Is the peripheral microcirculation a window into the human coronary microvasculature?

Abstract

An increasing body of evidence suggests a pivotal role for the microvasculature in the development of cardiovascular disease. A dysfunctional coronary microvascular network, specifically within endothelial cells-the inner most cell layer of vessels-is considered a strong, independent risk factor for future major adverse cardiac events. However, challenges exist with evaluating this critical vascular bed, as many of the currently available techniques are highly invasive and cost prohibitive. The more easily accessible peripheral microcirculation has surfaced as a potential surrogate in which to study mechanisms of coronary microvascular dysfunction and likewise may be used to predict poor cardiovascular outcomes. In this review, we critically evaluate a variety of prognostic, physiological, and mechanistic studies in humans to answer whether the peripheral microcirculation can add insight into coronary microvascular health. A conceptual framework is proposed that the health of the endothelium specifically may link the coronary and peripheral microvascular beds. This is supported by evidence showing a correlation between human coronary and peripheral endothelial function in vivo. Although not a replacement for investigating and understanding coronary microvascular function, the microvascular endothelium from the periphery responds similarly to (patho)physiological stress and may be leveraged to explore potential therapeutic pathways to mitigate stress-induced damage.

Keywords: Coronary; Endothelium; Microvasculature; Translational.

Figure 1.. Summary of techniques for evaluating in vivo human coronary microvascular function.

Evaluation of coronary microvascular function in vivo is performed via coronary catheterization procedure or using non-invasive imaging modalities (top panel). These techniques can be used to determine coronary flow reserve (CFR) as an indicator of coronary microvascular function in the absence of epicardial stenosis, yet its reliability is highly dependent on the method selected to induce maximal coronary hyperemia (e.g., adenosine, exercise) and the subject’s basal coronary flow. Due to these limitations, other equations for the assessment of coronary microvascular function have been proposed due to their seemingly improved repeatability and reduced influence of baseline hemodynamics (lower panel)(11, 104).

Figure 2.. Summary of techniques for evaluating human peripheral microvascular function.

Numerous in vivo techniques are available for studying the microvasculature in the sublingual area, retina, and forearm given the ease of access to these areas (see in figure descriptions of individual techniques). Compared to the coronary circulation, peripheral microvascular beds can be studied relatively non-invasively in a variety of populations (i.e., healthy and diseased) with more readily available equipment making the peripheral circulation an intriguing option for better understanding the mechanisms of microvascular dysfunction. In addition, ex vivo arterioles from humans, acquired from discarded surgical tissue or through adipose biopsies, allow for more thorough mechanistic studies (lower panel).

Figure 3.. Mechanisms of Flow-Induced Dilation in the Human Microvasculature During Health and Disease.

In healthy endothelium, shear-sensitive ion channels rapidly increase intracellular calcium to form a complex with calmodulin capable of activating endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO). NO diffuses into the smooth muscle and binds with soluble guanylate cyclase to increase intracellular guanosine 3’,5’-cyclic monophosphate (cGMP). This subsequently activates protein-kinase-G (PKG) which then inhibits L-type calcium channels, activates B_K-potassium channels, and activates myosin light chain phosphatase to illicit smooth muscle relaxation(105, 106). Endothelial calcium can also activate cyclooxygenases to convert arachidonic acids into prostacyclin, which stimulates smooth muscle adenylate cyclase through G_S signaling to increase cAMP levels(107). This process in turn inhibits myosin light chain kinase to prevent smooth muscle contraction. Arachidonic acid can also be manipulated by cytochrome P-450 enzymes to form eicosatetraenoic acids (EETs), which open calcium-activated potassium channels (BK_CA) in the smooth muscle cells(108) to elicit hyperpolarization and relaxation. Membrane bound G-protein coupled receptors (GPCRs) as well as PECAM-1/VEGFR/VE-cadherin adherence junction complexes are also key sensors of mechanotransduction(109). GPCRs activate calcium channels through PLC/IP3, and both GPCRs and junctional proteins activate PI3K/Akt and MAPK/ERK1/2 pathways to phosphorylate and activate eNOS. Shear also activates endothelial inward rectifying potassium channels which favor hyperpolarization that spreads to the smooth muscle through myoepithelial gap junctions to illicit dilation(110). In addition, endothelial hyperpolarization activates voltage gated Ca²⁺ channels and connexin junctions allow Ca²⁺ to enter adjacent endothelial cells, allowing for further amplification of and paracrine coordination of signaling(111). During disease, flow promotes H₂O₂ rather than NO production of which the source is primarily from endothelial mitochondria as well as NADPH-oxidase (NOX) enzymes, which then stimulates PKG within smooth muscle cells to open Ca²⁺-activated potassium channels and induce relaxation(112). Mitochondrial superoxide production is amplified by NOX activation, through reactive oxygen species (ROS)-induced ROS production(113). In addition, mitochondrial ROS production in response to flow has been linked to the activation of TRPV-4 Ca²⁺channels(114), as well as the shear-sensitive ceramide forming enzyme neutral sphingomyelinase(54).