In experimental studies in the dog, total proximal coronary artery occlusions of up to 15 minutes result in reversible injury, meaning that the myocytes survive this insult. The 15 minutes of ischemia, however, induce numerous changes in the myocardium, including certain monuments to the brief episode of ischemia that may persist for days. One of these monuments is stunned myocardium, which represents "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." The mechanism of stunning involves generation of oxygen radicals as well as alteration in calcium homeostasis and possibly alteration in contractile protein structure. Stunning has been observed in several clinical scenarios, including after percutaneous transluminal coronary angioplasty, unstable angina, stress-induced ischemia, after thrombolysis, and after cardiopulmonary bypass. Oxygen radical scavengers and calcium channel blockers have been shown to enhance function of stunned myocardium in experimental studies, and in a few clinical studies, calcium channel blockers have been shown to ameliorate stunning. Although brief periods of ischemia can contribute to prolonged left ventricular dysfunction and even heart failure, they paradoxically play a cardioprotective role. Episodes of ischemia as short as 5 minutes, followed by reperfusion, protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis that results from the test episode of ischemia. This phenomenon, called ischemic preconditioning, has been observed in virtually every species in which it has been studied and is a powerful cardioprotective effect. The mechanism of ischemic preconditioning involves both triggers and mediators and involves complex second messenger pathways that appear to involve such components as adenosine, adenosine receptors, the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, as well as others, including a paradoxical protective role of oxygen radicals. Both an early and a late phase of preconditioning have been described, and the mechanisms underlying their induction are under investigation. That preconditioning may occur in humans is suggested by the observations that repetitive balloon inflations in the coronary artery are associated with progressively less chest pain, ST-segment elevation, lactate production, the protective effects of preinfarction angina, the anginal "warm-up phenomenon," and studies performed on human cardiac biopsies that show metabolic properties suggesting preconditioning. Development of pharmacological agents that stimulate second messenger pathways thought to be involved in preconditioning, but without causing ischemia, could result in novel approaches to treating ischemia. Hence, on one hand, brief episodes of ischemia can have a negative effect on the heart: stunning; and on the other hand, they have a protective effect: preconditioning. The future challenge is how to minimize the stunning phenomenon and maximize the preconditioning phenomenon in clinical practice.

Diabetes mellitus is a major risk factor for adverse outcomes after acute coronary syndromes (ACS). Because this disease may be associated with increased platelet aggregation, we investigated whether diabetic patients with ACS derive particular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition.

This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiologic transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.

Angiographic restenosis after percutaneous coronary interventional procedures is more common than recurrent angina. Clinical and angiographic factors associated with asymptomatic versus symptomatic restenosis after percutaneous coronary intervention were compared.

In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs.

Elevated plasma levels of HDL cholesterol or apolipoprotein A-I, the major protein moiety of HDL particles, are protective against coronary artery disease. HDL particles remove cholesterol from peripheral cells and transfer it to the liver for bile acid synthesis. The interaction between lipoproteins is not mediated through simple contact between 2 phospholipid membranes but involves specific protein-receptor interactions, charged phospholipid-phospholipid contact, and activation of cellular signaling pathways. These lead to regulation of genes or the modification of proteins involved in vasomotor function, platelet activation, thrombosis and thrombolysis, cell adhesion, apoptosis and cell proliferation, and cellular cholesterol homeostasis.

High-protein diets have recently been proposed as a "new" strategy for successful weight loss. However, variations of these diets have been popular since the 1960s. High-protein diets typically offer wide latitude in protein food choices, are restrictive in other food choices (mainly carbohydrates), and provide structured eating plans. They also often promote misconceptions about carbohydrates, insulin resistance, ketosis, and fat burning as mechanisms of action for weight loss. Although these diets may not be harmful for most healthy people for a short period of time, there are no long-term scientific studies to support their overall efficacy and safety. These diets are generally associated with higher intakes of total fat, saturated fat, and cholesterol because the protein is provided mainly by animal sources. In high-protein diets, weight loss is initially high due to fluid loss related to reduced carbohydrate intake, overall caloric restriction, and ketosis-induced appetite suppression. Beneficial effects on blood lipids and insulin resistance are due to the weight loss, not to the change in caloric composition. Promoters of high-protein diets promise successful results by encouraging high-protein food choices that are usually restricted in other diets, thus providing initial palatability, an attractive alternative to other weight-reduction diets that have not worked for a variety of reasons for most individuals. High-protein diets are not recommended because they restrict healthful foods that provide essential nutrients and do not provide the variety of foods needed to adequately meet nutritional needs. Individuals who follow these diets are therefore at risk for compromised vitamin and mineral intake, as well as potential cardiac, renal, bone, and liver abnormalities overall.

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.

Coronary calcium is intimately associated with coronary atherosclerotic plaque development. The use of electron-beam computed tomography (EBCT) for accurate quantitative measurements has led to an increased interest in understanding the clinical importance of coronary calcium, particularly in terms of the ability to identify unstable coronary plaques that underlie the clinical acute coronary syndromes. Histopathologic studies have demonstrated that calcium is a frequent feature of ruptured plaques, but the presence or absence of calcium does not allow for reliable distinction between unstable versus stable plaques. This issue is complicated by the lack of a prospective definition for "unstable." Plaque rupture is sometimes found in apparently healthy subjects and in patients with clinically stable disease. Coronary atherosclerosis is a coronary systemic disease process. Imaging of coronary calcium, although unable to identify a localized unstable plaque, potentially can identify the more clinically pertinent "unstable patient." Almost all patients with a recent acute coronary syndrome have measurable coronary calcium because moderate-to-advanced coronary plaque disease is already present, although obstructive disease frequently is not. Prospective studies have demonstrated that extensive coronary calcium detected by EBCT is associated with a significantly increased incidence of subsequent myocardial infarction, need for revascularization, and coronary death. The incremental prognostic value of coronary calcium compared with that of risk factor assessment remains to be fully defined. The occurrence of an acute coronary syndrome is determined by many factors apart from the extent of atherosclerotic plaque disease. Large prospective trials in the general population are needed to define the subgroups that will benefit most from quantitative assessment of coronary calcium.