Introduction
Treatment of angina and evidence of myocardial ischemia on stress testing with no obstructive coronary artery disease (CAD) by angiography is a challenge. Previously referred to as cardiac syndrome X, this syndrome was believed to have a benign cardiovascular prognosis; however data from the NHLBI-Women’s Ischemia Syndrome Evaluation (WISE) and other studies demonstrate that up to 50% of these patients have coronary microvascular dysfunction (CMD), which carries an adverse cardiovascular prognosis. Patients with CMD are more likely to be mid-life women, who have a high frequency of atherosclerosis on intravascular coronary ultrasound (IVUS), and face a 2.5% annual adverse cardiac event rate, which includes myocardial infarction (MI), stroke, congestive heart failure, and sudden cardiac death. This rate of adverse events is notably higher compared with asymptomatic community controls. In addition to WISE, other studies in Europe and Canada have also reported on the elevated risk of adverse outcomes among those with ischemia and no obstructive CAD. Whereas coronary endothelial dysfunction and impaired microvascular vasodilatory reserve are of particular importance in the pathophysiology of ischemic heart disease in women, a recent study demonstrated that CMD may be highly prevalent in both men and women, although this remains to be confirmed by larger prospective studies. In addition to microvascular dysfunction, diagnoses to consider in patients with persistent angina and no obstructive CAD include coronary vasospasm (Prinzmetal angina) with and without myocardial bridging, abnormal cardiac nociception, as well as noncardiac etiologies. It is important for the clinician to keep in mind the wide differential diagnosis of patients who present with chest pain and are found to have no obstructive CAD ( Fig. 25.1 ).
Whereas CMD can be detected noninvasively by positron emission tomography (PET), stress cardiac magnetic resonance (CMR) imaging, and stress echo Doppler coronary flow reserve (CFR), depending on individual center expertise, the gold standard for its diagnosis is invasive coronary reactivity testing. Therapeutic success typically anchors on diagnostic certainty; coronary reactivity testing using intracoronary infusions of adenosine, acetylcholine, and nitroglycerin to assess microvascular and macrovascular (epicardial) endothelial and nonendothelial function ( Table 25.1 ) should be considered in patients with signs and symptoms of ischemia if no obstructive CAD is found. Coronary reactivity testing can be safely performed in catheterization laboratories with experienced operators. Both the endothelial- and nonendothelial-dependent abnormalities stratify patients at risk for future cardiovascular events, as well as characterizing mechanistic pathways to direct therapy.
| Microvascular Dysfunction | Macrovascular Dysfunction | |
|---|---|---|
| Nonendothelial dependent | Reduced CFR to adenosine (CFR ≤ 2.5) | Abnormal vasoreactivity to nitroglycerin (% diameter change < 20%) |
| Endothelial dependent | Reduced CBF to acetylcholine (% change in CBF ≤ 50%) | Abnormal vasoreactivity to acetylcholine (% diameter change < 5%) |
Two of the issues in diagnosis and, ultimately, treatment in symptomatic patients with ischemia but no obstructive CAD are the confusion in terminology in the literature to describe this group of patients, and the lack of standardized diagnostic criteria. To address these, the Coronary Vasomotion Disorders International Study Group (COVADIS) investigators have proposed international standards for the diagnostic criteria of coronary vasomotor disorders with the aim to facilitate research in this field and improve care in this patient population. Large, randomized, placebo-controlled therapeutic outcome trials are lacking, and current US guidelines do not specifically address diagnosis and treatment of CMD.
Therapeutic lifestyle change, low-dose aspirin, and lipid-lowering therapy are recommended due to the high prevalence of coronary atherosclerosis and risk of adverse cardiac events. Evidence collected in predominantly general cardiac syndrome X patients has investigated the use of β-blockers, angiotensin-converting enzyme inhibitors (ACE-I), l -arginine, nitrates, calcium-channel blockers, ranolazine, xanthine derivatives, α-blockers, enhanced external counterpulsation, cognitive behavioral therapy, tricyclic medication, and neurostimulation to improve symptoms, stress test parameters, and endothelial function with variable results. Treatment of patients should focus on two main goals: (1) antiatherosclerotic and anti-ischemic therapy to reduce adverse cardiac event risk, and (2) relief of angina to improve quality of life.
This chapter provides an overview of CMD and discusses currently available diagnostic methods of its detection, as well as pharmacologic and nonpharmacologic interventions that can be utilized for these patients, with the understanding that the best approach is to develop a regimen based on individual patient needs and characteristics. Given the unfolding knowledge, we propose that existing unstable angina/non–ST elevation MI guidelines for the treatment of cardiac syndrome X and chronic stable angina guidelines from the American Heart Association (AHA)/American College of Cardiology (ACC) be modified to include the therapeutic strategies reviewed here ( Box 25.1 ).
- 1.
Coronary Microvascular Dysfunction
- •
Abnormal Endothelial Function
- •
ACE-I
- •
HMG CoA reductase inhibitors (statins)
- •
l -arginine supplementation
- •
aerobic exercise
- •
EECP for refractory angina
- •
- •
Abnormal Nonendothelial Function
- •
β-blockers/medications with α- and β-blocking properties
- •
nitrates
- •
- •
Antianginal
- •
ranolazine
- •
ivabradine
- •
xanthine derivatives
- •
nicorandil
- •
- •
- 2.
Abnormal Smooth Muscle Function (Prinzmetal Angina)
- •
calcium-channel blockers
- •
nitrates
- •
- 3.
Abnormal Cardiac Nociception
- •
low-dose tricyclic medication
- •
spinal cord stimulation
- •
stellate ganglion blockade
- •
cognitive behavioral therapy
- •
ACE-I, Angiotensin-converting enzyme inhibitors; EECP , enhanced external counterpulsation.
∗ Proposed modification of existing American College of Cardiology /American Heart Association unstable angina and stable angina guidelines.
Terminology
Cardiac syndrome X is an outdated term that described the triad of typical anginal chest pain, evidence of ischemia by a positive exercise stress testing with ≥ 0.1 mV ST-segment depression, and normal-appearing coronary arteries on angiography. In 1973, Harvey Kemp first coined “cardiac syndrome X” in his editorial on a study by Arbogast and Bourassa. In their study, Arbogast and Bourassa compared two groups of patients who developed angina with atrial pacing: those with angiographically normal–appearing coronary arteries (group X) versus those with obstructive coronary atherosclerosis. A stricter definition consists of the following criteria: (1) exercise-induced, angina-like chest discomfort; (2) evidence of ischemia by ST-segment depression on electrocardiography during the anginal episode; (3) normal appearing coronary arteries on angiography; (4) no evidence of spontaneous or inducible epicardial coronary vasospasm; and (5) absence of cardiac structural pathology or systemic diseases, such as left ventricular hypertrophy, valvular heart disease, cardiomyopathy, or diabetes.
Historically, cardiac syndrome X patients formed an ill-defined subgroup of angina patients who were believed to have a benign syndrome with a good cardiovascular prognosis and were often dismissed from ongoing cardiac care. Despite decades of work in Europe and the United States, cardiac syndrome X remains a challenge to the practicing clinician, with no large randomized treatment or major adverse cardiac events (MACE) outcome trials. This is partly due to a lack of standardized diagnostic criteria and partly due to the diversity of mechanistic pathways that play a role in the pathophysiology of this heterogeneous disorder. Since the mid-2000s, with advances in diagnostic imaging modalities and invasive techniques to assess coronary physiology/flow and myocardial perfusion, it has become clear that at least 50% of cardiac syndrome X patients have CMD. The use of the term cardiac syndrome X is now considered outdated when referring to patients who have objective evidence of myocardial ischemia and no obstructive atherosclerosis.
Since 2013, the term MINOCA has been used to describe “myocardial infarction and no obstructive coronary artery disease” when the cause is not clear. Criteria for MINOCA include the universal definition of MI by troponin rise and ischemic symptoms or electrocardiogram (ECG) changes, and no significant coronary stenosis (> 50% or more in epicardial coronary arteries). The prevalence of MINOCA is estimated to be anywhere from 2% to 10% and is more likely to occur in women and those younger in age compared to those who present with obstructive CAD. A diagnosis of MINOCA should prompt the clinician to consider other causes of MI such as myocarditis, cardiomyopathy, coronary vasospasm, CMD, or a thrombotic disorder, as outlined by Pasupathy et al. in Table 25.2 . Most recently, the term ANOCA has been proposed to refer to those patients with “angina and no obstructive coronary artery disease.”
| Clinical Disorder | Diagnostic Investigation |
|---|---|
| Noncardiac Disorders | |
| Renal impairment | Serum creatinine |
| Pulmonary embolism | CTPA or ventilation/perfusion imaging |
| Cardiac Disorders | |
| Myocardial Disorders | |
| Cardiomyopathy (takotsubo, dilated, hypertrophic) | Left ventriculography, Echo, CMR |
| Myocarditis | CRP, CMR, EMB |
| Myocardial trauma or injury | History (trauma, chemotherapy), CMR |
| Tachyarrhythmia-induced infarct | Arrhythmia monitoring |
| Coronary Disorders | |
| Concealed coronary dissection (aortic dissection involving valve, spontaneous coronary dissection) | Echo, CT angiogram |
| Sympathomimetic-induced spasm | Drug screen (eg, cocaine) |
| Epicardial coronary spasm | ACh provocation testing |
| Microvascular spasm | ACh provocation testing |
| Microvascular dysfunction | CFR |
| Coronary slow flow phenomenon | TIMI frame count |
| Plaque disruption/coronary thrombus | Intravascular ultrasound |
| Coronary emboli | Echo (left ventricular or valvular thrombus) |
| Thrombotic Disorders | |
| Factor V Leiden | Thrombophilia disorder screen |
| Protein C & S deficiency | |
Epidemiology
The finding of no obstructive CAD in the setting of acute coronary syndrome (ACS), unstable angina, and stable ischemic heart disease is more prevalent in women compared with men ( Table 25.3 ). In the Coronary Artery Surgery Study (CASS) of 25,000 men and women with signs or symptoms of myocardial ischemia who underwent coronary angiography, 39% of women and 11% of men demonstrated no obstructive CAD. In a 2008 retrospective Canadian cohort of 32,856 patients suspected of ischemic heart disease who underwent coronary angiography, 23.3% of women versus 7.1% of men ( p < 0.001) had angiographically normal coronary arteries; women with no obstructive CAD were over four times more likely than men to be readmitted to the hospital for symptoms/ACS within 6 months. In the US National Cardiovascular Data Registry (NCDR) of patients undergoing coronary angiography for stable angina ( n = 375,886), 51.2% of women had no obstructive CAD compared with 33.3% of men, and based on these NCDR data, it has been estimated that approximately 3 million American women have CMD. Among the 168,322 women in the NCDR, black women had the lowest rate of significant obstructive CAD compared with Hispanic, Native American, Asian, and white, non-Hispanic women (41.7% vs 45.3%, 55%, 53%, and 50%, respectively). Numerous factors have been proposed to explain this sex difference in the presentation of ischemic heart disease. Due to a diffuse pattern of plaque deposition throughout the artery, and outward positive remodeling of the arterial wall, without having one specific clear area of stenosis in the artery, these lesions are not amenable to percutaneous interventions, and thus the patient gets falsely labeled as “no significant CAD.” In the WISE study of women with signs and symptoms of ischemia and no obstructive CAD on angiography, intravascular ultrasound demonstrated atherosclerotic plaque in up to 80% of the women.
| No./Total (%) | |||
|---|---|---|---|
| Women | Men | p Value | |
| Acute Coronary Syndrome | |||
| GUSTO | 343/1768 (19.4) | 394/4638 (8.4) | < 0.001 |
| TIMI 18 | 95/555 (17) | 99/1091 (9) | < 0.001 |
| Unstable angina | 252/826 (30.5) | 220/1580 (13.9) | < 0.001 |
| TIMI IIIa | 30/113 (26.5) | 27/278 (8.3) | < 0.001 |
| MI without ST-segment elevation | 41/450 (9.1) | 55/1299 (4.2) | 0.001 |
| MI with ST-segment elevation | 50/492 (10.2) | 119/1759 (6.8) | 0.02 |
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.
Pathophysiology
Symptomatic ischemic heart disease in those with no obstructive CAD represents a heterogeneous group of disorders with varying pathophysiologic mechanisms that often overlap ( Fig. 25.3 ). The normal endothelium is a protective barrier, antithrombotic and antiinflammatory, and also mediates vascular smooth muscle cell vasodilatation. The majority of coronary vascular resistance is determined by the coronary microvasculature; under normal physiologic conditions, only 10% of resistance is determined by epicardial coronary arteries. Whereas various autonomic, neurohormonal, and metabolic mechanisms influence myocardial blood flow, coronary endothelial dysfunction plays an important role in coronary vasodilator reserve. A diagnosis of coronary endothelial dysfunction can help direct the clinician to currently available treatments that target the endothelium, although large randomized controlled trials specifically in well-phenotyped patients with CMD are lacking. In symptomatic women with no obstructive CAD who underwent coronary reactivity testing, those who had a history of MI were found to have more coronary endothelial dysfunction compared to those with no history of MI. In addition to functional vascular abnormalities related to endothelial and microvascular dysfunction, plaque erosion and microembolization may play a greater role in ischemic heart disease in women.
Endothelial function is affected by aging, oxidative stress, changes in hormonal status, and conditions such as hypertension and diabetes. Bone marrow–derived endothelial progenitor cells have been shown to be important in vascular repair, and reduced numbers or regenerative capacity of these cells may play a role in microvascular dysfunction. Patients with microvascular dysfunction are more likely to have hypertension, insulin resistance, and hyperlipidemia compared to the general population; in the WISE study, traditional cardiac risk factors appeared to be modestly related to CMD when diagnosed by invasive coronary reactivity testing or when diagnosed by abnormal myocardial perfusion reserve index (MPRI) on CMR imaging. In 100 women suspected of ischemic heart disease (mean age 54 ± 10 years) with no obstructive CAD and with intravascular ultrasound–measured atherosclerosis, waist circumference and systolic blood pressure were independently associated with plaque presence and severity, after adjustment for multiple factors including age, diabetes, family history of CAD, hyperlipidemia, hormone replacement, and tobacco smoking.
Impaired sympathovagal balance determined by heart rate variability, and altered baroreflex sensitivity, has also been implicated in patients with cardiac syndrome X. Abnormal cardiac adrenergic nerve function measured by I- meta -iodobenzylguanidine ( m IBG) nuclear planar imaging in patients with cardiac syndrome X compared to normal patients has been reported previously.
It has been hypothesized that CMD can lead to decreased subendocardial perfusion and that repetitive bouts of microvascular ischemia may lead to microinfarctions, fibrosis, and diastolic dysfunction, with progressive myocardial injury and systolic dysfunction ( Fig. 25.4 ). In 2014, acetylcholine-induced coronary microvascular spasm was associated with diastolic dysfunction determined by echocardiography in patients with no obstructive CAD. We have demonstrated that in a cohort of women who underwent invasive coronary reactivity testing for the diagnosis of CMD, over one-third had elevated left ventricular end diastolic pressures > 15 mmHg. Given the current epidemic of heart failure with preserved ejection fraction, which also has a female predominance, a mechanistic link between CMD and heart failure with preserved ejection fraction (HFpEF) has been proposed and is under investigation.
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.
Diagnostic Testing
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.
- 1
If patient is able to exercise and no contradictions
- 2
If patient is able to exercise and has good windows for ultrasonography
- 3
Consider if exercise treadmill testing (ETT) and stress echo are not an option or equivocal; benefit of no radiation and expertise is available at our center
- 4
Consider if ETT and stress echo are not an option or equivocal; expertise available at our center, is a low radiation testing protocol, and can provide coronary calcium score
- ∗
Includes atypical symptoms
- ∗∗
Follow American College of Cardiology / American Heart Association stable ischemic heart disease guidelines
- ^
Does not apply in the acute setting or acute coronary syndrome within 4–6 weeks. Only applies to stable ischemic heart disease patients.
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.
Stress Echocardiography
CFR can be measured via Doppler echocardiography, although this method is typically not utilized in routine clinical practice in the United States. Those with low CFR on dobutamine stress echo have less favorable prognosis compared to those with normal flow reserve on stress echo. In a study of 1660 men and women with normal stress echocardiograms, CFR was measured in the left anterior descending artery in response to dipyridamole. Those with a low CFR (≤ 2.0) had a high annualized event rate compared to those with CFR ≥ 2.0 ( Fig. 25.9 ).
