Current Pharmaceutical Design - Volume 9, Issue 13, 2003

Cardiovascular disease is the leading cause of death in Western society. Extracellular matrix turnover is important in many cardiovascular pathologies, such as arterial remodeling, plaque rupture, restenosis, aneurysm formation and heart failure. Matrix metalloproteinases (MMPs) belong to a group of zinc and calcium dependent proteases and cause breakdown of the extracellular matrix. MMP inhibitors have been developed and tested for their effect on the outcome of oncological disease [1]. Recent preclinical research revealed that these MMP inhibitors could also have great potential in the field of cardiovascular disease. This preclinical research has encouraged investigators to design and start the first clinical studies with cardiovascular endpoints.In the present paper, the various aspects of MMP participation in cardiovascular disease will be summarized. Preclinical animal studies that demonstrated the effect and potential of applicable MMP inhibitors on different cardiovascular disease entities will be discussed. We will specifically focus on the role of MMPs and the potential of their inhibitors in de novo atherosclerotic plaque destabilization, arterial remodeling, restenosis after ballon angioplasty and stenting, aneurysm formation and heart failure. We conclude that MMP inhibitors are likely to be useful in the development of pharmacological approaches to reduce cardiovascular death, considering the positive outcomes after usage of MMP inhibitors in restenosis and arterial remodeling.

Cardiovascular atherosclerotic diseases remain leading causes of morbidity and mortality in the world. Despite the significant progress that has been made in the management of these diseases using medical, surgical and percutaneous therapies over the last three decades, there remains a significant population of patients who are not optimal candidates for surgical or percutaneous revascularization.Substantial research has focused on the administration of angiogenic growth factors, either as recombinant protein or by gene transfer, to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries, a strategy termed “therapeutic angiogenesis”. While many cytokines have angiogenic activity, the best studied both in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). This review will discuss gene transfer strategies for therapeutic angiogenesis in critical limb and myocardial ischemia.

Arterial stiffness is the most important cause of increasing systolic and pulse pressure, and for decreasing diastolic pressure with ageing. Many measures can be applied to quantify arterial stiffness, but all are approximations only, on account of the nonhomogenous structure of the arterial wall, its variability in different locations, at different levels of distending pressure, and with changes in smooth muscle tone. This article summarizes those indices with a focus on newer non-invasive methods and provides an overview of physiological, pathological and pharmacological influences on arterial hemodynamics.In the near future, the ability to detect and monitor subclinical arterial damage will improve cardiovascular risk stratification and act as a better guide in assessing the efficacy of therapeutic interventions than monitoring blood pressure alone. However, large-scale clinical trials are needed to prove the hypothesis that treatment of these new therapeutic targets will translate into clinical benefit, expressed in cardiovascular events or even mortality.

Activation of the renin-angiotensin-aldosterone system is associated with unsatisfactory outcomes in patients with hypertension and heart failure in that activation of this system is correlated strongly with both the incidence and extent of end-organ damage. Despite the availability of the angiotensin converting enzyme inhibitors (ACEi) and the angiotensin receptor blockers (ARB), unblocked aldosterone levels remain an important risk factor for cardiovascular disease progression. New preclinical data generated over the last few years strongly supports the hypothesis that aldosterone has important deleterious effects on the cardiovascular system independent of the classical action of this hormone on renal epithelial cells. The new selective aldosterone blocker, eplerenone, has been shown to produce significant cardioprotective and renoprotecive effects in experimental models of cardiovascular disease. Early clinical studies suggests that eplerenone may have important therapeutic benefit in the treatment of hypertension and heart failure post-myocardial infarction (post-MI).

Coronary artery stents have emerged as the preferred tool for percutaneous coronary interventions during the past decade by eliminating abrupt vessel closure and reducing restenosis compared with balloon angioplasty. While coronary artery stents prevent constrictive arterial remodeling and elastic recoil, the implantation is associated with more severe arterial vascular injury than balloon angioplasty alone. The arterial injury initiates a vasculoproliferative response with smooth muscle cell proliferation and migration as well as extracellular matrix formation, which may lead to severe neointimal hyperplasia with in-stent restenosis in 10-30% of cases. Sirolimus, a naturally occurring macrocyclic lactone, has been identified as a pharmacological cell cycle inhibitor with potent antiproliferative and antimigratory effects on vascular smooth muscle cells in vitro. The systemic administration of sirolimus has been shown to effectively reduce neointimal hyperplasia in experimental restenosis models. Subsequently, sirolimus has been incorporated at therapeutically important doses into biocompatible polymers, which made it suitable for stent-based drug elution. Investigation of sirolimus eluting stents in both experimental and clinical restenosis studies have demonstrated dramatic reductions in neointimal hyperplasia. Accordingly, sirolimus eluting stents offer an attractive mode of local drug delivery by minimizing systemic toxicity and maximizing local dose requirements. In addition, sirolimus eluting stents hold great promise to effectively prevent restenosis.