Mechanistic, Technical, and Clinical Perspectives in Therapeutic Stimulation of Coronary Collateral Development by Angiogenic Growth Factors

Abstract

Stimulation of collateral vessel development in the heart by angiogenic growth factor therapy has been tested in animals and humans for almost two decades. Discordance between the outcome of preclinical studies and clinical trials pointed to the difficulties of translation from animal models to patients. Lessons learned in this process identified specific mechanistic, technical, and clinical hurdles, which need to be overcome. This review summarizes current understanding of the mechanisms leading to the establishment of a functional coronary collateral network and the biological processes growth factor therapies should stimulate even under conditions of impaired natural adaptive vascular response. Vector delivery methods are recommended to maximize angiogenic gene therapy efficiency and reduce side effects. Optimization of clinical trial design should include the choice of clinical end points which provide mechanistic proof-of-concept and also reflect clinical benefits (e.g., surrogates to assess increased collateral flow reserve, such as myocardial perfusion imaging). Guidelines are proposed to select patients who may respond to the therapy with high(er) probability. Both short and longer term strategies are outlined which may help to make therapeutic angiogenesis (TA) work in the future.

De-novo collateral formation following acute myocardial infarction: Dependence on CCR2+ bone marrow cells

“…This would promote salvage of a portion of the area at risk, leading to a smaller final infarct volume. Neo-collateral formation would also speed delivery of cardiac and vascular progenitor cells to this area, which evidence suggests promote myocardial repair, neo-vascularization, favorable chamber remodeling, and recovery of function [1–4,45–55]. Although additional studies will be required to examine these hypotheses, our findings that infarct volume and heart function closely associate with the extent of neo-collateral formation in mice with differences in genetic background and mice genetically deficient in MCP1 or CCR2 are consistent with a beneficial effect of collateral formation even if it does not begin until 1-to-2 days after acute myocardial infarction.…”

Flk-1/KDR Mediates Ethanol-Stimulated Endothelial Cell Notch Signaling and Angiogenic Activity

“…For example, atherosclerotic plaque angiogenesis seems to characterize the inflammatory, more vulnerable plaque and a positive association between neovessel density and plaque rupture has been reported [21]. In contrast, coronary collateral angiogenesis in response to occlusion ischemia can compensate for loss of perfusion following myocardial infarct or stroke and in this way can protect tissues from ischemic damage [22] [23]. Clinical observations indicate that the extent of collateralization among patients with cardiovascular disease varies considerably [23–25], with the factors responsible for this variation unclear.…”

“…In contrast, coronary collateral angiogenesis in response to occlusion ischemia can compensate for loss of perfusion following myocardial infarct or stroke and in this way can protect tissues from ischemic damage [22] [23]. Clinical observations indicate that the extent of collateralization among patients with cardiovascular disease varies considerably [23–25], with the factors responsible for this variation unclear. An understanding of the contributing causes, which may include genetic elements or lifestyle habits such as drinking, is therefore desirable.…”

Pet Imaging and its Application in Cardiovascular Diseases

“…Proangiogenic therapy is currently undergoing clinical testing in patients suffering from ischemic heart disease, peripheral vascular disease, chronic wounds, and stroke. 36 Many factors have been found to contribute to the process of angiogenesis; among them, vascular endothelial growth factor (VEGF) and integrin  V  3 have …”