Thrombolytic therapy significantly improves the natural history of acute myocardial infarction, but recent data suggest that current reperfusion strategies have yet to realize the maximum potential for reduction of mortality and salvage of ventricular function. Coronary patency rates as high as 85% assessed by angiography 90 minutes after initiation of treatment greatly overestimate the efficacy of thrombolytic regimens, as this conventional angiographic "snapshot" view does not satisfactorily reflect the dynamic processes of coronary artery recanalization and reocclusion or the adequacy of myocardial perfusion. In fact, only the unusual patient appears to achieve optimal reperfusion for acute myocardial infarction, with a substantial deterioration of benefit in many patients due to insufficiently early or rapid recanalization, incomplete patency with TIMI grade 2 flow or critical residual coronary stenoses, absence of myocardial tissue reflow despite epicardial artery patency, intermittent coronary patency, subsequent reocclusion, or reperfusion injury. Recently developed techniques to critically assess the quality of reperfusion, coupled with the introduction of novel pharmacological agents and an improved understanding of the roles and mechanisms of existing thrombolytic and adjunctive drugs, have provided the opportunity to overcome many of the present limitations of reperfusion therapy. Emerging strategies to achieve optimal reperfusion are directed at enhancement of the velocity and quality of thrombolysis, amelioration of the adverse effects of reperfusion, and use of alternative pathways to myocardial salvage.

In a meta-analysis of 31 placebo-controlled trials on 1356 subjects, we examined the effect of omega-3 fatty acids in fish oil on blood pressure by grouping studies that were similar in fish oil dose, length of treatment, health of the subjects, or study design.

Amiodarone is a viable drug for preventing sudden cardiac death, particularly during the first year after MI. If larger trials confirm the aforementioned prospective trials of Ceremuzynski et al, Cairns et al, and the BASIS trial, the efficacy of amiodarone would outweigh the risk of its side effects during the first year after MI. Based on the long-term observation from the BASIS trial, the duration of amiodarone therapy need not be more than 1 year--which, as we have learned, is when these post-MI patients would benefit most from the drug. It is also likely that the effects of amiodarone would complement those of aspirin and angiotensin converting enzyme inhibitors. The SAVE, CONSENSUS II, and SOLVD trials demonstrated that captopril and enalapril did not reduce the mortality rate during the first year after MI, nor did they reduce the sudden cardiac death rate. Their beneficial effects became evident only during the second year and thereafter. Unlike other antiarrhythmic agents of various classes, amiodarone possesses antiarrhythmic properties but does not exert deleterious effects on ventricular function. More studies are needed to determine if the benefit of amiodarone could be enhanced by combination therapy (eg, angiotensin converting enzyme inhibitors, aspirin, or beta-blockers). Whether amiodarone will provide the same protection for patients who have poor left ventricular function or congestive heart failure is not known. The European and VA cooperative studies should help answer this question. If it turns out that amiodarone is beneficial, one must then determine whether higher doses of the drug will offer more protection, and, if so, if that greater protection would be offset by increased toxicity. How much amiodarone should be given to offer the most protection with the least risk? Another intriguing research question is this: If we treat patients with amiodarone for more than 1 year, would the drug continue to improve the mortality rate in subsequent years? Other studies are needed in patients at very high risk of sudden cardiac death (ie, those who have a low ejection fraction and high-density VPDs). A study comparing amiodarone and sotalol in high-risk patients for sudden cardiac death is also needed. These clinical studies should be carried out with basic science research investigating the actions of amiodarone at the molecular and cellular level in order to give us a better understanding of how the drug works.

Atrioventricular (AV) nodal reentry is a relatively common cause of regular, narrow QRS tachycardia. The underlying basis for this arrhythmia is functional (and anatomic) duality of pathways in the region of the AV node, although the exact boundaries of the reentrant circuit have not been convincingly defined. During the more common type of AV nodal reentry (seen in approximately 90% of cases), a slow conducting pathway is used in the anterograde direction, and a fast pathway is operative in the retrograde direction. In the uncommon form, the direction of impulse propagation within the reentrant circuit is reversed. In this article, the clinical, ECG, and electrophysiological features of AV nodal reentry as well as approaches to therapy are discussed.

The consensus of evidence from angiographic trials demonstrates both coronary artery and clinical benefits from lowering of lipids by a variety of regimens. The findings of reduced arterial disease progression and increased regression have been convincing but, at best, modest in their magnitude. For example, among those treated intensively in FATS, the mean improvement in proximal stenosis severity per patient was < 1% stenosis, and only 12% of all lesions showed convincing regression. In view of these modest arterial benefits, the associated reductions in cardiovascular events have been surprisingly great. For example, coronary events were reduced 75% in FATS; this was entirely a result of a 93% reduction in the likelihood that a mildly or moderately diseased arterial segment would experience substantial progression to a severe lesion at the time of a clinical event. We believe that the magnitude of the clinical benefit is best explained in terms of this observation, according to the following lines of reasoning. Clinical events most commonly spring from lesions that are initially of mild or moderate severity and then abruptly undergo a disruptive transformation to a severe culprit lesion. The process of plaque fissuring, leading to plaque disruption and thrombosis, triggers most clinical coronary events. Fissuring is predicted by a large accumulation of core lipid in the plaque and by a high density of lipid-laden macrophages in its thinned fibrous cap. Lesions with these characteristics constitute only 10-20% of the overall lesion population but account for 80-90% of the acute clinical events. In the experimental setting, normalization of an atherogenic lipid profile substantially decreases the number of lipid-laden intimal macrophages (foam cells) and depletes cholesterol from the core lipid pool. In the clinical setting, intensive lipid lowering virtually halts the progression of mild and moderate lesions to clinical events. Thus, the reduction in clinical events observed in these trials appears to be best explained by the relation of the lipid and foam cell content of the plaque to its likelihood of fissuring and by the effects of lipid-lowering therapy on these "high-risk" features of plaque morphology. The composite of data presented here supports the hypothesis that lipid-lowering therapy selectively depletes (regresses) that relatively small but dangerous subgroup of fatty lesions containing a large lipid core and dense clusters of intimal macrophages. By doing so, these lesions are effectively stabilized and clinical event rate is accordingly decreased.

Calcium homeostasis in cardiac myocytes results from the integrated function of transsarcolemmal Ca2+ influx and efflux pathways modulated by membrane potential and from intracellular Ca2+ uptake and release caused predominantly by SR function. These processes can be importantly altered in different disease states as well as by pharmacological agents, and the resulting changes in systolic and diastolic [Ca2+]i can cause clinically significant alterations in contraction and relaxation of the heart. It may be anticipated that a rapid increase in our understanding of the pathophysiology of Ca2+ homeostasis in cardiac myocytes will be forthcoming as the powerful new tools of molecular and structural biology are used to investigate the regulation of Ca2+ transport systems.