Determinants of Myocardial Lactate Production During Acetylcholine Provocation Test in Patients With Coronary Spasm

Background Myocardial lactate production in the coronary circulation during acetylcholine (ACh)‐provocation test (abbreviated as lactate production) provides supporting evidence for coronary spasm–induced myocardial ischemia. The purpose of this study was to examine the clinical features, predictive factors, and prognosis of patients with coronary vasospastic angina (VSA) and lactate production. Methods and Results We examined all 712 patients who underwent both myocardial lactate measurement during ACh‐provocation test in the left coronary artery and genetic screening test of a –786T/C polymorphism in the 5′‐flanking region of the endothelial nitric oxide synthase (eNOS) gene between January 1991 and December 2010. Lactate production was observed in 252 of the 712 patients and in 219 of 356 VSA patients diagnosed by ACh‐provocation test. Compared with lactate production–negative VSA patients, the lactate production–positive counterparts were more likely to be nonsmoker female diabetics with –786T/C eNOS polymorphism (61% vs 31%, P<0.001, 62% vs 34%, P<0.001, 24% vs 14%, P=0.016, and 25% vs 15%, P=0.018, respectively). Multivariable logistic regression analysis identified female sex, diabetes mellitus, and –786T/C eNOS polymorphism to correlate with lactate production (odds ratio 3.51, 95% CI 2.16 to 5.70, P<0.001; odds ratio 2.53, 95% CI 1.38 to 4.65, P=0.003; and odds ratio 1.85, 95% CI 1.02 to 3.35, P=0.044, respectively). Kaplan–Meier survival curve showed no difference in 5‐year survival rate free from major adverse cardiac events between lactate production–positive and –negative VSA patients (P=0.319). Conclusions The results indicated that female sex, diabetes, and mutation in –786T/C eNOS gene correlate with ACh‐provoked myocardial ischemia in patients with coronary spasm.

[1]  S. Hokimoto,et al.  Clinical Features and Prognosis of Patients With Coronary Spasm–Induced Non–ST‐Segment Elevation Acute Coronary Syndrome , 2014, Journal of the American Heart Association.

[2]  J. Kaski,et al.  Clinical Usefulness, Angiographic Characteristics, and Safety Evaluation of Intracoronary Acetylcholine Provocation Testing Among 921 Consecutive White Patients With Unobstructed Coronary Arteries , 2014, Circulation.

[3]  S. Hokimoto,et al.  Coronary Vasomotor Response to Intracoronary Acetylcholine Injection, Clinical Features, and Long‐term Prognosis in 873 Consecutive Patients With Coronary Spasm: Analysis of a Single‐Center Study Over 20 Years , 2013, Journal of the American Heart Association.

[4]  H. Shimokawa,et al.  Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association. , 2013, European Heart Journal.

[5]  K. Sakamoto,et al.  Microvascular Coronary Artery Spasm Presents Distinctive Clinical Features With Endothelial Dysfunction as Nonobstructive Coronary Artery Disease , 2012, Journal of the American Heart Association.

[6]  J. Kaski,et al.  High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). , 2012, Journal of the American College of Cardiology.

[7]  T. Akasaka,et al.  Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[8]  U. Sechtem,et al.  Coronary artery spasm as a frequent cause of acute coronary syndrome: The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) Study. , 2008, Journal of the American College of Cardiology.

[9]  K. Nakao,et al.  A −786T>C polymorphism in the endothelial nitric oxide synthase gene reduces serum nitrite/nitrate levels from the heart due to an intracoronary injection of acetylcholine , 2006, Pharmacogenetics and genomics.

[10]  Christopher J. Lyon,et al.  Insulin resistance and the endothelium , 2005, The American journal of medicine.

[11]  H. Fukuda,et al.  Frequency of Provoked Coronary Spasms in Patients Undergoing Coronary Arteriography Using a Spasm Provocation Test Via Intracoronary Administration of Ergonovine , 2004, Angiology.

[12]  Robert Elashoff,et al.  Coronary Vasomotor Abnormalities in Insulin-Resistant Individuals , 2004, Annals of Internal Medicine.

[13]  W. Hsueh,et al.  Role of endothelial dysfunction in insulin resistance. , 2003, The American journal of cardiology.

[14]  Y. Nishimura,et al.  Preference Toward a T-Helper Type 1 Response in Patients With Coronary Spastic Angina , 2003, Circulation.

[15]  S. Jacob,et al.  Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. , 2000, Circulation.

[16]  R. Mongiardo,et al.  Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction. , 2000, Circulation.

[17]  KazuwaNakao,et al.  T−786→C Mutation in the 5′-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated With Coronary Spasm , 1999 .

[18]  K. Nakao,et al.  T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. , 1999, Circulation.

[19]  N. Ochi,et al.  Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine. , 1999, The American journal of cardiology.

[20]  K. Kugiyama,et al.  Role of adenosine in pathogenesis of syndrome X: assessment with coronary hemodynamic measurements and thallium-201 myocardial single-photon emission computed tomography. , 1996, Journal of the American College of Cardiology.

[21]  P. Groop,et al.  Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. , 1996, Circulation.

[22]  M. Sampson,et al.  Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. , 1996, Journal of the American College of Cardiology.

[23]  E. Bassenge,et al.  Coronary vasomotor responses: Role of endothelium and nitrovasodilators , 1994, Cardiovascular Drugs and Therapy.

[24]  S. Moncada,et al.  Nitric oxide: physiology, pathophysiology, and pharmacology. , 1991, Pharmacological reviews.

[25]  K. Okumura,et al.  Circadian variation of plasma fibrinopeptide A level in patients with variant angina. , 1989, Circulation.

[26]  K. Kugiyama,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. , 1986, Circulation.

[27]  R. Furchgott Role of endothelium in responses of vascular smooth muscle. , 1983, Circulation research.

[28]  M. Bertrand,et al.  The provocation of coronary arterial spasm in patients with recent transmural myocardial infarction. , 1983, European heart journal.

[29]  H. Yasue,et al.  Coronary Arterial Spasm in Ischemic Heart Disease and Its Pathogenesis: A Review , 1983, Circulation research.

[30]  J. Kastor,et al.  Coronary hemodynamic and myocardial metabolic alterations accompanying coronary spasm. , 1979, The American journal of cardiology.

[31]  S. Chierchia,et al.  Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of "preinfarction" angina. , 1978, The New England journal of medicine.

[32]  H. Yasue,et al.  Prinzmetal's variant form of angina as a manifestation of alpha-adrenergic receptor-mediated coronary artery spasm: documentation by coronary arteriography. , 1976, American heart journal.

[33]  R. Frye,et al.  A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. , 1975, Circulation.

[34]  H. Yasue,et al.  Role of Autonomic Nervous System in the Pathogenesis of Prinzmetal's Variant Form of Angina , 1974, Circulation.

[35]  H. Ishizaka,et al.  Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. Hyperreactivity to the constrictor effects of acetylcholine and the dilator effects of nitroglycerin. , 1996, Journal of the American College of Cardiology.