Current Cardiology Reviews - Volume 10, Issue 1, 2014

In 1669, anastomoses between the right and left coronary artery were first documented by Richard Lower of Amsterdam. Using post-mortem imaging, a debate followed on the existence of structural inter-coronary anastomoses, which was not resolved before the first half of the 20ieth century in case of the presence of coronary artery disease (CAD), and not before the early 1960ies in case of the normal human coronary circulation by William Fulton. Functional coronary collateral measurements during coronary interventions were first performed only in the 1970ies, respectively in the early 1980ies. In humans, the existence of functional coronary collaterals in the absence of CAD has not been documented before 2003. Though the coronary collateral circulation has been recognized as an alternative source of blood supply to ischemic myocardium, its prognostic significance for the CAD population as a whole has been controversial until recently. The debate was due to different populations examined (acute versus chronic CAD, varying severity of CAD), to variable definitions of the term “prognosis”, to insufficient statistical power of the investigation with rare occurrence of prognostic endpoints, to short duration of follow-up and to blunt instruments employed for collateral assessment. Individually, it has been acknowledged that a well functioning collateral supply to a myocardial area at risk for necrosis reduces infarct size, preserves ventricular function, prevents ventricular remodelling and aneurysm formation. Collectively, evidence has accumulated only recently that an extensive coronary collateral circulation is a beneficial prognosticator quoad vitam. In a recent meta-analysis on the topic, the risk ratio to die from any cause for high vs low or absent collateralization in patients with subacute myocardial infarction was 0.53 (95% confidence interval 0.15–1.92; p=0.335), and for patients with acute myocardial infarction, it was 0.63 (95% confidence interval 0.29–1.39; p=0.257)¸ the relative risk to die from any cause for well vs poorly developed collaterals in patients with stable CAD was 0.59 (95% confidence interval 0.39–0.89), p=0.012.

Coronary artery hemodynamics are very different to that of the systemic arteries; unlike the systemic circulation, in the coronary circulation pressure is generated from both the proximal and distal end of the artery – due to the effect of contraction and relaxation of the myocardium on the microvasculature. As a result, the systemic artery hemodynamic model cannot be used to explain the pressure-flow relationship in the coronaries. Wave intensity analysis is an investigative tool that is able to distinguish simultaneous proximal and distal influences on coronary blood flow and is therefore uniquely suitable for the study of coronary haemodynamics. This review discusses the concept behind waveintensity analysis and evaluates how it has been used to characterise and provide new insights on coronary haemodynamics in health and disease.

The human coronary collateral circulation is prognostically relevant. The understanding of collateral formation and its determinants may guide future therapeutic strategies aiming at promoting collateral growth and functionality, and hence reducing the global burden of coronary artery disease (CAD).

The formation of collateral vessels (arteriogenesis) to sustain perfusion in ischemic tissue is native to the body and can compensate for coronary stenosis. However, arteriogenesis is a complex process and is dependent on many different factors. Although animal studies on collateral formation and stimulation show promising data, clinical trials have failed to replicate these results. Further research to the exact mechanisms is needed in order to develop a pharmalogical stimulant. This review gives an overview of recent data in the field of arteriogenesis.

While the existence of structural adaptation of coronary anastomoses is undisputed, the potential of coronary collaterals to be capable of functional adaptation has been questioned. For many years, collateral vessels were thought to be rigid tubes allowing only limited blood flow governed by the pressure gradient across them. This concept was consistent with the notion that although collaterals could provide adequate blood flow to maintain resting levels, they would be unable to increase blood flow sufficiently in situations of increased myocardial oxygen demand. However, more recent studies have demonstrated the capability of the collateral circulation to deliver sufficient blood flow even during exertion or pharmacologic stress. Moreover, it has been shown that increases in collateral flow could be attributed directly to collateral vasomotion. This review summarizes the pathophysiology of the coronary collateral circulation, ie the functional adapation of coronary collaterals to acute alterations in the coronary circulation.

A chronic total occlusion (CTO) describes a completely occluded coronary artery. This type of lesion is found in about 18% of all significant lesions in patients with coronary artery disease. A system of collateral connections are observed in almost all of these lesions, which have the capacity to prevent myocardial necrosis and may even uphold metabolic supply to the territory distal to an occlusion to maintain full contractile capacity. During exercise these collaterals are limited in their functional reserve, and more than 90% of patients with a well collateralized occlusion will experience ischemia. in the absence of ideal animal models that mimic the human collateral circulation, we need to rely on studies in man. The knowledge of collateral physiology in man has increased considerably over the past two decades with the advent of intracoronary sensors of coronary pressure and flow velocity. A number of basic physiologic questions have been answered by these studies. The blood supply through coronary arteries depends on a complex array of in general serial resistance systems, with an additional array of multiple parallel resistances on the collateral level. There seems to be a great interindividual variability in the ability to recruit preformed collateral connections in the case of an epicardial occlusion. Collateral function can develop to a similar functional level in patients post myocardial infarction with large akinetic territories as it does in patients with normal preserved regional function. The presence of viability is thus not a prerequisite for collateral development. The question of practical relevance in the era of interventional therapy of chronic occlusions is also, whether a patient with coronary artery disease will remain protected by collaterals after removing the obstruction in the collateralized artery, or whether collaterals regress and lose their functional capacity. Both developments are observed again mainly depending of individual predisposition.

Arteriogenesis as a way to restore blood flow after arterial occlusion has been under investigation for the treatment of coronary artery disease (CAD) for decades. Therapeutic approaches so far have included delivery of cytokines and growth factors as well as mechanical stimulation such as external counterpulsation. As knowledge on the mechanisms of arteriogenesis expanded, new therapeutic approaches have emerged. This review summarizes recent attempts to stimulate the growth of the coronary vasculature and discusses their potential in clinical application. This article also delivers an overview of current studies and trials on coronary arteriogenesis.

In the event of obstructive coronary artery disease, collateral arteries have been deemed an alternative blood source to preserve myocardial tissue perfusion and function. Monocytes play an important role in modulating this process, by local secretion of growth factors and extracellular matrix degrading enzymes. Extensive efforts have focused on developing compounds for augmenting the growth of collateral vessels (arteriogenesis). Nonetheless, clinical trials investigating the therapeutic potential of these compounds resulted in disappointing outcomes. Previous studies focused on developing compounds that stimulated collateral vessel growth by enhancing monocyte survival and activity. The limited success of these compounds in clinical studies, led to a paradigm shift in arteriogenesis research. Recent studies have shown genetic heterogeneity between CAD patients with sufficient and insufficient collateral vessels. The genetic predispositions in patients with poorly developed collateral vessels include overexpression of arteriogenesis inhibiting signaling pathways. New directions of arteriogenesis research focus on attempting to block such inhibitory pathways to ultimately promote arteriogenesis. Methods to detect collateral vessel growth are also critical in realizing the therapeutic potential of newly developed compounds. Traditional invasive measurements of intracoronary derived collateral flow index remain the gold standard in quantifying functional capacity of collateral vessels. However, advancements made in hybrid diagnostic imaging modalities will also prove to be advantageous in detecting the effects of pro-arteriogenic compounds.