Abstract: Objectives. Both diabetes mellitus (DM) and coronary artery spasm (CAS) are associated with endothelial dysfunction. Thus, a higher incidence of CAS is expected in diabetic patients (pts). We evaluated the impacts of DM and the status of blood sugar control on CAS with intracoronary acetylcholine (ACh) provocation test. Methods. A total of 986 pts (106 DM vs 880 non-DM pts) with angiographically normal coronary artery received ACh provocation test. Significant CAS was defined as a transient >90% luminal narrowing with concurrent chest pain and/or ST-segment changes. HbA1c <7% was considered a controlled blood sugar level. Results. The incidence of CAS was similar between patients with versus without DM (30.2% vs 23.5%; P=.13). Multivariable analysis showed that DM was not an independent risk factor for significant CAS (odds ratio [OR], 1.29; 95% confidence interval [CI], 0.81-2.07; P=.28). The angiographic characteristics of CAS were also similar between these two groups. Subgroup analysis regarding the impact of the status of blood sugar control on CAS showed that the incidence of CAS was similar between diabetic pts with versus without controlled blood sugar levels (35.4% vs 25.9%; P=.29). Multivariable analysis showed that the uncontrolled blood sugar level was not an independent risk factor for CAS (OR, 0.79; 95% CI, 0.29-2.13; P=.64). Conclusions. Despite the expected endothelial dysfunction, DM and the status of blood sugar control are not associated with CAS, suggesting the existence of different mechanisms for CAS and coronary artery disease.
J INVASIVE CARDIOL 2014;26(6):234-239
Key words: endothelial dysfunction, blood sugar control
Diabetes mellitus (DM) markedly increases the risk of all forms of cardiovascular disease including stroke, myocardial infarction, and heart failure.1,2 Substantial clinical and experimental evidences have shown that DM is associated with significant endothelial dysfunction, which represents a major pathogenic link between DM and coronary artery disease (CAD). Endothelial dysfunction plays a key role in the pathogenesis of microangiopathy and macroangiopathy in DM.3,4
Coronary artery spasm (CAS) plays an important role in the pathogenesis of vasospastic angina and acute coronary syndrome. Previous studies have shown that patients with CAS have a disturbance in the endothelial function of the coronary arteries.5-7 Thus, a higher incidence of significant CAS is expected in patients with DM. However, few studies designed to analyze the multiple risk factors for CAS have briefly evaluated the impact of DM on CAS, and no previous study to date has analyzed the impacts of the status of blood sugar control on CAS.8-11 Therefore, in the present study, we evaluated the impact of DM and the status of blood sugar control on CAS using intracoronary acetylcholine (ACh) provocation test.
Study population. A total of 4872 patients underwent coronary angiography from March 2004 to February 2007 at the Cardiovascular Center of Korea University Guro Hospital in Seoul, Korea. Among them, 1201 patients who had chest pain without significant coronary lesion (luminal narrowing <50%) underwent coronary angiography with intracoronary ACh provocation test. Patients were excluded if they had one of the following conditions: an angiographically visible atherosclerotic lesion, previous acute coronary syndrome, previous coronary artery bypass graft, previous percutaneous coronary intervention, advanced heart failure (New York Heart Association functional class III or IV), underlying hypertrophic cardiomyopathy, previous cerebrovascular disease, or any other serious medical conditions such as an increased creatinine level ≥2 mg/dL. Finally, a total of 986 patients were enrolled into the present study, including 106 patients with diabetes mellitus and 880 patients without diabetes mellitus.
During hospitalization, all patients received routine blood biochemistry examination including blood sugar determination, and the blood levels of hemoglobin A1c (HbA1c) were determined in all diabetic patients. The study protocol was approved by the institutional review board at Korea University, Guro Hospital and written informed consent was obtained from every patient before the study entry.
Acetylcholine provocation test. CAS was induced by intracoronary injection of ACh after diagnostic catheterization in the morning. The details of the method were previously reported.12,13 In brief, nitrates, calcium-channel blockers (CCBs), beta-blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), and other vasodilators or vasoconstrictors were withheld at least 72 hours 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-minute period, with 5-minute 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 (NTG) was given. Then, angiography was performed 2 minutes 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 left coronary artery were chosen according to the corresponding points on the electrocardiographic trace (QRS onset or end of T-wave) and analyzed using the proper quantitative coronary angiographic system of the catheterization laboratory (BH-3000; Philips). The quantitative measuring variable was described as percent change from baseline on angiogram. Two expert observers analyzed the angiographic images at right anterior oblique (RAO) 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.
Study definitions. DM was diagnosed according to one of the following criteria: (1) a history of diagnosed DM and treatment with medications, diet, and/or exercise; (2) the fasting blood glucose ≥126 mg/dL for at least 2 times; or (3) current use of hypoglycemic therapy to control DM. If the diabetic patient’s blood HbA1c level was <7%, he or she was identified as a patient with controlled blood sugar level, otherwise, as a patient with uncontrolled blood sugar level.
Hypertension: systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on at least 2 occasions, or use of antihypertensive pharmacological therapy to control blood pressure. Hyperlipidemia: total cholesterol level ≥200 mg/dL or current treatment with lipid-lowering drugs for controlling increased blood lipid level. Current cigarette smoking; active smoking within the past 12 months. Peripheral arterial disease (PAD): a claudication symptom with ankle brachial index (ABI) <0.90, and/or a claudication symptom with any angiographic finding of significant lesion (>70% stenosis) in the peripheral artery, and/or symptomatic carotid or subclavian arterial disease documented by image studies.
As shown in Figure 1, during the ACh provocation test, significant CAS was defined as a transient >90% decrease in 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 coronary artery had a >30% decrease in diameter on angiogram after intracoronary NTG infusion.12,13
Statistical analysis. All statistical analyses were performed using SPSS 11.0 (SPSS, Inc). 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 were analyzed with Chi-square (or Fisher’s exact) test between groups as appropriate. In order to exclude the confounding effects from the baseline clinical biases, multivariable logistic regression models were used to figure out the impact of DM and the status of blood sugar control on ACh-induced CAS. A 2-tailed P-value <.05 was considered to be statistically significant. Data were expressed as mean ± standard deviation.
Impact of diabetes on coronary artery spasm. The baseline characteristics stratified by diabetic and non-diabetic groups are shown in Table 1. Diabetic patients were older, had higher body mass index, and had more hypertension and hyperlipidemia than non-diabetic patients. Diabetic patients had higher systolic pressure and pulse pressure, and received more aspirin, cilostazol, ACEI, ARB, nitrates and statin treatments than non-diabetic patients.
As shown in Table 2, the characteristics of ACh provocation test were similar between patients with versus without DM, including the incidences of ACh-induced significant CAS, ST-segment change, chest pain, atrioventricular block, and myocardial bridge.
In patients who had significant CAS, the characteristics of CAS were also similar between patients with and without diabetes, including the maximal tolerable doses of ACh, spasm types (focal vs diffuse) and spasm vessel number (Table 3).
Multivariable logistic regression analysis of DM, age, gender, hypertension, hyperlipidemia, peripheral arterial disease, smoking, family history of CAD, and myocardial bridge showed that DM was not an independent risk factor for significant CAS (odds ratio [OR], 1.29; 95% confidence interval [CI], 0.81-2.07; P=.28) (Figure 2).
Impact of the status of blood sugar control on coronary artery spasm in diabetic patients. The subgroup analyses in diabetic patients with controlled versus uncontrolled blood sugar levels are listed in Table 4. The baseline characteristics were similar between these two groups except that diabetic patients with uncontrolled blood sugar levels were more likely to be male, and had higher blood levels of total cholesterol and triglyceride than those with controlled blood sugar levels. In addition, patients without controlled blood sugar levels were older, although not statistically significant and less likely to be current smokers. More patients with uncontrolled blood sugar levels received insulin and diet control, and fewer patients used oral hypoglycemic agents than those with controlled blood sugar. However it was not statistically significant.
The characteristics of ACh provocation test were similar between patients with controlled versus uncontrolled blood sugar levels, including the incidences of ACh-induced significant CAS, ST-segment change, atrioventricular block, and myocardial bridge (Table 5).
In the diabetic patients who had significant CAS, the characteristics of CAS were also similar between patients with controlled and uncontrolled blood sugar levels, including the maximal tolerable doses of ACh, spasm types (focal vs diffuse), and spasm vessel number (Table 6).
As shown in Figure 3, multivariable logistic analysis including status of blood sugar control, age, gender, hypertension, hyperlipidemia, peripheral arterial disease, smoking, family history of CAD, and myocardial bridge also showed that the uncontrolled blood sugar level was not an independent risk factor for significant CAS (OR, 0.79; 95% CI, 0.29-2.13; P=.64).
DM is associated with an increased risk of cardiovascular disease, even in the presence of intensive blood sugar control.14 Numerous clinical and experimental studies have demonstrated that endothelial dysfunction is closely associated with DM, and plays an important role in the progression of atherosclerosis in diabetic patients.3,4
There is increasing evidence suggesting that CAS is also closely associated with endothelial dysfunction.5-7,15 Kugiyama et al6 reported that there was a deficiency in endothelial nitric oxide (NO) activity in spasm arteries, which led to the supersensitivity of the coronary artery to the vasoconstrictor effect of ACh in patients with CAS. Similarly, another study from Kugiyama et al7 indicated that flow-dependent coronary dilation was impaired in spasm arteries, partly due to a deficiency in endothelial NO bioactivity. Recently, Yasue et al15 tested whether fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) could suppress CAS based on the hypothesis that CAS was associated with endothelial dysfunction. Their results showed that the addition of fluvastatin 30 mg/day to the conventional CCB therapy for 6 months significantly reduced the number of patients with ACh-induced CAS as compared with the conventional CCB therapy. Therefore, in view of the above studies,6,7,15 it seems reasonable to conclude that CAS is associated with coronary endothelial dysfunction.
In this scenario, we hypothesized that patients with DM would have a higher incidence of CAS because endothelial dysfunction is the common link between these two diseases. However, contrary to our initial expectation, the present study showed that the incidence of CAS did not differ significantly between diabetic patients and non-diabetic patients in spite of the existence of endothelial dysfunction in diabetic patients. In the present study, we performed a subgroup analysis in diabetic patients to determine the impact of the status of blood sugar control on the incidence of CAS because there is evidence suggesting that hyperglycemia is a major causal factor in the development of endothelial dysfunction in patients with DM, and effective blood sugar control can effectively improve endothelial function in diabetic patients.16-19 To the best of our knowledge, the impact of status of blood sugar control on CAS has not been reported so far. Our results showed that the incidence of CAS was similar between the diabetic patients with controlled versus uncontrolled blood sugar levels. Multivariable analysis suggested that the uncontrolled blood sugar level was not an independent risk factor for CAS. Thus, collectively, our results suggested that despite the expected endothelial dysfunction in patients with DM, neither DM itself nor the status of blood sugar control were associated with ACh-induced CAS.
Several studies have briefly evaluated the impact of DM on the incidences of CAS. Sugiishi et al11 showed that smoking was the major risk factor for CAS, while other cardiovascular risk factors such as dyslipidemia and DM were not associated with CAS. Kido et al20 also reported that smoking and family history in females were the most important risk factors for CAS, whereas other cardiovascular risk factors such as hypertension, hyperlipidemia, and DM did not show significant correlations with ACh-induced significant CAS. In addition, Xiang et al9 reported that there was no significant association between CAS and sex, age, hypertension and DM, but smoking and hyperlipidemia were independent risk factors for ACh-induced significant CAS. Therefore, together with our study, all of the above studies9,11,20 suggested that DM was not an independent risk factor for CAS even though it is a well established cardiovascular risk factor.
We speculate the reasons for the present results as follows. First, previous studies have suggested that the pathogenesis of coronary vasospasm in patients without significant coronary atherosclerosis was different from that of atherosclerosis because the major atherosclerotic risk factors such as hyperlipidemia and DM were not significantly associated with CAS.9,11,20 Second, ACh has dual effects on coronary artery tone depending on their intracoronary concentration. The normal response to ACh is vasodilation at small doses and vasoconstriction at higher doses when the direct vasoconstrictor effect of ACh overwhelms the stimulation of NO release. Thus, we feel that ACh-induced CAS in the present study does not necessarily signify endothelial dysfunction.21,22 Furthermore, lack of vasodilation at small doses of ACh or mild degrees of vasoconstriction, which was not recognized as significant CAS in the present study, also reflects endothelial dysfunction.23 Therefore, our study only suggests that neither DM nor the status of blood sugar control was associated with ACh-induced CAS, and it does not contradict the well-established conception that DM is closely associated with endothelial dysfunction. Third, some studies24,25 showed that endothelial dysfunction based hypercontraction of vascular smooth muscle played a key role in the development of CAS with the mechanisms including myosin light chain phosphorylation, Rho-kinase up-regulation, and smooth muscle phenotype conversion. However, due to the nature of retrospective analysis, we did not have detailed clues about it. Further studies are needed to explore the mechanisms behind the association between DM and CAS. In addition, in the present study, although current smoking was a risk factor for CAS in the univariable analysis, it was not an independent one after we performed multivariable logistic analysis. In order to exclude the co-analytic variables choosing biases, we used stepwise multivariable logistic analysis. We found that once we co-analyzed current smoking with DM, hypertension, family history of coronary artery disease and hyperlipidemia, which are the most common risk factors for coronary artery disease, current smoking was not an independent risk factor for CAS. Therefore, the relationship between current smoking and CAS might be relatively weak among the present study population. Interestingly, our results showed that hypertension was inversely associated with CAS. These results are consistent with the results from Sugiishi et al.11 Their study also showed that hypertension was inversely associated with CAS in a multivariable logistic analysis.
Study limitations. The present study had several obvious limitations. First, angiographic evaluation of the changes in epicardial coronary diameter after infusion of ACh as used in the present study mainly reflects the endothelial function of coronary conduit vessels. This assessment does not directly reflect the status of endothelial function of coronary microcirculation.26 DM, however, affects not only coronary conduit artery but also microcirculations. Thus, further studies measuring not only coronary conduit artery spasm but also coronary microvascular spasm in diabetic patients are needed. Second, Asians have a higher incidence of CAS as assessed by ACh infusion compared with Caucasians.27 Therefore, the vasomotor response to ACh in diverse racial groups will be required to clarify the clinical relevance of vasoconstriction in patients with DM in different ethnic populations. Third, due to the nature of retrospective analysis, we did not have detailed records about the incidence of spontaneous spastic angina. Therefore, the presence of spontaneous chest pain attack and ECG changes in the non-diabetic patients might mask the impact of DM on CAS in statistical analysis. Fourth, the use rate of statins is relatively low in patients with DM. Statins may possibly be therapeutic drugs for coronary spasm.15 However, the lower use rate of statins in the present study might have presented a good setting to evaluate the impact of DM on the incidence of coronary spasm with fewer confounding effects from the medical treatment.
Despite the expected endothelial dysfunction in diabetic patients, the present study shows that DM and the status of blood sugar control are not associated with ACh-induced significant CAS, suggesting the endothelial dysfunction caused by DM may not be the main mechanism inducing CAS. Therefore, further studies with prospective design are warranted to get more definite conclusions.
Acknowledgment. We thank Dr Young Jae Lee at Korea University College of Medicine for his editorial contribution.
- Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234.
- Kim JA, Koh KK, Quon MJ. The union of vascular and metabolic actions of insulin in sickness and in health. Arterioscler Thromb Vasc Biol. 2005;25(5):889-891.
- Hadi HA, Suwaidi JA. Endothelial dysfunction in diabetes mellitus. Vasc Health Risk Manag. 2007;3(6):853-876.
- Jansson PA. Endothelial dysfunction in insulin resistance and type 2 diabetes. J Intern Med. 2007;262(2):173-183.
- Kugiyama K, Murohara T, Yasue H, et al. Increased constrictor response to acetylcholine of the isolated coronary arteries from patients with variant angina. Int J Cardiol. 1995;52(3):223-233.
- Kugiyama K, Yasue H, Okumura K, et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation. 1996;94(3):266-271.
- Kugiyama K, Ohgushi M, Motoyama T, et al. Nitric oxide-mediated flow-dependent dilation is impaired in coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol. 1997;30(4):920-926.
- Takaoka K, Yoshimura M, Ogawa H, et al. Comparison of the risk factors for coronary artery spasm with those for organic stenosis in a Japanese population: role of cigarette smoking. Int J Cardiol. 2000;72(2):121-126.
- Xiang D, Kleber FX. Smoking and hyperlipidemia are important risk factors for coronary artery spasm. Chin Med J(Engl). 2003;116(4):510-513.
- Sueda S, Kohno H, Fukuda H, et al. Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations. Coron Artery Dis. 2004;15(8):491-497.
- Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation. 1993;87(1):76-79.
- Chen KY, Rha SW, Li YJ, et al. Impact of hypertension on coronary artery spasm as assessed with intracoronary acetylcholine provocation test. J Hum Hypertens. 2010;24(2):77-85.
- Chen KY, Rha SW, Li YJ, et al. Peripheral arterial disease is associated with coronary artery spasm as assessed by an intracoronary acetylcholine provocation test. Clin Exp Pharmacol Physiol. 2009;36(11):e78-e82.
- Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
- Yasue H, Mizuno Y, Harada E, et al. Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, on coronary spasm after withdrawal of calcium-channel blockers. J Am Coll Cardiol. 2008;51(18):1742-1748.
- De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes. Br J Pharmacol. 2000;130(5):963-974.
- Pieper GM, Jordan M, Adams MB, Roza AM. Restoration of vascular endothelial function in diabetes. Diabetes Res Clin Pract. 1996;(31 Suppl):S157-S162.
- Pieper GM, Jordan M, Adams MB, Roza AM. Syngeneic pancreatic islet transplantation reverses endothelial dysfunction in experimental diabetes. Diabetes. 1995;44(9):1106-1113.
- Hsueh WA, Lyon CJ, Quinones MJ. Insulin resistance and the endothelium. Am J Med. 2004;117(2):109-117.
- Kido S, Ishii Y, Hasebe N, et al. [Significance of coronary risk factors and coronary arteriosclerosis for coronary vasospasm]. J Cardiol. 1998;31(3):135-143.
- Newman CM, Maseri A, Hackett DR, el-Tamimi HM, Davies GJ. Response of angiographically normal and atherosclerotic left anterior descending coronary arteries to acetylcholine. Am J Cardiol. 1990;66(15):1070-1076.
- Yasue H, Horio Y, Nakamura N, et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation. 1986;74(5):955-963.
- Houghton JL, Davison CA, Kuhner PA, Torossov MT, Strogatz DS, Carr AA. Heterogeneous vasomotor responses of coronary conduit and resistance vessels in hypertension. J Am Coll Cardiol. 1998;31(2):374-382.
- Kandabashi T, Shimokawa H, Miyata K, et al. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation. 2000;101(11):1319-1323.
- Shimokawa H. Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J Cardiovasc Pharmacol. 2002;39(3):319-327.
- Barac A, Campia U, Panza JA. Methods for evaluating endothelial function in humans. Hypertension. 2007;49(4):748-760.
- Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction. Circulation. 2000;101(10):1102-1108.
*Joint first authors.
From the 1Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea, 2Cardiology Division, Nankai Hospital, Tianjin, China, 3Cardiology Division, the Second Hospital of Tianjin Medical University, Tianjin, China, and the 4Department of Cardiology, Eulji General Hospital, Eulji University, Seoul, Korea.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted August 5, 2013, provisional acceptance given September 3, 2013, final version accepted October 28, 2013.
Address for correspondence: Seung-Woon Rha, MD, PhD, FACC, FAHA, FESC, FSCAI, FAPSIC, Cardiovascular Center, Korea University Guro Hospital, 80, Guro-dong, Guro-gu, Seoul, 152-703, Korea. Email: firstname.lastname@example.org