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.

Figure 1

Mechanisms of vascular formation in the adult organism. Differences in induction, the participating factors, and the biological processes of angiogenesis, arteriogenesis, and vasculogenesis are illustrated. Factors shown in overlapping areas participate in both processes depicted by the overlapping circles. Ang-1 and Ang-2, angiopoietin-1 and -2; EC, endothelial cell; EPC, endothelial progenitor cell; FGF, fibroblast growth factor; GM-CSF, granulocyte and monocyte colony-stimulating factor; HGF, hepatocyte growth factor; HIF-1α, hypoxia-inducible factor 1α MCP-1, monocyte chemotactic factor 1; MMPs, matrix metalloproteases; NO, nitric oxide; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β VEGF, vascular endothelial growth factor. Modified from ref. with permission from Oxford University Press.

Figure 2

Schematic illustration of the two concepts of adaptive collateral development. The hemodynamic stimulus concept with large collateral arteries developing in normoxic myocardial regions (left) and the ischemic stimulus concept with collateral capillaries/arterioles developing in or near ischemic myocardial regions (blue shaded area) (right), based on measurement of peripheral coronary artery pressure (distal to feed artery stenosis). High peripheral pressure indicates the presence of collateral arteries, proximal to pre-capillary resistance vessels in the feed artery territory (left). Low peripheral pressure suggests that collateral vessels are located distal of pre-capillary resistance arterioles (right).

Figure 3

Growth factor gene delivery methods used to target the heart. Intramuscular (green) and intravascular via antegrade (through coronary arteries, red) or retrograde (through coronary veins, blue) routes. Schematic illustration of how these various methods allow the gene delivery vector to reach ischemic/peri-ischemic microvascular regions and/or pre-existing collateral vessels.

Figure 4

Schematic illustration of assessment of coronary collateral flow reserve. Diagram illustrating the principle of collateral flow assessment during coronary artery balloon occlusion using an angioplasty pressure or Doppler sensor guide wire, positioned distal to the occluded site. Signals (pressure or flow velocity) detected during angioplasty balloon occlusion in a poorly (left) or well collateralized myocardial region (right) are depicted. During vascular occlusion, the signals are proportional to blood flow through collateral vessels supplying the occluded vascular region. If the measurement is performed during vasodilation of the corresponding microcirculation (achievable during exercise or pharmacological stress), the signal represents maximal achievable collateral flow. CFR, collateral flow reserve.