Cardiac Chest Pain without Epicardial Stenosis: What Every Physician Needs to Know.
Patients with angina-like chest pain and objective evidence of ischemia in the setting of non-flow limiting epicardial coronary artery disease (CAD) are often diagnosed with cardiac syndrome X (CSX).
With advances in diagnostic technologies, we now have a better understanding of this patient population and there appears to be a spectrum of etiologies for patients presenting with angina in the setting of non-flow limiting epicardial CAD.
Cardiac causes include vasospastic angina, stress-induced cardiomyopathy, and coronary microvascular dysfunction.
Diagnostic testing for specific causes such as vasospastic angina and coronary microvascular dysfunction (Figure 1) are not part of routine diagnostic cardiac catheterization and often times are done only at specialized centers.
There is mounting evidence that a subgroup of these patients are at a significant risk of cardiovascular morbidity and mortality, and development of obstructive, flow limiting CAD in the future.
This review will focus on three known causes of cardiac chest pain without epicardial stenosis: coronary vasospasm (vasospastic angina), stress-induced cardiomyopathy, and coronary microvascular dysfunction.
II. Diagnostic Confirmation: Are you sure your patient has Chest Pain without Epicardial Stenosis?
Vasospastic angina: The exact cause of enhanced vasomotor tone is unknown. There is data to support the role of both the autonomic nervous system and endothelial dysfunction in mediating vasospasm. The vasoconstrictor response to acetylcholine and ergonovine suggests a role of the autonomic nervous system. There are studies which used I-123 metaiodobenzylguanidine (MIBG) imaging among patients with vasospastic angina and found evidence of enhanced parasympathetic activity and abnormalities in cardiac sympathetic tone in patients with vasospastic angina. Endothelial dysfunction has also been proposed to mediate increased contraction of vascular smooth muscle in the coronary circulation. And lastly, structural abnormalities such as increased intimal thickening in the coronary arteries that develop spasm may play a role.
Stress-induced cardiomyopathy: The prevailing mechanism for this disorder includes catecholamine excess with a role of diffuse severe microvascular injury, causing the classic apical ballooning abnormality. Several studies have shown increased levels of circulating catecholamines among patients presenting with stress-induced cardiomyopathy. To date, there are no specific genetic mutations or polymorphisms that are thought to mediate this response.
Coronary microvascular ischemia: To date, little is known about pathophysiologic cause for coronary microvascular ischemia and why there is a female propensity. Role of heightened pain awareness in these patients and the role of other metabolic and hormonal mediators remains unknown. Whether coronary microvascular disorder is an adaptive response for epicardial atherosclerosis and risk factors, such as hypertension, diabetes, and dyslipidemia remains unknown. Structural abnormalities, such as medial hypertrophy and fibrosis of arteriolar vessels have been described. Impaired nitric oxide release and activity has been suggested as a mediator. There is some evidence that not only is there abnormal vasodilation but also heightened vasoconstriction. Other studies have shown there to be a primary smooth muscle cell abnormality mediated by enhanced sodium-hydrogen (Na+-H+) exchanger activity in cell membranes. More recently, a role for intracellular rho-kinase, which may enhance vasoconstriction in vascular smooth muscle cells by facilitating calcium overload, has also been suggested in patients with angina and normal coronary arteries. And lastly, recent data suggest that low-grade inflammation might also play a pathogenetic role in the microvascular dysfunction with the presence of increased levels of markers of inflammation such as C reactive protein among patients with known microvascular angina.
Patients with angina-like chest pain with objective evidence of ischemia should be assumed to have epicardial CAD until proven otherwise. Once diagnostic coronary angiography confirms absence of flow limiting epicardial CAD, testing for other causes should be considered.
Cardiac chest pain without flow limiting epicardial CAD is more common among women than men. Patients with vasospastic angina may also have a history of vasospasm in other vascular beds, such as Raynaud disease with claudication in hands and fingers in response to the cold. Similarly, patients presenting with stress-induced cardiomyopathy typically have had an emotional trigger, such as an intense argument or witnessing tragic event, precipitate chest pain (Figure 2). Patients with coronary microvascular ischemia tend to have progressive symptoms of angina prior to presentation.
A. History Part 1: Prevalence:
In general this clinical presentation is much more common in women than men and patients are typically younger than those with angina due to obstructive, flow limiting epicardial CAD. Normal angiography is present in 10% to 25% of women vs. 6% to 10% of men who undergo coronary angiogram for chest pain and objective evidence of ischemia. This translates to approximately 60,000 to 150,000 women annually in the U.S. alone.
An undefined subset of these patients will have coronary vasospasm, stress-induced cardiomyopathy, and coronary microvascular dysfunction. Small studies report that 20% to 40% of patients with ischemic cardiac chest pain without flow limiting CAD have evidence of coronary microvascular ischemia.
B. History Part 2: Competing diagnoses that can mimic spasm and microvascular angina.
Differential diagnoses to consider for cardiac causes of chest pain and objective evidence of ischemia in the setting of non-flow limiting epicardial CAD are:
1.Vasospastic angina (variant angina or Prinzmetal’s angina).
2. Stress-related cardiomyopathy (also called apical ballooning syndrome or Takotsubo disease).
3. Coronary microvascular dysfunction or small vessel ischemia
Additional diagnoses to consider include:
4. Aortic dissection: a potential life-threatening disease, which may require emergent surgery.
5. Pulmonary embolism: chest pain and biomarker release can occur due to large pulmonary embolism.
6. Hypertrophic cardiomyopathy: a genetic heart disease affecting 1 in 500 persons. Myocardial ischemia is the main pathophysiologic feature. Myocardial ischemia is found often despite normal coronary angiography. Myocardial ischemia can contribute to complications, such as ventricular arrhythmias, sudden death, progressive left ventricular remodeling, and systolic dysfunction.
7. Anderson-Fabry disease: an X-linked deficiency of lysosomal α-galactosidase A. Patients with this disease often have angina, despite the presence of angiographically normal coronary vessels. The patients develop multiorgan damage from glycosphingolipid deposition.
C. Physical Examination Findings.
At presentation, the patient can be indistinguishable from a patient with angina due to flow limiting epicardial CAD. Patients can present with symptoms of stable angina to unstable symptoms with ST elevation myocardial infarction and cardiogenic shock. Physical examination may be completely normal. Or patients may exhibit signs and symptoms of heart failure if in cardiogenic shock with distended neck veins, S3 on cardiovascular auscultatory examination, and evidence of pulmonary edema on lung examination.
D. What diagnostic tests should be performed?
Patients presenting with chest pain concerning for angina should have an ECG performed. Depending on the findings on ECG and clinical presentation, decision to proceed to diagnostic coronary angiography should be made. Patients with stable syndromes may undergo stress testing to demonstrate ischemia on exertion or pharmacologic stress prior to angiography. On the other hand if there is a strong suspicion for ischemia based on resting ECG findings, diagnostic cardiac catheterization is reasonable.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
All patients presenting with signs and symptoms of ischemia should have:
1. Serum levels of cardiac biomarkers, such as CK, CK-MB, and troponin, obtained.
2. Complete blood count: to exclude severe anemia as the cause of inadequate perfusion resulting in demand ischemia.
3. Arterial blood gas: to evaluate for hypoxia.
4. Basic metabolic panel to assess electrolyte and renal function prior to possible cardiac catheterization.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Invasive coronary vasomotor function assessment
Once the diagnosis of cardiac chest pain and objective evidence of ischemia in the setting of non-flow limiting epicardial CAD has been established on coronary angiography, other testing can be performed to rule out or confirm the exact cause for presentation.
We will review three common presentations and the approach to their diagnosis:
1. Vasospastic angina: Spontaneous episodes of angina in association with ST segment elevation on the ECG may occur due to transient and abrupt spasm of epicardial coronary arteries causing myocardial ischemia. This syndrome has been called variant angina, vasospastic angina, or Prinzmetal’s angina. Although the pathogenesis of coronary vasospastic angina is not well understood, a focal, nonspecific coronary hyperreactivity of the vascular smooth muscle is commonly present in patients with vasospastic angina.
The autonomic nervous system is thought to play a role, more specifically represented by enhanced parasympathetic activity and activation of alpha adrenergic receptors. In addition, abnormal endothelial function leading to impaired flow-dependent coronary dilation due to decreased activity of the vasodilator nitric oxide, increased release and/or activity of the vasoconstrictors endothelin and serotonin, oxidative stress, and inflammation have also been proposed to play a role.
Confirmation of coronary vasospasm can be performed on coronary angiography. In general, those patients with vasospastic angina in whom angiography suggests normal coronary arteries present with nonexertional angina and ECG changes in the inferior wall distribution. The latter finding is consistent with the observation that coronary vasospasm most commonly occurs in the right coronary artery; however, other vessels may be involved.
Provocative tests using three different agents can—ergonovine, acetylcholine, and hyperventilation—can be performed in the catheterization laboratory and have been useful in making the diagnosis of suspected vasospastic angina. At present, pharmacologic provocative testing is not frequently performed and should only be employed with extreme care and by experienced teams.
Ergonovine is no longer used in the United States due to the potential for the induction of refractory spasm. Intravenous acetylcholine has been shown to induce epicardial coronary spasm and/or coronary microvascular spasm among patients with vasospastic angina and microvascular ischemia respectively. It is associated with a low frequency of serious complications (0.6 % in one report) and is preferred over other agents.
Non-invasive tools for assessing patients for coronary vasospasm include ergonovine stress echocardiography. This test has shown good sensitivity and specificity compared to angiographically provoked spasm. However, this test should be conducted with caution at experienced centers due to the risk of provoking irreversible spasm not responsive to nitroglycerin.
2. Stress-induced cardiomyopathy: Also known as apical ballooning syndrome or Takotsubo cardiomyopathy, this presentation is due to transient systolic dysfunction of the apical and/or mid segments of the left ventricle that mimics myocardial infarction in the absence of flow limiting epicardial coronary artery disease.
This disorder is more common in women than in men, with women accounting for 80% to 100% of cases in several studies. Patients presenting with this syndrome frequently have a physical or emotional trigger, such as death of relatives, catastrophic medical diagnoses, devastating financial or gambling losses, or natural disasters. It is believed that a catecholamine surge or coronary artery spasm or microvascular dysfunction may be responsible for chest pain in the setting of non-flow limiting coronary artery disease.
Coronary angiography typically demonstrates either normal vessels or mild to moderate coronary atherosclerosis. Left ventriculography shows a typical finding of apical and/or midsegment hypokinesis with hyperdynamic function of the basal segments.
Cardiac magnetic resonance (CMR) imaging may be helpful in differentiating stress-induced cardiomyopathy, which is characterized by the absence of delayed gadolinium enhancement, from myocardial infarction in which subendocardial delayed hyperenhancement is seen. CMR is also useful in differentiating stress-induced cardiomyopathy from myocarditis, which is characterized by patchy delayed hyperenhancement.
3. Coronary microvascular dysfunction: Small vessel ischemia is thought to be mediated by endothelial dysfunction or smooth muscle cell mediated microvascular spasm. Patients often will present with angina-like chest pain, objective evidence of ischemia, and non-flow limiting epicardial CAD on coronary angiography. Currently, no technique allows for direct visualization of coronary microcirculation, so investigations that rely on quantifying blood flow through the coronary circulation are commonly used to evaluate microvascular function.
This includes noninvasive tools such as cardiac MRI (CMR). CMR perfusion imaging is able to detect regional differences in myocardial blood flow. Significant correlation has been reported between invasively measured coronary flow reserve (CFR) to adenosine and dobutamine stress-induced perfusion defect score on CMR.
Other novel research tools have measured myocardial high-energy phosphates after hand-grip exercise using nuclear magnetic resonance spectroscopy and have provided evidence of myocardial ischemia, perhaps due to microvascular disease in a subset of patients with angina and non-flow limiting epicardial CAD on coronary angiography. Despite the promise of noninvasive imaging for the assessment of microvascular function, there continues to be limitations.
Invasive coronary vasomotor testing is a research and clinical tool considered to be the gold standard for establishing a diagnosis of coronary microvascular dysfunction. This encompasses both endothelial dependent dysfunction and nonendothelial dependent dysfunction.
Doppler flow method (Figure 3) has been used to measure flow response to agents known to affect the coronary microcirculation. Response to incremental doses of acetylcholine and to adenosine have been used to diagnose patients with coronary endothelial-dependent and nonendothelial-dependent dysfunction, respectively.
Coronary flow reserve is measured in response to adenosine and is a marker for nonendothelial-dependent coronary microvascular dysfunction. Normal response to adenosine is augmentation of blood flow greater than 2.5 times that at rest. A Doppler wire placed in the distal portion of a coronary artery measures baseline flow velocity and is then compared to flow velocity in response to adenosine.
Similarly, acetylcholine in graded doses is used to assess endothelial-dependent microvascular and macrovascular function. The absence of a vasodilatory response >50% in the epicardial coronary artery is considered an abnormal response. These enhanced testing techniques require meticulous technique and often performed at specialized centers with an interest in studying microcirculatory function.
More recently a method has been used to calculate an index of microvascular resistance (IMR). Using a coronary thermistor and pressure sensor tipped coronary wire, coronary blood flow is calculated using the thermodilution technique under basal and hyperemic conditions induced by intravenous adenosine. Similarly, distal coronary pressure is measured in response to hyperemia using intravenous adenosine.
IMR is then calculated as distal hyperemic pressure divided by the inverse of hyperemic coronary blood flow or more simply, distal pressure × hyperemic transit time. Using animal modes of microcirculation, IMR of 20 has been defined as the upper limit of normal.
Abnormal IMR among patients undergoing percutaneous coronary revascularization in the setting of ST segment elevation myocardial infarctions predicted size of infarct and abnormal wall motion score on echocardiography. Data on use of IMR to assess coronary microvascular dysfunction among patients with angina-like chest pain and objective evidence of ischemia in the setting of non-flow limiting epicardial CAD is still emerging.
Once a diagnosis of angina-like chest pain and objective evidence of ischemia in the setting of non-flow limiting epicardial CAD is made, management depends on the cause for presentation. In general, in the acute setting the overall goal of initial management is to relieve chest pain and ensure normal physiologic parameters for blood pressure, heart rate, and oxygenation. For the rare patient who presents in cardiogenic shock, hemodynamic support with placement of an intraaortic balloon pump may be required.
1. Vasospastic angina: Treatment of vasospastic angina is based on understanding the underlying mechanism of arterial spasm. Increased coronary hyperreactivity mediated via enhanced smooth muscle tone is frequently present. Medical therapy includes risk factor modification, such as cessation of smoking and lipid lowering.
Specific pharmacologic therapy includes:
Calcium channel blockers (nifedipine, diltiazem, and verapamil)
Statin therapy – endothelial dysfunction may play a role in development of vasospastic angina and may benefit from statin therapy.
Both classes of drugs, calcium channel blockers and nitrates, are effective in preventing vasoconstriction and promoting vasodilation in the coronary vasculature.
2. Stress-induced cardiomyopathy: Patients presenting with stress-induced cardiomyopathy require supportive care for the short term and long term. Medical therapy for acute systolic dysfunction should be instituted with:
These medications optimize left ventricular remodeling and fluid status. Patients should get a follow-up study to evaluate left ventricular function in 6 to 8 weeks. The majority of patients will have full recovery of ventricular function.
3. Coronary microvascular dysfunction: Patients with abnormal microvascular function have been shown to have adverse long-term prognosis. To date, only small-scale studies have shown impact of a few drugs on microvascular function. Treatment of subjects should focus on antiatherosclerotic and antiischemic therapy to reduce risk of adverse cardiac events and to reduce symptoms of angina and improve quality of life. Patients with known microvascular dysfunction should be treated aggressively with lifestyle and pharmacologic interventions for secondary prevention of ischemic heart disease. This includes:
Lipid lowering agent to current ACC/AHA and ATP III-NCEP goals.
Beta-blockers – Several beta-blockers have been studied including atenolol and more selective nebivolol. Some studies have reported that beta-blockers improve symptoms, exercise tolerance, and ST segment depression on Holter monitoring in patients with proven coronary microvascular dysfunction. Atenolol has been compared to amlodipine and isosorbide-5-mononitrate and showed a greater degree of angina relief. Among patients with evidence of increased adrenergic tone, such as high heart rate or decreased heart rate variability during 24-hour Holter monitoring, or a rapid increase of heart rate and/or blood pressure during exercise, beta-blockers are a good first option.
Angiotensin converting enzyme Inhibitors (ACE-I) – The renin–angiotensin system has been proposed to play a role in causing microvascular dysfunction. Recent trial data did show a modest improvement in CFR among patients treated with enalapril compared to placebo. In addition, other studies have shown that enalapril may enhance nitric oxide availability and improve microvascular dysfunction.
Nitrates – may have no effect on vessels smaller than >100 μm. However, nitrate therapy has been shown to improve symptoms among some patients with microvascular ischemia.
Ranolazine – is a new antianginal agent that alters late sodium current and reduces calcium overload in the myocyte. A small trial in women with microvascular dysfunction demonstrated angina improvement on ranolazine compared to a placebo, as well as trends towards improvement in myocardial perfusion abnormalities by cardiac magnetic resonance imaging.
Nonpharmacologic treatment should include:
Cognitive behavioral therapy – a recent study showed that an 8-week program of the cognitive behavioral approach of autogenic training improved frequency and severity of symptoms in women with ischemia and non-obstructive coronary arteries.
Cessation of cigarette smoking.
Management with Co-Morbidities
Patients who present with angina-like chest pain and objective evidence of ischemia in the setting of non-flow limiting epicardial CAD are often given a clean bill of health based on absence of significant epicardial CAD. Although a good portion of patients do not have a cardiac cause of chest pain, there are some patients who will benefit from evaluation of other causes as listed above.
In our practice, we perform IMR testing on all patients who meet criteria of angina-like chest pain with objective evidence of ischemia and non-flow limiting CAD. We do not routinely assess for coronary spasm unless the history strongly suggests it. Further management is based on IMR findings with a focus on risk reduction and symptom relief.
Patient Safety and Quality Measures
A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
1. Adherence to prescribed management plan: including pharmacologic, nonpharmacologic, and lifestyle modification.
2. Provision of secondary prevention strategies: blood pressure and cardiac work reduction, lipid management, and antiplatelet therapy.
3. Appropriate lifestyle modification to limit coronary risk factors: smoking cessation, isometric exercise, and weight reduction.
4. Compliance with medical follow-up and imaging.
B. What's the Evidence for specific management and treatment recommendations?
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- Cardiac Chest Pain without Epicardial Stenosis: What Every Physician Needs to Know.
- II. Diagnostic Confirmation: Are you sure your patient has Chest Pain without Epicardial Stenosis?
- A. History Part 1: Prevalence:
- B. History Part 2: Competing diagnoses that can mimic spasm and microvascular angina.
- C. Physical Examination Findings.
- D. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- Long-term management.
- Management with Co-Morbidities
- Patient Safety and Quality Measures
- A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
- B. What's the Evidence for specific management and treatment recommendations?