CLINICAL STUDY: MYOCARDIAL ISCHEMIA
Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina
Hongtao Sun, MD*,
Masahiro Mohri, MD, PhD*,*,
Hiroaki Shimokawa, MD, PhD*,
Makoto Usui, MD*,
Lemmy Urakami, MD* and
Akira Takeshita, MD, PhD*
* Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
* Reprint requests and correspondence:Dr. Masahiro Mohri, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
mmohri{at}med.kyushu-u.ac.jp
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Abstract
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OBJECTIVES: We aimed to test the hypothesis that coronary microvascular spasm (MVS) alone causes myocardial ischemia in patients with angina attributable to epicardial coronary spasm, and to determine whether there is a difference in clinical characteristics between those with and without microvascular spasm.
BACKGROUND: Patients with "vasospastic angina" have epicardial coronary artery spasm, but it is unknown whether coronary microvessel disease also contributes to the occurrence of angina in these patients.
METHODS: We studied 55 consecutive patients with angina in whom epicardial coronary spasm was provoked by intracoronary acetylcholine (ACH).
RESULTS: In 14 patients (25.5%, Group 1), submaximal dose of ACH induced myocardial ischemia (chest pain, ischemic electrocardiogram changes, lactate production) without large epicardial spasm, suggesting the occurrence of coronary microvascular spasm. By contrast, the remaining 41 patients (Group 2) had evidence of myocardial ischemia only when epicardial spasm was angiographically demonstrated. The Group 1 patients were predominantly women (p < 0.05) and had a history of prolonged (>30 min) chest pain (p < 0.05), whereas the Group 2 patients were more likely men and smokers (p < 0.01).
CONCLUSIONS: Myocardial ischemia most probably due to coronary MVS was demonstrated in a sizable portion of patients with epicardial vasospasm, preferentially in women having both typical and prolonged anginal pain. The result suggests that coronary microvascular disease may also contribute to angina in patients with "vasospastic angina."
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Abbreviations and Acronyms
| | ISDN | | ACH | | acetylcholine | | ECG | | electrocardiogram | | ISDN | | isosorbide dinitrate | | MVS | | microvascular spasm |
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Patients with angina caused by epicardial coronary artery spasm are diagnosed as having "vasospastic angina" or "variant angina" (1–3). However, whether the functional abnormality of coronary microvessels also contributes to the occurrence of myocardial ischemia has never been examined in these patients.
It may be of clinical importance to determine the presence or absence of coronary microvessel disease or spasm in patients given a diagnosis of vasospastic angina. First, a generalized smooth-muscle hypercontraction has been supposed to exist in those with vasospastic angina, as evidenced by relatively high prevalence of migraine and/or Raynaud’s disease (4,5). It may be that constrictor response also is exaggerated in the coronary microcirculation. In this context, we and others have shown that coronary microvascular spasm (MVS) could cause myocardial ischemia even in the absence of epicardial coronary stenosis or obstruction in humans (6,7). Furthermore, calcium channel blockers are widely used for patients with epicardial spasm (8), but they are reportedly of limited efficacy in patients with angina of microvascular origin (9,10).
Thus, we aimed to test the hypothesis that coronary MVS alone causes myocardial ischemia in patients with documented epicardial coronary artery spasm and to determine whether there is a difference in clinical characteristics between those with and without microvascular spasm.
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Methods
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Patients.
We studied consecutive patients with angina-like chest pain who underwent coronary arteriography. Inclusion criteria included no fixed stenosis (>50%) in any major epicardial coronary arteries or branches at baseline arteriography. Patients with significant coronary artery disease, severe valvular heart disease, idiopathic dilated or hypertrophic cardiomyopathy or chronic renal failure were prospectively excluded. The study protocol was approved by the Institutional Ethical Committee on Human Research and written informed consent was obtained from each patient before the study.
Study protocol
Cardiac catheterization was performed with patients in the fasting state after 5 mg oral diazepam. No patient had been on long-acting calcium channel blockers, and all cardiovascular medications, including calcium channel blockers, were discontinued at least 24 h before the study. Sublingual nitroglycerin was used when necessary. Coronary arteriography was done by the femoral approach. A 6F pacing catheter was placed in the right ventricle to prevent bradycardia during acetylcholine (ACH) infusion. Another 6F catheter was put in the coronary sinus vein to sample blood for the measurement of lactate concentration.
Our ACH testing protocol for provocation of coronary spasm was reported previously (7,11). Briefly, graded doses of ACH (10, 30 and 100 µg) were infused over 30 s into the left coronary artery via a 6F Judkins catheter while systemic arterial pressure and 12-lead electrocardiogram (ECG) were continuously monitored. One minute after each dose of ACH was given, paired samples of 2 ml of blood were collected from the coronary artery and coronary sinus vein. Biplane coronary arteriograms then were taken to assess the lumen diameter of large epicardial coronary segments. When chest pain, ECG changes or epicardial spasm did not occur, we gave the next dose of ACH. When epicardial coronary spasm was provoked at any dose of ACH, 1 to 2 mg isosorbide dinitrate (ISDN) was administered in the left coronary artery and coronary arteriograms were taken.
We found that in a subset of patients undergoing ACH testing, chest pain, ischemic ECG changes or both developed without angiographically demonstrable epicardial spasm. Under such circumstances, we did not give nitrates and carefully observed the patient by continuously monitoring arterial blood pressure and 12-lead ECG and by taking coronary arteriograms at intervals of 1 to 2 min to confirm the absence of epicardial spasm. In most cases, chest pain and ECG changes subsided spontaneously within minutes, and we then moved on to the next dose of ACH. When angina or ECG changes lasted for >5 min even in the absence of epicardial spasm, ISDN was given in the left coronary artery; these patients were diagnosed as having microvascular angina and excluded from the analysis because of the absence of angiographically demonstrable epicardial spasm.
Measurements
Quantitative coronary arteriography was performed with a Siemens biplane cineangiographic system (Bicor and Hicor, Siemens, Erlangen, Germany). Nonionic contrast material (Iomeprol, Eisai, Tokyo, Japan) was used. The accuracy and precision of our system were validated with precision-drilled models (12,13). Measurements were done three times at 10 segments of the left coronary artery (left main trunk; proximal, middle and distal segments of the left anterior descending artery; first and second diagonal branches; proximal and distal segments of the left circumflex artery; obtuse marginal branch and posterolateral branch), and the segment that showed the largest constrictor response was used for analysis. We defined epicardial coronary artery spasm as diameter reduction of >75% as compared with that after administration of ISDN (7,11,14).
We considered that myocardial ischemia was of microvascular origin when ACH induced angina, ischemic ECG changes or both in association with myocardial lactate production (coronary sinus concentration > arterial concentration) but no epicardial coronary spasm (7). Demonstration of lactate production was a prerequisite for the diagnosis of myocardial ischemia in this setting.
The standard 12-lead ECG was continuously monitored throughout the study and recorded at 25 mm/s at baseline and after the administration of each dose of ACH and isosorbide dinitrate. Electrocardiogram changes were considered ischemic when a transient ST segment depression or elevation of >0.1 mV at 80 ms after the J point was noted in at least two leads. Care was taken not to record ECG shortly after injection of contrast material. Lactate concentration of sampled blood was immediately measured with a lactate analyzer (2300 Stat Plus, YSI, Yellow Spring, Ohio). Myocardial lactate extraction ratio was calculated as ratio of coronary arteriovenous difference in lactate concentration to arterial concentration.
Statistics
Data are presented as mean ± SD. Unpaired t tests and chi-square tests were used for comparison of continuous and discrete variables between groups, respectively. Comparison of changes in lumen diameter and lactate metabolism between groups was by two-way analysis of variance. A p value of <0.05 was considered statistically significant.
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Results
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Constrictor responses of epicardial coronary artery and myocardial lactate metabolism.
We studied 55 consecutive patients in whom intracoronary ACH provoked spasm at one or more of epicardial coronary arterial segments. The "maximal dose" of ACH, defined as the dose that induced significant epicardial spasm, was 10 µg in 2 patients, 30 µg in 13 and 100 µg in 40. We found that 14 (25.5%, Group 1) of the 55 patients had evidence of myocardial ischemia (chest pain and/or ECG changes, and lactate production) at the submaximal dose of ACH without epicardial coronary spasm (Fig. 1). By contrast, the remaining 41 patients (Group 2) developed chest pain, ischemic ECG change or lactate production only at the maximal dose of ACH associated with epicardial spasm.
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Figure 1 Representative coronary arteriograms and electrocardiograms (ECGs) of a 58-year-old female patient having both microvascular and epicardial spasm. Baseline coronary arteriogram of the left coronary artery and ECG were normal. Intracoronary acetylcholine (ACH) 30 µg induced chest pain, ST depression (V4 to V6) and lactate production, but no epicardial spasm. These ischemic symptoms and signs spontaneously subsided in approximately 4 min. Acetylcholine 100 µg provoked a high-degree hyperconstriction (spasm) at the middle portion of the left anterior descending artery (arrowhead), associated with chest pain and ST elevation (I, II, aVL, V3 to V6). Isosorbide dinitrate (ISDN) relieved angina and ischemic ECG changes, and coronary arteriogram showed normal coronary artery.
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Figure 2 summarizes changes in myocardial lactate metabolism and diameter of epicardial coronary artery. Myocardial lactate production, direct evidence of myocardial ischemia, was demonstrated both at the submaximal and maximal doses of ACH in Group 1, whereas it was demonstrated only at the maximal dose of ACH in Group 2. It should be noted that epicardial coronary constrictor responses were virtually identical between the two groups (Fig. 2B).
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Figure 2 Myocardial lactate extraction ratio (A) and coronary lumen diameter assessed by quantitative arteriography (B) at baseline (BSL), at submaximal and maximal doses of acetylcholine (ACH) and after isosorbide dinitrate (ISDN). Lactate extraction ratio was significantly different between groups (p < 0.01 by two-way analysis of variance) at the submaximal dose (p < 0.01 by ad-hoc t test). Lumen diameter is expressed as percentage of that after ISDN administration. Closed circles = Group 1 patients with evidence of microvascular spasm (MVS); open squares = Group 2 patients without evidence of MVS.
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Clinical characteristics
Age was similar between the groups with and without MVS (Table 1). There was a predominance of women in Group 1 (p < 0.05) and current smoking was more prevalent in Group 2 (66% vs. 21%, p < 0.01). Rest angina was common in both groups. However, eight of the 14 patients in Group 1 (57%) had experienced chest pain lasting for 30 min or longer before the study, whereas 10 of the 41 in Group 2 (24%) had had such symptoms (p < 0.05).
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Discussion
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The novel finding of the present study is that myocardial ischemia, most probably due to coronary microvascular spasm, was demonstrated in approximately one-fourth of the studied patients with angina due to angiographically documented epicardial spasm. Thus, the present study has for the first time suggested that coronary microvessel disease might also contribute to angina in patients with "vasospastic angina."
Myocardial ischemia of microvascular origin.
In a subset of our patients (Group 1), the submaximal dose of intracoronary ACH induced myocardial ischemia, as evidenced by myocardial lactate production without epicardial spasm. Importantly, the degree of epicardial coronary constriction in these patients was comparable to that in Group 2 patients. These results suggest that coronary MVS may be the most likely cause for the occurrence of myocardial ischemia in Group 1 (7). It should be noted, however, that MVS was not demonstrated in our patients. In this context, "microvascular spasm" has been hypothetical and should be interpreted as such. Difference between nonspecific vasoconstriction and pathological hyperconstriction (spasm) may lie in the magnitude of constriction and the presence or absence of evidence of myocardial ischemia. In the present study, we demonstrated myocardial lactate production and therefore speculate that these patients most likely had severe spasm at the level of coronary microcirculation.
We do not preclude the possibility that microvascular constriction would have coexisted in Group 2 patients at the maximal dosage of acetylcholine. Therefore, our results should be interpreted as evidence suggesting that there is a subgroup (Group 1) of patients with vasospastic angina in whom constrictor response to vasoactive substances is augmented to a greater degree in coronary microvessels than in epicardial segments. Such hypersensitivity at the level of coronary microvessels would cause rest angina of microvascular origin.
The patients with evidence of both microvascular and epicardial spasm were characterized by predominance of women and a history of relatively long-lasting chest symptoms. It has been reported that cardiac syndrome X or microvascular angina affects postmenopausal women more frequently (7,15–18). Furthermore, Kaski et al. (15) also reported that chest pain lasting for >30 min was not uncommon in cardiac syndrome X. These lines of evidence suggest that coronary MVS may actually contribute to angina in our patients. By contrast, those without evidence of such microvascular abnormality were more likely men and smokers, which accords with previous reports demonstrating that smoking is a risk factor for coronary artery spasm (14,19).
Study limitations
It is known that angina due to epicardial coronary artery spasm is relatively more common in the Japanese than in the Caucasian population (20). Whether the finding of the present study can safely be extrapolated to Caucasian patients remains to be seen. Second, in this prospective analysis we had analyzed only clinical background such as associated coronary risk factors, and more detailed characterization of patients with microvascular dysfunction needs to be determined in future studies.
Clinical implication and conclusions
Coronary MVS and resultant myocardial ischemia were not rare in patients with angina caused by epicardial coronary artery spasm. From a therapeutic point of view, calcium channel blockers are extremely effective for epicardial spasm, but they are reportedly of limited efficacy in patients with microvascular angina (9,10). Physicians should be aware of the possibility that coronary MVS may also contribute to chest symptoms in those given a diagnosis of vasospastic angina and carefully assess the presence or absence of coronary microvessel disease for the appropriate management of these patients.
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Footnotes
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Supported by grants from the Japanese Ministry of Science, Education, and Culture, Tokyo, Japan, and supported in part by a grant from the Japan Cardiovascular Research Foundation, Osaka, Japan.
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Abstract
Methods