Abstract
Background:
Although guidelines recommend intracoronary acetylcholine (ACh) and ergonovine (ER) provocation testing for diagnosis of vasospastic angina, the feasibility and safety of sequential (combined) use of both pharmacological agents during the same catheterization session remain unclear.
Objectives:
In this study, we investigated the feasibility and safety of sequential intracoronary ACh and ER administration for coronary spasm provocation testing.
Methods:
The study included 235 patients who showed positive results on ACh and ER provocation testing. Initial intracoronary ACh administration was followed by ER administration for left coronary artery (LCA) spasm provocation testing. Subsequently, the right coronary artery (RCA) was subjected to sequential ACh and ER administration for provocation testing. The primary outcome of the study was the safety of sequential intracoronary ACh and ER provocation testing, which was assessed based on a composite of all-cause death, sustained ventricular tachycardia and fibrillation, and cardiogenic shock.
Results:
Even in patients with negative results on sequential intracoronary ACh and ER provocation testing in the LCA and only ACh administration into the RCA, additional administration of ER into the RCA showed a positive provocation test result in 33 of 235 (14.0%) patients; three (1.3%) patients developed adverse effects (cardiogenic shock occurred in all cases) during LCA provocation testing. We observed no deaths attributable to spasm provocation testing.
Conclusion:
Sequential administration of intracoronary ACh and ER was associated with a relatively low major complication rate and may be safe and potentially useful for diagnosis of vasospastic angina.
Plain language summary
Coronary spasm represents a subtype of ischemic heart disease, potentially leading to heart attack. Although guidelines recommend intracoronary administration of different pharmacological agents, acetylcholine (ACh) and ergonovine (ER), for coronary spasm provocation testing, the feasibility and safety of sequential (combined) use of both drugs are unclear. In the present study, we showed that sequential administration of intracoronary ACh and ER was associated with a relatively low major complication rate and may be safe and potentially useful for diagnosis of coronary vasospasm.
Introduction
Epicardial coronary artery disease represents a subtype of ischemic heart disease, which can be documented on coronary computed tomography and invasive angiography. Ischemic heart disease may exist even in patients in whom significant epicardial lesions are not detected. Vasospastic angina (VSA), which is an important subset of ischemic heart disease, negatively affects a patient’s quality of life and is associated with acute myocardial infarction and cardiac death.1,2 However, VSA is often underdiagnosed globally. 3 Guidelines recommend invasive evaluation with cardiac catheterization such as intracoronary provocation testing using acetylcholine (ACh) and ergonovine (ER) administration for diagnosis of VSA to improve patient outcomes in cases in which noninvasive testing remains inconclusive.1,4 Both ACh and ER are useful and safe for intracoronary provocation testing, although these pharmacological agents behave differently in vivo. 5 ACh actions are mediated via cholinergic muscarinic receptors, whereas ER produces its effects via serotonergic activity. 5 Therefore, the mechanism underlying the role of ACh and ER in intracoronary provocation testing for diagnosis of VSA differs. Only a few studies have reported diagnostic methods and results of provocation testing using intracoronary ACh and ER administration during the same cardiac catheterization session,6–8 and limited data are available. In this study, we investigated the safety and potential usefulness of coronary spasm provocation testing using novel sequential intracoronary ACh and ER administration for diagnosis of VSA.
Methods
Study population
This single-center, retrospective, observational study was performed at the Fukuyama Cardiovascular Hospital in Japan. As per our hospital protocol, coronary spasm provocation testing is performed using sequential intracoronary ACh and ER administration (Figure 1). Between July 2016 and February 2020, 638 patients underwent intracoronary coronary spasm testing, of whom 388 with negative provocation test results were excluded from the study. Of the remaining 250 patients, 15 with deviations in the provocation protocol were also excluded. Finally, we investigated 235 patients who underwent intracoronary ACh and ER provocation testing and showed positive results. The study was performed in accordance with the Declaration of Helsinki.
Protocol of sequential intracoronary ACh and ER spasm provocation testing.
Intracoronary spasm provocation testing
Administration of all vasodilators, such as calcium channel blockers and long-acting nitrates (except short-acting sublingual nitroglycerin), was discontinued at least 24 h before intracoronary spasm provocation testing. The femoral artery and vein were predominantly used as approach sites. A temporary pacing electrode was inserted into the right ventricle after control angiography, except in patients with permanent pacemaker implantation. Initially, intracoronary ACh (50 μg) was injected into the left coronary artery (LCA), followed by 100 μg of intracoronary ACh (Figure 1). After the ACh test, intracoronary ER (40 μg) was injected into the LCA. Thereafter, intracoronary ACh (50 μg) was injected into the right coronary artery (RCA), followed by intracoronary ER (40 μg). Intracoronary ACh and ER were injected into the coronary arteries over 20–30 s, and coronary angiography was performed 1 min after each agent was administered. ACh and ER were administered at 3-min intervals. Intracoronary isosorbide dinitrate was administered after a positive result was observed on spasm provocation testing and/or intracoronary ER injection (40 μg) into the RCA, and coronary angiography was performed (Figure 1). A positive result on spasm provocation testing was defined as angiographic coronary vasospasm, which presented as total or subtotal occlusion secondary to either ACh or ER injection, accompanied by chest pain and/or ischemic electrocardiographic changes. 1 VSA was defined as a positive result on spasm provocation testing.1,9–11
Outcomes and statistical analysis
The primary outcome of this study was safety of sequential intracoronary ACh and ER provocation testing. The safety endpoint was a composite of all-cause death, sustained ventricular tachycardia and fibrillation that necessitated electrical cardioversion, and cardiogenic shock within 24 h after provocation testing. 12 The timing of a positive spasm induced by provocation testing was also recorded. Descriptive statistical analysis was performed using the SAS software (version 9.3, SAS Institute, Cary, NC, USA). Continuous and categorical variables are expressed as mean ± standard deviation and numbers (percentages), respectively. p Value <0.05 was considered statistically significant.
Results
Table 1 summarizes patient and procedural characteristics. Indications for invasive diagnostic procedures included diagnosis of VSA (n = 125) and myocardial infarction with non-obstructive coronary arteries (n = 49), coronary endothelial function assessment at follow-up angiography after percutaneous coronary intervention (n = 57), and miscellaneous factors (n = 4) (Table 1). All patients eventually showed positive results on spasm provocation testing performed per the aforementioned protocol (Figure 1). Figure 2 illustrates the timing of the positive provocation test result observed after each dose of ACh and ER. Even in patients who showed a negative result following ACh (50 and 100 μg) and ER (40 μg) administration into the LCA and ACh (50 μg) administration into the RCA, administration of ER (40 μg) into the RCA led to a positive provocation test result (Figure 2). Adverse events occurred in three (1.3%) patients; all three patients developed cardiogenic shock accompanied by significant coronary vasospasm during LCA provocation testing (Table 2). These patients received intracoronary nitrates and intravenous norepinephrine and recovered successfully. No patient died secondary to spasm provocation testing.
Patients and procedural characteristics.
CAG, coronary angiography; FU, follow-up; MINOCA, myocardial infarction with non-obstructive coronary arteries; PCI, percutaneous coronary intervention; VSA, vasospastic angina.
Rates of positive provocation test results with each dose of ACh and ER.
Details in patients with adverse events during spasm provocation testing.
ACh, acetylcholine; CS, cardiogenic shock; ER, ergonovine; IC, intracoronary; ISDN, isosorbide dinitrate; IV, intravenous; LCA, left coronary artery.
Discussion
The present study highlights the feasibility of sequential intracoronary ACh and ER provocation testing with an adverse event rate of approximately 1.0%. ACh provocation testing followed by ER administration into each coronary artery successfully identified patients with VSA in whom diagnosis of VSA may have been missed if they were to undergo only intracoronary ACh provocation testing, which underscores the potential usefulness of sequential (combined) ACh and ER provocation testing for VSA diagnosis.
VSA negatively affects patients’ quality of life and may precipitate acute myocardial infarction and cardiac death.1,2 Specific therapeutic interventions improve symptoms and outcomes in patients with VSA13,14; therefore, accurate diagnosis is clinically important. The American and European guidelines recommend intracoronary ACh provocation testing for diagnosis of VSA3,15; whereas Japanese guidelines recommend intracoronary ACh and ER provocation testing. 1 ACh is a vasoactive agent, and its vasospastic effect on coronary arteries is mediated via cholinergic receptors on vascular smooth muscle cells. 16 The action of ACh on intact endothelial cells produces vasodilatation via nitric oxide release; however, endothelial injury causes insufficient nitric oxide release to counteract the stimulated muscarinic receptors, which results in vasoconstriction. ER is another vasoactive substance that mainly acts on vascular smooth cells via serotonergic receptors to produce vasoconstriction. 16 Although the mechanism underlying ER-induced coronary vasospasm remains unclear, ER-induced hypercontraction of smooth muscle may be associated with coronary artery atherosclerosis. 17 An experimental study in dogs reported that endothelial denudation and a high-cholesterol diet led to local atherosclerotic changes with smooth muscle hypersensitivity to ER. 17 In Japan, intracoronary ACh provocation testing is increasingly being performed across hospitals, whereas ER provocation testing is declining. 18 Studies have reported differences between the effects of intracoronary ACh and ER provocation testing on VSA diagnosis; ACh testing showed higher sensitivity and was associated with a higher risk of adverse events. 19 Considering the differences in the pharmacological behavior of these agents in vivo, 5 it is reasonable to conclude that combined use of ACh and ER for intracoronary spasm provocation testing may show better diagnostic ability.
Currently, only a few studies have reported the safety and potential usefulness of intracoronary ACh and ER provocation testing during the same cardiac catheterization session. Sueda et al. 6 observed that approximately 10% of patients who undergo intracoronary spasm provocation testing with sequential ACh and ER administration showed positive results only after ER injection and not after ACh administration. Another study has reported that among 20 patients with positive provocation test results, intracoronary ACh did not produce coronary vasospasm in five patients; however, intracoronary ER provocation led to significant vasospasm in four of these five patients. 5 Therefore, compared with exclusive ACh or ER provocation testing, the combined use of intracoronary ACh and ER may be associated with better diagnostic ability for VSA and may particularly show higher sensitivity. In this study, VSA would remain undiagnosed in 33 of 235 (14.0%) patients if intracoronary ER (40 μg) provocation testing of the RCA had not been performed. Safety may be an important consideration during sequential intracoronary provocation testing. Sueda 7 observed that the incidence of severe adverse events, including ventricular arrhythmia and cardiogenic shock was 0.9% in patients who underwent sequential ACh and ER administration for provocation testing, which is consistent with our results. Considering that the major complication rate during intracoronary ACh provocation testing may be relatively higher in Asian than in Western populations (2.3% versus 0.0%) (as reported by a recent systematic review), 20 the incidence of severe adverse events observed in this study (1.3%) may be acceptable. Therefore, the results of the present study might provide corroborative evidence to support the usefulness of intracoronary provocation testing using sequential ACh and ER for diagnosis of VSA.
Study limitations
Following are the limitations of this study: (a) The retrospective design of this single-center study is a drawback. Owing to the moderate sample size, the number of major complications was low in this study. Sample size calculations were not performed because of the retrospective nature of the study. (b) The relatively high rate of previous myocardial infarction may have affected the study results.21,22 (c) Owing to the lack of a negative control, further analysis of adverse events was not performed. Although complications may occur during intracoronary provocation testing in patients with positive test results, 23 such adverse events may be observed even in patients with negative test results. Therefore, further investigations are warranted to confirm the safety of sequential spasm provocation testing in all patients who undergo such testing regardless of test results. (d) Non-administration of ACh (20 μg) into the LCA and RCA may not necessarily be recommended by domestic guidelines. 1 Intracoronary ACh and ER testing protocols vary widely across hospitals and countries and require standardization.19,20 (e) Although overall most patients had chest symptoms at baseline in this study, the indication for sequential provocation testing included VSA diagnosis and endothelial function assessment. Indeed, nine (3.8%) patients did not have any chest symptoms. Considering that intracoronary ACh evaluation differs between evaluation of the presence of coronary endothelial dysfunction and coronary vasospasm, 24 our study results should be interpreted with caution. (f) The potential role of sequential provocation testing for diagnosis of coronary microvascular spasms was not addressed in this study.
Conclusion
Sequential administration of intracoronary ACh and ER during the same catheterization session may be safe and potentially useful, with a relatively low major complication rate. Further studies are warranted to confirm the potential usefulness of the combined use of different pharmacological agents for intracoronary provocation testing for accurate diagnosis of VSA.
