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 Table of Contents  
Year : 2018  |  Volume : 2  |  Issue : 1  |  Page : 5-11

Heart or Mind? Unexplained chest pain in patients with and without coronary disease

1 Department of Child Neuro-Psichiatry-University Hospital Policlinic of Milano, Milano, Italy
2 Department of Cardiology, University Hospital San Raffaele, Milano, Italy

Date of Web Publication4-Feb-2019

Correspondence Address:
Dr. Gabriele Fragasso
Department of Cardiology, University Hospital San Raffaele, via Olgettina 60, Milano 20132
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/hm.hm_14_18

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Patients with unexplained chest pain continue to present a difficult challenge for clinicians, especially for cardiologists. Approximately 20% of patients undergoing diagnostic coronary arteriography for acute or chronic cardiac ischemia have angiographically normal coronary arteries. In these cases, patients with chest pain are usually reassured by their physician and other causes of substernal chest pain are searched. However, apart from a sizeable proportion of patients with gastroesophageal disorders, the remaining patients remain symptomatic without apparent reasons. The mechanism behind this phenomenon is likely to be the result of a combination of functional or anatomical abnormalities in the coronary microcirculation, a metabolic disorder which affects the handling of energy substrates by the heart, insulin resistance and neuropsychological components affecting pain perception. These patients often exhibit an increase in sympathetic outflow to the cardiovascular system, which might account for the reduction in coronary flow reserve, changes in metabolic utilization and development of insulin resistance that are seen in some of these patients. Therapeutically, beta-blockers appear to be most effective in controlling the symptoms associated with this condition, although those calcium antagonists which do not affect the neurohormonal system may be of some utility in patients with primary microvascular angina, in which microvascular spasm is operating or in whom excessive constriction of the distal component of the coronary circulation limits the vasodilatory reserve. This article reviews the clinical presentation, differential diagnosis, and approach to evaluation and therapy of this complex group of patients.

Keywords: Angina, chest pain, coronary slow flow, myocardial perfusion scintigrapphy, nonobstructive coronary artery disease, normal coronary arteries, positive exercise test, prognosis, sympathetic nervous system

How to cite this article:
Garroni D, Fragasso G. Heart or Mind? Unexplained chest pain in patients with and without coronary disease. Heart Mind 2018;2:5-11

How to cite this URL:
Garroni D, Fragasso G. Heart or Mind? Unexplained chest pain in patients with and without coronary disease. Heart Mind [serial online] 2018 [cited 2023 May 29];2:5-11. Available from: http://www.heartmindjournal.org/text.asp?2018/2/1/5/251483

  Introduction Top

Approximately 20% of patients complaining of chronic or acute chest pain, with and without inducible myocardial ischemia, have angiographically normal epicardial coronary arteries. However, the angiographic definition of normal coronary arteries is quite subjective, mainly depending from the reporting physician sensitivity. Most reported series include a quite heterogeneous pattern of patients, comprising those with completely smooth coronary vessels, those with the subcritical coronary atherosclerotic burden and those previously revascularized and no evidence of restenosis.

The mechanisms responsible for the syndrome of angina without anatomic evidence of angiographically significant coronary disease are probably varied and remain largely speculative.[1] Three main hypotheses have so far been put forward. The first argues that the disease is caused by myocardial ischemia and suggests that the dominant abnormality resides in the coronary microcirculation which is either functionally or anatomically abnormal. The second hypothesis supports the idea that a metabolic disorder which affects the handling of energy substrates by the heart muscle is primarily responsible for the condition. The third denies the syndrome the dignity of being a cardiac disease and suggests that symptoms, although sometimes so severe as to impair patients' quality of life, are in fact the result of increased sensitivity to algogenic stimuli arising from a variety of organs, including the heart. There is probably some truth in each of these theories, and their relative role is likely to be different in individual patients. Accordingly, their relative weight in reported series is likely to be variable, depending on the selection criteria, the activity of the disease, the adequacy of the techniques employed to answer specific questions and last but not least, the investigator's cultural bias. Furthermore, one should not forget that our ability to define anatomical “normality” on purely angiographic criteria is far from ideal. Coronary atheroma is primarily a disease of the vascular wall that encroaches on the lumen only at a late, advanced stage when it becomes “angiographically evident.” Therefore, while our anatomical definitions should be reviewed critically, the possibility that “angiographically invisible” atheroma may produce gross alterations in the coronary responses to physiological and pharmacological stimuli should be kept in mind. In the next paragraphs, the available evidence supporting the different pathogenetic hypotheses, which have been formulated in an attempt to explain the occurrence of anginal attacks in the absence of “significant” obstructive coronary artery disease, will be summarized.

Angina and normal coronary arteries (syndrome X)

Originally described by Kemp in 1973 and named ‘syndrome X,[2] the syndrome of angina and normal coronary arteries comprises a probably heterogeneous group of patients presenting with typical chest pain, a positive exercise stress test, angiographically smooth epicardial coronary arteries and no clinical or angiographic evidence to suggest the presence of spasm. In 1981, Opherk et al.[3] observed a markedly reduced vasodilator capacity in response to dipyridamole and abnormal lactate extraction during atrial pacing in 21 patients with angina and angiographically normal coronary arteries. Myocardial biopsies consistently showed abnormal pathological findings, consisting of moderate to severe mitochondrial swelling. The authors concluded that myocardial ischemia was the likely cause of chest pain in patients with angina and normal coronary arteries. They hypothesized that the reduced dilator capacity observed in their patients was either the result of metabolic alterations in the formation of transmitter substances or in the function of coronary receptors responsible for vasodilatation. Some years later, Cannon et al.[4] came to similar conclusions after showing, again using atrial pacing, that patients with angina and normal coronary arteries could not decrease coronary vascular resistance to the same extent as normal controls. They also observed that the limitation in vasodilator capacity could be affected, in a dynamic fashion, by agents that are known to interfere with coronary vascular tone, such as ergonovine. They suggested that sustained or transient constriction of coronary microvessels could, at least in part, contribute to the pathophysiology of the syndrome.

Abnormalities of microvascular circulation

The above-reported observations generated the notion that the pathophysiological denominator common to most patients with angina and angiographically smooth coronary arteries was a functional or anatomical abnormality of the small coronary vessels. Later on, isolated reports suggested the possibility that transient, severe, active constriction of the coronary microcirculation had the potential for critically impairing myocardial perfusion and causing ischemia. Based on these observations, and by analogy with the pathophysiological classification of “macrovascular” angina, one can assume that the abnormalities of the microvascular circulation may cause ischemia and angina by the following mechanisms: (a) “primary” forms may be due to transient reduction in regional myocardial perfusion, either related to abnormal constriction of coronary microvessels or to reversible intravascular plugging by blood constituents; (b) “secondary” forms may be caused by a limitation in coronary flow reserve, that can be either due to anatomical restriction of vascular cross-section or to reduced vasodilator capacity. Theoretically, the former can be caused by medial hypertrophy, recurrent distal embolization, or thrombosis; the latter can be related to a reduced ability of either the myocardium or the microvasculature to produce vasoactive metabolites. Alternatively, the underlying abnormality can be represented by the impaired capacity of the distal bed to correctly translate the biochemical messages that physiologically promote vasodilatation; (c) in mixed forms (probably the most common presentation) the two pathophysiological mechanisms may coexist, in variable combinations, and play different relative roles within the individual patient.

Significance of myocardial perfusion abnormalities in patients with microvascular coronary artery disease

Although multiple pathogenetic causes have been hypothesized, coronary microvascular dysfunction appears as a likely mechanism in a sizeable proportion of patients with angina and angiographically normal coronary arteries. Some studies conducted in patients with cardiac Syndrome X reported reduced progression of the angiographic dye (“slow-flow”) and suggested that this phenomenon could be possibly caused by small vessel disease.[5],[6],[7],[8],[9] Furthermore, in small patients series with slow-flow, histologic evidence of small vessel coronary disease has been described.[10],[11] Direct evidence of transient reversible myocardial underperfusion during myocardial perfusion scintigraphy (MPS) occurring during slow-flow has been demonstrated and associated with a worse long-term prognosis.[12]

In a more recent study, also the conventional stress/rest MPS has been confirmed to be a very useful prognostic tool in patients with angina and normal coronary arteries,[13] where the observation of stress perfusion defects had conventionally been considered as a “false positive” result. In this study, prognosis in patients with normal coronary arteries, but scintigraphic evidence of relatively mild inducible myocardial hypoperfusion was not as good as in patients with normal perfusion, especially in terms of morbidity. In fact, in those Syndrome x patients showing transient scintigraphic perfusion defects, a worse combined survival and hospitalization and greater and longer symptomatic burden requiring multidrug therapy were observed. More specifically, the significant increment of the secondary end-point (cardiovascular hospitalizations) and the greater symptomatic burden in the positive MPS group, clearly indicate a worse functional prognosis in these patients. This observed incremental predictive value of MPS for future events confirm the results of two other recent studies, demonstrating significant differences in patients prognosis between positive and negative MPS patients with angiographically “nonsignificant” coronary artery disease.[14],[15] On the other hand, these results also indirectly confirm the association between a negative MPS and very low event rates.[16]

Microvascular induced myocardial ischemia

The concept that searching for ischemia rather than epicardial vessels stenosis could be more effective in risk stratification has different physiological explanations. The mechanisms by which prognosis in Syndrome X patients could be worse in patients with positive MPS are probably related to an effective reduction of microcirculation vasodilatory reserve[17],[18] being the cause of symptoms, positive response to exercise testing and inducible scintigraphic defects.[18],[19],[20],[21] Abnormal subendocardial hypoperfusion has been detected in angina and angiographically normal coronary arteries by cardiac magnetic resonance imaging[22] supporting the concept that chest pain in these patients may be related to nontransmural myocardial ischemia. This hypothesis is supported by cardiac magnetic resonance spectroscopy data reported by Buchthal et al.[23] showing reduced myocardial ratios of phosphocreatine to adenosine triphosphate, consistent with cellular ischemia, in some women with chest pain and normal coronary arteries.

The role of endothelial dysfunction

In patients with chest pain and normal angiograms, abnormalities of the coronary microcirculation have been attributed to endothelial dysfunction.[24],[25],[26],[27] Although most studies have shown that patients with angina and normal coronary arteries bear a benign prognosis,[28],[29],[30],[31],[32] recent investigations indicate that in patients with nonobstructive coronary disease and evidence of myocardial ischemia, the presence of endothelial dysfunction[33],[34] and the long-term persistence of chest pain are significantly associated with adverse cardiovascular events.[35] In a study population of 42 women with angina and angiographically normal coronary arteries, approximately 30% of those exhibiting severe endothelial dysfunction developed the coronary disease during a 10-year follow-up.[36] This data confirm that in patients with angina, positive exercise test and normal coronary arteries, the presence of endothelial dysfunction is associated with potentially inducible myocardial hypoperfusion and a worse prognosis.[12] Therefore, the occurrence of exercise-induced ST-segment changes and perfusion abnormalities, especially if associated with coronary endothelial dysfunction, should not be regarded as a false-positive result, as they could predict a worse outcome.

As for those patients with angina, positive exercise ECG but normal perfusion scintigraphy, the mechanisms beyond the ECG changes are difficult to discriminate.[37] Yet, despite they are often considered as false-positive tests, they may represent an earlier stage of microvascular dysfunction.[38]

Altered pain perception patients with angina and smooth coronary arteries

Patients with angina and normal coronary arteries may have enhanced sensitivity to painful stimuli. To investigate the hypothesis, patients with normal coronary arteries and patients with chronic stable coronary disease were studied using a battery of painful stimuli.[39] Patients with normal coronary arteries had a significantly lower threshold and tolerance for forearm ischemia and electrical skin. Thus, patients with smooth coronary arteries in this study had a significantly lower threshold and tolerance values for forearm ischemia and for electrical skin stimulation. These differences in sensitivity to pain may partly explain a higher incidence of painful ischemic episodes detected by ambulatory electrocardiographic monitoring during unrestricted daily life. On this basis, a group of 29 patients with angina and normal coronary arteries was subsequently studied using positron-emission computed tomography (CT) scanning.[40] Quantitative measurements of regional myocardial perfusion were obtained, using 15-oxygen-labeled water, both at rest and during dipyridamole infusion. Coronary flow reserve (calculated as the ratio between hyperemic and resting flow) was not significantly different when patients with angina and normal coronary arteries were compared with a matched population of healthy controls with no symptoms or risk factors of cardiovascular disease and normal resting and exercise ECG. Although the hyperemic response to dipyridamole was normal, the majority of patients with angina and normal coronary arteries experienced pain and nearly one-third had diagnostic ST-segment changes. The authors concluded that their study “cast further doubt on ischemia as the basis of the reported chest pain, at least in the majority of patients.” They also stressed the potential importance of sympathetic activation in the syndrome, as the interactions of the central and sympathetic nervous system can certainly influence pain perception.

The hypothesis that altered nociceptive perception may play a major role in determining cardiac pain in these patients received further support from the observation that the anti-depressant drug, imipramine, markedly improves symptoms in patients with chest pain and normal coronary angiograms.[41] As the effect of imipramine was unrelated to the results of extensive cardiac testing, the authors concluded that it was mediated by a visceral analgesic mechanism. The rationale for this study was based on the observation that imipramine is used successfully in a wide range of chronic pain syndromes, such as diabetic neuropathy, postherpetic neuralgia, migraine headache, and esophageal pain. However, it must also be remembered that imipramine also affects sympathetic nerve traffic by affecting norepinephrine re-uptake. Furthermore, only a minority (22%) of the study patients really fulfilled the diagnostic criteria of syndrome X and the effects of the drug were not apparently related to the presence or absence of documented ischemia. Curiously enough, the authors of the study, Cannon et al., were among the first to propose microvascular disease as a cause of angina in patients with angiographically normal coronary arteries. In summary, although altered pain perception may certainly play an important role in the syndrome of angina and normal coronary arteries, the evidence gathered so far is probably insufficient to justify the position that, in most of these patients, the heart is “entirely normal” and anxiety or neurosis are the real problem.

Sympathetic overactivity: A unifying pathogenic hypothesis for angina and normal coronary arteries

Excessive stimulation of the sympathetic nervous system is well known to exert a variety of cardiovascular effects that include increased myocardial oxygen demand and constriction of both epicardial and intramyocardial coronary arteries which, in turn, reduce coronary flow reserve. The combination of increased demand and reduced vasodilator capacity may certainly promote the development of a supply/demand imbalance, not severe enough to cause “full-blown” myocardial ischemia and yet sufficient to induce subtle alterations of various cardiac functions. This interpretation could explain, for instance, the presence of resting diastolic dysfunction,[42] the increase in regional glucose uptake[43] and the interstitial deposition of gadolinium.[44] It is likely that the reversal of these abnormalities by long-term treatment with beta-blockers is the result of reduced myocardial oxygen consumption enabling a better supply/demand ratio. Furthermore, prolonged administration of these agents may also cause the sympathetic tone to decrease.

As already discussed, some patients with angina and normal coronary arteries preferentially utilize lipid fuel for myocardial energy production and have proportionally lower oxidation of carbohydrates. Increased sympathetic activity can, by itself, contribute to this phenomenon[45],[46] and beta-blockers may, potentially, reverse it.[47] Furthermore, these agents reduce the levels of circulating free fatty acids that are typically increased by adrenergic stimulation.[47]

Mechanisms responsible for increased sympathetic tone

The mechanisms responsible for the increased sympathetic tone in these patients remain unclear. Certainly, anxiety and a tendency to overreact to emotions and stressful situations can be, at least in part, responsible for the excessive adrenergic activity. This could explain the above-described symptomatic relief obtained in some of these patients with low-dose tricyclic antidepressants such as imipramine.[41] Finally, insulin resistance has also been suggested to contribute to the pathophysiology of the syndrome[48] and once again, excessive sympathetic activity may play a major role. Indeed, there are several mechanisms by which excessive sympathetic activity may lead to insulin resistance. Skeletal muscle vasoconstriction may increase the diffusion distance between the nutritional blood vessel and the metabolizing cell. This will impair the delivery of glucose to the muscle cell, thereby creating a state of relative insulin resistance.[49] In addition to the effect of vasoconstriction, sympathetic stimulation can also induce acute insulin resistance through alpha-adrenergic receptors and blockade with propranolol can reinstate a normal glucose uptake.[50] Whatever the mechanism, insulin-resistant states, such as diabetes and hypertension, have been linked with reduced activity of endothelium-derived relaxing factor.[51],[52] Insulin has also been shown to prompt smooth muscle cell proliferation in man.[53] Such mechanisms may contribute to an abnormal vasoconstrictive response in syndrome X, leading to ischemia.

In summary, excessive activation of the sympathetic outflow to the cardiovascular system can induce a number of effects that may account for many of the abnormalities that are typically found in patients with angina and angiographically smooth epicardial coronary arteries. Although many of these effects may play some role in determining the disorder, it is likely that the most relevant ones are the reduction in vasodilator reserve caused by a-mediated coronary constriction, along with increased metabolic demand.

Angina in patients with subcritical coronary disease

The cause of chest pain in ischemic heart disease caused by coronary atheroma is yet under investigation. One-fourth of acute myocardial infarctions occur without symptoms. A greater magnitude of ischemia was considered in the past as a potential cause of angina. Stimulation of the left ventricular stretch receptors was proposed as a possible mechanism for the occurrence of cardiac pain. However, in patients with angina at rest, transient asymptomatic ST segment shifts have been shown to be consistently associated with large changes in left ventricular volume, similar to those observed during painful episodes. Therefore, the rate and extent of acute left ventricular dilatation do not appear to be factors directly causing anginal pain.[54]

In the previous paragraphs, we have underlined the roles of different pathogenetic mechanisms affecting the cardiac microcirculation and provoking ischemia and chest pain in patients with otherwise normal coronary arteries. These mechanisms could certainly be at work also in patients with noncritical atheroma. On this basis, as for patients with syndrome X, the development of ischemic episodes and angina is not a remote possibility. Rather, the ischemic burden could even be greater, because the atherosclerotic process likely extended to the small vessels could represent an additive factor to functional abnormalities. It has been shown that after a successful coronary angioplasty a sizeable proportion of patients often show an early positive exercise and that this could be mainly related to vasoconstriction at the site of dilation and in the distal microcirculation mediated by the release of vasoconstrictor substances.[55] A recent analysis by Huki has evidenced that, when systematically assessed, a considerable number of patients present with an abnormal exercise result and angina after complete and uncomplicated percutaneous revascularization.[56] Accordingly, these patients complain about the impaired quality of life. The prevalence of persisting angina and inducible ischemia after angioplasty largely exceeds the restenosis rate. The findings of the study of Huqi et al. are consistent with previous large clinical trials that have reported that many patients with angina present with abnormal stress test results and complain about angina symptoms after coronary revascularization.[57],[58],[59],[60]

A very recent meta-analysis has shown that prognosis in patients with angina without obstructive CAD is quite heterogeneous and inconsistently defined among studies.[61] In general, this condition is associated with a low incidence of death or nonfatal myocardial infarction. However, outcomes appear to be extremely variable, and worse in patients with a higher burden of cardiovascular risk factors, “some” coronary atherosclerosis, typical angina, and well-documented myocardial ischemia.[12],[13],[14],[15] However, overall these patients carry a high rate of rehospitalization for cardiovascular causes, suggesting serious patient disability, important impairment in quality of life and implying consequent high consumption of health resources.[61]

Stenosis severity does not necessarily mean severe ischemia

As described in the previous paragraphs, myocardial ischemia can occur in the presence of normal epicardial coronary arteries, through different pathophysiological mechanisms. On the other hand, it is also possible that intermediate coronary artery stenoses (50%–70% lumen reduction) do not produce significant myocardial ischemia. To better direct revascularization strategies, since the early 1990s fractional flow reserve (FFR) has been developed as an invasive measurement of the functional significance of stenoses in the epicardial coronary arteries. In fact, coronary angiography does not accurately determine the hemodynamic significance of coronary stenoses. This limitation of coronary angiography is particularly relevant in view of the fact that the benefits of coronary revascularization are mainly attributable to the reduction of ischemia.[62] On this ground, physiologic lesion assessment in the catheterization laboratory has become the gold standard to assess whether intermediate stenosis is responsible for inducible ischemia. FFR is defined as a ratio of the maximal myocardial blood flow in the presence of stenosis to the theoretical normal maximal flow in the same distribution. The measurement of FFR has been shown to be useful in assessing whether or not to perform coronary percutaneous intervention (PCI) on “intermediate” stenoses. The FFR cut-off value ≤0.80 has been validated in many different subsets of patients. FFR value ≤0.80 corresponds to inducible ischemia and most likely will require interventional treatment. Stenoses that score above this threshold can be safely and adequately treated by medical therapy without the need for PCI. In fact, decision making for PCI guided by FFR is associated with favorable clinical outcomes compared with plain angiography-guided PCI.[63]

Recent technical developments have introduced the concept of noninvasive FFR measurement in the context of computed standard coronary CT angiography (FFRCT) enabling combined anatomic and hemodynamic assessment of a coronary lesion by a single noninvasive test.[64] Results from clinical studies underline the effectiveness of evolving noninvasive algorithms for FFR assessed through CT imaging.[65]

Mental components of angina

The association between angina and mental stress-induced myocardial ischemia is an established notion. This association has been shown to be independent of traditional coronary artery disease risk factors and occurring mainly in women.[66],[67] As outlined above, coronary microvascular dysfunction could represent the main mechanism of mental stress-induced myocardial ischemia.[68] Alternatively, reported angina can be a marker of psychologic distress. This is suggested by the consistent association observed between chest pain/angina and symptoms of psychosocial distress, such as depression, anxiety, and perceived stress, in both patients and controls, consistent with many previous reports.[69],[70]

Anxiety and depression are the most frequent psychopathological disorders co-occurring with heart diseases. Prompt control of these disorders helps to ameliorate the symptoms and improve the prognosis. Pharmacological intervention, if needed, should be lied out as soon as possible. Benzodiazepines are the most suitable drugs for the treatment of anxiety and depression comorbid with heart disease, diazepam in simple anxiety, and alprazolam when of depressive tendency. Our experience, on short and long-term treatment of anxiety and depression in cardiac patients with benzodiazepines, represents further support to its beneficial effects in the prognosis of this population.[71],[72]

  Conclusions Top

Approximately 20% of patients undergoing diagnostic coronary arteriography for acute or chronic cardiac ischemia have angiographically normal coronary arteries. The mechanism behind this phenomenon is likely to be the result of a combination of functional or anatomical abnormalities in the coronary microcirculation, a metabolic disorder which affects the handling of energy substrates by the heart, insulin resistance and a neurological component affecting pain perception. Indeed, it has been demonstrated that these patients often exhibit an increase in sympathetic outflow to the cardiovascular system, which might account for the reduction in coronary flow reserve, changes in metabolic utilization, and development of insulin resistance that are seen in some of these patients. Therapeutically, β-blockers appear to be most effective in controlling the symptoms associated with this condition.

Inducible myocardial ischemia in patients with angina and angiographically smooth coronary arteries could discriminate patients with a more severe prognosis, especially in terms of further hospitalization and symptomatic burden. On this ground, the clinical tendency to dismiss abnormal exercise perfusion findings as false-positive in these patients may be unjustified. Further studies in larger populations are obviously necessary to confirm these concepts. However, for the present time, a careful follow-up of patients with angina and angiographically normal coronary arteries developing transient inducible ischemia is suggested.

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