The study flow chart was shown in Figure 1. A total of 986 patients, 685 patients with hypertension and 301 patients with normotension were enrolled into this study. The study protocol was approved by the institutional review board at Korea University, Guro Hospital (Seoul, Korea) and written informed consent was obtained from every patient before study entry.

Coronary artery spasm was induced by intracoronary injection of ACh after diagnostic catheterization in the morning. The details of the method were reported earlier.^{10, 11} In brief, nitrates, calcium channel blockers (CCBs), β-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and other vasodilators or vasoconstrictors were withheld at least 72 h before coronary angiography. ACh was injected in incremental doses of 20 (A1), 50 (A2) and 100 (A3) μg into the left coronary artery over a 1 min period with 5 min intervals to the maximum tolerated dose under continuous monitoring of electrocardiogram (ECG) and blood pressure. Angiography was repeated after each ACh dose. After that, an intracoronary infusion with 0.2 mg nitroglycerin was given. Angiography was then performed 2 min later. If focal or diffuse significant vasoconstriction of coronary arteries was induced with any dose of ACh, the ACh infusion was stopped. End-systolic and end-diastolic images for each segment of the left coronary artery were chosen according to the corresponding points on the electrocardiographic trace (QRS onset or end of T wave) and analysed using the proper quantitative coronary angiographic system of the catheterization laboratory (BH-3000, Philips, Amsterdam, The Netherlands). The quantitative measuring variable was described as percent change from baseline on an angiogram. Two expert observers analysed the angiographic images at right anterior oblique cranial views and the evaluated QCA data were entered into the database. The percent diameter change was measured at the most severely narrowed site of the significantly spastic artery.

Brachial blood pressure was measured in triplicate in the right arm with a cuff and mercury sphygmomanometer after the patient rested in a seated position for 5 min. The average of the last two measurements was used as brachial blood pressure. Pulse pressure was calculated as the difference between systolic and diastolic pressures. Hypertension was diagnosed according to the following criteria: (1) a history of diagnosed hypertension status and treatment with medications, diet and/or exercises; (2) systolic blood pressure ⩾140 mm Hg or diastolic blood pressure ⩾90 mm Hg on at least two occasions; (3) current use of antihypertensive pharmacological therapy to control hypertension.¹² In this retrospective study, we reviewed all the hypertensive patients' in-hospital medical records about blood pressure before the temporal cessation of vasodilators; if the hypertensive patient's systolic blood pressure was ⩾140 mm Hg or diastolic blood pressure was ⩾90 mm Hg with the treatment of antihypertensive agents on calm occasions, he or she was identified as an uncontrolled blood pressure patient or else as a controlled blood pressure patient.

Hyperlipidaemia was defined as total cholesterol level ⩾200 mg per 100 ml or current treatment with lipid-lowering drugs. Current cigarette smoking was defined as active smoking within the past 12 months. Diabetes was defined as fasting blood glucose ⩾126 mg per 100 ml, or the use of hypoglycaemic agents or insulin. Peripheral arterial disease (PAD) was defined as a claudication symptom with ankle brachial indexes <0.90, and/or a claudication symptom with any angiographic finding of significant lesion in the peripheral artery and/or symptomatic carotid or subclavian arterial disease documented by image studies.

During the ACh provocation test, significant CAS was defined as a >70% decrease in the arterial luminal diameter with concurrent chest pain and/or ST-segment elevation or depression ⩾1 mm. Myocardial bridge was considered when the characteristic phasic compression of the coronary artery had a >30% decrease in diameter on the angiogram after intracoronary nitroglycerin infusion.^{10, 11}

All the statistical analyses were performed using SPSS 11.0 (SPSS Inc., Chicago, IL, USA). For continuous variables, differences between groups were evaluated by unpaired t-test or Mann–Whitney rank-sum test. For discrete variables, differences were expressed as counts and percentages and analysed with χ² (or Fisher's exact) test between groups as appropriate. Multivariate logistic regression analysis, which included baseline confounding factors, was used for assessing the independent impact of hypertension or the status of blood pressure control on ACh-induced significant CAS. A two-tailed P-value of <0.05 was considered to be statistically significant. Data were expressed as mean±standard deviation (s.d.).

The baseline clinical characteristics of normotensive and hypertensive patients are presented in Table 1. Patients with hypertension were older, had higher body mass index, systolic and diastolic blood pressure, pulse pressure and more frequently had diabetes, hyperlipidaemia and PAD, but less frequently had current smoking compared with those with normotension. Accordingly, hypertensive patients had higher rates of use aspirin, β-blockers, CCBs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and statins than did normotensive patients. Even though there was a trend towards a higher level of blood triglyceride in hypertensive patients, the blood levels of total cholesterol, low- and high-density lipoprotein cholesterol were similar between these two groups, reflecting the higher rate of use statins in hypertensive patients.

The characteristics of ACh provocation test were presented in Table 2. The reference diameters (mm) (1.84±0.49 vs 1.81±0.47, P=0.504) and diameter narrowing (%) (37.64±34.42 vs 39.39±32.75, P=0.729) of the coronary artery after ACh infusion were similar between patients with and without hypertension. Furthermore, the reference diameters of the coronary artery after nitroglycerin infusion were also similar between these two groups (mm) (2.58±0.54 vs 2.66±0.59, P=0.119). On account of the above results, the incidences of ACh-induced significant CAS did not differ significantly between patients with and without hypertension (35.8 vs 39.2%, P=0.303). During ACh provocation test, the incidences of ST-segment change, chest pain, atrioventricular block and myocardial bridge were similar between these two groups.

In patients who had significant CAS, the characteristics of CAS were also similar between patients with and without hypertension, including the maximal tolerable doses of ACh, spasm types (focal vs diffuse) and spasm vessel number (Table 3).

As shown in Figure 2, the univariate logistic analysis in the general study population showed that ageing, male, hyperlipidaemia, current smoking, PAD and myocardial bridge were risk factors for ACh-induced significant CAS. However, multivariate logistic analysis showed that besides ageing, male, PAD and myocardial bridge, hypertension was an independent predictor, too. Hypertension was negatively associated with ACh-induced CAS in multivariate logistic analysis (odds ratio: 0.70, 95% confidence interval: 0.51–0.94, P=0.020).

The baseline clinical characteristics of hypertensive patients with and without controlled blood pressure were similar, except that hypertensive patients with controlled blood pressure more frequently had hyperlipidaemia and PAD, and had higher rates of use nitrates and CCBs but a lower rate of use angiotensin II receptor blockers than those with uncontrolled blood pressure (Table 4).

The characteristics of ACh provocation test showed that although the diameter narrowing after ACh infusion were similar between these two groups, hypertensive patients with controlled blood pressure had a significantly higher incidence of significant CAS (45.2 vs 27.9%, P<0.001). More patients in the controlled blood pressure group had myocardial bridge and chest pain during the provocation test than did those in the uncontrolled blood pressure group (Table 5).

In the hypertensive patients who had significant CAS, the characteristics of CAS were also similar between patients with and without controlled blood pressure, including spasm types (focal vs diffuse) and spasm vessel number. However, there was a trend towards a higher rate of significant CAS at A2 dose in hypertensive patients with controlled blood pressure than in those without controlled blood pressure (61.7 vs 51.0%, P=0.093) (Table 6).

The multivariate logistic analysis, including the aforementioned parameters, showed that uncontrolled blood pressure was negatively associated with ACh-induced significant CAS (odds ratio: 0.56, 95% confidence interval: 0.40–0.79, P=0.001) (Figure 3).

This study has several obvious limitations. First, even though we minimized the confounding effects from the baseline biases with the multivariate logistic analysis, it is possible that some potential confounders might have crept in. However, we tested CAS in a relatively large study population, which is helpful in minimizing the confounding effects from the baseline biases. Second, angiographic evaluation of the changes in epicardial coronary diameter after the infusion of ACh as used in this study mainly reflects the functional status of coronary conduit vessels but not that for coronary microcirculation because hypertension affects not only the coronary conduit artery but also microcirculations.^{23, 24} Thus, further studies measuring not only the coronary conduit artery spasm but also the coronary microvascular spasm in hypertensive patients are needed. Third, although we had carefully made the diagnosis of hypertension and thoroughly collected the information in detail about blood pressure for every patient, we did not collect the patient's blood pressure during the provocation test. However, some patients' blood pressure level might have obviously changed after they stopped their antihypertensive treatment. Fortunately, no patient in this study was found to have cardiovascular complications because of the provocation test and the temporal medication cessation.