Over 40% of patients with angina symptoms suggestive of obstructive coronary artery disease present normal coronary arteries at angiography. Numerous studies have shown, in many of these patients, that the symptoms are secondary to a coronary microcirculatory dysfunction, hence the term microvascular angina (MVA).1
A MVA could be secondary to functional/structural dysfunction of the coronary microcirculation occurring in the settings of specific cardiac diseases (e.g. cardiomyopathy), or systemic conditions (e.g. collagen diseases), and is defined as secondary MVA. On many other occasions, MVA derives from a specific and isolated coronary microvascular dysfunction, and accordingly is defined as primary MVA.2
The clinical presentation of primary MVA is defined by the triad:
- Chest pain (angina), mainly with effort (sometimes also at rest).
- ECG ischemic changes (ST segment depression) during an exercise stress test or other noninvasive tests for inducible myocardial ischemia.
- Normal coronary arteries at angiography.3
Not always MVA presents with a stable angina pattern that is effort-related; some patients, indeed, present with an acute coronary syndrome pattern, with resting chest pain and repolarization ECG changes, sometimes also with increased serum markers of myocardial necrosis, leading to the definition of this particular presentation as unstable (or acute) MVA.2
MVA is characterized by a transient myocardial ischemia secondary to a dysfunction of the resistance coronary vessels (<500 μm) that, because of their small size, are not visualized at coronary angiography.4 The ischemic origin of the symptoms is derived by the typical changes of the ST segment during the stress test, but also by episodes of ST segment depression with daily activities recorded during ambulatory ECG monitoring, or by reversible perfusion defects at stress radionuclide study (exercise or pharmacological).5
Some authors challenged the ischemic origin of effort angina in these patients with normal epicardial coronary vessels, because whenever these patients were studied with stress echocardiography (exercise or pharmacological), they did not present global or regional impairment of the left ventricular wall motion,6 which is more specific for myocardial ischemia than ECG changes or perfusion defects. Nonetheless, the coronary microvascular dysfunction in these patients has a scattered pattern throughout the myocardium, and the ischemic areas are spaced out with areas of myocardium with normal or even increased contractility, making the small areas with reduced contractility scarcely visible.
Even though the diagnosis of myocardial ischemia could be difficult in these patients, many studies have consistently demonstrated a coronary microcirculation dysfunction.7
Coronary microcirculation dysfunctions are documented, in first instance, by a reduced vasodilator response of the small resistance coronary arteries.8
The dysfunction could affect both the endothelium-independent (challenges with adenosine, dypiramidole, papaverine, all acting directly by relaxing the smooth muscle cells of the small resistance arteries media), and the endothelium-dependent (challenges with acetylcholine and cold pressor test, acting by the release of vasodilators, mainly nitric oxide) vasodilation activity.
The impairment of coronary microvascular vasodilation has been demonstrated with a variety of techniques, both invasive (e.g. thermodilution and intra-coronary Doppler), and noninvasive (positron emission tomography, magnetic resonance, contrast enhanced trans-thoracic echo-Doppler). Some studies further revealed, at least in some patients, an increased vasoconstrictive microcirculation response to acetylcholine and ergonovine, as evidenced by a significant coronary flow reduction at rest.
The causes of microvascular dysfunction, though, remain elusive. The prevalence of the common cardiovascular risk factor is similar to the patients with obstructive coronary disease. Some studies suggested an increased adrenergic tone, following the documentation of upsurge in the effort chronotropic response and a reduced heart rate variability, as well as an abnormal uptake of meta-iodo-benzyl-guanidine (analog of norepinephrine), marked with iodine 123, by the myocardial adrenergic fibers, suggesting a possible involvement of these fibers in the pathogenesis of microcirculatory dysfunction. Another possible cause could be found in the increased subclinical inflammatory status, as manifested by higher plasma levels of C-reactive protein (CRP), as well as increased insulin-resistance, common in these patients.9 Lastly, a role could be played by an estrogen deficit, stemming from the epidemiologic observation that the majority of patients with MVA are women in premenopause or menopause.
Interestingly, some studies revealed that a significant portion of patients with MVA have an abnormal cardiac nociceptive perception, characterized by an abnormal pain threshold for cardiac stimuli usually innoxious, as well as a reduced central tolerance for repeated noxious stimuli. These anomalies enhance the perception of pain even for negligible degrees of ischemia, explaining the discrepancy between perceived symptoms and the limited evidence of ischemic changes.
A diagnostic algorithm for MVA is presented in Fig. 1.
It would be useful to be able to differentiate, among patients with effort angina, those with MVA from those with obstructive coronary disease, relying only on clinical information and noninvasive testing, thus avoiding the risk and the costs of coronary angiography.
Unfortunately, in general, it is not clinically possible to categorize with certainty these patients. Nonetheless, some features of the angina pain could direct the diagnosis toward MVA. In particular, typical of MVA is the prolonged duration of pain after effort, and an erratic effect of sublingual nitrates. Whenever this pattern occurs, particularly in women, there is a strong suggestion for the microvascular origin of the symptoms.
Diagnostic testing rarely contributes to the differential diagnosis. The exercise stress test is not dissimilar among MVA and obstructive coronary disease patients, as well as stress scintigraphic scan, which, in 50% of the patients with MVA, reveals perfusion defects indistinguishable from those of patients with obstructive ischemic problems.
On the other hand, stress echocardiography (exercise or pharmacological), whenever negative for global or regional impairment of the left ventricular wall motion in patients with angina and ECG changes of the ST segment strongly suggest a microvascular origin of the symptoms, albeit a mild obstructive form of coronary artery disease could not be completely ruled out.
Repeating the exercise stress test after sublingual nitrates could facilitate the diagnosis of patients with MVA.10 Although the ischemic changes improve in patients with obstructive coronary disease, the action of sublingual nitrates is variable and erratic in patients with MVA, and in some cases, in fact, they show an earlier occurrence of ischemic changes, such as ST segment depression, during effort.
Today, patients with a strong index of suspicion for MVA could undergo a coronary CT scan rather than an invasive angiography to assess the status of epicardial coronary vessels.
Since the first epidemiologic reports, the prognosis of patients with MVA has been reported as excellent,11 and several later studies confirmed the incidence of major adverse cardiovascular events (death, myocardial infarction, heart failure) as very low, and similar to the general population.12 Nonetheless, some recent clinical studies reported an increase in adverse cardiovascular events in these patients as compared with the asymptomatic counterpart.13 These studies included, though, more heterogeneous patient populations, such as those with sub-critical coronary stenosis (<50%), those with ventricular wall motion abnormalities and a variety of arrhythmias. Only a specifically designed and powered (number of patients and adequate follow-up) study will be able to solve the issue of the prognosis of patients with microvascular dysfunction.
In any case, 20% of patients with MVA experience a worsening of their symptoms, with angina episodes more frequent and prolonged, occurring sometimes at rest, and difficult to handle clinically. The frequency and intensity of these episodes prompt frequent ambulatory visits, diagnostic noninvasive and invasive testing, and even repeated hospital admissions. Accordingly, the patient's quality of life is negatively affected, making MVA a significant condition from a personal, social, and economic perspective.
The therapeutic approach to patients with MVA should be based on the pathophysiology leading to the clinical symptoms (Fig. 2). Initial treatment includes the classical antiangina medications. First-line treatment should include β-blockers, particularly whenever there is evidence of increased adrenergic tone (elevated baseline heart rate, rapid heart rate, and/or blood pressure increase during exercise stress test). Calcium-antagonist drugs, like verapamil or diltiazem, could represent an alternative to β-blockers, particularly in patients with a highly variable angina threshold and/or rest pain or in patients for whom β-blockers are not advisable [significant asthma, severe chronic obstructive pulmonary disease (COPD)].14
Ranolazine and ivabradine15 are antiangina medications of more recent use, and can be helpful as second-line drugs in MVA. Some patients could benefit from the use of xanthines (theophylline), which act not only by improving ischemia through a ‘reverse coronary steal’ mechanism, but also by decreasing pain perception through antagonism of the effect of adenosine, an important mediator of ischemic cardiac pain. Beneficial effects could be derived by using statins and ACE-inhibitors for their effect on the endothelium and the renin–angiotensin system. Patients with refractory chest pain could improve by drugs acting directly on the transmission of cardiac pain, such as imipramine.14
Whenever angina persists despite optimal medical treatment, electric spinal stimulation may be recommended. The rationale for this treatment resides both in the modulation of the transmission of the ischemic pain to the cerebral cortex, and in the direct effect on myocardial ischemia by modulation of adrenergic activity.14
Conflicts of interest
There are no conflicts of interest.
1. Cannon RO 3rd, Epstein SE. Microvascular angina
’ as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol
2. Lanza GA, Crea F. Primary coronary microvascular dysfunction
: clinical presentation, pathophysiology, and management. Circulation
3. Lanza GA. Cardiac syndrome X: a critical overview and future perspectives. Heart
4. Kemp HG Jr. Left ventricular function in patients with the anginal syndrome and normal coronary arteriograms. Am J Cardiol
5. Kaul S, Newell JB, Chesler DA, Pohost GM, Okada RD, Boucher CA. Quantitative thallium imaging findings in patients with normal coronary angiographic findings and in clinically normal subjects. Am J Cardiol
6. Nihoyannopoulos P, Kaski JC, Crake T, Maseri A. Absence of myocardial dysfunction during stress in patients with syndrome X. J Am CollCardiol
7. Chauhan A, Mullins PA, Taylor G, Petch MC, Schofield PM. Both endothelium-dependent and endothelium-independent function is impaired in patients with angina pectoris and normal coronary angiograms. Eur Heart J
8. Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary angiograms. N Engl J Med
9. Dean JD, Jones CJ, Hutchison SJ, Peters JR, Henderson AH. Hyperinsulinaemia and microvascular angina
(‘syndrome X’). Lancet
10. Lanza GA, Manzoli A, Bia E, Crea F, Maseri A. Acute effects of nitrates on exercise testing in patients with syndrome x. clinical and pathophysiological implications. Circulation
11. Kaski JC, Rosano GMC, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function: long-term follow-up study. J Am CollCardiol
12. Lamendola P, Lanza GA, Spinelli A, et al. Long-term prognosis of patients with cardiac syndrome X. Int J Cardiol
13. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J
14. Lanza GA, Parrinello R, Figliozzi S. Management of microvascular angina
pectoris. Am J Cardiovasc Drugs
15. Villano A, Di Franco A, Nerla R, et al. Effects of ivabradine and ranolazine in patients with microvascular angina
pectoris. Am J Cardiol