Despite historical focus on the epicardial coronary macrovessels, the microvessels represent the predominant resistance within the coronary flow circuit and are innumerable in comparison to the epicardial vessels seen during invasive coronary angiography. Interest in and knowledge about diseases of the coronary microvessels has grown dramatically in the past few decades, while clinical awareness and adequate treatment options have lagged. These disease processes also suffer from a lack of consistent terminology, leading to widespread use of catchall names such as open artery ischemic heart disease, ischemic heart disease without obstructive coronary artery disease, microvascular angina, and cardiac syndrome X. After a comprehensive review of the literature, Vermeltfoort and colleagues concluded that there was no consensus regarding the definition of cardiac syndrome X.3 Thus we have recommended that this term not be used in favor of specific description of the clinical and microvascular findings.4 A comprehensive understanding of coronary microvessels is vital (Fig. 35–3)5 because in some cohorts, particularly women, angina without obstructive coronary artery disease (CAD) exceeds angina with obstructive CAD.
Coronary microcirculation. Extensive collateral circulation of 10 to 20 μm diameter vessels imaged in this ex vivo arteriogram of the heart. Reproduced with permission from Berry C, Balachandran KP, L’Allier PL, et al: Importance of collateral circulation in coronary heart disease. Eur Heart J. 2007 Feb;28(3): 278-291.5
Risk factors for developing CMD have some overlap with traditional cardiovascular risk factors. Diabetes mellitus, hyperlipidemia, and hypertension have been correlated with endothelial dysfunction (ED).6,7,8 Although the causal relationships between these factors and CMD have not been well defined, systemic inflammation likely plays a role. Illnesses such as obesity and diabetes are recognized as inflammatory processes and are linked to CMD.9,10 In addition, some systemic inflammatory processes, such as psoriasis and inflammatory bowel disease, are less typically considered to be related to heart disease but have been linked to CMD as well.11,12 Strong correlations have been observed between CMD and collagen vascular diseases.13
Aside from inflammatory processes, primary hyperparathyroidism has been recently described as a cause of CMD. In a study of 100 hyperparathyroidism patients, coronary flow reserve (CFR) was lower than case-matched normal subjects, and 27 had CFR of less than or equal to 2.5. Among these 27 patients, all had restoration of normal CFR after parathyroidectomy.14 Another cohort of 56 hyperparathyroidism patients were noted to have CMD as well as left ventricular hypertrophy and diastolic dysfunction; substantial improvements were noted after surgical resection of the parathyroid glands.15 In multiple logistic regression analysis that included total serum calcium level, only parathyroid hormone level increased the probability of CFR less than or equal to 2.5. These findings directly implicate elevated parathyroid hormone levels as a completely reversible cause of CMD.
Other lines of evidence, however, suggest that there are as of yet unidentified factors contributing to clinical and laboratory measures of CMD.16,17,18 Obstructive atherosclerosis is discussed elsewhere in this text; however, it should be noted that CMD and atherosclerosis frequently coexist. In some cases, both are overtly observed while in others a seemingly normal coronary angiogram underestimates large burden of atherosclerotic plaque.19,20 Although multiple studies have linked atherosclerosis risk factors (eg, age, history of hypertension, systolic blood pressure, inflammatory markers) with CMD, these factors have only a small contribution to reduced CFR.18 However, recent data suggest that in addition to age, hydraulic factors related to conduit artery stiffness, such as aortic pulse wave velocity and central aortic blood pressure, provide a major contribution to reduced CFR.16 Sometimes these myocardial scars are not localized to the distribution of a major coronary artery, perhaps suggesting an inflammatory cause for the area of infarction.21 Myocardial infarction can also be observed in patients without obstructive atherosclerosis, although when examined with intravascular ultrasound (IVUS), ulcerated plaque is often noted.22
The endothelium plays a pivotal role in coronary autoregulation by release of compounds, including nitric oxide (NO), other reactive oxygen species, and arachidonic acid metabolites with a key mechanism being the production of NO from L-arginine.23 The NO is produced in response to many stimuli, including shear stress, sympathetic tone, and muscarinic activation by acetylcholine. Endothelial release of NO elicits dilation and helps preserve normal parenchymal function by inhibiting inflammation, proliferation, and thrombotic processes.1 NO also regulates expression of adhesion molecules, inhibits glycoprotein IIb/IIIa, and inactivates activated B lymphocytes, cells that may reside in or migrate into the vascular wall.
In addition to the effect of NO, the endothelium helps regulate vascular tone through the production of prostacyclin, natriuretic peptides, endothelin, thromboxanes, and prostaglandins. Dysfunction of the endothelium is closely related to a number of risk factors for developing atherosclerotic plaque and may exist on a continuum of atherosclerotic disease.24 Oxidized low-density lipoprotein, for example, is key to both ED and plaque formation. Presence of oxidized lipids stimulates production of free radicals such as superoxide, which neutralizes biologically active NO.25 Reduced biologically active NO can then alter any of the normal processes it regulates. Increases in platelet activation through the glycoprotein IIb/IIIa pathway may predispose patients to thrombus formation, leading to acute coronary syndromes (ACS) without obstructive CAD.
Smooth Muscle Dysfunction
Coronary smooth muscle cells are regulated by both endothelium-dependent and endothelium-independent mechanisms. Specific pharmacological testing can be performed to make some distinctions between the two. Smooth muscle dysfunction can manifest in a variety of ways. An increase in the activational state of coronary vascular smooth muscle cells may result in spasm specifically in the microvasculature, sparing the macrovessels but resulting in the same clinical presentation.26 Chronically elevated tone in the microvessel musculature may be an etiology of “slow flow” on coronary angiography,27 which could also explain the observation of angina at rest sometimes reported in these patients.
Nonobstructive Coronary Atherosclerosis
Moving along the spectrum of coronary diseases, nonobstructive coronary atherosclerosis is the next step moving from isolated CMD toward obstructive or occlusive CAD. Historically, it was thought that conditions leading to myocardial ischemia, other than obstructive CAD, were uncommon or rare. This was despite evidence that a nontrivial proportion of patients with angina symptoms and ischemia on stress testing that were noted to have normal coronary arteries on angiography.28 This phenomenon has been explained away as “false-positive” stress testing. Meanwhile, contemporary data show us that 20% to 30% of angina patients continue to have symptoms despite technically successful revascularization of the coronary arteries. In large international registries of patients referred for coronary angiography, the prevalence of nonobstructive CAD in women with angina symptoms may be as high as 65%.29 This is less common in men, but not negligible at 14% to 32%.29,30
The condition of angina with so-called “normal angiography” or more accurately termed nonobstructive CAD (Fig. 35–4) is increasingly observed and is significantly more frequent among women than men.31 In a study of 11,223 men and women undergoing invasive coronary angiography to evaluate anginal symptoms, one-third of men and two-thirds of women have nonobstructive CAD.30 This observation is despite the fact that women generally present for evaluation of symptoms at a later age than men, with a higher prevalence of cardiac risk factors, including hypertension, diabetes, and dyslipidemia. As previously stated, angina with nonobstructive CAD has substantial overlap with CMD. In a study of 1439 patients with angina and nonobstructive CAD, comprehensive assessment for endothelium-dependent CMD with acetylcholine and endothelium-independent coronary flow velocity reserve with adenosine was performed. Evidence of CMD on one or both tests was found in 81% of patients.32 More detailed analysis with IVUS and coronary computed tomography (CT) has demonstrated that most patients with “normal angiography” actually harbor atherosclerotic plaque that does not encroach on the lumen. In other cases, patients may have long segments of mild, uniform narrowing, resulting in significant decreases in perfusion by fractional flow reserve.
Classification of ischemic heart disease patients. CAD, coronary artery disease; CVD, cardiovascular disease; FFR, fractional flow reserve; IHD, ischemic heart disease; LV, left ventricular. Reproduced with permission from Pepine CJ, Ferdinand KC, Shaw LJ, et al: Emergence of Nonobstructive Coronary Artery Disease: A Woman’s Problem and Need for Change in Definition on Angiography. J Am Coll Cardiol. 2015 Oct 27;66(17):1918-1933.4
These patients were presumed to have trivial mortality risk, an assumption that has since been proven incorrect. Although the presence of obstructive CAD imparts a higher risk of cardiovascular events during follow-up, patients with nonobstructive CAD are still at elevated risk as compared to healthy cohorts. Data from the Women’s Ischemia Syndrome Evaluation (WISE) showed that at 10 years follow-up, women with nonobstructive CAD fared worse than those with no detected CAD (ie, no stenosis > 20% luminal narrowing).33 The Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM) is a CT coronary angiography registry, which showed similar findings. In CONFIRM, among 24,775 patients undergoing CT coronary angiography, risk of death at 2.3 years was 60% higher for patients with nonobstructive CAD as compared to those with what appeared to be “normal” coronary arteries.34 In nonobstructive CAD patients, the extent of coronary plaque is linked to future cardiovascular events. A cohort of 3242 patients undergoing CT coronary angiography for suspected CAD were divided into nonextensive nonobstructive, extensive nonobstructive, and obstructive CAD groups and compared to those with normal coronary arteries. The hazard ratios for death or myocardial infarction at 3.6 years were 3.1, 3.0, and 3.9 respectively, demonstrating the marked risk of nonobstructive CAD.35 Bridging the gap between CMD and nonobstructive CAD, low CFR has been directly linked to adverse events.36 In the cohort study by Jespersen, patients with angina and nonobstructive CAD (adjusted hazard ratio, 1.85) or normal coronary arteries (adjusted hazard ratio, 1.52) both had elevated risk for cardiac events versus a reference population (Fig. 35–5).30
Survival free of major adverse coronary events (MACE) stratified by severity of coronary disease. The top panel shows results for men and the bottom for women stratifying survival free of MACE over 7 years of follow-up. Patients with anginal symptoms and normal coronaries or nonobstructive coronary artery disease (CAD) have higher risk than those without symptoms. 1VD, one vessel disease; 2VD, two vessel disease; 3VD, three vessel disease; CA, coronary arteries; Dif. nonobstr., diffuse nonobstructive. Reproduced with permission from Jespersen L, Hvelplund A, Abildstrøm SZ, et al: Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events, Eur Heart J. 2012 Mar;33(6):734-744.30
In addition to the hazard associated with nonobstructive CAD, it is a very costly condition. Patients incur notable direct (office visits, hospitalizations, cardiovascular testing) and indirect (lost wages, travel) costs. In a cohort of 883 women followed for 5 years in the WISE, the estimated lifetime cost associated with nonobstructive CAD was similar to that with one-vessel obstructive CAD (~ $767,288).37
Aside from the chronic risks associated with nonobstructive CAD in patients with chronic stable anginal symptoms, these patients also may develop ACS. A recent meta-analysis of randomized trials of ACS patients found that approximately 10% have no obstructive CAD at the time of angiography.38 Although data on this condition are heterogeneous, with wide ranges of angiography use and prevalence of nonobstructive CAD, they indicate that an ACS patient with nonobstructive CAD is more likely to be a woman without diabetes or prior CAD/myocardial infarction. Death or myocardial infarction rates at 30 days for these patients appear lower than for patients with obstructive CAD (odds ratio 0.15, 95% confidence interval 0.11-0.20). The Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Registry documents a similar overall prevalence with nonobstructive CAD (~9.5%) in non-ST-segment elevation ACS patients: ~15.1% of female patients, 6.8% of male patients.39
To evaluate for the presence of CMD, a provocative agent and a measurement technique must be selected. Within the provocative agents, some are dependent on healthy, functional endothelium, whereas others act directly on vascular smooth muscle and are considered endothelium-independent.
The most commonly used pharmacological agent for endothelium-dependent testing is acetylcholine, which must be administered via the intracoronary route. In normal coronary arteries, acetylcholine releases NO from endothelium, overriding its direct effects at the vascular smooth muscle muscarinic receptor to induce vascular smooth muscle contraction, resulting in vasodilation. In arteries with diseased or dysfunctional endothelium, insufficient biologically active NO is released in response to acetylcholine. The drug’s direct effect to activate vascular smooth muscle predominates and vasoconstriction occurs. Acetylcholine can be used effectively for distinguishing normal coronaries from those with epicardial spasm and/or microvascular spasm.40,41
Adenosine is the most commonly used so-called “endothelium-independent” pharmacological agent. It can be given by bolus intracoronary injection or intravenously, by constant infusion. Activation of adenosine A2A receptors on vascular smooth muscle results in reproducible smooth muscle relaxation. Regadenoson is a selective adenosine A2A receptor agonist also used in pharmacologic stress testing because of reduced side effects (eg, less bradycardia related to stimulation of adenosine A1 and less bronchoconstriction related to stimulation of adenosine A2B receptors, respectively). Regadenoson has a 2- to 3-minute biological half-life, compared with adenosine’s 10-second half-life. As a result, regadenoson stress protocols use a single bolus, instead of a 4- to 6-minute continuous infusion, as with adenosine. Dipyridamole is sometimes used as an alternative agent.
Another important concept to understand is that adenosine receptors are present in endothelium. As much as 25% of the hyperemic response obtained with intravenous adenosine infusion (140 μg/kg/min dose) is the result of endothelial-dependent vasodilation because it can be blocked by infusion of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase.42 A similar endothelial-related response is reasonable to expect if very high doses of intracoronary adenosine are used (ie, intracoronary doses that match the intravenous adenosine effect).
In addition to invasive testing strategies, CMD can be measured using noninvasive methods. Noninvasive testing of the coronaries with single-photon emission CT myocardial perfusion imaging may demonstrate ischemia in some patients with CMD. However, the test methods do not allow for reliable isolation of the microvasculature from obstructive atherosclerosis. Advances in positron emission tomography (PET) of global and regional CFR in response to adenosine may allow for noninvasive evaluation of the microvasculature.
Perfusion imaging with PET is currently considered the reference standard for assessment of myocardial blood flow achieved by quantifying uptake of a specific radioisotope per gram of myocardium. Abnormal flow reserve to adenosine by this technique has been independently linked with adverse cardiovascular outcomes.43 Multislice detector CT with iodinated contrast can provide an estimate of myocardial blood flow and CFR by measuring attenuation changes over time in basal and hyperemic conditions and plotting time-attenuation curves. The 320-row scanners permit acquisition of a full cardiac tomographic dataset within a single heartbeat, reducing iodine contrast volumes and radiation doses.
Pulsed-wave Doppler recording of left anterior descending artery coronary blood flow velocity by transthoracic echocardiography before and during adenosine infusion appears to be a reliable noninvasive method to assess CFR noninvasively. As such, it is now assigned the same class (IIb) recommendation as intracoronary adenosine testing during coronary angiography in the European guidelines. Others have proposed using myocardial contrast echocardiography to detect perfusion defects and estimate CFR.
Invasive measurement of coronary blood flow and CFR is predominantly performed using an intracoronary Doppler flow wire (Fig. 35–6).44 The wire directly measures coronary blood flow velocity and can be combined with a pressure sensor. Volumetric blood flow can be calculated as the product of velocity and vessel lumen area measured by quantitative coronary angiography or IVUS. The technique is limited to laboratories with extensive expertise in the intracoronary use of these Doppler wires. Accurate measurement of the vessel lumen can be difficult, adequate administration of vasodilator agents requires optimal guide catheter placement, and common artifacts must be recognized and accounted for. Thermodilution and gas exchange techniques have been described but are not commonplace.45
Invasive assessment of the microcirculation. Illustration of how the coronary arteries can be interrogated for coronary flow reserve using pressure transducing coronary wires and intracoronary infusions of medications. APV, average peak velocity; DT, deceleration time; QCA, quantitative coronary angiography. Reproduced with permission from Schächinger V, Zeiher AM: Coronary microcirculation. Pathophysiology, clinical relevance, and importance for regenerative therapy after myocardial infarction. Herz. 2005 Nov;30(7):641-650.44
Treatments for CMD and nonobstructive CAD have not been rigorously studied in large controlled trials. Guideline recommendations are sparse because the evidence base is lacking. The most recent US guidelines for stable ischemic heart disease do not provide substantial recommendations for patients with nonobstructive CAD despite that fact that many statin trials have documented reduced progression of atherosclerosis in vessels with nonobstructive disease. Patients with CMD and nonobstructive CAD are often dismissed from specialty care based on the belief that their symptoms are not related to coronary dysfunction. This neglect is compounded when symptoms are overlooked in the primary care setting. Among the few recommended treatments for CMD and nonobstructive CAD, most have been adopted from the treatments for angina pectoris related to obstructive coronary atherosclerosis. Angiotensin II inhibition (either by converting enzyme angiotensin-inhibition or angiotensin receptor blockade) and statins have shown promise by reducing symptoms and improving CFR in several randomized trials of small sample size.46,47 Several pilot type trials using the late sodium channel inhibitor ranolazine in a population of predominantly women with angina and no obstructive CAD suggested favorable short-term effects, but the drug did not appear to reduce symptoms or improve myocardial perfusion reserve by cardiac magnetic resonance imaging (MRI) in a more definitive, randomized, placebo-controlled trial of 142 subjects.48