Atherosclerosis is a multifactorial disease for which a number of risk factors have been well identified, including hypertension, hypercholesterolemia, smoking, diabetes, and ageing. However, growing evidence suggests that the individual burden of currently known cardiovascular risk factors is not the only determinant of atherosclerosis.

Aggressive therapy with the lipid-lowering drugs statins has substantially reduced cardiovascular risk in the setting of both primary and secondary prevention; in general, these drugs provide a 25% to 40% relative risk reduction in major adverse cardiovascular events such as death, myocardial infarction, and stroke. However, statin treatment fails to prevent 60% to 75% of events, and even with more aggressive treatment of conventional risk factors atherosclerosis will probably not be eradicated. Moreover, clinical research has revealed that severe clinical manifestations of atherosclerosis are due to "unstable" plaques prone to fibrous cap rupture or plaque surface erosion, which trigger thrombus formation and vessel lumen occlusion, rather than lumen stenosis stemming from exaggerated plaque growth. Acute ischemic events are thus the major cause of atherosclerotic morbidity and mortality. Early revascularisation using percutaneous coronary intervention coupled with antithrombotic and fibrinolytic therapies have reduced the occurrence of death or myocardial infarction in coronary patients. Yet, a threshold level of benefit appears to have been achieved with this strategy, and recent clinical trials aimed at evaluating the efficacy of new antithrombotic or fibrinolytic agents, or new drug combinations, have only shown marginal improvement as regards overall occurrence of clinical events. Therefore, there is an urgent need for a more profound understanding of the critical mechanisms involved in atherosclerotic plaque development and its complications in order to conceive novel diagnostic and therapeutic approaches aimed at preventing or limiting the progression of disease, and at promoting the functional recovery of organs injured by ischemia. Advances in research in vascular biology have indicated that endothelial dysfunction and inflammation are the two major determinants in the development of atherosclerotic lesions. Moreover, inflammation is a hallmark of unstable atherosclerosis. It is therefore logical to propose that new treatment strategies aimed directly at reversing endothelial dysfunction and reducing inflammation, especially in a plaque-specific manner, will be of major benefit against atherosclerotic plaque progression and acute ischaemic events.

For those patients who avoid or survive an acute ischaemic event, the end stage of advanced coronary atherosclerosis is likely to be heart failure. The incidence of heart failure has been rising alarmingly throughout the EU and Europe, especially as the population ages; most heart failure patients are in the 65 years plus age group.

In stable patients, heart failure is believed to result from chronic ischemia, while in patients who have suffered myocardial infarction this is compounded by reduction in the amount of viable myocardium. Improved prevention and treatment of unstable atherosclerosis and myocardial infarction may actually have contributed to the increased incidence of heart failure.
In particular, patients who survive large myocardial infarctions are the most likely to suffer adverse remodelling of their remaining myocardium and subsequent heart failure. Since the underlying pathology is ischemic, there is a growing belief that revascularization therapy must be developed to combat heart failure. Surgical and percutaneous revascularization procedures have been implemented throughout the EU for symptomatic coronary artery disease and have become the most commonly performed of all interventions.

Concurrently, there is growing body of knowledge regarding post-ischemic neovascularization through therapeutic angiogenesis/vasculogenesis. Initially this focussed on the possibility of stimulating existing endothelial cells to undergo angiogenesis or existing collateral arteries to enlarge. Recently, however, appreciation of the potential of resident stem cells and circulating endothelial progenitor cells has led to a revolutionary change in thinking. The new therapeutic strategy focuses on the ability to stimulate homing and expansion of stem cells to generate new arteries and thereby promote post-ischemic organ recovery.