locomotion were seen at some doses of all drugs. Results show for the first time that systemic administration of a dopamine D1-like receptor agonist produces a place preference and are consistent with previous findings showing that dopamine D1-like receptor activation produces reward-related learning.

The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.

BACKGROUND: In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. METHODS: In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. RESULTS: The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. CONCLUSIONS: These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.

Current incidence and determinants of perioperative myocardial infarction in coronary artery surgery.

Increasingly, patients undergoing coronary artery bypass grafting (CABG) are elders, have had previous CABG, and have poor left ventricular function. To evaluate determinants of perioperative myocardial infarction (PMI) after isolated CABG, 499 consecutive patients were reviewed. Definite PMI (total peak creatine kinase [CK] > 700 U/L, creatine kinase MB [CK-MB] > 30 ng/ml, and new pathologic electrocardiographic Q waves) occurred in 25 patients (5.0%) and probable PMI (total peak CK > 700 U/L, CK-MB > 30 ng/ml, and a new wall-motion abnormality) occurred in 10 (2.0%) patients. According to multivariate logistic regression analysis, independent risk factors for definite or probable PMI (adds ratios; 95% confidence intervals) were emergency surgery (3.1; 1.1 to 8.4; p = 0.003), aortic cross-clamp time > 100 minutes (4.2; 1.6 to 11.2; p = 0.004), myocardial infarction in the preceding week (2.6; 1.0 to 6.4; p = 0.04), and previous revascularization (2.4; 1.1 to 5.2; p = 0.02). In conclusion, both preoperative and intraoperative factors influence the risk of PMI after CABG. Despite changes in the profile of patients undergoing CABG, the incidence of PMI in this tertiary center is comparable with that found in earlier series, probably because of improvements in surgical techniques and postoperative care.

Risk stratification after myocardial infarction in the thrombolytic era.

Most patients with acute myocardial infarction do not receive or are ineligible for thrombolytic therapy, and thus their prognosis is worse than that of the populations studied in the major, randomized, lytic therapy trials. We need to devise a cost-effective strategy with which to appropriately stratify these patients. Simple, easily ascertained clinical variables that are evident soon after hospital admission can identify higher-risk patients, who are likely to be older and less able to adequately complete an exercise test. In some patients, nuclear imaging tests are appropriate; low-dose dobutamine echocardiography and ambulatory ECG monitoring may also have a role. Greater use of routine cardiac catheterization (with assessment of ventricular function) might be the most appropriate way to stratify patients because it may overcome some of the limitations of noninvasive testing, will clearly define high-risk patients, and may facilitate early discharge from the hospital. Left ventricular function and the patency of the infarct-related artery will be determined, and patients with left main coronary disease, significant three-vessel coronary artery disease, and two-vessel coronary disease (especially with proximal left anterior descending coronary artery involvement) will be identified. An aggressive strategy of revascularization to improve survival in appropriate patients may be employed. Greater use of routine coronary arteriography after acute myocardial infarction would inevitably lower the threshold for inappropriate, potentially risky, and expensive further interventions. We need to focus our attention on the most appropriate strategies for the management of patients whose prognosis is worse than the prognosis of those who receive lytic therapy after acute myocardial infarction.

Effect of infarct artery patency on prognosis after acute myocardial infarction. The Survival and Ventricular Enlargement Investigators.

BACKGROUND: In patients with acute myocardial infarction (MI), early restoration of patency of the infarct-related artery (IRA) leads to preservation of left ventricular function and improved clinical outcome. However, there is evidence that the benefits associated with a patent IRA are out of proportion to the observed improvement in ventricular function and may result not only from salvage of ischemic myocardium but also from the opening of the IRA beyond a narrow postinfarct time window. The objectives of this study were (1) to assess the effect of IRA patency on outcome of patients after acute MI with left ventricular dysfunction while controlling for differences in left ventricular ejection fraction and the extent of coronary disease and (2) to determine the effect of angiotensin-converting enzyme (ACE) inhibitor therapy on patients with patent as well as occluded infarct arteries. METHODS AND RESULTS: The Survival and Ventricular Enlargement (SAVE) study consisted of 2231 patients with a documented MI and a left ventricular ejection fraction < or = 40%. They were randomized to the ACE inhibitor captopril (50 mg TID) or placebo 3 to 16 days after MI and were followed for an average of 3.5 years. Left ventricular ejection fraction, measured with radionuclide left ventriculography, was repeated at the end of the follow-up period. The 946 patients in whom the patency of the IRA was established before randomization form the basis of this study. At cardiac catheterization averaging 4.2 days after infarction, 30.7% of patients had an initially occluded IRA. After revascularization, 162 of the 946 patients (17.1%) were left with an occluded IRA at the time of randomization. The 162 patients with persistently occluded IRAs and 784 with patent IRAs had similar clinical baseline characteristics, but those with occluded arteries had a slightly lower ejection fraction than the 784 patients with patent infarct arteries (30% versus 32%, P = .01). Cox proportional-hazards analyses showed that the independent predictors of all-cause mortality were hypertension (relative risk [RR] 1.94, P < .001), number of diseased coronary arteries (RR 1.68, P < .001), occluded IRA (RR 1.49, P = .039), ejection fraction (RR 1.36, P < .001), age (RR 1.10, P = .030), and use of beta-adrenergic receptor blocking agents (RR 0.60, P = .007). Independent predictors of a composite end point consisting of cardiovascular mortality, morbidity, or reduction of ejection fraction of > or = 9 units were occluded IRA (odds ratio [OR] 1.73, P = .002), hypertension (OR 1.71, P < .001), number of diseased vessels (OR 1.38, P < .001), ejection fraction (OR 1.18, P = .003), use of beta-adrenergic receptor blocking agents (OR 0.67, P = .007), and randomization to captopril (OR 0.70, P = .009). CONCLUSIONS: IRA patency within 16 days after MI predicts a favorable clinical outcome, independent of the number of obstructed coronary arteries or of left ventricular function. The beneficial effect of ACE inhibition is independent of patency status of the IRA. These findings support the need for additional, prospective clinical trials of late reperfusion in MI patients.

Nitrate tolerance in angina therapy. How to avoid it.

Tolerance is the attenuation, or loss, of one or several of the effects of organic nitrates after long term administration. All organic nitrate regimens using frequent doses of long-acting nitrates (3 or more times daily), continuous delivery systems [transdermal nitroglycerin (glyceryl trinitrate) patches or continuous intravenous infusions of nitroglycerin] or long-acting (sustained release) preparations will result in partial or complete nitrate tolerance. There are several proposed mechanisms which may contribute to the development of tolerance including activation of neurohormonal mechanisms, plasma volume expansion and depletion of intracellular sulfhydryl cofactors. To avoid tolerance to long term nitrate therapy, regimens should be tailored to provide a 10- to 12-hour nitrate-free interval when possible. This means that antianginal prophylaxis can only be provided by nitrate therapy for some portion of each day, and that some patients will develop an increase in angina in the nitrate-free intervals which will necessitate short term therapy with sublingual nitroglycerin or a similar preparation.

Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators.

BACKGROUND: In the Survival and Ventricular Enlargement (SAVE) trial, recurrent myocardial infarction (MI) was the most important predictor of a poor outcome and conferred a sevenfold increase in risk of death. The purpose of this study was to determine the predictors of recurrent MI in study participants and to examine the influence of the angiotensin-converting enzyme inhibitor captopril on this and other myocardial ischemic events. METHODS AND RESULTS: The 2231 patients had survived the acute phase of MI (3 to 16 days) and had a radionuclide ventricular ejection fraction < or = 40%. Patients were randomly assigned to receive double-blind treatment with either placebo or captopril and were followed for an average of 42 months. The influence of captopril on recurrent MI, cardiac revascularization procedures, and hospitalization with unstable angina was examined. The likelihood of recurrent MI was greater in patients with an MI or functional disability before the index infarction and higher systolic pressure (all P < .001) but was not influenced by baseline left ventricular ejection fraction. Therapy with captopril reduced the risk of development of recurrent MI by 25% (95% confidence intervals, 5% to 40%; P = .015) and the risk of death after recurrent MI by 32% (95% confidence intervals, 4% to 51%; P = .029). Captopril-assigned patients were also less likely to require cardiac revascularization procedures (P = .010), but hospitalization for unstable angina was unaltered. When all three of these major coronary ischemic events were considered together, captopril therapy reduced the risk (14% risk reduction; 95% confidence intervals, 0% to 26%; P = .047). CONCLUSIONS: In post-MI patients with asymptomatic left ventricular dysfunction, long-term administration of captopril reduced recurrence of MI and the need for cardiac revascularization but had no influence on the rate of hospitalization with a discharge diagnosis of unstable angina. The finding that the recurrence of MI was independent of left ventricular ejection fraction suggests that captopril could be useful in preventing recurrent MI in patients with more preserved left ventricular function. The need for cardiac revascularization was reduced in patients receiving long-term captopril therapy, suggesting either an anti-ischemic effect or the ability of the angiotensin-converting enzyme inhibitor to modify the atherosclerotic process in survivors of MI.

Pharmacologic management of angina and acute myocardial infarction.

A concise overview of the pharmacologic management of chronic stable angina, unstable angina, and acute myocardial infarction is presented. Nitrates, beta blockers, and calcium antagonists increase exercise tolerance and decrease symptoms in patients with chronic stable angina, and aspirin may prevent myocardial infarction. In unstable angina, aspirin reduces mortality; heparin may prevent myocardial infarction; and nitrates, beta blockers, calcium antagonists, and heparin may decrease angina. In acute myocardial infarction, thrombolytic therapy, aspirin, beta blockers, and intravenous nitrates may decrease mortality, whereas calcium antagonists do not affect mortality. Intravenous magnesium may decrease the incidence of ventricular tachycardia, ventricular fibrillation, and mortality in patients with acute myocardial infarction. The administration of angiotensin-converting enzyme (ACE) inhibitors after the acute phase of myocardial infarction may decrease mortality and prevent reinfarction in patients with left ventricular dysfunction.

The role of dipyridamole in addition to low dose aspirin in the prevention of occlusion of coronary artery bypass grafts.

One hundred and one subjects were randomised to receive either aspirin 100 mg or aspirin 100 mg + dipyridamole 300 mg daily before undergoing coronary bypass surgery. The drugs were commenced at least 36 hours before operation and patients were followed for one year. There were three perioperative deaths and 37 withdrawals, of which 14 were drug related (aspirin four, aspirin + dipyridamole ten). Cineangiocardiograms at nine weeks and one year showed vein graft patency rates of 93% and 87% for subjects treated with aspirin alone; and 90% and 89% in those who received aspirin+dipyridamole. During the follow-up period 14% of 232 coronary lesions in the aspirin treated group advanced by more than two grades compared with 15% of 315 lesions in the aspirin+dipyridamole group. The study did not establish superiority of one regimen over another in terms of graft patency or progress of lesions in native vessels. However, low dose aspirin was better tolerated than combination therapy.