Physiological Consequences of Coronary Arteriolar Dysfunction and Its Influence on Cardiovascular Disease

Abstract

To date, the major focus of diagnostic modalities and interventions to treat coronary artery disease has been the large epicardial vessels. Despite substantial data showing that microcirculatory dysfunction is a strong predictor of future adverse cardiovascular events, very little research has gone into developing techniques for in vivo diagnosis and therapeutic interventions to improve microcirculatory function. In this review, we will discuss the pathophysiology of coronary arteriolar dysfunction, define its prognostic implications, evaluate the diagnostic modalities available, and provide speculation on current and potential therapeutic opportunities.

Introduction

Current approaches to diagnose and treat atherosclerosis-related disorders arise from decades of research into the associated pathological changes that occur in large conduit vessels, such as lipid-laden, neointimal plaque formation in coronary arteries (33). Coronary angiography is the gold-standard technique to evaluate coronary stenosis severity. Medical treatment seeks to reduce lipid deposition and counteract thrombus formation in large coronary vessels, and interventional approaches, like coronary stenting, target sites of plaque-induced obstruction. However, a number of early studies identified commonalities between arterial and arteriolar pathophysiology in atherosclerotic development, such as increased endothelial adhesion molecule expression and lipid deposition in both large and small vessels (24, 33, 55), despite absence of plaque formation in arterioles. Descriptions of myocardial ischemia and chest pain in patients with normal angiograms (52, 61) and awareness of abnormalities in arteriolar vasomotor responses in atherosclerotic animals (21, 92, 105) also provided early indications of pathological changes in otherwise plaque-free arterioles. Still, the major historical emphasis on large vessels is not surprising. Several factors have contributed to this trend, including a relative dearth of clinical tools to directly evaluate in vivo microvascular function in humans (37), and lack of overt plaque formation in microscopically visible arterioles vs. arteries where macroscopic plaque formation has been noted for over a century (33, 55). This has resulted in a virtual absence of FDA-approved therapies developed to specifically address microvascular dysfunction (69).

Challenging the status quo and rapidly reshaping our understanding of coronary atherosclerosis and coronary artery disease (CAD) are emerging reports that microvascular dysfunction may occur before large-vessel dysfunction (88) and may be the predominant driver of major adverse cardiac events in the presence or absence of diseased coronary arteries (3, 15, 38, 103, 104). Therefore, although pathology in this segment of the circulation is more difficult to detect clinically, it may carry greater prognostic significance than the degree of obstruction in larger coronary arteries. This review summarizes key findings related to coronary arteriolar dysfunction that define its critical role in cardiovascular disease and suggest that arterioles should be prioritized in the ongoing development of novel diagnostic and therapeutic strategies to combat CAD.

Overview of Coronary Arteriolar Function

Coronary arterioles have an endothelial and well-innervated smooth muscle cell layer and are typically defined as resistance microvesssels with an internal luminal diameter of ~80–100 µm (22, 46). During resting conditions, most of the heart’s vascular resistance is generated by coronary arterioles that maintain a relatively high threshold level of myogenic tone (22, 68), resulting in a major drop in pressure across the arterioles (46). Accordingly, vasodilator reserve is typically between three and five times basal flow, providing oxygen for potentially large increases in metabolic demand associated with conditions like exercise (46, 67). Various factors [metabolites, extravascular compression, pressure, flow (flow-mediated dilation, FMD), and neurohumoral factors] influence vascular tone, and the signaling pathways responsible for the control of arteriolar tone in humans have been reviewed elsewhere (12, 37).

Benefitting from the fractal branching pattern of the vascular tree (8), the microcirculation (arterioles, capillaries, and venules) maximizes its spatial distribution and adjacency to each parenchymal cardiomyocyte, while minimizing its volume. As a result, the local arteriolar environment is poised to profoundly influence cardiac physiology on a cellular and tissue level, and any changes in surrounding cell types can likewise impact arteriolar function. For example, cross talk between arterioles and cardiomyocytes is essential for metabolic dilation (89, 90). It is also believed that factors released from endothelial or smooth muscle cells can modulate, for example, collagen metabolism in cardiac fibroblasts (34).

Emerging Evidence Implicates Coronary Arteriolar Dysfunction in Disease

Techniques to Assess Arteriolar Function

Several technological approaches provide insight into coronary vascular dynamics. In vivo methods to detect coronary blood flow include the TIMI frame count, which requires intracoronary dye injection but has been well-validated as a predictor of outcomes post-infarction (4). Intracoronary Doppler velocimetry can be used in the cath laboratory to assess coronary flow velocity reserve as an indicator of microvascular dilator capacity (102). Coronary flow reserve can also be determined non-invasively by echo Doppler using the instantaneous wave-free ratio (23). Contrast echocardiography can also be used to assess vasodilator reserve in the heart (93). Positron emission tomography (PET) supplies quantitative information about myocardial perfusion non-invasively and is considered the “gold standard” for measuring myocardial perfusion (26). PET can measure endocardial vs. epicardial flow distribution, which is critical for evaluating the extent of myocardial ischemia since altered transmural distribution can augment pathophysiological changes arising from arteriolar dysfunction. Magnetic resonance (MR) angiography can also assess, with contrast, myocardial perfusion (29). A new non-invasive approach based on T1 cardiac MR removes the need for contrast or radiation and corresponds well with invasive measurements of epicardial and microvascular dysfunction (62).

Direct evaluation of the local arteriolar environment is not clinically feasible in vivo, so clinical studies using the above techniques currently categorize arteriolar dysfunction as an impairment in regional or global blood flow. However, coronary conduit arteries can impair blood flow independent of arteriolar dysfunction. To distinguish between abnormal flow associated with a flow-limiting epicardial stenosis and abnormal flow arising from microvascular dysfunction, two different measurement techniques are applied. A widespread classification scheme uses fractional flow reserve (FFR), an indicator of obstructive epicardial CAD, and coronary flow velocity reserve (CFR), an indicator of coronary microvascular dilator reserve. FFR is captured during maximal hyperemia—typically after infusion of adenosine—and measures the change in pressure across a stenosis using a Doppler guidewire (42). CFR compares the level of blood flow at rest and during peak flow, and assesses microvascular function when FFR is normal (71). Although these studies can be used to interrogate the effect of plaques on blood flow and categorize different clinical populations, they only describe measurements of resting and peak blood flow (a relatively crude and limited assessment of arteriolar function), and fail to address nuances of arteriolar dysfunction such as endothelium-specific changes in mediators of vasodilation or separation of endothelial and smooth muscle contributions to dilator compromise. Furthermore, most approaches only serve to confirm or suggest associations between arteriolar dysfunction and disease pathology.

To address this limitation of in vivo approaches, ex vivo videomicroscopy allows researchers to explore mechanisms of arteriolar dysfunction in greater detail. This technique involves isolating arterioles from harvested tissue and cannulating these vessels in a warmed organ bath. Once cannulated, the isolated arterioles are pressurized, and changes in internal diameter are recorded on a video monitor attached to an inverted microscope. A wide range of experimental conditions are possible with this technique, such as endothelial denudation, pretreatment of arterioles with compounds that affect mRNA and protein levels (e.g., viruses and pharmacological agents), use of fluorescently labeled compounds to assess changes in redox state or to track intracellular trafficking of molecules, evaluation of flow and agonist-induced dilator mechanisms, and more. This technique has generated substantial data regarding the specifics of arteriolar physiology, described in the next section, and removes the potential confounding influence of neurohumoral, extravascular, myogenic, and many paracrine influences that modulate coronary arteriolar resistance (68). Although more mechanistic than in vivo measurements of CFR, this approach does not yield insight into all nuances of arteriolar dysfunction, such as the possible interaction between arterioles and cardiac fibroblasts, neurohumoral modulation, or the role for blood constituents on vascular function.

Clinical Outcomes and Effect of Arteriolar Dysfunction on Coronary Physiology

Studies examining the relationship between outcomes and microvascular vs. large-vessel dysfunction (CFR vs. FFR, respectively) have risen sharply in recent years. Four distinct patient populations have been identified: 1) patients with normal epicardial and microvascular function (normal FFR and CFR), 2) patients with epicardial dysfunction but no microvascular dysfunction (normal FFR and abnormal CFR), 3) those with epicardial and microvascular dysfunction (abnormal FFR and CFR), and 4) patients with sole microvascular dysfunction (normal CFR and abnormal FFR) (2, 60, 103). Stratifying patient responses in this way has identified a strikingly high rate of cardiac events in those with microvascular dysfunction (populations 3 and 4). That is, the rate of adverse cardiac events seems to follow CFR more than FFR (70, 81, 101, 103) and is independent of sex (74). These recent reports have increasingly shifted attention from obstructive epicardial CAD to the influence of microvascular dysfunction within the context of CAD.

Why might arteriolar dysfunction more than large-vessel disease strongly influence CAD prognosis (103)? It is important to note that, although the location of pathology and the specific mechanisms involved may differ, many of the underlying physiological concepts that explain the detrimental effect of large-vessel disease recur in a discussion of the consequences of arteriolar dysfunction. These concepts relate to impaired blood flow and resulting ischemia, loss of nitric oxide with endothelial dysfunction, and widespread inflammation due to immune cell activation (17, 36, 84).

Since arterioles rather than arteries are the gatekeepers of myocardial perfusion, and the heart needs to precisely modify its flow on a rapid beat-to-beat time frame based on changing metabolic needs, dysregulation of cardiac blood flow arising from arteriolar dysfunction has grave consequences. The critical role of arterioles in the control of blood flow to tissues and their tight integration into surrounding tissue structures suggest that arteriolar dysfunction can profoundly influence development of tissue ischemia. In regions of the circulation subserved by conduit arteries with obstructive disease, the responsibility for maintaining blood flow depends on compensatory downstream arteriolar dilation through autoregulatory changes in overall vascular resistance. If arteriolar dysfunction is present, CFR declines, microvascular resistance is elevated, and this robust compensatory dilation cannot be achieved (28, 103). As a result, the local tissue is more susceptible to the development of ischemia (FIGURE 1). Even in the absence of epicardial stenoses (normal angiogram) and any cardiac or systemic diseases characterized by microvascular dysfunction, coronary arteriolar dysfunction may occur and lead to clinically detectable tissue ischemia on EKG (1). These findings emphasize that, although the affected area of the coronary circulation may differ, the result is similar.

FIGURE 1.

Arteriolar dysfunction can produce ischemia in the absence of a flow-limiting stenosis

Top left: at rest, arterioles display a high level of resting tone, which determines the basal blood flow through the upstream arteries. Bottom left: during times of increased oxygen demand, CM release vasoactive metabolites (1), which leads to a drop in arteriolar resistance (2). The decreased arteriolar resistance elicits increased flow in upstream arteries (3), causing increased NO release and oxygen delivery to downstream capillaries (4), as well as FMD in the artery (5), further increasing flow. Top right: in the presence of a diffuse but non-flow-limiting stenosis, arterial resistance and coronary flow are not affected. Bottom right: when arteriolar dysfunction is present, CM release vasoactive metabolites (1) but arterioles do not respond with appropriate vasodilation (2), and arteriolar resistance remains high. In the absence of a drop in arteriolar resistance, the necessary increase in flow is attenuated (3), FMD does not occur (4), and ischemia results from the mismatch between metabolic demand and flow. R, resistance; FMD, flow-mediated dilation; NO, nitric oxide; CM, cardiomyocytes.

Aside from impairments in overall blood flow, the local environment is likely altered with disease onset, and arteriolar-released factors may contribute to this change. For example, it has been postulated that a transition from endothelial release of nitric oxide to hydrogen peroxide (H₂O₂) observed in human coronary arterioles affected by CAD may be an early pathogenic step in the progression of CAD (37, 64). Since hydrogen peroxide can readily move across cell membranes, this may define a novel pathway by which arteriolar dysfunction—defined here as a transition in the release of endothelial-derived factors rather than compromised blood flow—could exert a persistent proinflammatory influence on cardiac tissue and precipitate adverse outcomes, independent of the extent of upstream plaque formation. Although yet untested, in the presence of arterial plaques, release of hydrogen peroxide could compound existing pathology through activation of inflammation and worsen outcomes, for example, by increasing susceptibility to plaque rupture. Until in vivo approaches allow for evaluation of microvascular parameters beyond blood flow, these provocative pathways lack strong clinical validation. Such an investigation should be essential to demonstrate whether arteriolar dysfunction drives development of epicardial stenosis over time.

Mechanisms of Arteriolar Dysfunction in CAD

The presence of arteriolar dysfunction, its impact on blood flow and tissue-arteriole cross talk, and its prognostic importance in patients with cardiac disease is increasingly apparent. Looking toward the future, to develop effective arteriolar-targeted therapies for CAD, we must understand what mechanisms and pathways contribute to arteriolar dysfunction. Based on previous reports, largely performed using the videomicroscopy preparation, key candidates can be grouped into several major categories: endothelial-derived factors [nitric oxide (NO), epoxyeicosatrienoic acids (EETs), mitochondrial hydrogen peroxide (H₂O₂)], ion channels, metabolic factors, and myogenic mechanisms.

Therapies to enhance NO delivery, including direct NO donors and inhibitors of NO breakdown, have been studied (65). Some of these drug classes may have advantageous effects on arterioles—although they have largely been tested within the context of large-vessel dysfunction, necessitating additional arteriole-specific studies—but there are unique aspects of the microcirculation that suggest that refined strategies are needed. Loss of NO as a mediator of FMD does indeed occur in arterioles with the onset of CAD (64), and this appears to be specific to CAD rather than age-related arteriolar pathology (14). However, direct NO donors, in doses sub-threshold for dilation, may paradoxically compromise rather than improve arteriolar dilation in the presence of CAD by inhibiting flow-induced mitochondrial production of H₂O₂ (14).

EETs are endogenous lipids generated by metabolism of arachidonic acid via cytochrome P450 epoxygenases. EETs represent an important but relatively understudied vasodilator pathway in coronary arterioles (57, 59). EET-mediated signaling is masked in arterioles from patients with CAD but can emerge as a vasodilator when H₂O₂ is inhibited (58). The pleiotropic protective effects of EETs on the coronary circulation are known (57). Stimulating EET release or inhibiting its catabolism to inactive dihydroxy metabolites (DHETE) with soluble epoxide hydrolase inhibitors could enhance both arteriolar dilation and non-vasomotor pathways to promote arteriolar health, although some concerns for off-target effect in the pulmonary circulation exist (43, 56).

Mitochondrial H₂O₂ is known to be elevated in response to shear in arterioles from patients with CAD (11, 49). Although mitochondrial H₂O₂ appears to preserve dilation when NO levels fall (64), it can promote inflammation in the vessel wall itself and in surrounding structures (37). Since EETs can maintain dilation when H₂O₂ is inhibited, targeting mitochondrial H₂O₂ should limit its damaging effects on arterioles and surrounding tissues without compromising arteriolar dilation. Recent studies have also expanded this research area and identified factors that affect mitochondrial H₂O₂ release in arterioles by either reducing it (including the enzyme telomerase reverse transcriptase and the transcriptional coactivator PGC-1alpha) or increasing its generation (e.g., sphingolipid ceramide) (11, 32, 37, 49). In addition to mitochondrial release of H₂O₂, several other mitochondrial pathways have been identified that contribute to the regulation of vascular tone, such as depolarization (51), damage associated molecular patterns (48), coupling factor 6 (77, 78), and humanin (7).

Similar to the EET-H₂O₂ interaction described above, there are many reports demonstrating the resilience of arteriolar dilation; that is, arterioles demonstrate a remarkable capacity to maintain dilation when these individual dilator pathways are compromised. For example, in mice lacking eNOS, skeletal muscle arteriolar dilation is preserved by compensatory release of an endothelial hyperpolarizing factor (females) or cyclooxygenase-derived prostaglandins (males) (40, 97). In human arterioles isolated from patients without cardiovascular disease, NO produces dilation at rest, but its bioavailability is compromised by abrupt increases in intraluminal pressure. However, dilation is maintained by H₂O₂ and thus serves as a compensatory vasodilator (9). Given the critical role of arterioles in maintaining perfusion to downstream tissue beds, possessing these backup vasodilator pathways may help to maintain perfusion in the presence of acute vascular stress. Conversely, arteriolar dysfunction likely occurs when this vasodilatory reserve is exhausted. Clarifying the cellular mechanisms controlling these compensatory pathways may expose new therapeutic targets to restore vasodilatory plasticity in diseased arterioles.

In many studies, these individual factors are often described as exclusive and independent vasodilators (e.g., fully NO- or H₂O₂-dependent dilation). Studies have also characterized a provocative and potentially unique aspect of the microcirculation: the ability to simultaneously recruit multiple vasodilator agents (e.g., NO and H₂O₂) (37, 40, 58). Notably, this phenomenon appears to be unique to arterioles (94, 99). Perhaps more importantly, recent studies even suggest that optimal arteriolar function exists when multiple concurrent vasodilators are present, particularly as a protective mechanism against acute vascular stress (47, 49, 50, 86, 99). In contrast, arterioles relying on a single vasodilator agent—either NO or H₂O₂—display blunted dilation after exposure to an abrupt rise in intraluminal pressure (9, 49), a pathogenic stimulus with great relevance for acute atherosclerosis-related cardiac events (95). This dysfunction does not occur in arterioles that rely on multiple vasodilator agents (47, 49). This evidence underscores the complexity of arteriolar dilation and supports a “poly-pill” (i.e., multiple pharmacological agents in a single formulation) rather than single-target approach to guide drug development. That is, instead of restoring only NO or EET bioavailability in the presence of arteriolar dysfunction, encouraging release of multiple vasodilator factors may be preferable. The feasibility and benefit of introducing >1 vasodilator in arterioles affected by CAD was recently validated (49).

Aside from endothelial-derived changes, shifts in smooth muscle vasomotor properties are also observed in arterioles from subjects with CAD. Ion channels are a prime example. In healthy human coronary arterioles, arteriolar dilation relies on both voltage-gated and large-conductance calcium-activated potassium channels (75). In contrast, in arterioles affected by CAD, dilation depends on endothelial transient receptor potential vanilloid type 4 (TRPV4) channel activation (16). Regarding ion channels localized to smooth muscle cells, the activation of large-conductance potassium channels (106) rather than voltage-gated channels (75) contributes more to arteriolar dilation in the context of CAD.

Most in vitro studies examining mechanisms of arteriolar dysfunction in CAD have largely been performed during flow- or agonist-induced dilation. However, given that both myogenic and metabolic responses also have a prominent governing effect on arteriolar tone (19), more effort should be directed at exploring the possible dysregulation of these key physiological processes. Both myogenic and metabolic vasomotor responsiveness may be altered in CAD, which could adversely influence arteriolar regulation of blood flow. There is some early support for disrupted NO-dependent metabolic dilation in the coronary microcirculation of patients with atherosclerosis or its risk factors due to loss of NO bioavailability (85). It is possible to evaluate both myogenic responses and metabolic dilation using videomicroscopy (72, 89, 100), and studies exploring how these processes are corrupted in CAD may yield greater understanding of underlying pathophysiology and identify new therapeutic directions. Similarly, the interaction between myogenic and flow-induced dilation can be studied in vitro (54) and may be altered by disease.

Although these mechanisms emphasize the highly specialized and distinct physiology of coronary arterioles relative to that of coronary arteries, it is critical to mention that these mechanisms are often conserved across arteriolar beds. For example, a rise in mitochondrial H₂O₂ with the onset of CAD occurs in peripheral adipose, pericardial adipose, and atrial arterioles obtained from human subjects (32, 49). Although not described specifically in relation to CAD, these changes have also been observed in renal arterioles with clear effects on arteriolar function (41). Therefore, given the growing number of diseases that have been linked to arteriolar dysfunction (37), the relevance of widespread investment in arteriole-related research extends beyond CAD.

Other Disease States in Which Microvascular Dysfunction Occurs

Since arterioles are predominant regulators of vascular tone and resistance across most vascular beds, it is perhaps least surprising that arteriolar dysfunction has been identified within the context of systemic hypertension (30). Here too the definition of arteriolar dysfunction is largely restricted to its physiological role in regulating vascular tone and predominantly categorized as impaired dilation or enhanced constriction, but can also include rarefaction, inflammation, thrombogenicity, loss of barrier function, and vascular remodeling (30). Blunted myogenic- and agonist-induced responses in various vascular beds (mesenteric, cerebral, renal) have been reported with hypertension (10, 13, 44).

Diabetes is a classic example of microvascular dysfunction and seems to incorporate the broadest definition of arteriolar dysfunction, encompassing compromised vascular wall integrity with increased permeability, impaired dilation, oxidative stress, remodeling, and luminal obstruction (31, 76), as well as impaired angiogenesis (98). Arteriolar consequences manifest as diabetic retinopathy, peripheral vascular disease, cognitive decline, and renal dysfunction. Impaired dilation in coronary arterioles has also been noted, similar to that observed in CAD (5, 6, 53, 83). In both conditions, coronary arteriolar dysfunction has been linked to disturbances in ion channel function (63, 73). The striking overlap between coronary arteriolar dysfunction in CAD and diabetes helps to explain why diabetes accelerates progression of CAD. Even in the absence of CAD, diabetic microvascular dysfunction may give rise to diabetic cardiomyopathy (45).

Several cardiac-specific disorders are characterized by arteriolar dysfunction. The classic example is syndrome X, which refers to clinically detectable ischemia on EKG but normal coronary angiograms (1). Syndrome X is more likely to appear in postmenopausal females. A rapidly expanding area of interest is the involvement of arterioles in heart failure with preserved ejection fraction (HFpEF) (27, 80, 96), possibly as an early and inciting event (18). Although systolic function is normal in these patients, morbidity and mortality parallel that of the more traditional form of heart failure with reduced ejection fraction. Preliminary evidence classifies this arteriolar dysfunction as an impairment in the dilatory response to bradykinin (25). Both arteriolar dysfunction (blunted endothelium-dependent dilation and reduced hyperemic coronary flow responses, reflective primarily of arteriolar smooth muscle dysfunction) and impaired diastolic filling occur in an aged rat model free from hypertension and atherosclerosis. These changes are reversed by exercise training (39).

It is possible that increased awareness of arteriolar dysfunction in other human diseases besides CAD will catalyze interest in arteriolar dysfunction across disciplines and may eventually urge clinicians to more aggressively target arterioles in patients, particularly those with multiple diseases characterized by arteriolar dysfunction (e.g., common scenario of single patient carrying a diagnosis of both CAD and HTN).

Therapeutic Considerations

There is thus great importance in emphasizing development of novel approaches to combat arteriolar dysfunction. With respect to possible pharmacological approaches, existing therapies developed and validated for various cardiovascular disorders (statins, aspirin, ACE-inhibitors, and beta-blockers) may serve as effective treatments for microvascular dysfunction. However, the results summarized in recent reviews (69, 91) are disappointing; most of the listed drugs failed to improve symptoms (angina) or CFR, and some even worsened these parameters. These studies primarily evaluated effects on symptoms or microvascular resistance rather than more objective clinical outcomes (69). This lack of efficacy of existing drugs is unfortunate but could be explained by the previously mentioned pathological heterogeneity between conduit and arteriolar phenotypes in patients with CAD. Even in different areas of the same arterial tree, arterial and microvascular-derived ECs are characterized by profoundly different genetic (and presumably proteomic) profiles (20). Like ECs, smooth muscle cells represent a heterogenous population throughout the vascular system, with diverse embryological origins (66). Given these differences, traditional cardiovascular pharmacological agents may not be targeting responsible pathways at the level of the arterioles.

Moving forward, it will be important to continue to search for possible treatment options for arteriolar dysfunction with a refined approach informed by the unique nature of arteriolar physiology. Some possibilities based on available drugs include PDE-3 inhibitors (increase cAMP; e.g., cilostazol), ranolazine (blocks late inward sodium currents in cardiomyocytes and reduces stiffness, thus alleviating extravascular compressive forces on the microcirculation), PDE-5 inhibitors (indirectly restore NO), or mitochondrial reactive oxygen species inhibitors [noted to play a key role in microvascular pathologies, especially in diabetes (79)]. For a more comprehensive discussion of existing and emerging agents to treat microvascular dysfunction, the reader is referred to Ref. 35. One available drug that more selectively affects arteriolar dilation is adenosine. However, adenosine was developed to assess coronary function during maximal hyperemia, not treat arteriolar dysfunction; in fact, adenosine may reduce rather than increase coronary perfusion through a coronary steal phenomenon. Although adenosine has arteriolar effects, flooding the system with supraphysiological doses of a direct vasodilator like adenosine—especially a vasodilator that is not implicated in the development of cardiovascular disease—is not a tailored therapeutic approach.

Adenosine serves as a case-in-point of the glaring issue facing the available therapeutic toolbox to treat arteriolar dysfunction. Most of the indicated drugs were not developed with restoration of arteriolar function as a primary goal. As a result, the beneficial effects of these drugs on microvascular parameters are serendipitous rather than intentional. One potential approach is to identify arteriole-specific mechanisms occurring during development of CAD. For example, restoring physiological release of a dilator or dilator pathway that is compromised during onset of cardiovascular disease may be one such mechanistic, evidence-based approach. Several of these pathways were noted above, like the transition in ion channel-based signaling in the presence of CAD. Although some arteriolar changes are observed across vascular beds (e.g., transition to H₂O₂-dependent dilation), other studies have also demonstrated some organ-specific (patho)physiological mechanisms that may allow for organ-specific drug targeting.

Likewise, there is also the potential to develop arteriole-specific agents that are trafficked to the (coronary) arterioles in the same way that novel chemotherapeutic agents are harnessing the specificity of nanoparticle-based carriers (82) or the tumor cell membrane’s electric properties (87) to deliver treatment directly to the cancer cells. For example, targeting cell surface markers expressed primarily on damaged or diseased microvascular endothelium or developing therapeutics based on the unique genetic profile of arteriolar endothelial and smooth muscle cells may enable this directed therapeutic approach.

Aside from suggesting how we may develop novel tools to address specific mechanisms of arteriolar dysfunction precisely at the arteriolar level, it is also important to note the strong additional clinical appeal of targeting the arterial system. Relative to other organ systems, the arteriolar system is most ideally suited for therapeutics since any agent delivered via IV first interacts with the vasculature. It is the only organ that has the potential to be targeted by systemic approaches without effects on other tissue beds. Together, this appreciation of arteriolar dysfunction in various diseases, specific underlying (patho)physiological mechanisms, the unique profile and make-up of arterioles, and the ability to obtain direct access to the arteriolar system frames the fight against arteriolar dysfunction as a pressing, personalized, and clinically feasible endeavor. Given the arteriole-specific mechanisms noted here and above, there are already several candidates to exploit in future drug development.

Summary and Future Directions

Clinical studies have described the clear contribution of coronary microvascular dysfunction to coronary artery disease. Future work should continue to unravel underlying mechanisms. Arteriole-specific therapeutic approaches are lacking and represent a dire clinical void. Development of these therapies should allow clinicians and researchers to evaluate the clinical benefit of improving arteriolar function in humans.