Cardioprotection during ischemia by coronary collateral growth

Abstract

Ischemic heart diseases (IHD) cause millions of deaths around the world annually. While surgical and pharmacological interventions are commonly used to treat patients with IHD, their efficacy varies from patient to patient and is limited by the severity of the disease. One promising, at least theoretically, approach for treating IHD is induction of coronary collateral growth (CCG). Coronary collaterals are arteriole-to-arteriole anastomoses that can undergo expansion and remodeling in the setting of coronary disease when the disease elicits myocardial ischemia and creates a pressure difference across the collateral vessel that creates unidirectional flow. Well-developed collaterals can restore blood flow in the ischemic area of the myocardium and protect the myocardium at risk. Moreover, such collaterals are correlated to reduced mortality and infarct size and better cardiac function during occlusion of coronary arteries. Therefore, understanding the process of CCG is highly important as a potentially viable treatment of IHD. While there are several excellent review articles on this topic, this review will provide a unified overview of the various aspects related to CCG as well as an update of the advancements in the field. We also call for more detailed studies with an interdisciplinary approach to advance our knowledge of CCG. In this review, we will describe growth of coronary collaterals, the various factors that contribute to CCG, animal models used to study CCG, and the cardioprotective effects of coronary collaterals during ischemia. We will also discuss the impairment of CCG in metabolic syndrome and the therapeutic potentials of CCG in IHD.

Keywords: cardioprotection; coronary circulation; coronary collateral growth; ischemia.

Fig. 1.

Clinical aspect of coronary collaterals. A: schematic showing calculation of the collateral flow index (CFI). P_ao, mean aortic pressure; P_occl, distal intracoronary occlusive pressure. CFI can be calculated as follows: (P_occl – CVP)/(P_ao – CVP), where CVP is central venous pressure. B: CFI as calculated by Stoller et al. in different systemic arterial territories. CA, coronary artery; left SCA, left subclavian artery; RA, renal artery; left SFA, left superficial femoral artery. C: schematic showing the orientation of the right and left internal thoracic (mammary) arteries with respect to the heart. The internal thoracic arteries give rise to the pericardiacophrenic arteries, which supply blood to the heart. Stoller et al. (63) reported increased CFI (in the right CA) in patients whose distal right internal thoracic arteries had been closed permanently. This figure was created by modifying graphic elements freely available from Servier Medical Art (https://smart.servier.com/) under a Creative Commons Attribution 3.0 Unported License.

Fig. 2.

Stimulation of coronary collateral growth. A: the work flow of experimental stimulation of coronary collateral growth (CCG). B–D: three-dimensional reconstruction of microcomputed tomography images of the vasculature in the rodent heart. B: vascular tree of a heart without the stimulation of repetitive ischemia (RI). C: artist’s rendering of vascular tree of a heart with the stimulation of RI. D: vascular tree of a heart without the stimulation during the ligation of the left anterior descending coronary artery (LAD). Note the lack of vascular perfusion in the collateral dependent zone. E: artist’s rendering of vascular tree of a heart with the stimulation during ligation of the LAD. Note repetitive ischemia stimulated growth of coronary collaterals (pink) and provides an alternate supply route, bypassing the site of LAD ligation.

Fig. 3.

Summary of the various clinical and experimental approaches that have been used to promote coronary collateral-mediated cardioprotection in ischemic heart disease. CFI, collateral flow index; ECP, external counterpulsation; EECP, enhanced external counterpulsation; ISRT, individual shear rate therapy; FMD, flow-mediated dilation; VEGF, vascular endothelial growth factor; G-CSF, granulocyte colony-stimulating factor; MCP1, monocyte chemoattractant protein-1; FGF, fibroblast growth factor. This figure was created by modifying graphic elements freely available from Servier Medical Art (https://smart.servier.com/) under a Creative Commons Attribution 3.0 Unported License.