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Evidence that an excess of plasma free fatty acids (FFA) might lead to primary ventricular fibrillation and sudden cardiac death has hardened over the 36 years since the hypothesis was proposed. When the sympathetic nervous system is stimulated during the onset of an acute coronary syndrome, catecholamine-induced tissue lipolysis occurs, with a surge of plasma FFA. This may overload the acutely ischaemic myocardium and impair glucose utilization. Myocardial oxygen consumption can increase in regional areas of ischaemia, and could lead to abnormal electrophysiological conduction and refractoriness, with irreversible ventricular arrhythmias. Efforts to combat the adverse effects of excess FFA include beta-blockade, increasing glucose availability and extraction, or inhibition of lipolysis. This last approach appears promising, but no method has yet been clearly shown to prevent primary ventricular fibrillation or sudden cardiac death. The hypothesis remains viable. More research is needed to derive treatment that can be applied as soon as the onset of acute myocardial ischaemia is suspected.

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Fatal ventricular fibrillation is a common complication of acute coronary syndromes. Effective preventive measures are not available. Immediate restriction of free fatty acid availability should optimize ischemic myocardial metabolism, reduce ventricular vulnerability, and increase glucose utilization. Rapid inhibition of lipoprotein lipase activity will achieve this. The clinical effects of antilipolytic treatment require further study.

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CONTEXT: Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events. OBJECTIVE: To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events. DESIGN AND SETTING: A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia. PATIENTS: A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction. INTERVENTIONS: Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission. MAIN OUTCOME MEASURES: Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization. RESULTS: A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001). CONCLUSION: For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.

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BACKGROUND: Mivazerol is a drug with alpha2-agonist properties that reduces post-ganglionic noradrenaline availability and spinal efferent sympathetic output. METHODS: A double-blind randomized placebo-controlled trial was conducted in 61 European centers during a 2.5-yr period on 2,854 patients: 1,897 with coronary heart disease and 957 patients without overt coronary heart disease but classified as at high risk for it. The present analysis was restricted to those patients with previous known coronary heart disease of whom 48% had vascular surgery, 32% non-vascular thoracic or abdominal surgery, and 20% orthopedic surgery. Mivazerol or placebo were given intravenously from the induction of anesthesia for up to 72 h. RESULTS: In the 1,897 patients with established coronary heart disease, mivazerol did not reduce the primary endpoint--the combination of myocardial infarction or death--or all-cause deaths significantly. A preplanned subgroup analysis of 904 patients with known coronary heart disease undergoing vascular surgery showed that there were fewer primary endpoints in those receiving mivazerol (risk ratio [RR], 0.67; 95% CL, 0.45-0.98; P = 0.037) and fewer cardiac deaths (6 of 454 vs. 18 of 450: RR, 0.33; 95% confidence limits, 0.13-0.82; P = 0.017). The all-cause death rate was also decreased (RR, 0.41; 95% CL, 0.18-0.91; P = 0.024), although there was no significant reduction in myocardial infarction. CONCLUSION: The alpha2-adrenergic agonist, mivazerol, did not alter the rates of myocardial infarction or cardiac death in patients with known coronary heart disease undergoing noncardiac surgery. However, it may have protected patients undergoing vascular surgery from further coronary events, and a specific study of such patients is now indicated.

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A specific alpha(2) agonist, mivazerol, known to be effective in reducing myocardial ischaemia when given intravenously immediately before an exercise tolerance test, produced a significant increase in exercise duration and time to the onset of angina when given orally over a two week period to 25 patients with stable angina. A non-significant trend to reduction in electrocardiographic signs of ischaemia was also noted. The clinical relevance of this improvement now needs to be tested in larger numbers.

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In arguing for a conservative view of the need for and wisdom of lowering plasma cholesterol, or low density lipoprotein cholesterol, in advanced age, three considerations are taken into account. These are: plasma cholesterol concentrations decrease spontaneously with age, as does their association with vascular disease; the absence of data to demonstrate the benefits of lowering cholesterol levels in the elderly; and conflicting priorities (including the cost of treatment) in the care of the elderly. Patients with known coronary heart disease who have received lipid-lowering treatment for some years could continue to be treated with these drugs beyond the age of 75, though even this decision should depend on clinical judgement.

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The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.

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The evidence from formal, controlled, long-term clinical trials that changes in dietary fats reduce the incidence of ischemic (coronary) heart disease (IHD) is unimpressive. Mostly these trials were underpowered and in several the rigor of dietary control in the intervention and control groups was inadequate. Six controlled clinical trials in healthy people of diets low in saturated fat and cholesterol, also accompanied by changes in other risk factors, were unsuccessful in reducing the incidence of IHD. An exception was the Oslo trial in which concurrent cigarette smoking was almost halved. Similarly, in the only two clinical trials of the secondary prevention of IHD through use of diets low in saturated fats and cholesterol there was no significant effect on IHD recurrence rate. This may relate to poor compliance outside strict clinic conditions. In contrast, five of six secondary prevention trials in which diets low in saturated fats were supplemented with polyunsaturated fats reduced IHD deaths and, to a lesser extent, all-cause mortality. No formal trial has been reported of the effects on IHD of diets high in monounsaturated fats. The greatest benefit for patients with IHD has come from diets supplemented with n-3 fatty acids (two trials), and this benefit was independent of changes in plasma lipoproteins. The evidence from these clinical trials indicates that more emphasis should be given in national and international dietary recommendations to supplementation with polyunsaturated fats, particularly foods rich in n-3 fatty acids, than to diets low in total and saturated fats.

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