Old and new cardiovascular risk factors: from unresolved issues to new opportunities.

With the aim of identifying areas that may deserve some further thinking the present review deliberately points out controversial issues in cardiovascular research and risk assessment. In the first part of the review general aspects are addressed regarding the evaluation of risk factors. A first point of concern is the frequent practice of combining different vascular events and effects in different vascular beds into a single endpoint. Furthermore, verification of vascular events in clinical reality may be surprisingly inaccurate. Problems in risk assessment also arise from overlapping properties (shared pathophysiological pathways) of traditional risk factors like hypertension, obesity and diabetes. In the second part of the review unresolved issues concerning selected established and emerging risk factors are discussed. The difficulty of establishing causality in cardiovascular disease is addressed, using modification of LDL cholesterol and accumulating evidence for pleiotropic effects of the LDL cholesterol-lowering statins as an example. As an alternative or supplement to the notion of LDL-related cardiovascular risk it is proposed to distinguish between statin-sensitive and statin-insensitive cardiovascular risk. Finally the future prospects of selected new and emerging risk factors like CRP, homocysteine, asymmetrical dimethylarginine (ADMA), oxLDL, and isoprostanes are evaluated. In summary, imprecise terminology and varying definitions of "cardiovascular risk" may lead to a considerable blurring of our current risk estimates, which may also explain some presently controversial issues. With several new risk factors and substantial changes in lifestyle and treatment patterns on the horizon major changes in the hierarchy of risk factors may be inevitable.