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Ischaemic heart disease
Angina pectoris in patients with normal coronary angiograms: current pathophysiological concepts and therapeutic options
  1. Ali Yilmaz,
  2. Udo Sechtem
  1. Division of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
  1. Correspondence to Dr Ali Yilmaz, Division of Cardiology, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, Stuttgart 70376, Germany; ali.yilmaz{at}rbk.de

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The presence of angina pectoris (AP) in patients with either normal coronary angiograms or with non-obstructive coronary artery disease (CAD) is not only a frequent clinical finding but also a clinical and therapeutic challenge. Only recently, Patel et al evaluated the diagnostic yield of coronary angiography—regarding the presence or absence of obstructive CAD—among almost 400 000 patients with suspected CAD.1 Although the majority (70%) of these patients was suffering from chest pain symptoms, only 37.6% of them demonstrated obstructive CAD by invasive coronary angiography (defined as diameter stenosis >50% of the left main coronary artery or >70% of a major epicardial vessel). This surprising finding raises the following question: how should we explain the presence of AP symptoms (typical enough to motivate coronary angiography) in patients without obstructive CAD? Moreover, we need to consider the following clinical issues: (1) non-obstructed coronary arteries are also found in a sizeable subgroup of ≥10% of patients who undergo urgent coronary angiography due to angina accompanied by troponin elevation, and these patients represent a high risk group with a worse prognosis even in the absence of obstructive CADw1–w3; and (2) the presence of myocardial ischaemia in the absence of obstructive CAD still predicts cardiovascular outcome and is associated with higher rates of anginal hospitalisation, repeat catheterisation, and greater treatment costs.w4 Therefore, further evaluation of the underlying pathophysiology and potential treatment options in patients presenting with AP in the absence of obstructive CAD is a clinically highly relevant issue.

In the following review, different (sometimes overlapping) pathophysiologies causing symptoms of AP in the absence of obstructive CAD are discussed, and current diagnostic as well as therapeutic options are illustrated.

The patient with ‘hypertensive heart disease’

Obviously, hypertension is a frequent and important cardiovascular risk factor. As recently summarised by Raman et al,2 hypertension is a predisposing factor not only for the development of heart failure symptoms, atrial fibrillation, and ventricular arrhythmias, but also for ischaemic heart disease and the risk of myocardial infarction.w5 Structural alterations in patients with hypertensive heart disease comprise cardiomyocyte hypertrophy, expansion of interstitial and perivascular fibrosis by progressive collagen accumulation, and increased arterial stiffness (figure 1). These alterations are not only associated with left ventricular hypertrophy and an increase in left ventricular mass, but also with a decrease in intramyocardial capillary density and arteriolar wall thickening. As a result of these structural alterations, both epicardial CAD as well as microvascular disease may occur in patients with hypertensive heart disease and cause symptoms of AP.

Figure 1

Hypertensive heart disease involves disparate elements, ranging from aortopathy to myocardial remodelling and even peripheral energy utilisation that interact to produce sequelae such as heart failure, arrhythmias, and ischaemic events. LA, left atrium; LV, left ventricle. Reprinted with permission from Raman et al.2

The association between hypertension and microvascular dysfunction (resulting in symptoms of AP and dyspnoea in addition to a reduced coronary flow reserve) is well established.w6–w11 Previous studies have revealed those aforementioned structural changes of the microvasculature as well as functional abnormalities such as endothelial dysfunction with decreased nitric oxide production. Furthermore, previous nuclear imaging based studies showed a low specificity (as low as 36%) for the detection of CAD in hypertensive patients, owing to scintigraphic defects caused by microvascular dysfunction in the absence of significant epicardial stenosis.w6 w9 Therefore, it is believed that those aforementioned structural and functional alterations in hypertensive patients cause a coronary vasomotor dysfunction, which in turn may cause symptoms of AP as well as myocardial ischaemia in the absence of obstructive CAD.3 w10 Recently, Escaned et al demonstrated that both arteriolar obliteration and capillary rarefaction have an independent influence on microcirculatory haemodynamics (figure 2).4 They clearly proved the link between microvascular structural changes and functional impairment, which in turn may result in clinical symptoms and pathological non-invasive stress test results in the absence of significant epicardial stenosis.

Figure 2

Histological examples of myocardial arterioles and box plots of arteriolar obliteration index in healthy control and allograft endomyocardial biopsies illustrating microvascular structural changes. Reprinted with permission from Escaned et al.4

Interestingly, most available imaging modalities—apart from stress echocardiography—that assess the haemodynamic significance of ‘epicardial’ CAD have a moderate to low specificity for detection of obstructive epicardial CAD,w7 w11 raising the possibility that these techniques may detect true perfusion abnormalities in the context of angina without visible coronary stenosis.w12 Only in the case of stress echocardiography has a satisfactory diagnostic specificity (80–91%) for the detection of obstructive CAD been demonstrated and attributed to the absence of wall motion abnormalities in patients with myocardial ischaemia not caused by epicardial stenosis.w6 Coronary vasomotility and/or microvascular disorders have been discussed as possible explanations for the presence of myocardial ischaemia in the absence of obstructive CAD.w13 5 In the last few years, cardiovascular magnetic resonance (CMR) imaging with adenosine-stress first-pass perfusion (perfusion-CMR) has been shown to be a sensitive non-invasive method for the detection of myocardial ischaemia caused by obstructive CAD.6 However, pathological perfusion-CMR results also do not allow a perfusion defect due to significant epicardial stenosis to be differentiated from one due to a coronary vasomotility disorder (figure 3). Therefore, patients with hypertension were even excluded from studies that assessed the diagnostic accuracy of perfusion-CMR in suspected CAD in order to keep the specificity high.w14 Many patients with hypertension nevertheless undergo myocardial perfusion imaging (by nuclear techniques or increasingly CMR) in two common clinical scenarios:

  1. They present with typical AP or angina-like symptoms (usually dyspnoea upon exertion or atypical angina) or

  2. They are asymptomatic but either have ST depression during exercise stress testing or are felt to be at very high risk for the development of epicardial CAD because of additional atherosclerotic risk factors.

Figure 3

Upper panel: Cine, stress-perfusion, and rest-perfusion cardiac magnetic resonance (CMR) images of a patient with unstable angina pectoris. A large subendocardial perfusion defect extending from the anteroseptal segment to the inferoseptal segment was documented during adenosine stress (red arrows). Mid and lower panel: The left coronary artery (as well as the right coronary artery, not shown) of this patient did not show any significant stenosis at baseline. During intracoronary acetylcholine infusion there was no significant epicardial vasoconstriction; however, the patient felt the same chest pain as she did at home and demonstrated ST segment elevation in leads V1–V3. After infusion of glyceryl trinitrate the patient's chest pain and the ECG changes disappeared while there was only a mild epicardial vasodilation. Hence, microvascular disease was diagnosed in this patient. Reprinted with permission from Yilmaz et al.3

Patients with positive tests usually undergo coronary angiography in order to definitely verify or rule out potentially hazardous obstructive epicardial CAD. A large number of those patients will not have relevant epicardial disease.3 w15 These patients are commonly reassured that they are ‘healthy’. Such a statement can be surprising and even shocking for the patient, who may suffer from severe typical or atypical AP symptoms.w16 Therefore, the clinician should not be content with a normal or near normal coronary angiogram, but consider a coronary vasomotility disorder as underlying disease for symptoms of AP and/or myocardial ischaemia. On the other hand, what may look like a coronary stenosis may not always be the cause of the patient's symptoms, which is becoming increasingly obvious with the increasing use of fractional flow reserve measurements before coronary interventions.7 This indicates that epicardial and microvascular disease may coexist.8 Hence, the task of the clinician is becoming more challenging when dealing with patients complaining of AP.

In patients without severe epicardial disease—for example, patients with hypertensive heart disease—clinical studies have suggested an improvement of structural and functional alterations as well as a relief in clinical symptoms on treatment with ACE inhibitors and/or calcium antagonists.w17–w19

The patient with ‘microvascular disease’

Abnormalities in the structure and function of the microvasculature occur not only in cases of hypertensive heart disease but also in many other clinical and pathological conditions. The main epicardial coronary arteries run on the surface of the myocardium and bifurcate into smaller arteries and arterioles, thereby forming a tree-like network while spirally penetrating into the mid- and subendocardium where they empty into a capillary (non-tree-like) network with interconnections.9 These capillaries drain into post-capillary venules which are directed from the endocardium to the epicardium and finally form larger veins. Large coronary arteries (diameter >500 μm) are called conduit vessels because they contribute <5% to total coronary resistance, while prearterioles (diameter 100–500 μm) and arterioles (diameter <100 μm) cause the major flow resistance (resistance vessels). Hence, a dysfunction of small resistance vessels (pre-arterioles and arterioles with a diameter <500 μm)—which are not visible at coronary angiography—has been suggested to be responsible for microvascular disease.

We mention microvascular dysfunction throughout this paper. Thus, it may be appropriate to briefly review the normal function of this important part of the coronary tree. Under normal conditions, arterioles dilate or constrict in response to surrounding myocardial metabolic conditions to match flow appropriate to myocardial oxygen demands.10 Hence, dysfunction of the microvasculature may occur as a consequence of disturbances in the complex signalling pathways in endothelial as well as smooth muscle cells, but also as a consequence of abnormal production of molecules necessary for normal signalling.

It should be emphasised that direct in vivo visualisation of the microvasculature is still not possible in humans. However, the function of the microvasculature can be assessed by employing invasive and non-invasive methods. Coronary flow can be quantitated using intracoronary Doppler registration, whereas positron emission tomography or perfusion-CMR measure myocardial blood flow (figure 4). For example, coronary flow measurements both at rest and during maximal hyperaemia (eg, using adenosine) with an intracoronary Doppler wire permit assessment of coronary flow reserve, which is usually impaired in patients with microvascular disease. Accordingly, the (auto-)regulation and modulation of coronary blood flow in response to different stimuli (such as physical exercise, mental pressure or sensation of cold) is disturbed in patients with microvascular disease, which in turn may cause symptoms of either AP and/or dyspnoea. Particular attention should be paid not only to those patients presenting with typical AP, but also to those patients presenting with recurrent unexplained (chronic) dyspnoea in the presence of normal left ventricular systolic function; symptoms in such patients may also reflect microvascular disease and be caused by increased left ventricular stiffness, resulting in increased left ventricular filling pressures and diastolic dysfunction.w20

Figure 4

Positron emission tomography/CT hybrid images of a 63-year-old man with suspected coronary artery disease, atypical chest pain, and 2 mm ST depression on the ECG at the exercise test. In hybrid images, stress myocardial perfusion was reduced in most regions (green and blue). However, both coronary CT angiography and invasive coronary angiography showed normal coronary arteries, indicating possible microvascular disease. Reprinted with permission from Kajander et al.11

Recently, Camici and Crea suggested a clinical classification of microvascular diseases into four groups12:

  • The first group encompasses patients with traditional coronary risk factors (smoking, hypertension, hyperlipidaemia, and diabetes) in the absence of obstructive CAD and myocardial diseases. These traditional cardiovascular risk factors may lead to microvascular disease and subclinical coronary atherosclerosis. In these patients, microvascular disease can be identified, for example, by non-invasively demonstrating a globally reduced coronary flow reserve. Microvascular function may improve by instituting treatments aimed at reducing the burden of risk factors.

  • The second group comprises patients with myocardial diseases such as primary cardiomyopathies (eg, dilated or hypertrophic cardiomyopathy) as well as secondary cardiomyopathies (eg, diabetic or valvular), in whom adverse remodelling of intramural coronary arterioles is occurring. The underlying mechanisms causing microvascular disease in this group encompass expansion of interstitial and perivascular fibrosis, capillary rarefaction, and increased arterial stiffness. The pathophysiological overlap between the first group and this group may be illustrated by focusing on patients with diabetes: the presence of diabetes may not only lead to functional abnormalities such as coronary endothelial dysfunction, thereby causing an impaired coronary flow reserve, but may also result in diabetic cardiomyopathy which is characterised by structural changes such as interstitial and perivascular fibrosis associated with severe microvascular diseasew21 (figure 5). Whether medical treatment may improve the massive disturbance of microvascular function in these patients is unclear.

  • The third group encompasses patients with obstructive CAD. Not only patients with angina but normal coronary arteries, but also those with impressive and even obstructive plaque formation by coronary angiography, may suffer from microvascular disease. Obviously, coronary atherosclerosis is a diffuse disease process affecting not only a single coronary artery but rather the whole coronary tree. Accordingly, impaired coronary flow reserve in addition to impaired glucose metabolism as signs of microvascular disease were documented in ‘normal’ arteries and ‘normal’ (remote) myocardial segments, respectively, not directly affected by the infarcted myocardium in patients with single vessel disease.w22 Microvascular disease and microvascular spasm may also be the cause of increased interstitial fibrosis found in the remote myocardium of such patients.w23 Hence, a critical epicardial stenosis and/or a plaque rupture with subsequent coronary obstruction may represent a late stage in the development of coronary atherosclerosis (figure 6). In patients suffering from combined epicardial and microvascular disease, symptoms of AP may persist even after treating a critical stenosis and/or obstructed coronary segment, since diffuse microvascular disease still exists. In this group, appropriate medical treatment may improve or abolish the symptoms due to microvascular disease.

  • The last group is denoted ‘iatrogenic coronary microvascular dysfunction’ and encompasses patients with coronary revascularisation—for example, distal embolisation. Obviously, the washout of thrombotic tissue from the epicardial area of coronary obstruction to the distal microvascular area during a coronary intervention results, on the one hand, in an unobstructed epicardial coronary artery, but on the other hand will lead to diminished coronary flow due to diffuse microvascular embolisation. Hence, in this group, even though pharmacologic treatment may restore coronary flow, the change in clinical outcome will be primarily based on the resulting perfusion and status of the microvasculature.

Figure 5

Mild myocardial interstitial fibrosis stained in blue with Masson trichrome (white arrows) in a patient with long duration type 1 diabetes mellitus at autopsy, with (A) perivascular fibrosis and (B) mild fibrosis between myocytes. Reprinted with permission from Konduracka et al.w42

Figure 6

Cascade of mechanisms and manifestations of ischaemia having an impact on ischaemic heart disease risk in women. Reprinted with permission from Shaw et al.13

Taken together, microvascular disease is far more common than, for example, obstructive CAD, since (1) different cardiovascular risk factors, and (2) different coronary and myocardial diseases may cause microvascular dysfunction. In fact, in patients fulfilling the strictest definition of cardiac syndrome X microvascular disease seems to be an independent disease entity.w24 Therapy should aim at treating and/or eliminating the underlying disease. However, since microvascular disease may have severely advanced before the first clinical symptoms occur, successful therapy of microvascular disease is often difficult—and much more challenging than treating the immediate underlying disease such as hypertension or diabetes.

Calcium antagonists and nitrates are the most commonly used agents in patients with AP symptoms. However, the use of nitrates may be disappointing, particularly in patients with microvascular disease, as neither coronary blood flow nor subendomyocardial flow will increase following intracoronary glyceryl trinitrate (GTN) application in some patients with non-obstructive CAD.14 w25 w26 This disappointing finding is explained by the observation of some groups that GTN dilates larger conduit vessels, whereas smaller resistance regulating arterioles remain unaffected because these vessels lack the necessary GTN converting enzymes—at least in some animal models.15 Hence, treatment of anginal symptoms in patients with mainly microvascular disease may be disappointing since these patients often do not react to GTN and hence do not benefit from GTN treatment. However, about 50% of patients improve with nitrates such as pentaerythrityl tetranitrate, which suggests some heterogeneity in the underlying pathological substrate in the microvasculature.

The patient with ‘cardiac syndrome X’

In principal, cardiac syndrome X (CSX) is diagnosed in those patients who have typical ‘exertional’ AP and demonstrate ST segment depression during exercise ECG in addition to a completely normal coronary angiogram, but who do not have cardiovascular risk factors for CAD such as hypertension or hypercholesterolaemia.10 w27 w28 However, today the term CSX is also used for those patients demonstrating exertional AP and myocardial ischaemia during exercise ‘with’ cardiovascular risk factors.w29

Cannon et al were the first to suspect microvascular dysfunction as the underlying cause for chest pain in patients with CSX in 1988.10 Since that time, numerous studies have been published addressing the underlying pathophysiology in patients with CSX.5 16 w13 w30 As recently reviewed by Wu,w30 endothelial dysfunction and/or microvascular dysfunction frequently occur in ‘normal’ people who just have coronary risk factors, but there is usually no associated ischaemia, ST segment depression or chest pain in the majority of these people. Therefore, an important question still to be answered is whether microvascular dysfunction may indeed lead to ischaemia, ST segment depression, and most importantly chest pain in patients with CSX. For example, Panting et al demonstrated subendocardial perfusion defects in patients with CSX based on perfusion-CMR studies.5 However, Vermeltfoort et al could not reproduce these findings using a similar approach.w31 More recently, Monaco et al found a significant impairment of cardiac uptake of iodine-123-meta-iodobenzylguanidine (MIBG) on myocardial scintigraphy, indicating abnormal function of cardiac adrenergic nerve fibres and also abnormalities in coronary microvascular function in patients with CSX.16 Most likely, these discrepant findings are due to the fact that the effects of microvascular disease in terms of causing objective ischaemia and chest pain are importantly modulated by the extent of the disease (rarefaction and anatomic/functional narrowing of the microvessels) and the pain perception of the patient.

Like other forms of microvascular disease, CSX is more frequent in female than male patients. This may be the result of risk factor clustering, vascular inflammation and remodelling, and hormonal alterations.13 Therapeutically, a recent pilot study (randomised, double blind, placebo controlled, crossover trial) found that anginal symptoms in women with angina, no obstructive CAD, and >10% ischaemic myocardium on adenosine stress CMR imaging, were significantly improved by ranolazine compared with placebo.w32

The patient with ‘variant angina’ or ‘Prinzmetal's angina’

In his landmark paper of 1959, Prinzmetal et al described “another type of angina pectoris which appears to be a separate entity, and has not been set apart from the heterogeneous group of anginal syndromes. It does not show the two major characteristics of the classic form and, in addition, has other important clinical and experimental differences. In this variant type of angina the pain comes on with the subject at rest or during ordinary activity during the day or night. It is not brought on by effort. During an attack, the ST segments are transiently and often remarkably elevated and there are reciprocal ST depressions in the standard leads”.17 Importantly, none of those patients studied by Prinzmetal and colleagues underwent coronary angiography, and in no patient was the angiographic morphology of spasm demonstrated. Nevertheless, Prinzmetal et al postulated an increase of ‘tonus’ at the site of a subcritical stenosis as a prerequisite for Prinzmetal's or variant angina, the hallmark of which is the association with ST segment elevation.17 Today, the patient with Prinzmetal's or variant angina is clinically characterised by recurrent episodes of resting chest pain associated with reversible ST segment ‘elevation’ and preserved exercise tolerance in the absence of obstructive CAD.w33 Angiography during an ischaemic episode or invasive provocative testing with acetylcholine or ergonovine should typically demonstrate a subtotal/total occlusive spasm of a major epicardial coronary artery (figure 7). The mechanism of angina in patients with Prinzmetal's angina more likely differs from the mechanism of other forms of angina that occur in the much larger group of patients demonstrating ST segment depression, both during the angina attack as well as during provocative testing. In these patients acetylcholine testing does not show focal occlusion but does show distal diffuse epicardial spasm or no significant epicardial vasomotion. Thus, Prinzmetal's angina is rare and only represents one extreme aspect of a continuous spectrum of vasospastic myocardial ischaemia.

Figure 7

Coronary angiograms of the left coronary artery at baseline, during increasing doses of acetylcholine infusion and after glyceryl trinitrate (GTN) infusion in a patient with atypical angina. At baseline, minor non-obstructive atherosclerotic coronary wall irregularities are seen in the proximal left anterior descending artery (LAD, red arrow). Angiography during invasive provocative testing with acetylcholine demonstrated a subtotal/total occlusive spasm of the proximal LAD. After infusion of GTN, the LAD spasm and the patient's chest pain quickly disappeared.

Patients with resting angina not accompanied by ST segment elevation and preserved exercise tolerance will be more common, as the periodically increased vasomotor tone will only rarely result in total occlusion of a major epicardial coronary artery but will result more commonly in significant transient vasoconstriction (without total occlusion). Hence, the term ‘vasospastic angina’ encompasses both those patients with traditional ‘variant’ or Prinzmetal's angina but also those with only transient vasoconstriction with reversible ST segment ‘depression’. The exact subcellular mechanisms responsible for coronary spasm still remain to be elucidated, although interesting data have been obtained from animal models.w34 A coronary vasomotility disorder may be caused by severe endothelial dysfunction due to a decreased bioavailability of the vasodilator nitric oxide (NO), as this pathophysiology has previously been suggested as a possible mechanism for coronary vasospasm.w35 However, this hypothesis of endothelial dysfunction is competing with the view of coronary smooth muscle cell hyperreactivity as the underlying cause for coronary vasospasm.w34

Since patients suffering from vasospastic angina will often show normal coronary arteries or non-obstructive CAD during coronary angiography, the clinician ignoring the potential diagnosis of coronary vasospasm may misleadingly either attribute the patient's symptoms to a non-cardiac or psychosomatic origin or even perform stenting of a moderate, non-critical stenosis in an effort to treat the patient's problem. Since coronary vasospasm may be an occasional occurrence and may not occur during a normal 24 h Holter ECG, Prinzmetal himself noted that establishing the diagnosis of vasospastic angina by recording an ECG during an acute attack might not be an easy task.17 Consequently, current guidelines recommend (among others) intracoronary provocative testing to identify coronary spasm in patients with normal findings or non-obstructive lesions on coronary angiography presenting with the clinical picture of coronary vasospasm.w12

Patients with variant or vasospastic angina should be treated symptomatically with calcium antagonists and nitrates.w12 Moreover, they should receive a statin—independent of their cholesterol value—since additional statin therapy has been shown to decrease the number of patients with coronary vasospasm by ∼30% after 6 months of treatment.w36 Whether ß-blocker therapy in these patients is beneficial or rather detrimental is still discussed controversially. While early clinical data suggest against the use non-specific ß-blocking agents such as propranolol, due to an increase in the frequency of AP symptoms,w37 preclinical data support the use of ß1-specific ß-blockers such as metoprolol in case of coronary vasospasm.w38

The young patient with ‘acute myocarditis’ mimicking acute myocardial infarction

Young patients, particularly males, with acute chest pain syndrome in whom CAD is very unlikely on the basis of their risk profile are a frequent clinical challenge in the emergency room. Such patients may even present with ST segment elevations in the resting ECG and elevated cardiac enzymes in their blood analysis, suggesting acute ST elevation myocardial infarction. In such a scenario, acute coronary obstruction (for example, by spontaneous coronary dissection) as well as acute aortic dissection need to be first ruled out, for example, by invasive angiography and CT, respectively. After obstructive CAD and aortic dissection have been excluded, the most important differential diagnosis in troponin positive patients is acute myocarditis.18 19

Men are twice as likely as women to present with clinical signs of acute myocarditis.w39 Virus genomes indicating myocarditis are commonly found in patients clinically presenting with a picture mimicking acute myocardial infarction, but demonstrating normal coronary anatomy.19 What is the cause of the patient's chest pain and ECG changes? Initially, it was thought that these findings represented the effects of myocardial damage caused by the inflammation and the virus. Although it has been shown that peripheral and coronary endothelial function is impaired in patients with myocardial virus persistence, and that this impairment is even more pronounced in the case of both myocardial virus persistence and inflammation,w40 w41 this does not explain the clinical symptom of resting chest pain in subjects with acute myocarditis. Recently, we were able to demonstrate that coronary vasospasm may explain the chest pain symptoms in patients with acute myocarditis, although other effects of viral inflammation may contribute to the clinical picture (figure 8).20 Hence, myocardial inflammation or virus persistence, or both, may be associated with or even cause a coronary vasomotility disorder, enabling the occurrence of coronary vasospasm and causing acute chest pain syndromes, particularly in young patients with no risk factors for CAD. Presently, there is no targeted specific therapy for acute myocarditis complicated by coronary vasospasm, and current recommendations comprise mainly anti-anginal therapy with calcium antagonists and nitrates in those patients with documented coronary vasospasm. However, this type of acute vasospasm is a self-limiting disease and resting chest pain spontaneously subsides usually after a few days.

Figure 8

Young male patient with acute myocarditis presenting with a clinical picture of acute coronary syndrome. Upper panel: Baseline coronary angiograms did not show any significant stenosis (only left coronary artery is shown). During intracoronary acetylcholine infusion diffuse epicardial coronary vasospasm occurred (red arrows) in the left anterior descending artery (LAD) and the left circumflex artery (LCX) and the patient felt the same chest pain as he did at home. After intracoronary glyceryl trinitrate infusion the chest pain as well as the coronary vasospasm disappeared. Mid panel: Cine cardiac magnetic resonance (CMR) images revealed a normal systolic function. However, late gadolinium enhancement (LGE) and T2 weighted oedema CMR images were suggestive of acute myocarditis with myocardial damage in the subepicardium of the left ventricular free wall (red arrows). Lower panel: Endomyocardial biopsies were taken from the left ventricular free wall and trichrome staining revealed accumulation of inflammatory cells and essential structural abnormalities indicative of myocarditis. Immunohistochemical staining with anti-CD68 antibodies proved the accumulation of macrophages and confirmed the diagnosis of acute myocarditis (courtesy of Professor K Klingel and Professor R Kandolf from the University of Tübingen). Reprinted with permission from Yilmaz et al.w43

Conclusions

AP is a frequent clinical finding in patients without obstructive CAD. It may be caused by coronary vasomotility disorders which comprise epicardial as well as microvascular dysfunction. Traditional risk factors (such as hypertension and diabetes) as well as cardiomyopathies (such as hypertrophic cardiomyopathy) may be associated with functional as well as structural changes such as endothelial dysfunction, interstitial and perivascular fibrosis, capillary rarefaction, and increased arterial stiffness. These functional and structural changes are major predisposing factors for the occurrence of both epicardial coronary vasospasm and microvascular disease, and cause the occurrence of AP in the absence of obstructive CAD. Targeted therapy is primarily aimed at eliminating the underlying risk factor and/or disease. However, treatment may be challenging, particularly if microvascular disease is the major problem.

Angina pectoris in patients with normal coronary angiograms: key points

  • The presence of angina pectoris (AP) in patients with either normal coronary angiograms or with non-obstructive coronary artery disease (CAD) is not only a frequent clinical finding but also a clinical and therapeutic challenge.

  • Structural alterations in patients with hypertensive heart disease comprise not only left ventricular hypertrophy and an increase in left ventricular mass but also a decrease in intramyocardial capillary density and arteriolar wall thickening, resulting in both epicardial CAD as well as microvascular disease.

  • Microvascular structural changes may lead to functional impairment and result in clinical symptoms and pathological non-invasive stress test results in the absence of significant epicardial stenosis.

  • Abnormalities in the structure and function of the microvasculature occur not only in cases of hypertensive heart disease but also in many other clinical and pathological conditions comprising the presence of traditional risk factors (such as hypertension and diabetes) as well as cardiomyopathies (such as hypertrophic cardiomyopathy).

  • Cardiac syndrome X is diagnosed in those patients who have typical ‘exertional’ AP and demonstrate ST segment depression during exercise ECG in addition to a completely normal coronary angiogram.

  • The patient with Prinzmetal's or variant angina is clinically characterised by recurrent episodes of resting chest pain associated with reversible ST segment ‘elevation’ and preserved exercise tolerance in the absence of obstructive CAD.

  • The term ‘vasospastic angina’ encompasses both those patients with traditional ‘variant’ or Prinzmetal's angina and those with only transient vasoconstriction with reversible ST segment ‘depression’.

  • Myocardial inflammation and/or virus persistence may be associated with a coronary vasomotility disorder enabling the occurrence of coronary vasospasm and causing acute chest pain syndromes, particularly in young patients without risk factors for CAD.

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References

  1. An excellent review regarding the pathophysiology of hypertensive heart disease.
  2. A clinical study clearly demonstrating the presence of myocardial perfusion defects by non-invasive CMR in patients without obstructive CAD.
  3. An excellent study demonstrating the link between microvascular structural changes and functional impairment which in turn may result in clinical symptoms in the absence of significant epicardial stenosis.
  4. A very comprehensive and well written review on microvascular angina, focusing on the potential underlying pathophysiology.
  5. An interesting study focusing on the detection of obstructive CAD by cardiac positron emission tomography/CT imaging, also nicely demonstrating the presence of extensive myocardial ischaemia in some patients without obstructive CAD.
  6. A comprehensive review on microvascular disease focusing on the diagnosis and classification of this disorder.
  7. A comprehensive review summarising the current knowledge regarding the pathophysiology of ischaemic heart disease, with particular focus on females without obstructive CAD.
  8. A challenging preclinical study systematically evaluating the effect of GTN in microvessels.
  9. One of the first studies introducing a variant form of angina or Prinzmetal's angina.
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Footnotes

  • Funding AY is financially supported by a grant from the Robert-Bosch-Foundation (grant-ID I1).

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests.

  • Provenance and peer review Commissioned; internally peer reviewed.