CHAPTER 35: NONOBSTRUCTIVE ATHEROSCLEROTIC AND NONATHEROSCLEROTIC CORONARY HEART DISEASE

Although obstructive coronary atherosclerosis and myocardial infarction tend to be predominant topics when discussing coronary heart disease, many other clinically relevant processes affect the coronary arteries. In this chapter, we will discuss a wide array of nonobstructive atherosclerotic and nonatherosclerotic coronary heart diseases. Our discussion will begin with pathology of the coronary artery intima and media, then move to diseases that affect the entire coronary tree, and conclude with physical abnormalities of the coronary arteries and mechanical disruption of coronary blood flow. Most of these diseases, however, can overlap and adversely interact. For example, coronary microvascular dysfunction (CMD) contributes to angina in patients with obstructive atherosclerosis, coronary spasm can occur at both micro and macro levels, and inflammatory disease can have an impact on the entire coronary tree.

The normal arrangement of the coronary arteries is for the left main artery and right coronary artery to arise from the ascending aorta, 1 to 2 cm above the base of their respective coronary sinuses. The left main artery divides into anterior descending and circumflex branches, which travel in the interventricular and atrioventricular grooves, respectively. The right coronary artery also travels in the atrioventricular groove on the right side of the heart, typically terminating in the posterior descending artery in the inferior interventricular groove. Each vessel gives rise to branch vessels to create a comprehensive network of epicardial conduits. Vessels branch and decrease in size, from prearterioles to arterioles to capillaries. Myocardial blood flow is regulated mostly in the coronary microcirculation, where only small changes in arteriolar diameter can result in large changes in conductance and flow, as predicted by Poiseuille’s law (Fig. 35–1).¹ For example, a 20% reduction in arteriolar diameter results in a more than 100% increase in resistance and reduces blood flow by more than 50%.

The coronary arteries are lined by the intima (endothelial cells and internal elastic lamina), the media (vascular smooth muscle cells), and adventitia (eg, external elastic lamina, fibroblasts, vasa vasorum) (Fig. 35–2).² Many macrovascular diseases result from mechanical disruption of one or more of these layers, whereas microvascular diseases predominantly result from dysfunction of endothelial cells and/or vascular smooth muscle cells.

The endothelium functions as a mechanical barrier and also produces a variety of regulatory compounds. This layer also serves as the attachment point for surface molecules that attract or repel platelets, leukocytes, and soluble compounds in the blood. The elastic lamina act as a barrier and reinforces the structure of the coronary artery. Contractile tone of the smooth muscle layer regulates resistance to blood flow, thus controlling the volume and distribution of blood flow. This layer also proliferates in response to various disease states. Cells in the adventitial layer nourish the artery, secrete vasoactive substances, and provide the nervous system with feedback on its function.

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.

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

Endothelial Dysfunction

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.

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

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

Evaluation and Treatment

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 A_2A receptors on vascular smooth muscle results in reproducible smooth muscle relaxation. Regadenoson is a selective adenosine A_2A 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 A_2B 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

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

Spasm of the coronary arteries was suggested by Osler in 1910⁴⁹ and proposed based on observed clinical and electrocardiogram (ECG) findings by Prinzmetal and coworkers in 1959.⁵⁰ It was then documented angiographically by Gensini and colleagues in the early 1960s.⁵¹ The syndrome included symptoms typical of angina pectoris, but occurring at rest and typically associated with transient elevation of the ST segments. Maseri and coworkers, in multiple reports from 1975 to 1995, provided experimental confirmation that coronary spasm was a central mechanism involved in a variety of ischemic syndromes and not limited to that described by Prinzmetal as variant angina. The contemporary term then became vasospastic angina. Because epicardial spasm has a much wider clinical spectrum of symptoms and ECG findings, and may sometimes overlap with CMD, we prefer to use the simpler and clinically broader term, coronary spasm⁵² (Fig. 35–7).⁵³

The clinical findings (symptoms and ECG changes) associated with coronary spasm may occur without ST-segment elevation, and in fact they are often associated with ST-segment depression and/or T-wave changes and may also at times result from small-vessel or regional coronary dysfunction. Depending on the severity and duration of spasm and the coexistence of obstructive CAD, myocardial necrosis, ventricular tachycardia/fibrillation, heart block, and/or sudden death can occur. The specific etiology of the spasm is not known but is thought to be related to both neurologic and pharmacologic stimuli that activate vascular smooth muscle to contract, severely reducing luminal diameter and hence limiting regional blood flow (Fig. 35–8).⁵⁴

In addition to spontaneous occurrence, coronary spasm may occur in a variety of clinical situations, including general anesthesia; allergic reaction (histamine-induced, hypersensitivity angina); use of ergoline derivatives (eg, bromocriptine, methylergonovine, pergolide, lisuride); thyrotoxicosis; hypercholinergic crisis; use of triptans, dobutamine infusion during stress testing; use of capecitabine, dolasetron (5-hydroxytryptamine antagonist); and illicit substance use (eg, cocaine, butane, amphetamines, 3,4-methylenedioxy-methamphetamine [MDMA]). Coronary spasm can occur with mechanical stimulation related to catheter manipulation for diagnostic or interventional procedures (eg, angiography or catheter/balloon angioplasty); however, catheter-related spasm is a benign condition unrelated to the clinical syndrome described above. Recent reports⁵⁵ suggest a possible connection between inflammatory disease and vasospastic angina. Minor elevations of serum C-reactive protein suggest chronic low-grade inflammation may be involved in the pathogenesis of coronary spasm.^56,57 Elevated serum eosinophils,⁵⁸ monocytes,⁵⁹ and mast cells have been implicated in coronary spasm.

Coronary spasm is more common in younger patients and women than angina pectoris occurring because of obstructive atherosclerosis. However, some degree of atherosclerosis (as intimal thickening by IVUS or at autopsy) is likely present in all cases of coronary spasm. In patients dying with spasm, severe plaque was observed in a substantial proportion of sampled coronary segments (Fig. 35–9).⁶⁰ Atherosclerosis produces profound alteration of vascular responses that may lead to spasm in the coronary as well as the cerebrovascular bed. Leukocytes and platelets likely play an important role in the pathophysiology of spasm. Cigarette smoking and Asian ethnicity are risk factors for spasm, whereas other traditional cardiovascular risks are not strongly associated. Some patients have clustered angina episodes, experiencing two to four at a time before relief; episodes typically last for minutes at a time. Spasm is frequently observed in patients with ACS and must be considered as part of the diagnostic evaluation, particularly when the degree of atherosclerotic obstruction observed angiographically fails to explain the ischemic syndrome.⁶¹

A scoring system has been proposed to estimate risk of major adverse cardiac events (MACE) in patients with vasospasm (Table 35–1).⁶² Using this system, patients can be stratified into low, moderate, and high risk of MACE. Early repolarization pattern on the resting ECG has been suggested as a predictor of cardiac events.⁶³

Pharmacological agents, such as ergonovine, ergometrine, or acetylcholine, are used to test for the presence of coronary spasm during invasive angiography when spasm does not occur spontaneously during the procedure. Ergonovine activates multiple receptors (alpha-adrenergic, dopaminergic, and serotonin [5-HT]) directly activating vascular smooth muscle. The drug can be given intravenously in doses from 0.05 to 0.40 mg or by the intracoronary route with modest accuracy for determining the presence of spasm. The drug can result in prolonged spasm and must therefore be given in a controlled clinical environment (ie, during angiography), where intracoronary nitroglycerin can be administered rapidly if needed. Unfortunately, it causes a generalized constriction of coronary arteries even when given to patients without spasm and an elevation of systemic blood pressure. This makes interpretation of anything, except subtotal occlusion associated with symptoms and ECG changes, difficult for the occasional user to interpret, particularly when the patient also has obstructive CAD.

Acetylcholine dilates arteries with functioning endothelium by stimulation of endothelial muscarinic receptors to release NO. When the endothelium is not functioning normally and/or vascular smooth muscle is activated, acetylcholine causes constriction. Acetylcholine is infused directly into the coronary artery, usually over 1-minute intervals separated by 5 minutes, starting at 25 μg and increasing by 25-μg increments to a maximum of 100 to 200 μg. In general, patients with spasm will experience focal or sometimes generalized spasm with acetylcholine, although patients without vasospasm but with ED will experience a more diffuse, less severe constriction of the artery. Focal spasm may portend a worse prognosis versus more diffuse spasm, in response to acetylcholine infusion.⁶⁴

Treatment of patients with coronary spasm includes elimination of risk factors, particularly smoking and exposure to noxious fumes such as those related to smoke and gasoline engine exhaust. Calcium antagonists are the cornerstone of treatment, sometimes with addition of nitrates. We have at times combined a dihydropyridine calcium antagonist with a nondihydropyridine (verapamil or diltiazem) for patients not adequately responsive to one agent. Nitrate therapy may not improve outcomes when added to calcium antagonist therapy.⁶⁵ However, nitrate tolerance is always a concern in these patients because nitrates are so effective in relieving and preventing symptoms related to coronary spasm. Cilostazol has recently been suggested to be effective for selected patients with coronary spasm not controlled by a calcium antagonist.⁶⁶ The benefit of alpha-adrenergic blockers and beta-blockers is limited, and use of these agents may limit dosing of more effective calcium antagonists due to hypotension.⁶⁷

The coronary arteries can be affected by systemic inflammatory illnesses, both general inflammatory diseases and those specific to vascular structures. Vasculitides are commonly organized by the size of the vessels affected: large (such as the aorta), medium (such as coronary vessels), and small (such as arterioles). Despite this nomenclature, vessel involvement is not limited to one vessel size and the disease processes commonly span multiple vessel size ranges. Cardiologists may encounter these diseases in the process of evaluating patients with nonspecific symptoms, such as fatigue. Recurrent fevers may prompt cardiology referrals requesting evaluation of the patient for endocarditis. A high index of suspicion must be kept to diagnose these diseases. A table of processes that may manifest with coronary arteritis is provided (Table 35–2). The effect of systemic vasculitides is variable, because some, but not all, contribute to accelerated atherosclerosis.⁶⁸

Infectious agents may play a role in a number of vasculitides. Hepatitis B is linked to polyarteritis nodosa, and hepatitis C is a causative agent of cryoglobulin-related vasculitis. Bacteria associated with vasculitis include Rickettsiae, Coxiella, Mycoplasma, and Toxoplasma. Viral agents include herpes, Epstein-Barr, parvovirus, cytomegalovirus, and varicella.⁶⁹

Large-Vessel Vasculitis

Takayasu’s Arteritis

The pathological cause of Takayasu’s arteritis is not precisely known, but it is widely thought to result from an autoimmune process mediated by T cells and affect the vasa vasorum of large vessels with leukocyte infiltration. The disease is most prevalent in Asia and the Middle East, with a female predominance and a peak incidence in the third decade of life.⁷⁰ Some familial cases have been reported, but the disease is generally considered sporadic. Early symptoms are nonspecific (fatigue, fever), whereas late manifestations include vision loss, renal impairment, and stroke. Although coronary involvement is thought to be uncommon, perfusion defect may be seen in a majority of patients, despite a lack of cardiac symptoms.⁷¹ In a cardiology context, consideration should be given for this disease in young patients presenting with myocardial infarction and low risk of atherosclerosis. No specific serum test is available; markers of inflammation (C-reactive protein, sedimentation rate) are commonly used in facilitating diagnosis. Treatment is based on steroid suppression. CT and specifically PET/CT are useful for assessing arterial dilation and inflammatory activity in the vessels (Fig. 35–10).⁷⁰

Giant Cell Arteritis

Also known as temporal arteritis because of a predilection for the temporal arteries, giant cell arteritis (GCA) is a vasculitis predominantly of older (> 50 years) patients. Infiltration of the intima with giant cells can result in granuloma formation and thickening of the internal elastic lamina. Blindness and stroke are unfortunate presentations, whereas headache and fever are a more common combination. In rare cases, GCA may present initially with coronary manifestations.⁷² A meta-analysis comparing GCA to non-GCA patients found that the subsequent risk of CAD was not different between the groups, although it is limited by high heterogeneity of the studies.⁷³ GCA is commonly diagnosed by biopsy of affected arteries, which is not feasible for the coronaries. Imaging studies may show pathological thickening of the large vessels (Fig. 35–11).⁷⁴ Treatment is with immunosuppression.

Medium-Vessel Vasculitis

Polyarteritis Nodosa

Polyarteritis nodosa is a chronic systemic disease caused by necrotizing vasculitis most often affecting the skin and peripheral nerves. The disease is caused by an autoimmune response to an infectious agent, most commonly hepatitis B virus. As a result of vaccination in western populations, hepatitis B is decreasing infrequency, as is polyarteritis nodosa. Being linked to hepatitis B, the peak incidence is in the 40- to 50-year age range with a male predominance. Coronary artery involvement is present in a minority of cases (4%–30%).⁷⁵ The coronaries can become thrombosed, resulting in infarction, or become aneurysmal and possibly rupture (Fig. 35–12).^76,77,78 No laboratory tests are specific for polyarteritis nodosa; antineutrophil cytoplasmic antibodies (ANCA) are typically negative. A five-factor score can be used to estimate risk of mortality, which is dependent on the organ systems involved.⁷⁹ Immune-modulating drugs, including steroids, cyclophosphamide, azathioprine, and methotrexate, are used for treatment.

Kawasaki Disease

Kawasaki disease is a common childhood vasculitis that can manifest with coronary abnormalities. The disease is also known as mucocutaneous lymph node syndrome and is rare in adults. Typical presentation includes erythema of mucous membranes (conjunctivitis, mucositis, rash) and lymphadenopathy. An infectious agent is suspected, but no causative agent has been identified.⁸⁰ Widespread inflammation of medium-sized arteries results in coronary artery aneurysms, typically developing between 4 days and 4 weeks of symptom onset for about 25% to 30% of patients who are not treated early. Pathologically, necrotizing angiitis of the vaso vasorum damages the media and adventitia. Risk factors for aneurysm development are described in Table 35–3. Researchers encourage the use of standardized Z-scores of aneurysm size in order to optimize comparisons in the medical literature.⁸¹ Widespread use of intravenous immunoglobulin has resulted in dramatic reductions in morbidity and mortality. Treatment with other immune modulating drugs is a current area of study.⁸² Spontaneous regression of the aneurysm occurs in about half of vessels 1 to 2 years after illness, predominantly determined by the size of the initial aneurysm. Aside from aneurysm development, other cardiac structures and function may be affected. Pericarditis, myocarditis, and arrhythmias have been reported. Noncoronary vascular symptoms include peripheral ischemia and, rarely, gangrene.

When Kawasaki disease goes undiagnosed in childhood, adults can suffer from late clinical manifestations (Fig. 35–13). In long-term (30 years) follow-up of Kawasaki patients, only 36% remained free of cardiovascular events.⁸³ A recent cohort of adult patients with coronary aneurysm noted during angiography found that 22% were believed to have “definite” Kawasaki disease as a child.⁸⁴ Echocardiographic evaluation of adults with history of Kawasaki disease suggests that persistent changes in the coronary intima may be a way to detect latent cardiovascular risk.⁸⁵ Late treatments of coronary artery aneurysm are similar to those for any other etiology. If ischemia or ACS develops, appropriate medical therapy is warranted and revascularization options span surgical and percutaneous methods. Retrospective data suggest that routine use of anticoagulation is associated with lower risk of occlusion, infarction, and death.⁸⁶

Small-Vessel Vasculitis

ANCA-Associated Vasculitis

Within small-vessel vasculitides, two general groups emerge, those with ANCA and those mediated by immune complexes. The ANCA-associated diseases include microscopic polyangiitis, granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), and eosinophilic polyangiitis (formerly Churg-Strauss syndrome). These diseases are most commonly diagnosed in older adults and most commonly affect the kidneys, lungs, eyes, nerves, and skin. Presentations include glomerulonephritis, cough, pleuritic pain, conjunctivitis, optic neuropathy, peripheral neuropathy, and purpura. Serum tests and biopsies of affected organs are helpful in establishing the specific diagnosis. Cardiac involvement may not be considered part of the typical presentation. However, if an extensive evaluation is conducted, half of patients may have some cardiac abnormalities.⁸⁷ Cardiac MRI often demonstrates myocardial scarring.^88,89 Treatment options vary based on the specific processes observed and severity of disease. Immunomodulating drugs are the cornerstones of therapy.

Immune Complex–Mediated Small-Vessel Vasculitis

There are several small-vessel vasculitides without ANCA, such as antiglomerular basement membrane disease (formerly Goodpasture’s disease), cryoglobulinemia, and IgA vasculitis (formerly Henoch-Schonlein purpura). These diseases share the fact that immune complexes are deposited in vessel walls and damage the small vessels of the body. As with the ANCA-associated diseases, the lungs, kidneys, skin, and nerves are the most commonly affected organ systems. Little has been written about coronary involvement, but case reports linking these diseases to the heart have been published.^90,91 Depending on the severity of symptoms and the organs involved, supportive treatment or immunosuppressive therapy may be used.^92,93,94

Thromboangiitis Obliterans (Buerger Disease)

Thromboangiitis obliterans is an uncommon, poorly understood non-necrotizing vasculitis strongly linked to smoking. It typically manifests as a peripheral vascular disease affecting the lower extremities. Claudication leading to ischemia, ulcer formation, and gangrene is a common sequence in the clinical presentation. Infectious, genetic, immunological and hypercoagulability causes have been proposed. Rarely, the coronaries may be involved.⁹⁵ Histopathologic review of biopsy specimens can distinguish this from other vasculitides. Tobacco cessation is thought key to management; no specific therapies alter the course of the disease and medical/surgical therapy is focused on relieving ischemic symptoms.

For some patients with advanced ischemic and nonischemic heart disease, orthotopic heart transplantation is a treatment option. More than 5000 heart transplants are performed worldwide annually—more than 2000 in the United States alone. After the initial surgical procedure, patients are required to maintain a strict regimen of immunosuppressive and anti-infective medications to prevent complications. These medication regimens have extended the average survival for heart transplant patients to over 10 years. With the additional longevity, diseases such as transplant vasculopathy (TV) have become more common, with TV now the leading cause of late death after transplantation.⁹⁶

TV is a process whereby the coronary arteries become diffusely and circumferentially narrowed with progressive luminal loss. The process differs from typical atherosclerotic processes. Findings often seen include: smooth muscle cell proliferation in the intima, fibrosis, and accumulation of T-lymphocytes (Fig. 35–14).⁹⁷ Separate from these events, atherosclerotic plaque may be present in the donor heart at the time of transplantation or develop subsequently. The process occurs in roughly one-fourth of patients after 5 years and one-half after 10 years. Greater donor age, younger recipient age, history of hypertension, and immune mismatches are risk factors for developing TV.

Clinically, patients may present with progressive anginal symptoms, graft dysfunction (ie, systolic dysfunction), or sudden death. Myocardial infarction can occur with or without symptoms because of variable innervation of the transplanted heart. A variety of techniques may be used to diagnose TV, including stress testing, coronary CT, and invasive coronary angiography with or without IVUS.⁹⁷ Most transplant centers screen their transplant patients with one or more of these techniques.

TV has few therapeutic options, with repeat transplantation being the only definitive treatment. Statins, calcium antagonists, and angiotensin-converting enzyme inhibitors have all demonstrated some effect at reducing TV.⁹⁸ Some immunomodulating drugs may be more effective than others.⁹⁹ Percutaneous coronary intervention is an option for focal stenoses but is not feasible for diffuse narrowing. Antiplatelet agents may be given to reduce risk of myocardial infarction, although the evidence supporting this is limited.¹⁰⁰

Anomalous Coronary Arteries

The normal origin and course of the coronary arteries is described above; variation from this pattern is observed in approximately 1% to 2% of people. Patterns of variation include anomalous origin (coronary atresia, separate ostia for circumflex and anterior descending arteries, coronary arising from the wrong aortic cusp, coronary arising from the pulmonary artery), anomalous course (interarterial, intraarterial, retroaortic), and anomalous branching (single coronary artery) (Fig. 35–15). Two of the most commonly observed patterns are right coronary arising from the left cusp coursing between the aorta/pulmonary artery and circumflex artery arising from the right sinus coursing retrograde around the aorta and not between the great arteries.¹⁰¹ Origin of the entire coronary circulation from a single aortic ostium is termed single coronary. This anomaly is rare in the absence of other associated anomalies of the heart. Atresia of one of the two main coronary ostia may occur and may result in myocardial ischemia and infarction in infancy or childhood. The involved vessel becomes dependent on collateral coronary blood flow from the contralateral coronary artery.

Anomalous left coronary artery arising from the pulmonary artery (ALCAPA; also known as Bland-White-Garland syndrome) results in a different pathology than other anomalies involving the coronaries from the aorta. This condition is frequently fatal in the infant period of life. Those surviving into adulthood typically have developed a robust collateral flow system where the myocardium is supplied with oxygen from the right coronary alone and flow is reversed in the left system into the pulmonary artery (Fig. 35–16).¹⁰² This causes a coronary steal phenomenon, left ventricular dysfunction, and sometimes ischemia and even sudden death.

Some of these patterns may be associated with myocardial ischemia and raise concern for adverse events, including sudden death.¹⁰³ The primary concern among these anomalies relates to arterial courses between the aorta and pulmonary artery. Normally, the coronary ostia are round to oval in shape, but in this anomaly, the coronary artery has an acute angle of origin that makes the ostium slitlike in shape. The mechanism of ischemia, infarction, and/or sudden death in this coronary anomaly may relate to the shape of the coronary ostium of the anomalous vessel. A multitude of causal mechanisms have been advanced, including hypoplasia of the artery, the acute angle of origin, a flaplike mechanism of the endothelium at the origin, and direct compression of the artery between the great arteries. Although the precise mechanism is unclear, what appears to occur is that with increased cardiac output, some combination of hemodynamic changes (eg, increase in systolic pressures, aortic dilation with stretching of the aortic wall) results in diminished flow down the coronary artery, leading to ischemia and all of its potential complications: angina, syncope, arrhythmia, infarction, and so on. Further investigation into the mechanisms of ischemia is underway.¹⁰⁴ Single coronary arteries do not commonly have the same acute takeoff/narrowing but may have elevated risk of adverse cardiac events caused by excessive blood flow in the single artery (Figs. 35–17, 35–18, and 35–19).^105,106

When compared to patients with coronary arteries that do not travel between the great arteries, patients with an interarterial/intraarterial course are more likely to undergo surgical revascularization and may be at higher risk for myocardial infarction and/or sudden death.¹⁰¹ Perhaps the most comprehensive understanding of risk associated with anomalous coronaries comes from Eckart, who reviewed sudden deaths in 6.3 million military recruits.¹⁰⁷ This selected population had gone through screening necessary for military service; 126 deaths were observed (64 caused by an identifiable cardiac abnormality) at a rate of 13.0 per 100,000 recruit years. Among them, anomalous coronary arteries were considered responsible for one-third of deaths (21 of 64), all of which were left coronary arteries arising from the right sinus with a course between the aorta and pulmonary artery (Fig. 35–20).¹⁰⁸

Less clear is the relationship between anomalous coronaries and clinical symptoms such as dyspnea, angina, and syncope, particularly among the elderly patients undergoing evaluation. For example, acute chest pain is a common reason to seek emergency medical care and cardiac CT is growing in popularity as an imaging methodology to evaluate acute chest pain patients. Given that 1% to 2% of people have anomalous coronary arteries, an increasing number may be detected that otherwise are actually incidental findings, unrelated to the clinical presentation.¹⁰⁹ When these anomalies are discovered in older patients, aggressive management becomes difficult to justify as these defects, present from birth, have not caused myocardial infarction or death in the patients up to the time of their discovery. Surgical revascularization can be performed; often surgeons request evidence of myocardial ischemia before embarking on a repair. Surgical approach is individualized to the anatomy of the patient and could take the form of reimplantation, pulmonary artery relocation, surgical repair of the coronary ostium, bypass grafting, or unroofing.¹¹⁰ Surgical management of anomalous coronary from the pulmonary artery is typically achieved with coronary reimplantation.^111,112

Myocardial Bridging

Coronary arteries typically course over the epicardial surface of the heart. Occasionally, segments of varying lengths may travel within the myocardium and reappear on the epicardium more distally in the arterial course. This is sometimes referred to as a tunneled artery, but the clinical phenomenon is most often referred to the description of the overlying muscle, a myocardial bridge. On pathological specimens, the coronary artery is surrounded, not by epicardial fat, but by myocardium. These can be observed during coronary angiography, where the lumen of the tunneled segment of the vessel decreases, particularly during systole. Autopsy studies suggest that myocardial bridges are much more common (> 15%) than observed on angiography (< 1%), likely because the degree of bridging and compression of the vessel lumen is variable, possibly relating to the varying depth of the tunneled segment within myocardium (Figs. 35–21, 35–22, and 35–23).^113,114,115

Myocardial bridging appears to be more common than is clinically manifest; therefore, evaluating the hemodynamic significance of a bridge is an area without uniform agreement. Conceptually, compression of a tunneled artery should be limited mostly to myocardial systole because coronary blood flow occurs predominantly during diastole. However, many bridges also restrict expansion of the coronary artery in diastole. Additionally, augmentation of coronary blood flow required to meet increasing demands such as exercise is often accompanied by an increase in flow during systole because diastole is progressively limited by the increase in heart rate. Thus ischemia, myocardial infarction, arrhythmias, and sudden death have all been attributed to myocardial bridging.¹¹⁶ A variety of techniques, including fractional flow reserve, nuclear myocardial perfusion imaging, IVUS, and intracoronary Doppler have been used to investigate the perfusion consequences related to bridging.^117,118 Bridges are frequently associated with other abnormalities, such as ED, microvascular dysfunction, spasm, and other coronary pathologies.³¹ Antianginal agents such as calcium antagonists and beta-blockers have been used as a conservative treatment, whereas surgery has been used for those with persistent symptoms and evidence of ischemia.¹¹⁹

Coronary Artery Fistulas

An abnormal communication between an epicardial coronary artery and a cardiac chamber, major vessel (vena cava, subpulmonary veins, pulmonary artery), or other vascular structure (mediastinal vessels, coronary sinus) is known as a coronary artery fistula. An example of a fistula between the left circulation and the pulmonary artery is illustrated in Fig. 35–24. These anomalies can be congenital or acquired; they can be present at birth or be observed later in life (Table 35–4). Congenital fistulas result from failure of fetal structures such as splanchnic veins or intramyocardial trabecular sinusoids to regress. The latter of these persist as Thebesian veins of normal anatomy.¹²⁰ Fistulas may be associated with other congenital abnormalities, including atrial/ventricular septal defects, patent ductus arteriosus, pulmonary atresia, and tetralogy of Fallot. Acquired fistulas can result from intracardiac operations, trauma, and transcatheter procedures as a result of abnormal healing between the damaged circulatory chambers and vessels.

Fistulas that connect the left circulation to left-sided chambers may not result in clinical disease and be incidentally found on angiography (Fig. 35–25).¹²¹ However, some will raise diastolic pressure in the affected chamber, causing dilation or hypertrophy. Fistulas between the left and right circulation result in shunt of blood flow, which may be clinically relevant, depending on the volume of flow. Fistulas predispose to endocarditis and may also present with continuous murmur, myocardial ischemia/angina, acute myocardial infarction, sudden death, coronary steal, congestive heart failure, arrhythmias, or coronary aneurysm formation.^120,122

Historical data on prevalence from angiographic cohorts is typically about 0.1%; contemporary CT-based cohorts report a higher prevalence up to 0.9%.^123,124,125 Lim and colleagues found the most common fistula to be coronary artery to pulmonary artery; however, in this CT-based cohort, the authors may have been less likely to detect direct connections from a coronary artery to a cardiac chamber. CT can readily detect surplus vessels but cannot readily detect a direct connection through the myocardium without the advantage of seeing active flow of contrasted blood from the coronary artery into the heart chambers.

If patients present with heart failure or ischemia symptoms, the traditional evaluation often includes coronary angiography, which is the most reliable method of detecting coronary fistulas. Patients with incidentally found, asymptomatic, left-to-left fistulas can be managed conservatively and will often remain stable and symptom-free for long periods of time. Interventional occlusion or surgical repair is indicated for patients with symptoms attributable to the fistula or heart failure/cardiac remodeling caused by shunting of blood. Successful repair can usually be achieved with low likelihood of residual shunting in long-term follow-up.¹²¹ Percutaneous closure can also be performed.¹²⁶

Coronary Artery Aneurysms

An aneurysm of the coronary artery is a pathological dilation of the entire vessel wall: intima, media, and adventitia. Normal coronary artery diameter is 4.5 mm for the left main down to 1.9 mm in the distal portion of the left anterior descending artery; a typical coronary artery measures 2 to 3 mm.¹²⁷ Of note, women have smaller coronary arteries than men, even when corrected for body size. “Giant” aneurysms are often defined as those with diameters more than four times the normal diameter, but dilations of 20, 30, and 40 mm are not uncommon.¹²⁸ Aneurysms are present in about 1% of people at autopsy, the most common (up to 50% of cases) etiology is dilation secondary to vessel damage from atherosclerosis.¹²⁹ The malformation can be congenital or acquired secondary to atherosclerosis, trauma (external or iatrogenic), or inflammatory illnesses. Percutaneous coronary interventions with stenting or angioplasty, atherectomy, and laser-based procedures all can result in aneurysm formation. Kawasaki disease and Takayasu’s arteritis are two of the inflammatory conditions most commonly associated with aneurysm formation (Table 35–5).

Aneurysms are typically asymptomatic and sometimes incidentally found on CT, angiography or, rarely, on echocardiography.¹³⁰ Ischemia and ACS can occur if thrombus formation results in luminal narrowing, embolization, or occlusion. Mass effects, such as superior vena cava syndrome, have been reported in patients with giant aneurysms. Treatment of aneurysms should include medical management of any underlying conditions. For those with ischemic symptoms, revascularization may be pursued. Surgical ligation or bypass was more common in the past; however, percutaneous techniques such as embolization and stenting are now more frequent. Stents covered with impervious graft material, such as polytetrafluoroethylene can create an exclusion of the aneurysmal segment and restore normal flow.^131,132 Patients who present with ACS can be especially challenging because layers of mural thrombus can form in large aneurysms where stasis of flow promotes clotting. Angiography does not readily demonstrate whether thrombus is newly formed or chronic. Because thrombosis in these vessels is a known complication, both antiplatelet and anticoagulation medications are commonly used, although the quality of the supporting evidence is low.

Dissection refers to the separation of arterial wall layers and can occur spontaneously or as a secondary event. As a result, two lumens develop within the vessel a “true lumen” that represents the normal channel for blood to flow and a false lumen, which is a channel the blood flows into and does not have the characteristics wall layers of a normal coronary artery. Depending on the nature and severity of the dissection, the false lumen can compress or occlude the true lumen resulting in ischemia, infarction, or death (Fig. 35–26).¹¹⁵

Spontaneous or primary dissections are less common than secondary and are most commonly reported in young women, often associated with pregnancy.¹³³ The condition is rare, or at least rarely reported, with only 440 cases in the MEDLINE database between 1931 and 2008.¹³⁴ In a review of those cases, 70% (n = 308) were in women and 26.1% overall (n = 80) were pregnant; 83.8% of pregnancy-related dissections occurred in the postpartum period. Dissection can also be caused by cocaine use, connective tissue disorders, systemic inflammatory conditions, atherosclerosis, or iatrogenic causes. Heavy aerobic exercise and isometric physical activity have been reported as triggers of dissection. The heart is protected from chest trauma by the ribcage. However, blunt force trauma, crush injuries, and penetrating (stabbing and missile) injuries can still damage the heart: the pericardium, myocardium, valves, and the coronary arteries. Laceration of the coronaries occurring with stab and gunshot wounds is particularly problematic because the resulting bleeding can lead to tamponade (Figs. 35–27¹³⁵ and 35–28¹³⁶).^135,136

A dissection in the ascending thoracic aorta can propagate toward the heart and result in coronary dissection. Vessels can dissect in antegrade (toward the distal vessel) or retrograde (toward the vessel origin) patterns. If the intima is disrupted across the circumference of a vessel (which can occur during balloon angioplasty), a “spiral” dissection can occur where the vessel appears angiographically to dissect from side to side with a thin layer of endothelial tissue visible within the vessel lumen (Fig. 35–29).¹¹⁵

The signs and symptoms of dissection are similar to ACS resulting from atherosclerotic disease: chest pain, ischemic ECG changes, and elevated cardiac biomarkers.¹³⁵ With modern equipment, the rate of dissection during coronary intervention and interrogation is low (< 1%).¹³⁷ Percutaneous and surgical treatments are options; however, many dissections are managed conservatively without need for revascularization.¹³⁸ Antegrade dissections are often treated with stenting to prevent further propagation of the dissection and ischemic complications. Because of the direction of blood flow, retrograde dissections can often be treated conservatively (ie, without further intervention). Spiral dissections are technically challenging from a percutaneous perspective and often managed either conservatively or with surgical revascularization if ischemic symptoms develop.