Identifying and Overcoming Obstacles in Angiogenic Gene Therapy for Myocardial Ischemia

Abstract

Well-developed coronary collateral vessels in patients with symptomatic coronary artery disease were shown to be associated with reduced future cardiovascular morbidity and mortality. However, the majority of patients with coronary artery disease lack adequate functional coronary collateral circulation. Stimulation of collateral vessel development by angiogenic growth factor therapy (therapeutic angiogenesis) has been tested in many clinical trials in the past, but the potential of this new treatment paradigm has not been realized yet in late stage clinical trials. Mechanistic insights into collateral vessel development and the collective clinical experience in the past decade identified specific obstacles that might have impeded the progress in the field. This review identifies some of the key conceptual, technical, and clinical hurdles and recommends strategies to overcome them in future clinical trials.

S-adenosyl-L-methionine improves ventricular remodeling after myocardial infarction by regulating angiogenesis and fibrosis

“…However, Stewart et al [21] found no significant difference in the cardiac capillary density and blood flow between the VEGF group and the placebo group in the clinical study of MI patients. Other studies have also found that MI patients treated with bFGF alone did not significantly recover blood flow around the infarcted myocardium, and did not significantly recover cardiac function [22]. It was discovered that VEGF or bFGF alone does not significantly improve the blood flow of myocardium.…”

Relationship between thrombospondin-1, endostatin, angiopoietin-2, and coronary collateral development in patients with chronic total occlusion

“…[24] However, stimulation of collateral vessel development by angiogenic growth factor (VEGF and FGF) therapy generated disappointing efficacy outcomes in late-stage clinical trials. [25] The exact reasons for this have not been determined yet. Perhaps a switch of focus from angiogenic to angiostatic factors will help to get better mechanistic understanding of adaptive vascular responses in the heart, which may favor therapeutic angiogenesis in the future.…”

Prognostic Implications of Coronary Collaterals in Transmural Infarct-Related Percutaneous Coronary Interventions

“…14 The so-called therapeutic angiogenesis by delivery to the heart of angiogenic growth factors for the development of revascularization and CCBF has been tested but is not in late-stage clinical trials. 15,16 Clinical trial evidence supports that in patients with CAD, vasculogenesis has potential for development of CCBF, with benefit for the ischemic heart from various growth factors and transplanted bone marrow–derived angioblasts. 17 A nicotinamide adenine dinucleotide phosphate oxidase may be important for early compensatory CCBF through various intermediates and ultimate dependence on generation of hydrogen peroxide.…”