Angina in Patients with Evidence of Myocardial Ischemia and No Obstructive Coronary Artery Disease

Symptoms

Stable angina is the most frequent initial manifestation of ischemic heart disease in women whereas acute MI and sudden death are more common initial presentations in men. Women report more angina than men, in part due to higher somatic awareness in women. Whereas both men and women experience typical and atypical anginal symptoms, approximately half of men have typical symptoms versus one-third of women. In a recent large multi-center study of symptomatic men and women with suspected CAD, chest pain was the primary symptom in approximately three-fourths of both men and women, although more women characterized the pain as crushing, pressure, squeezing, or tightness. Patients with CMD may have both typical and atypical symptoms of angina. In addition to exercise-induced or exertional symptoms, they may report symptoms at rest and prolonged symptoms. Dyspnea with exertion is common, and should be considered an angina equivalent. Because routine cardiac stress testing is designed to detect obstructive CAD, CMD can be missed. Given the atypical symptoms and nondiagnostic testing results, these patients may be misdiagnosed as having a psychiatric or gastrointestinal cause of their symptoms. Endothelial dysfunction, smooth muscle dysfunction, impaired microvascular vasodilatory capacity, elevated resting vasomotor tone, and abnormal cardiac nociceptive abnormality contribute to various degrees in an individual patient. Given the high burden of cardiovascular risk factors and associated morbidity, it is reasonable to empirically treat for CMD if diagnostic testing for its detection is not available.

Persistent chest pain at 1 year after angiography in women with no obstructive CAD predicts cardiovascular events, with twice the rate of composite events [nonfatal MI, stroke, heart failure, and cardiovascular (CV) death] compared to those without persistent chest pain. It is estimated that approximately 50% of women who present for chest pain evaluation continue to have symptoms at 5 years. These patients present repeatedly to clinicians and emergency rooms seeking answers for their persistent symptoms and have considerable associated anxiety due to the absence of a clear diagnosis; they undergo repeated cardiac testing, contributing to high healthcare costs. In the WISE study of 883 women, those with no obstructive CAD had an average lifetime cost estimate of $767,288 (95% confidence interval [CI] $708,480–$826,097), with expenses increasing as the number of vessels with CAD increased ( Fig. 25.2 ).

Medical conditions such as depression and anxiety can also contribute to angina and need to be appropriately addressed and managed, as patients with persistent chest pain but no coronary obstruction have a higher prevalence of depression and anxiety and are more likely to need psychiatric medication. Along with esophageal dysmotility disorders, a panic disorder should also be considered in those with recurrent chest pain that is out of proportion to objective evidence of ischemia found on testing. In one study of symptomatic patients with angiographically normal coronary arteries, 34% were found to meet Diagnostic and Statistical Manual of Mental Disorders criteria for having a panic disorder. In a pilot study from Amsterdam of 20 patients with chest pain and no obstructive CAD on angiography who were screened with State Scale and Trait Scale of the State-Trait Anxiety Inventory, those with high anxiety had more ischemia on myocardial perfusion imaging compared to those with low anxiety. In 2014, Vaccarino et al. reported a sex difference in mental stress–related myocardial ischemia in patients with a history of MI. Mental stress–induced ischemia was more common in younger women (age ≤ 50 years) compared to age-matched men, and this sex difference was not evident in those older than age 50 years. Mental stress has been associated with coronary endothelial dysfunction, and younger women may be particularly susceptible to adverse cardiac effects of mental stress.

Coronary Microvascular Dysfunction with Significant Coronary Artery Disease

CMD may occur concomitantly with significant obstructive coronary atherosclerosis. This may become evident when patients remain symptomatic despite percutaneous coronary intervention; in such cases, coronary vasospasm related to stent placement and/or CMD should be suspected. The phenomenon of no-reflow after intervention is associated with worse prognosis, and no-reflow is believed to occur due to abnormal microvascular function. CMD cannot be excluded as a cause of angina in those with obstructive CAD, because in the same patient, angina can occur due to dynamic epicardial stenosis and/or microvascular dysfunction and/or coronary spasm. This point is emphasized in the 2013 European Society of Cardiology (ECS) guidelines on the management of stable coronary artery disease. For the diagnosis of microvascular angina, the ECS guidelines provide a class IIa recommendation for dobutamine stress echocardiography and IIb for invasive coronary reactivity testing. In contrast, the current US ACC/AHA guidelines on stable ischemic heart disease do not address specifics of diagnostic testing for CMD.

Coronary Microvascular Dysfunction with Structural and Infiltrative Myocardial Disease

Studies on patients with cardiac syndrome X often excluded patients with structural heart disease such as hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy. The WISE study also excluded those with structural heart disease and/or cardiomyopathy. CMD has been demonstrated in those with hypertrophic and infiltrative cardiomyopathies such as amyloidosis. Whereas a diagnosis of microvascular dysfunction is typically made in those patients where structural heart disease such as HCM is excluded, one should note that patients with HCM have been shown to have a low CFR compared to healthy individuals. HCM patients with a low CFR had higher 3-year event rates compared to those with normal flow reserve (79% vs 17%, p < 0.0001). Furthermore, those HCM patients who were asymptomatic but had an abnormal CFR had a 10-fold increased risk of events (including death, unstable angina, nonfatal MI, hospitalizations for heart failure, syncope, atrial fibrillation, and implantable cardioverter defibrillator implantations). A majority of HCM patients have been shown to have abnormal CFR by echocardiography.

Coronary Microvascular Dysfunction and Takotsubo Cardiomyopathy

Also known as stress-induced cardiomyopathy or broken heart syndrome , Takotsubo cardiomyopathy (TTC) is much more common in women compared to men, with a majority of cases occurring in postmenopausal women. Typically associated with a catecholamine surge due to a stressor (which can be emotional distress or physical stress), it resembles acute coronary syndrome, with troponin elevation and ECG changes. Obstructive CAD is not found on angiography and characteristic wall motion abnormalities are noted, with basal hyperkinesis and apical akinesis or hypokinesis. Reverse forms of TTC with apical hyperkinesis and basal akinesis, as well as biventricular forms, have also been described. Previously thought to have a good prognosis because it is a reversible cardiomyopathy, recent data indicate that it may not be as benign. Whereas various mechanisms are under investigation in TTC, including cardiac adrenergic dysfunction and multivessel spasm, impaired coronary endothelial function and vascular reactivity has been demonstrated in those patients with a history of TTC. Vascular disorders such as Raynaud’s and migraine, which tend to be more common in women, are also associated with TTC, implicating a more generalized vascular endothelial dysfunction.

Coronary Slow Flow Phenomenon

When contrast is injected into the coronary ostia, if there is a delay in the opacification of the coronary artery, this microvascular dysfunction-related phenomenon is described as coronary slow flow phenomenon, which occurs in 1–3% of coronary angiograms. It is generally defined as Thrombolytic In Myocardial Infarction (TIMI) grade 2 flow in the absence of obstructive CAD, with a transit time of three or more heart beats for contrast to travel to distal vessels. The TIMI frame count has also been used to define coronary slow flow, and this phenomenon of slower opacification is more often observed in men when coronary angiography is performed in the setting of acute coronary syndrome. It can present with rest or exertional pain, and abnormal microvascular resistance has been implicated. On endomyocardial biopsy of symptomatic patients with coronary slow flow, small vessel medial hypertrophy, myointimal proliferation, and endothelial abnormalities have been reported. Similar to microvascular angina, patients may present with recurrent chest pain and undergo repeat hospitalizations. In the WISE study of women with no obstructive CAD, a longer TIMI frame count independently predicted hospitalization for angina. Nitrates are not particularly helpful in slow flow because they are epicardial vasodilators, with little impact on microvascular tone. Dipyridamole is a vasodilator that has been studied in coronary slow flow, and the newer generation β-blocker nebivolol has been shown to improve CFR in patients with coronary slow flow. Nebivolol is a unique β-blocker as it potentiates nitric oxide effects leading to vasodilation and is also an antioxidant. The T-type calcium-channel blocker (CCB) mibrefradil (not available in the United States) has been shown to improve TIMI frame count and angina frequency by 56% compared to placebo in patients with coronary slow flow, which implicates smooth muscle dysfunction in coronary slow flow phenomenon.

Invasive Coronary Reactivity Testing

Patients who continue to have angina and have some objective evidence of myocardial ischemia or injury (such as abnormal stress testing or history of non–ST-segment elevation myocardial infarction [NSTEMI]), and who are suspected to have CMD, can be offered invasive coronary reactivity testing to clarify the diagnosis and to help guide therapy. Vasoactive agents such as adenosine, acetylcholine, and nitroglycerin can be used to test endothelial and nonendothelial macro- and microvascular function. In response to acetylcholine and nitroglycerin, coronary artery diameter changes can be assessed by quantitative coronary angiography. At time of printing, there are no guideline-recommended or standardized protocols for assessing coronary microvascular function, and centers that perform coronary reactivity testing have their own individual protocols.

Coronary reactivity testing can be helpful to clarify the etiology of symptoms in patients with objective evidence of ischemia who do not have obstructive CAD. Briefly, a Doppler flow wire is placed in the epicardial coronary vessel, and the hyperemic response to a potent vasodilator (typically adenosine) is noted by change in coronary flow velocity ( Fig. 25.5 ). The intracoronary dose of adenosine used in the WISE study to assess myocardial flow reserve (18–36 μg) tests the nonendothelial-dependent microvascular response. In the WISE study of 159 symptomatic women (mean age 52.9 years) who underwent coronary reactivity testing for suspected CMD, 47% had a CFR ≤2.5 after intracoronary adenosine. We have reported that low- and high-dose intracoronary adenosine (18 μg vs 36 μg) produced similar augmentation in coronary flow velocity, and 47% of women demonstrate abnormal adenosine response with CFR ≤2.5.

To test the coronary endothelial-dependent response, intracoronary acetylcholine in increasing concentrations is typically used, and coronary diameter change is noted visually and by quantitative coronary angiography. Acetylcholine stimulates the healthy endothelium to release nitric oxide, which in turn mediates vascular smooth muscle cell relaxation via cyclic guanosine monophosphate (cGMP). It must be noted that the entire epicardial vessel should be assessed in response to intracoronary acetylcholine because distal vasoconstriction can often be missed if one is focused only on the proximal segments of the epicardial vessel. Failure to dilate in response to acetylcholine indicates impaired endothelial function ( Fig. 25.6 ). In the WISE study of women with no obstructive CAD who underwent coronary reactivity testing, 58% of patients had epicardial coronary endothelial dysfunction. Coronary blood flow can be calculated by the following equation that incorporates the diameter change as well as flow velocity change to acetylcholine: Coronary blood flow = Pi x [vessel diameter/2] ² x (average peak velocity/2). ² Whereas designations of endothelial- versus nonendothelial-dependent responses are helpful conceptually, one must recognize that there is significant overlap in these mechanistic pathways. Piek et al. have shown that coronary flow capacity, which combines CFR and maximal hyperemic average peak flow velocity, improves prediction of major adverse cardiovascular outcomes, compared with CFR alone.

In the Coronary Artery Spasm as a Frequent Cause for Acute Coronary Syndrome (CASPAR) study, approximately 50% of patients with acute coronary syndrome with no obstructive CAD were found to have coronary vasospasm on intracoronary acetylcholine provocation testing. Ong et al. have also reported a high percentage of patients with microvascular spasm, defined in their study as electrocardiographic changes indicative of ischemia, and reproduction of patient symptoms in response to acetylcholine, without overt epicardial spasm seen on angiography.

In a study by Hasdai et al. in 203 patients (158 women, 45 men; mean age 51 years) without evidence of obstructive CAD, over 50% had an abnormal coronary reactivity testing result (11.3% had an abnormal adenosine response, 29.2% had an abnormal acetylcholine response, and 18% had abnormalities in response to both adenosine and acetylcholine).

Currently, coronary reactivity testing is performed selectively at specialized centers. The approach used in our center is shown in Fig. 25.7 . We have reported on the safety of coronary reactivity testing using intracoronary adenosine (18 μg and 36 μg), acetylcholine (graded infusions of 0.364 μg and 36.4 μg over 3 min), and nitroglycerin (200 μg) in the left coronary artery. When performed by experienced operators in 293 women in the WISE study, there were no reactivity testing–related deaths, and two serious adverse events (0.7%; one dissection and one MI from spasm); MACE rate at 5.4 years of follow-up in this study was 8.2%. In a European study of 921 patients (362 men) with no obstructive CAD who underwent intracoronary acetylcholine provocation testing (with graded doses of 2, 20, 100, and 200 μg infused over 3 min in the left coronary artery), no fatal or serious adverse complications were reported. In this study, 1% of the patients ( n = 9) had minor complications, including nonsustained ventricular tachycardia, paroxysmal atrial fibrillation, symptomatic bradycardia, and catheter-induced proximal right coronary artery spasm.

Noninvasive Imaging Modalities

Exercise Treadmill Testing

In a 2014 consensus statement from the AHA on evaluation of women with suspected ischemic heart disease, exercise treadmill testing (ETT) remains as first-line, since it is widely available, relatively inexpensive, and provides excellent prognostic information based on metabolic equivalents of task (METS) achieved and functional capacity ( Fig. 25.8 ). Reproduction of symptoms during an ETT is important to consider when interpreting the ETT. ST-segment depression on exercise ECG testing or during an anginal episode can indicate ischemia related to obstructive CAD or microvascular dysfunction. A positive ETT with no obstructive CAD on angiography can lead to a conclusion of “false-positive” ETT; however, CMD should be considered as an etiology in such patients.