The not-so-short list of reasons for angina

by P. G. Camici, Italy

Vita Salute University and
San Raffaele Hospital
Milan, ITALY

Atherosclerotic disease of the epicardial coronary arteries has been accepted as the cause of angina pectoris for more than two centuries. Subsequently, spasm of the epicardial coronary arteries was recognized as an adjunctive functional mechanism of myocardial ischemia and angina. However, the epicardial arteries, often referred to as the conductance vessels, are only one segment of the arterial coronary circulation. These vessels give rise to smaller arteries and arterioles, which in turn feed the capillaries and constitute the coronary microcirculation, the main site of myocardial blood flow regulation. The term “coronary microvascular dysfunction” was coined to provide an overarching definition that would encompass a large number of clinical scenarios characterized by evidence of a reduced coronary flow reserve and evidence of ischemia that could not be explained by an epicardial stenosis. It was also realized that coronary microvascular dysfunction could coexist with coronary artery disease, providing added prognostic value. In conclusion, angina is the main symptom of myocardial ischemia, which, for several decades, was thought to be only caused by either structural or functional disease of the epicardial coronary arteries. However, it has recently become apparent that dysfunction of the coronary microcirculation, alone or in combination with epicardial disease, is another mechanism of myocardial ischemia and angina.

Over 200 years ago, Heberden described a relationship between anginal pain and the heart.1 The role of sympathetic afferents in cardiac nociception was recognized a century later, and the causal contribution of reversible myocardial ischemia was suggested by Keefer and Resnik in 1928.1 The anatomical pathways for the transmission of peripheral painful stimuli were established mostly on the basis of invasive experiments in animals. However, beyond the thalamic level, the central connections mediating visceral pain perception and the affective response to it have remained unclear for many years. Positron emission tomography (PET) is a powerful technique for assessing regional brain function. PET quantifies regional cerebral blood flow, a highly reliable index of cerebral glucose consumption, which increases regionally when a given cerebral territory is activated.2 Rosen et al have applied this technique to define the functional central nervous pathways activated during angina pectoris in patients with coronary artery disease (CAD).3 They found that, in addition to the hypothalamus and thalamus, several cortical structures were activated bilaterally during an episode of angina. The same authors subsequently demonstrated that in patients with CAD and “silent” ischemia there was still evidence of thalamic activation, as in patients with angina, but that cortical activation was limited to the right frontal region. These authors therefore concluded that abnormal central processing of afferent pain messages from the heart may play a determining role in silent myocardial ischemia (Figure 1).

Figure 1. Central neural activation during angina.
Changes in regional cerebral blood flow (rCBF) during anginal pain induced by intravenous infusion of dobutamine were measured in patients with stable angina
pectoris and angiographically proven coronary artery using dynamic positron emission tomography with oxygen-15 labeled water. Compared with the resting state,
angina was associated with increased rCBF in the hypothalamus and periaqueductal gray, and bilaterally in the thalamus, lateral prefrontal cortex, and left inferior
anterocaudal cingulate cortex (bottom panel). Compared with angina patients, an equivalent stress upon the hearts of silent ischemia patients produced the same
degree of thalamic activation, but significantly less cortical activation, especially with respect to the anterior and ventral cingulate and basal frontal cortices (top panel).
From reference 2: Rosen et al. Ann Int Med. 1996;124;939-949. ©1996, American College of Physicians.

Figure 2. Relation between stenosis severity and coronary flow
Coronary flow reserve (the ratio of maximum myocardial blood flow to baseline
flow) decreases significantly as coronary stenosis severity increases.
Modified from reference 12: Uren et al. New Engl J Med. 1994;330:1782-1788.
© 1994, Massachusetts Medical Society. All rights reserved.

Myocardial ischemia and angina

Patients with chronic angina have an increased risk of major cardiovascular events.4,5 Factors associated with an increased risk of myocardial infarction or death in angina patients include advanced age, severe angina, coexisting chronic kidney disease and diabetes, abnormal myocardial function, and the inability to perform a stress test.6-8 These patients also have substantial rates of complications,9 leading to increased health care expenditures.8 Furthermore, anginal symptoms can seriously restrict their everyday activities and quality of life, and often lead to premature retirement in patients of working age.

Angina caused by obstructive CAD

Angina pectoris is caused by myocardial ischemia, and atherosclerotic disease of the epicardial coronary arteries has been accepted as the cause of angina pectoris for more than two centuries.10,11 The clinical manifestations of chronic CAD are related to the progressive impairment of tissue perfusion due to the growth of plaque inside the vessel lumen, which leads to a progressive reduction in the coronary flow reserve (CFR)— ie, the ratio of coronary blood flow during near-maximal coronary vasodilatation to baseline flow (Figure 2).12 The clinical counterpart of the reduction in CFR is demand ischemia and effort angina. Generally, these patients have risk factors for CAD and the diagnosis of typical, stable angina includes predictable and reproducible chest pain or discomfort induced by physical activity or by emotional stress. The symptoms can get worse in cold weather or after a meal and are relieved by rest or sublingual nitroglycerin. Stress testing using noninvasive techniques, such as nuclear perfusion imaging or echocardiography, can provide evidence of regional reversible per fusion abnormalities or regional contractile abnormalities generally associated with ST-segment depression on an electrocardiogram (ECG). Coronary angiography typically demonstrates the presence of one or more stenosis in the epicardial coronary arteries, usually reducing the lumen by more than 70%.

Angina caused by coronary spasm

Clinically, not all patients present with the classic (typical) anginal symptoms described above. Symptoms may occur at rest, rather than on exertion. Attacks may occur at night, generally in clusters, and patients may have a negative treadmill stress test. During an attack the ECG shows ST-segment elevation. Symptoms and ECG changes generally subside promptly after administration of nitrates.13 Many of these patients may have concurrent atherosclerosis of a major coronary artery, but this is often mild or not in proportion to the severity of symptoms. This condition was first described as “a variant form of angina pectoris” in 1959 by the American cardiologist Dr Myron Prinzmetal. Prinzmetal angina—also known as variant angina—is a syndrome that typically consists of angina at rest occurring in cycles. It is caused by coronary vasospasm, which is brought about by contraction of the smooth muscles in the vessel wall.14

Specific provocative testing, normally carried out during coronary angiography has been used for more than 40 years to provoke an attack when Prinzmetal angina is suspected. At present, intracoronary injection of acetylcholine is used during monitoring of patient symptoms, ECG, and angiographic documentation of coronary artery spasm. Alternatively, the alkaloid ergonovine can be administered by intravenous or intracoronary injection.15 A positive test must induce all of the following in response to the provocative stimulus: (i) reproduction of the usual chest pain, (ii) ischemic ECG changes, and (iii) >90% vasoconstriction on angiography. Moreover, total/ subtotal vasoconstriction may occur within the confines of one isolated coronary segment (focal spasm) or in at least two adjacent coronary segments (diffuse spasm).15 Spasm may be induced at the site of an atheromatous plaque, but also in angiographically normal vessels. Common side effects of intravenous ergonovine include headache, nausea, and hypertension. Both intracoronary and intravenous administrations of the alkaloid carry a small risk of ventricular fibrillation, myocardial infarction, or spasm refractory to systemic nitrates requiring intracoronary nitroglycerin. Acetylcholine has a shorter half-life than ergonovine and is safer, although it may induce atrio-ventricular blocks or bradycardia, as well as ventricular arrhythmias.16 Ong et al studied a large consecutive cohort of patients (n=921) who underwent diagnostic angiography for suspected myocardial ischemia and were found to have unobstructed coronary arteries.17 Intracoronary acetylcholine testing was performed in all of them. The overall frequency of epicardial spasm was 33.4%. In addition, 24.2% of the patients had microvascular spasm (ie, angina and ischemic ECG shifts without epicardial spasm during acetylcholine administration) (Figure 3, page 20). No major complications were observed, and only 1% of the patients had minor complications such as transient arrhythmias.

Angina caused by coronary microvascular dysfunction

A sizeable proportion of patients undergoing coronary angiography for anginal symptoms are found to have normal coronary arteries or nonobstructive CAD (stenosis <50%). For many years there was uncertainty regarding the real significance of anginal symptoms that are accompanied by electrocardiographic evidence of ischemia during stress.18 A study published by Cannon and Epstein in 1988 demonstrated that, compared with a group of asymptomatic controls, in patients with chest pain and angiographically normal coronary arteries, the coronary microcirculation has a heightened sensitivity to vasoconstrictor stimuli and a limited microvascular vasodilator capacity during atrial pacing. This condition was termed “microvascular angina.”19

It is worth noting that the epicardial coronary arteries—often referred to as the conductance vessels—are only one segment of the arterial coronary circulation. These vessels give rise to smaller arteries and arterioles, which in turn feed the capillaries and constitute the coronary microcirculation, the main site of myocardial blood flow regulation.20 The coronary arterial system is composed of three compartments that have different functions, although the borders of each compartment cannot be clearly defined anatomically. The large epicardial coronary arteries, which have a diameter ranging from approximately 500 μm to 2 to 5 mm, constitute the proximal compartment. They have a capacitance function and offer little resistance to coronary blood flow. During systole, they accumulate elastic energy as they increase their blood content by up to about 25%. This elastic energy is converted into blood kinetic energy at the beginning of diastole and contributes to the prompt reopening of the intramyocardial vessels that are squeezed closed during systole. The prearterioles, which have a diameter ranging from approximately 100 μm to 500 μm, and are characterized by a measurable pressure drop along their length, constitute the intermediate compartment. These vessels are not under direct vasomotor control by diffusible myocardial metabolites because of their extramyocardial position and wall thickness. Their specific function is to main- tain pressure at the origin of the arterioles within a narrow range when coronary perfusion pressure or flow changes. Proximal prearterioles are more responsive to changes in flow, whereas distal prearterioles are more responsive to changes in pressure. Finally, the intramural arterioles form the more distal compartment; they have diameters of less than 100 μm and are characterized by a considerable drop in pressure along their path. Under resting conditions, the tone of the coronary microvasculature is high. This intrinsically high resting tone allows the coronary circulation to increase flow when myocardial oxygen consumption increases through rapid changes in small vessel diameter, a mechanism known as functional hyperemia. The fall in arteriolar resistance drives a number of subsequent vascular adaptations that involve both prearterioles and arteries. The initial arteriolar response is due to the strict cross-talk that exists between these vessels and contracting cardiomyocytes, which is the basis of metabolic vasodilatation.

Figure 3.
Epicardial and microvascular
A and B. Left coronary artery
angiograms and ECGs of a
patient with epicardial spasm.
Note the diffuse, but distally
accentuated narrowing of
the left anterior descending
artery during acetylcholine
(ACH) infusion (arrows)
together with ischemic ECG
shifts (A) and the resolution
of both findings after intracoronary
nitroglycerine (B).
C and D. Example of a patient
with microvascular spasm.
During ACH infusion the
patient experienced angina
pain (angina reproduction),
and there were ischemic
ECG changes, but no epicardial
constriction (C). After
intracoronary nitroglycerine
infusion, the chest pain and
ECG changes resolved (D).
From reference 17: Ong et al.
Circulation. 2014; 129:1723-
1730. © 2014, American
Heart Association, Inc.

Figure 4. Mechanisms
of myocardial ischemia.
In addition to the “classic”
mechanisms (ie, atherosclerotic
disease and vasospastic
disease) that lead to myocardial
ischemia, coronary microvascular
dysfunction has recently
emerged as a “third”
potential mechanism of myocardial
ischemia. As with the
other two mechanisms, coronary
microvascular dysfunction
(alone or in combination with
the other two) can lead to
transient myocardial ischemia
in patients with coronary artery
Abbreviations: CAD, coronary
artery disease; CFR, coronary
flow reserve; CMD, coronary
microvascular dysfunction.
From reference 21: Crea et al.
Eur Heart J. 2014;35:1101-
1111. © 2013, The Author. All
rights reserved.

There is no technique at present that allows the direct visualization of the coronary microcirculation in vivo. Coronary microcirculatory function can be indirectly assessed using several invasive and noninvasive techniques that enable the measurement of parameters such as myocardial blood flow and CFR, which, under normal circumstances, are strongly dependent on the functional integrity of the coronary microcirculation.

The development and refinement of noninvasive cardiac imaging over the past two decades has provided new tools for the identification of preclinical disease. A bulk of studies, mainly using PET for the noninvasive quantification of regional myocardial blood flow, have demonstrated that dysfunction of the coronary microcirculation occurs in many clinical conditions in the absence of demonstrable stenoses in the large epicardial arteries. Studies in asymptomatic subjects, but with risk factors for CAD such as hypercholesterolemia, essential hypertension, diabetes mellitus, and smoking, have provided evidence of how these risk factors translate into measurable damage to the coronary microcirculation.20

The term “coronary microvascular dysfunction” (CMD) was coined to provide an overarching definition that would encompass a large number of clinical scenarios characterized by evidence of a reduced CFR and evidence of ischemia that could not be explained by an epicardial stenosis.21 It was also realized that CMD could coexist with CAD, thereby providing added prognostic value (Figure 4).20 Coronary microvascular dysfunction can result from functional and/or structural alterations. The importance of these mechanisms seems to vary across clinical settings, but several of them may coexist in the same condition (Table I).22 Clinically, CMD can be severe enough to cause myocardial ischemia in isolation or in conjunction with the traditional “epicardial” mechanisms.

Camici and Crea20 have proposed a clinical classification of CMD into four main types on the basis of the clinical setting in which it occurs: type 1 CMD occurs in the absence of CAD and myocardial diseases; type 2 CMD occurs in patients with evidence of myocardial disease; type 3 CMD occurs in patients with obstructive CAD; and type 4 CMD—also known as iatrogenic CMD—occurs after interventions such as bypass surgery, percutaneous revascularization, etc…. Discussing type 2 CMD is beyond the scope of this article so it will not be described below.

Type 1 CMD
Type 1 CMD is the functional counterpart of traditional coronary risk factors and is the cause of microvascular angina. Microvascular angina is the prototypical clinical manifestation of type 1 CMD. Primary stable microvascular angina is defined as the occurrence of anginal attacks in relation to effort, in the absence of obstructive CAD, myocardial disease, and any other significant cardiovascular disease. In these patients CMD is the cause of myocardial ischemia and chest pain. Microvascular angina is caused by a variable combination of: (i) structural abnormalities; (ii) alterations in endothelium-dependent vasodilatation; (iii) alterations in endothelium-independent vasodilatation; (iv) enhanced pain perception.21

Table I. Coronary microvascular dysfunction classification.
Abbreviations: CAD, coronary artery disease; PCI, percutaneous coronary intervention.
From reference 21: Crea et al. Eur Heart J. 2014; 35:1101-1111. © 2013, The Author. All rights reserved.

Type 3 CMD
In patients with obstructive CAD, the development of myocardial ischemia during increased oxygen demand is generally attributed to an inadequate increase in flow due to exhaustion of the CFR. However, it is worth noting that there is only a weak correlation between stenosis severity and CFR in vivo, which suggests that other factors might contribute to the development of myocardial ischemia. For instance, there is evidence that, on a background of optimal medical therapy, revascularization by percutaneous coronary interventions (PCIs) can improve anginal symptoms compared with medical therapy alone.

However, in a substantial proportion of patients, the prevalence of angina at follow-up remains high despite successful revascularization. For instance, in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) more than 30% of patients were still experiencing angina 1 year after PCI, and at the 5-year follow-up the incidence of angina was not significantly different from that in patients who did not undergo a revascularization procedure.

These findings suggest that, although revascularization is effective in removing coronary stenosis and its hemodynamic consequences, other mechanisms, including CMD, contribute to the pathogenesis of ischemia and angina in these patients.20-23 Another proof of the importance of CMD in patients with CAD comes from PET studies showing that the inclusion of CFR in risk prediction models resulted in the correct reclassification of risk in a substantial proportion of patients, including a sizeable proportion of those at intermediate risk. CFR is an integrated measurement of the function of both the macroand microvasculature. An abnormal CFR gives incremental risk stratification over and above that obtained by the conventional semi-quantitative evaluation of myocardial perfusion studies (ie, summed rest and stress scores).20-23

In summary, in patients with obstructive CAD, angina can be suspected to have a microvascular origin in those who have prolonged angina or angina that is poorly responsive to sublingual nitrates. Similarly, a microvascular origin can be suspected in patients in whom angina is more severe than predicted by the severity of coronary stenoses. Finally, it may be suspected in patients in whom the angina threshold is remarkably variable, although this variability can also be accounted for by the presence of “dynamic” stenoses.

Type 4 CMD
Coronary revascularization by PCI or bypass surgery can induce a transient impairment of CFR in the territory subtended by a successfully recanalized artery. This is most likely triggered by an intracoronary reflex resulting in a reversible α-adrenergic receptor–mediated constriction of coronary micro-vessels limiting hyperemic blood flow, which can be prevented by giving α-adrenergic receptor antagonists before the procedure. This phenomenon may contribute to the delayed improvement in exercise-induced myocardial ischemia that can be observed after successful PCIs.20


Angina is a symptomatic manifestation of myocardial ischemia. Structural (CAD) and functional (spasm) disease of the epicardial coronary arteries were thought to be the only mechanisms of myocardial ischemia for several decades. However, it has recently become apparent that dysfunction of the coronary microcirculation, alone or in combination with CAD, is another mechanism of myocardial ischemia and angina.■

1. Camici PG, Pagani M. Cardiac nociception. Circulation. 2006;114:2309-2312.
2. Rosen SD, Paulesu E, Nihoyannopoulos P, et al. Silent ischaemia as a central problem: regional brain activation compared in silent and painful myocardial ischemia. Ann Int Med. 1996;124;939-949.
3. Rosen SD, Paulesu E, Frith CD, et al. Central nervous pathways mediating angina pectoris. Lancet. 1994;344:147-150.
4. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation. 2015; 131(4):e29-e322.
5. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350-1357.
6. Daly CA, De Stavola B, Sendon JL, et al. Predicting prognosis in stable angina— results from the Euro heart survey of stable angina: prospective observational study. BMJ. 2006;332:262-267.
7. Henry TD, Satran D, Hodges JS, et al. Long-term survival in patients with refractory angina. Eur Heart J. 2013;34:2683-2688.
8. Povsic TJ, Broderick S, Anstrom KJ, et al. Predictors of long-term clinical endpoints in patients with refractory angina. J Am Heart Assoc. 2015;4(2):e001287.
9. Cavender MA, Alexander KP, Broderick S, et al. Long-term morbidity and mortality among medically managed patients with angina and multivessel coronary artery disease. Am Heart J. 2009;158:933-940.
10. Abrams J. Chronic stable angina. N Engl J Med. 2005;352:2524-2533.
11. Ohman EM. Chronic stable angina. N Engl J Med. 2016;374:1167-1176.
12. Uren NG, Melin JA, De Bruyne B, et al. Relation between myocardial blood flow and the severity of coronary artery stenosis. New Engl J Med. 1994;330:1782- 1788.
13. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949-3003.
14. Prinzmetal M, Kennamer R, Merliss R, et al. Angina pectoris. I. A variant form of angina pectoris: preliminary report. Am J Med. 1959;27:375-388.
15. Beltrame JF, Crea F, Kaski JC, et al; Coronary Vasomotion Disorders International Study Group (COVADIS). International standardization of diagnostic criteria for vasospastic angina. Eur Heart J. 2015 Aug 4;pii:ehv351. Epub.
16. Kinlay S. Coronary artery spasm as a cause of angina. Circulation. 2014;129: 1717-1719.
17. Ong P, Athanasiadis A, Borgulya G, et al. Clinical Usefulness, Angiographic Characteristics, and Safety Evaluation of Intracoronary Acetylcholine Provocation Testing Among 921 Consecutive White Patients With Unobstructed Coronary Arteries. Circulation. 2014;129:1723-1730.
18. Cannon RO 3rd, Camici PG, Epstein SE. The pathophysiologic dilemma of angina- like chest pain despite normal coronary angiograms. Circulation. 1992;85: 883-892.
19. Cannon RO 3rd, Epstein SE. « Microvascular angina » as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol. 1988;61:1338- 1343.
20. Camici PG, Crea F. Coronary microvascular dysfunction. New Engl J Med. 2007;356:830-840.
21. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: An update. Eur Heart J. 2014;35:1101-1111.
22. Camici PG, d’Amati G, Rimoldi O. Coronary microvascular dysfunction: mechanisms and functional assessment. Nat Rev Cardiol. 2015;12:48-62.
23. Camici PG, Crea F. Microvascular angina: A women’s affair? Circ Cardiovasc Imaging. 2015;8:e003252.

Keywords: angina pectoris; coronary anatomy; coronary artery disease; coronary microvascular dysfunction; coronary spasm; myocardial ischemia