classic angina; emotional stress is a common trigger.
Exercise ECG testing is frequently positive in these patients (50–70%),5,6 partly from the underlying CAD, and partly from exercise- induced vasospasm.
C. Diagnosis of vasospasm
Epicardial (macrovascular) vasospasm is definitely diagnosed on coronary angiography when the following three features occur, spontaneously or with provocation:6,120,121,122
Focal or diffuse vasospasm leading to ≥75% dynamic luminal reduction. One study used a 90% cutoff122
ST-segment elevation or depression
Reproduction of the patient’s symptoms
Microvascular vasospasm is diagnosed when ST-segment changes and symptoms occur with provocation, without any visualized spasm.6 An additional feature of microvascular spasm is a slow coronary flow (delayed TIMI frame count) without epicardial obstruction.
When present spontaneously, vasospasm is frequently confused with a true fixed obstruction; the diagnosis of vasospasm is made when the stenosis improves to <50% with intracoronary NTG administration. While it is reasonable to administer NTG whenever any coronary stenosis is seen, to rule out a dynamic component before any PCI, vasospasm is particularly suspected when the stenosis is concentric with smooth borders. Conversely, ostial spasm occurring at the catheter tip does not have a diagnostic value. The dose of intracoronary NTG is 50-200 mcg- studies suggest no further coronary dilatation with doses beyond 200 mcg.
Vasospasm may be provoked with intracoronary ergonovine, or safer yet, slow intracoronary acetylcholine boluses (very quick offset). Angiographic vasospasm without symptoms or ECG changes is suspicious but not diagnostic of vasospastic angina.
Although acetylcholine provocation is safe, it is not routinely performed at many institutions. The diagnosis is presumptive in a patient with the following triple combination: rest angina or effort angina, no angiographic CAD, and documentation of transient ST changes on stress ECG or ambulatory ECG. ST changes being infrequently documented, provocative testing is preferably performed and alters chronic management.122
In vessels with normal endothelial function, acetylcholine induces the synthesis of NO and coronary vasodilatation. In vessels with endothelial dysfunction, the endothelium cannot generate NO, hence acetylcholine directly acts as a vasoconstrictor.
D. Frequency of vasospasm in patients with exertional chest pain and no significant CAD
One study assessed patients (age 63 ± 10) with a predominantly exertional chest pain and unobstructed coronary arteries (<20%) on angiography. Among patients who underwent a stress ECG before angiography, half had ischemic ECG changes. Upon provocative testing with acetylcholine, 62% of all patients developed macrovascular or microvascular spasm (28% macrovascular, 34% microvascular). Macrovascular spasm was often diffuse and distal.6,121 Most of these patients were women.
Thus, macrovascular vasospasm, and more so, microvascular dysfunction, not only cause rest angina but are also a common cause of exertional angina in patients without CAD.120-122 The stimulation of adrenergic α-receptors may induce epicardial coronary spasm. Alternatively, the epicardial or microvascular spasm induced by acetylcholine testing may be a marker of abnormal coronary vascular tone that prevents appropriate micro- and macrovascular dilatation with exercise.
E. Treatment and prognosis of macrovascular vasospasm
An underlying significant CAD is treated with PCI or CABG as appropriate. Beware that, sometimes, the lesion is only moderate and not hemodynamically significant, but becomes significant when vasospasm aggravates it; in those cases, revascularization is not indicated and good results are obtained with CCBs.
In the absence of severe CAD, CCBs are first-line therapy. CCBs are very effective (control of symptoms in 83% of patients),123 and spontaneous remission is also very common.116-118 Nitrates may also be used, but are less effective (31%).123 β-Blockers may exaggerate vasospasm through blocking the β2-receptor, but may be beneficial in patients with a fixed stenosis and exertional symptoms. In comparison with CCB monotherapy, the combination of CCB and statin has been shown to dramatically reduce vasospasm in one trial.124
The long-term risk of cardiac events is intermediate and is partly related to the extent of underlying CAD.4,5 In five series, patients without CAD had a lower, but still significant, risk of MI (up to 15%),5,115,118,119,123 VT (25%),5,118,123 syncope from arrhythmia (20%), and particularly cardiac arrest (2.5%)115,119 at several years of follow-up; these patients, for the most part, were not receiving CCB. In fact, vasospasm has been well documented as a cause of cardiac arrest in five patients without significant CAD; CCB prevented ergonovine-induced spasm and arrhythmias in these patients.125 The severity of vasospasm, as evidenced by the severity and extent of ST elevation, correlates with adverse events and ventricular arrhythmias regardless of the underlying CAD.115,119 Similarly, prior MI or cardiac arrest are strong predictors of future events.119
Patients receiving CCBs have a much more benign course with much less angina, much less unstable angina (6% at 3 years), and 10× lower risk of MI and cardiac death (<3% at 3 years), which suggests the great efficacy of CCBs.115,117,119,122 However, in patients who have already had a cardiac arrest, CCB therapy does not fully eliminate the risk of VF, and ICD may be justified (in one series, 15% of patients receiving ICD had appropriate shocks despite CCB therapy; in another series, > 50% had VT/VF or ICD shock despite CCB therapy).119,126 Abstinence from smoking and alcohol is also associated with a reduction of events.
Appendix 3. Microvascular endothelial dysfunction
Microvascular dysfunction has two forms, both reflective of endothelial dysfunction:
1 Microvascular spasm, which is part of the spectrum of coronary vasospasm
2 Impaired capacity to vasodilate the microcirculation and increase myocardial flow during exercise (<2.5 x increase)
It is diagnosed by either one of the following:
(1) Provocative coronary testing with acetylcholine, seeking ST-segment and chest pain response
(2) Demonstration of impaired coronary microvascular dilation and coronary flow reserve after adenosine (<2.5× increase in coronary flow, measured with a coronary flow wire).6,127–129
(3) Slow angiographic flow in the absence of CAD (“coronary slow flow phenomenon”).
LVEDP is frequently elevated and may be the consequence or the cause of impaired coronary flow. Along those lines, microvascular dysfunction may be secondary to left ventricular hypertrophy.129
The diagnosis of vasospasm or microvascular dysfunction is often made presumptively in a patient with chest pain, documented ST changes or convincing ischemia on stress testing, and no significant CAD. While the stress test is sometimes considered falsely positive (e.g., artifact), patients with convincing angina and ischemic ECG or imaging defects most likely have microvascular dysfunction, or, less frequently, macrovascular spasm. Indeed, one study has found a correlation between impaired coronary response to acetylcholine
