I. Microvascular and Coronary Microvascular Dysfunction: What every physician needs to know.

Cardiovascular disease remains the number one killer of women in the Western world.  There is a growing body of research demonstrating sex differences in presentation, etiology, and outcomes in women with ischemic chest pain.

Many studies have discovered that women are more likely than their male counterpart to have chest pain with normal coronary arteries demonstrated on coronary angiograms.  Up to 50% of women who are referred for angiography for signs and symptoms of ischemia are found to have normal coronary arteries.

Patients who have signs and symptoms of myocardial ischemia in the absence of coronary artery disease (CAD) are often labelled as Cardiac Syndrome X, and nearly 70% of these patients are women.  There is an increased risk of the development of adverse events in patients who have elevated risk factors.

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Investigation is needed to further identify and define the possible etiologies of what causes chest pain despite having normal coronary arteries. The Women’s Ischemia Syndrome Evaluation (WISE) has defined a dominant subset of patients with CSX to have microvascular angina (MVA) and coronary microvascular dysfunction (CMD). CMD is defined by the presence of myocardial ischemia and the presence of coronary vascular dysfunction in the macro or microvascular bed.

This can manifest as chest pain or abnormal ischemic responses to stress with hemodynamic changes, ECG changes, myocardial perfusion, or regional wall motion abnormalities.  CMD is a major etiologic mechanism for signs and symptoms of ischemia in the absence of obstructive CAD.  CMD is associated with an increased risk of a myocardial infarction (MI) and coronary death in women compared to men with CMD.

The etiology of CMD can be partially explained by endothelial dysfunction defined by abnormalities in the vasomotor or metabolic regulators of the macro and micro coronary arteries and arterioles in the setting of subclinical atherosclerosis.  There are many proposed pathophysiologic mechanisms including autonomic imbalance, nitric oxide-endothelin imbalance, coronary endothelial dysfunction, and reduced coronary flow reserve.  Evaluation and treatment of chest pain in women remains challenging in the medical field and further understanding in presentation, pathophysiology, evaluation, and treatment is key in providing proper care. 

II. Diagnostic Confirmation: Are you sure your patient has CMD?

The clinical criteria necessary to establish a diagnosis of CMD is as follows:

  • Persistent symptoms of ischemia, e.g. angina or angina equivalent.

  • Objective evidence of ischemia, e.g. abnormal stress testing or evidence of acute myocardial infarction (AMI). 

  • No obstructive coronary artery disease (CAD), e.g. normal or <50% epicardial luminal stenosis on coronary angiography.

In patients who meet the above criteria, further diagnostic testing including specialized noninvasive cardiac testing or invasive coronary reactivity testing can confirm the diagnosis.

A. History Part I: Pattern Recognition:

CMD which is defined as having symptoms and signs of myocardial ischemia in the absence of obstructive CAD, is classically acknowledged as a female predominant disorder.  These women are often peri menopausal or postmenopausal with their onset of symptoms between the ages of 40 to 50 years, although women in the WISE study range from 21-90 years of age.

In general, there are no typical signs or symptoms that would point towards CMD as the cause of chest pain as they are often indistinguishable to those who have chest pain caused by obstructive CAD, making pattern recognition difficult. 

These symptoms may include middle or upper back pain, shortness of breath, paroxysmal nocturnal dyspnea, nausea, vomiting, indigestion, loss of appetite, weakness and fatigue, dizziness and palpitations all of which are more often seen in women versus men presenting with acute coronary syndrome (ACS).  Women who present with ACS more frequently have unstable angina versus AMI, less marked ST segment changes, and are a decade older than men presenting with ACS.

They are also more likely to have comorbidities such as diabetes, hypertension, and heart failure.  The presence of obstructive CAD can be more accurately predicted in men compared to women.  Cardiovascular risk factors, such as hypertension, family history, smoking history, and raised serum concentration of lipids were poor discriminators between women with chest pain with obstructive CAD versus without obstructive CAD. There are some clues in a patient’s history that may suggest the presence of CMD despite “normal” angiograms; these include a variable threshold of physical activity that provokes angina; radiation of the discomfort to the sub mammary areas, and associated mental stress, or palpitation. 

A recent study demonstrated that chest pain that persists for years after angiography in women with no obstructive CAD is associated with future development of coronary atherosclerosis.  Other potential factors that are being investigated include duration of exposure to risk factors versus merely their existence, inflammation, and inflammation-mediated autoimmune diseases commonly encountered in females and their relation to general vasculopathy as well as possible genetic differences contributing to sex-related gene expression and their effects on cardiovascular function.

B. History Part 2: Prevalence:

In a large study that evaluated both men and women with chest pain and evidence of ischemia undergoing coronary angiogram, approximately 40% of women versus only 8% of men were found to have nonobstructive CAD.  Similar findings were reported in the CASS registry where nearly 25,000 patients were characterized after undergoing coronary angiography further pointing toward a female predominance. 

Retrospective studies have looked at patients who presented with ACS and have calculated 10% to 25% of women with normal coronary angiograms versus 6% to 10% of men.  It is estimated that 60,000 to 150,000 women annually, who present with ACS or MI, will have normal coronary arteries. 

Women have higher mortality rates after a MI and have worse outcomes after coronary artery bypass grafting suggesting differences in the pathophysiology of ischemic heart disease.  One proposed mechanism that may play a part in these sex differences is the role of CMD.

Results from the NHLBI WISE study evaluating women with chest pain and normal coronary arteries, demonstrated that approximately 50% had subnormal coronary flow velocity reserve suggesting underlying microvascular dysfunction.  The prevalence of CMD and MVA is uncertain; however, given that cardiovascular disease is the number one killer in women and that women are more likely to have normal coronary arteries on angiogram, it is likely that this phenomenon is prevalent and underdiagnosed.  Further research continues to provide insight as how to best recognize, diagnose, and treat women with CMD.

C. History Part 3: Competing diagnoses that can mimic CMD.

Patients who have angina or angina equivalent symptoms with signs of ischemia on noninvasive testing should undergo evaluation and monitoring based on cardiac risk factors based on guidelines, including evaluation for obstructive CAD, as appropriate.  Prior studies demonstrate that the presence of obstructive CAD can be predicted with less certainty in women compared to men, likely due to CMD in women.  There are other causes of chest pain with normal coronary arteries that have been well described. The cardiac differential diagnosis for chest pain with normal coronary arteries that can mimic CMD includes coronary spasm, coronary bridging, slow flow phenomenon, and apical ballooning syndrome also known as Takotsubo cardiomyopathy.

Epicardial coronary vasospasm, also known as Prinzmetal’s angina, is described as angina that occurs mostly at rest, lasting up to 15 minutes and often occurring between night and early morning.  Epicardial coronary vasospasm can be diagnosed by transient ST changes that resolve spontaneously or with nitroglycerin.  Provocation testing may also be used in establishing a diagnosis and can help corroborate the clinical and electrocardiographic diagnosis.

Coronary bridging is a congenital anomaly that involves a segment of a coronary artery that is buried in the myocardium and results in compression of the artery during systole.  This can be detected using coronary computed tomography imaging, invasive coronary angiogram with vasoactive stressors, intracoronary Doppler studies and intravascular ultrasonography.

Another etiology of chest pain with no obstructive CAD is the slow coronary flow phenomenon that is an angiographic finding that is characterized with delayed opacification of the distal vasculature in the absence of significant epicardial disease or stenosis.  As opposed to abnormal coronary flow reserves in the face of demand seen with CMD, the slow coronary flow phenomenon is associated with decreased coronary flow velocity at rest.

Takotsubo cardiomyopathy, also known as transient left apical ballooning syndrome, is largely confined to the female gender and is defined as having acute onset of chest pain, transient apical wall motion abnormalities, mild elevation of cardiac markers, dynamic electrocardiographic changes, the absence of CAD, and is often preceded by an emotional or physical trigger.

Noncardiac etiologies of chest pain should also be considered, including gastrointestinal pathology (dyspepsia, esophageal spasm, etc.), musculoskeletal, pulmonary, psychiatric disorders, and abnormal cardiac pain perception, and have been reviewed elsewhere.

D. Physical Examination Findings.

Physical examination in patients with CMD is often normal and noncontributory.  In some patients with elevated left ventricular end-diastolic pressure as a consequence of CMD compromising left ventricular function, one may find elevated jugular venous pressure or signs of decompensated heart failure in advanced cases. 

Physical examination findings may also provide clues that the patient has a higher likelihood of having coronary vascular disease, such as findings consistent with carotid vascular disease, peripheral vascular disease, or renal-vascular disease.  Interestingly, ophthalmic examination revealing retinal arterial narrowing, a measure of CMD, has been shown to relate to CVD risk and mortality in women but not in men.

Physical examination is also important for evaluating other causes of chest pain.   Cardiac examination findings may suggest arrhythmia or valvular pathology requiring further evaluation.  Chest wall tenderness may suggest costochondritis or rib fracture as an etiology.  Significant pulmonary findings may suggest mass, infectious process, pneumothorax, asthma or chronic obstructive pulmonary disease, etc. 

Examination findings may also suggest systemic autoimmune, neurologic, or malignant processes that may explain the patient’s chest pain or may put the patient at higher risk of having CMD.

E. What diagnostic tests should be performed?

Physical examination is not sufficient to confirm the diagnosis of CMD.  In those whose clinical history is suggestive, further diagnostic tests should be pursued for definitive diagnosis.  Options include noninvasive testing modalities or invasive coronary reactivity testing, which remains the gold standard testing method for the diagnosis of CMD. 

Provocative coronary reactivity testing using intracoronary adenosine, acetylcholine, and nitroglycerin to assess microvascular and macrovascular (epicardial) endothelial and nonendothelial function (Table 1) and has an established safety record.  Making the diagnosis of CMD allows for risk stratification of patients for future adverse cardiovascular events, as well as characterization of mechanistic pathways to direct therapy and improve the likelihood of therapeutic success.

Table 1.

Coronary Reactivity Testing Guide

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted? 

There are no laboratory tests that can establish the diagnosis of CMD.  In those presenting acutely with chest pain and suspected CMD, prompt evaluation for ACS with serial ECGs and troponins in a monitored setting should not be delayed.  In those that are stable, laboratory testing should aim at risk stratifying the patient (lipid profile, fasting glucose, BUN/Cr, hsCRP), and evaluating for other contributors of symptoms.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted? 

Documenting ischemia in patients with persistent chest pain and nonobstructive coronary angiography is essential in establishing a diagnosis and risk-stratifying patients with suspected CMD.  Noninvasive testing, such as single photon emission computed tomography (SPECT), positron emission testing (PET), and stress magnetic resonance imaging (MRI), may be useful to identify a pattern of abnormal myocardial perfusion suggestive of CMD, however because the pattern of ischemia is diffuse and non-segmental, these tests can be insensitive.

CMD in the absence of obstructive CAD may not consistently produce ischemia that can be detected with traditional noninvasive imaging.  This inconsistency may result from the fact that traditional nuclear imaging techniques rely on detection of abnormalities that are compared to a normalized myocardium, and consequently diffuse ischemic disease may be missed and appear as normal.  In such cases, or for patients in whom there are contraindications to noninvasive testing, there should be evaluation with invasive coronary reactivity testing to establish a definitive diagnosis and treatment strategy.  Advanced imaging that measures coronary blood flow reserve including positron emission tomography (PET) and cardiac magnetic resonance imaging (cMRI) can measure and hold promise for noninvasive detection of CMD. 

III. Management.

In contrast to obstructive CAD, there are no interventional treatment strategies, such as angioplasty or coronary stenting that are appropriate in CMD.  CMD therapies focus on anti-atherosclerotic and anti-ischemic therapy to reduce cardiovascular risk and relieving angina and improving quality of life.  The risk factors seen in CVD, such as tobacco use, hyperlipidemia, hypertension, and diabetes are also seen in patients with CMD and aggressive management of these risk factors is appropriated.

Lifestyle changes, such as smoking cessation, weight loss, and nutrition counselling, are important for reducing angina and due to the risk factor burden and presumably improving coronary microvascular dysfunction, although clinical outcome trials are needed.  The vast majority of WISE CMD patients have atherosclerosis detected on angiogram or coronary intravascular ultrasound, and therefore low dose aspirin and statin therapy can be considered for prevention of cardiovascular events.  Cardiac rehabilitation should be considered and encouraged in patients with CMD as this has been shown to increase exercise capacity and provide symptom relief.

Along with therapeutic lifestyle change related to nutrition for low-density lipoprotein cholesterol (LDL-C) lowering, statins should also be initiated.  Statin therapy has been shown to improve coronary flow reserve, as well as improve exercise tolerance and reduce angina.  The anti-inflammatory effect of statins on endothelial function has also been shown to be beneficial. The 2013 ACC/AHA lipid guidelines use a risk calculator to calculate a patient’s atherosclerotic cardiovascular disease (ASCVD) score to guide intensity of statin therapy.

In terms of reducing the frequency and severity of angina, there are different pharmacologic options for those with CMD. Beta blockers have been shown to be effective in treating angina in CMD.  Beta blockers that have alpha-blocking properties, such as labetalol and carvedilol, may be preferred in patients with CMD due to their ability to improve coronary flow reserve in the setting of ischemic heart disease.  Overall, beta blockers have been shown to be most effective compared to calcium channel blockers (CCB) or nitrates in reducing symptoms specifically in patients with CSX.

CCBs have been shown to improve angina and exercise tolerance in CMD.  They also reduce systemic vascular resistance and vasodilate the peripheral arteries, which may help to improve symptoms of angina.

Angiotensin converting enzyme inhibitors (ACE-I) or angiotensin renin blockers (ARB) help with regulating blood pressure, endothelial dysfunction, and vascular inflammation.  They may be used in CMD to improve coronary endothelial function and have been shown to improve CFR and exercise tolerance in patients with CSX and presumably CMD.

Nitrates can be used in angina management.  They stimulate cyclic guanosine monophosphate production, relaxing vascular smooth muscle cells, dilating peripheral arteries, and relieving angina.  Sublingual nitrates may not work in coronary microvascular dysfunction, however due to epicardial coronary endothelial dysfunction, they may be effective in approximately 50% of patients with angina and CMD.

Ranolazine is a new antianginal therapy for treating stable angina in patients with CAD.  Ranolazine is unique in that it produces antianginal effects without altering blood pressure or heart rate.  This medication was not shown to improve angina in those with CMD, however there is still some evidence showing benefits in those with typical angina and those with more severe CMD, and therefore should be considered in patients who are refractory to beta blockers, CCBs, and nitrates or as first line therapy in patients with contraindication to traditional antianginal medications.

Enhanced external counter pulsation (EECP) has been shown to reduce persistent angina and improve endothelial function in patients with angina due to CMD and can be used in refractory angina.

Tricyclics such as imipramine and amitriptyline can be used to treat patients with chest pain due to abnormal cardiac nociception. Imipramine has been shown to reduce frequency of angina episodes.

L-arginine, a precursor of nitric oxide, used over 6 months can lead to improved endothelial function.

Aminophylline, a non-selective adenosine receptor antagonist, may be of benefit as adenosine is thought to mediate cardiac chest pain.

Phosphodiesterase inhibitors, which increase the bioavailability of nitric oxide, also have a potential role in angina and CMD. Further research is needed to assess safety and efficacy. 

A. Immediate management.

Patients who are presenting to the emergency department with chest pain with objective evidence of ischemia should be evaluated for ACS. While the WISE study demonstrates an elevated adverse event rate in subjects with signs and symptoms of ischemia but no obstructive CAD, event rates are relatively lower compared to subjects with obstructive CAD, particularly with regard to STEMI, and thus less emergent invasive management may be warranted. In patients who are stable, immediate management should target symptom control and risk factor management. Further diagnostic studies may also be necessary to establish a diagnosis or for further risk stratification.

B. Physical Examination – Tips to Guide Management.

In patients who are on medical therapy for CMD, vitals obtained during physical examination are important in monitoring blood pressure and heart rate control.  Otherwise, there are no specific physical examination findings that can help monitor response to therapy, rather focus should be put on clinical history and symptoms to guide management.  Achieving risk factor control goals and optimal medical therapy is also essential for management.

C. Laboratory Tests to Monitor Response and Guide Management.

Aggressive lipid management may be appropriate and should be monitored for compliance based on the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (ASCVD).  Assessment for adherence, response to therapy, and adverse effects may be appropriate. In addition to monitoring lipids, patients who warrant treatment with diuretics or ACE/ARB therapy should have electrolytes and renal function monitored.

D. Longer-term Management.

The longer-term goals of management are symptom control and reducing the ASCVD risk of major CVD adverse outcomes, often involving aggressive anti-atherosclerotic and anti-ischemic therapy.  In addition to pharmacologic therapy, therapeutic lifestyle change is also recommended, including increasing cardiac rehabilitation/physical activity, smoking cessation, and incorporating a heart healthy diet.

Healthcare professional counseling, that includes a nutritionist and cardiac rehabilitation, is ideal.  Patients should be encouraged to participate in a cardiac rehabilitation program to improve their exercise tolerance, as physical conditioning has been shown to be effective for increased exercise capacity and symptom relief.

E. Common Pitfalls and Side-Effects of Management

Some common pitfalls and side effects encountered when managing CMD include achieving symptomatic relief without the unwanted side-effects common to antianginal treatment.  The following are common side effects to monitor while initiating treatment for CMD.

Beta blockers:  bradyarrhythmia, hypotension, dizziness, fatigue, and hair loss

ACE-I/ARB: Hypotension, hyperkalemia, dizziness, syncope, cough, abnormal renal function tests

CCBs: Bradyarrhythmia, peripheral edema, dizziness, headache, fatigue

Nitrates: hypotension, flushing, headaches, dizziness

Statins: abdominal pain, myalgias, increased liver enzymes

Ranolazine: Prolonged Q–T interval, constipation, nausea, dizziness, syncope, headaches

IV. Management with Co-Morbidities

As with any other chronic disease that needs long-term risk reduction and therapy, it is important to consider comorbidities when initiating and monitoring treatment for CMD.  Comorbid conditions should be monitored and treated appropriately, especially those that increase CVD risk.

In patients with multiple comorbid conditions, multidisciplinary care and communication between treating providers is essential.  Also special attention should be paid to medication adverse effects, interactions, and contraindications, as this patient population is at high risk for polypharmacy.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with CMD are often faced with poor management, often as a result of missed diagnostic opportunities by providers or the false notion that CMD is a benign condition.  The prognosis of CMD indicates a 2.5% annual adverse cardiac event rate, which includes MI, stroke, congestive heart failure, and sudden cardiac death.  Additional outcome measures, including reduced functional ability secondary to chest pain was reported in half of women with nonobstructive CAD, repeated angiography rate was 13.2%, and the repeated hospitalization after 1-year follow-up was 1.8-fold higher than those with 1-vessel disease.

Important measures to prevent readmission of patients with CMD include improved awareness of ischemic heart disease and gender specific differences in CVD.  Improved patient and provider education about CMD pathophysiology, appropriate management, and outcomes will ensure adequate treatment of these patients that at times pose significant management difficulties. Patient compliance with therapy and self-monitoring (i.e., chest pain diaries, home blood pressure logs, etc.) are important components to achieving therapeutic success.  In addition to education and appropriate diagnosis and treatment, outpatient clinician availability is important to prevent readmission. 

B. What's the Evidence for Specific Management and Treatment Recommendations?

Benjamin, EJ, Smith, SC, Cooper, RS, Hill, MN, Leupker, RV. “Task force #1-magnitude of the prevention problem: opportunities and challenges. 33rd Bethesda Conference.”. J Am Coll Cardiol. vol. 40. 2002. pp. 588-603. (This reference highlights the functional disability in patients with symptoms and nonobstructive coronary arteries.)

Bugiardini, R, Bairey, Merz, CN. “Angina with “normal” coronary arteries a changing philosophy.”. JAMA. vol. 293:. 2005;. pp. 477-84. (This article reviews patients with angina and normal coronary arteries and discusses the differences in presentation and prognosis among men and women.)

“Microvascular angina and the continuing dilemma of chest pain with normal coronary angiograms.”. J Am Coll Cardiol. vol. 54. 2009. pp. 877-85. (In this article the author discusses the evidence for microvascular angina as a cause for myocardial ischemia and the need for further investigation to understand the pathophysiology in order to tailor future therapies.)

Johnson, BD, Kelsey, SF, Bairey Merz, CN, Shaw, LJ, Redberg, RF. “Clinical risk assessment in women: chest discomfort. Report from the WISE study.”. In CAD in Women: Evidence-Based Diagnosis and Treatment,. 2003;. pp. 129-42. (This article provides an overview of evidence based diagnosis and treatment in those with symptomatic women.)

Stone, NJ, Robinson, JG, Lichtenstein, AH. “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.”. JACC. vol. 63. 2014. pp. 2889-2934. (This articles outlines the current guidelines in statin therapy and atherosclerotic cardiovascular disease prevention.)

Reis, SE, Holubkov, R, Smith, C. “Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study.”. Am Heart J. vol. 141. 2001. pp. 735-41. (In this multicentered study, 159 women with no obstructive CAD underwent invasive evaluation of their coronary microvascular as well as comprehensive risk factor analysis. It concluded that coronary microvascular dysfunction was present in one half of the women.)

Samin, A, Nugent, L, Mehta, P, Shufelt, C, Noel Bairey, Merz C.. “Treatment of angina and microvascular coronary dysfunction.”. Current Treatment Options in Cardiovascular Medicine. vol. 12. 2010. pp. 355-64. (In this article, treatment options as well as further risk stratification of patients with microvascular coronary dysfunction are discussed.)

Shaw, LJ, Bairey Merz, CN, Pepine, CJ. “Insight from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.”. J Am Coll Cardiol. vol. 47. 2006. pp. S4-S20. (This review highlights gender specific issues in ischemic heart disease presentation, evaluations, and outcomes. An overview of currently available diagnostic tests is also discussed.)

Shaw, LJ, Bairey Merz, CN, Reis, SE. “Ischemic heart disease in women: Insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. Part I: Sex Differences in Traditional and Novel Risk Factors, Symptom Evaluation and Gender-Optimized Diagnostic Strategies.”. J Am Coll Cardiol. vol. 47. 2006. pp. S4-S20.. (This article provides information on risk factors for women with ischemic heart disease.)

Von Mering, GO, Arant, CB, Wessel, TR. “Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).”. Circulation. vol. 109. 2004. pp. 722-5. (This article outlines the prognosis in women with abnormal coronary reactivity.)

Mehta, PK, Bairey Merz, CN, Bonow, RO. “Treatment of angina in subjects with evidence of myocardial ischemia and no obstructive coronary artery disease. In:”. Philadelphia, PA: Elsevier;. 2011.. (This chapter summarizes the current evidence for treatment of myocardial ischemia in patients with no obstructive coronary artery disease.)

Lewis, JF, Bairey Merz, CN, Goldman, MB, Troisi, R, Rexrode, KM. “Diagnosis and Treatment of Ischemic Heart Disease in Women. In:”. Elsevier. 2012;. pp. 975-989. (In this book chapter, ischemic heart disease, including obstructive and non obstructive coronary heart disease was discussed. Diagnosis and treatment modalities are outlined for women with ischemic heart disease.)

Dean, J, Deal Cruz, Sherwin,, Mehta, PK, Bairey Merz, CN. “Coronary microvascular dysfunction: sex-specific risk, diagnosis, and therapy.”. Nature Reviews Cardiology,. vol. 12. 2015. pp. 406-414. (In this review, specific therapies for coronary microvascular dysfunction are highlighted.)