Coronary Spastic Angina Group Research Articles

East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome.

Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.

Plasma fibrinogen level is related to intimal pathology in coronary spastic angina

Fibrinogen promotes atherosclerosis and thrombosis. To evaluate the possibility that plasma fibrinogen levels represent a marker of atherosclerosis or are a predictor of cardiac events in coronary spastic angina, we studied the relation between plasma fibrinogen values and coronary angioscopic findings. We measured plasma fibrinogen in 20 patients with coronary spastic angina, 19 patients with chronic stable angina and 22 control subjects. Percutaneous angioscopic examination was performed in the patients with coronary spastic angina at the site of vasospasm induced by acetylcholine and in those with chronic stable angina at the site of organic coronary stenosis. Fibrinogen levels were significantly higher in those with coronary spastic angina (308.4±83.0 mg/dl) and chronic stable angina (289.4±69.3 mg/dl) than in the controls (239.5±49.9 mg/dl) (p<0.01, coronary spastic angina vs control;p<0.05 chronic stable angina vs control). Angioscopy showed intimal injuries (hemorrhage, flap, thrombus and/or ulcer) in 9 of the 20 (45%) coronary spastic angina patients, and flap or ulcer in 2 of the 19 (11%) chronic stable angina patients. Hemorrhage and/or thrombus were shown in 6 of the 20 coronary spastic angina patients. In the coronary spastic angina group fibrinogen levels were significantly higher (p<0.05) in those with than without hemorrhage and/or thrombus (365.3±97.4 mg/dl vs. 238.9±65.4 mg/dl). These results suggest that elevated fibrinogen levels in patients with coronary spastic angina are associated with atherosclerosis and thrombus formation.

Airway Hyperresponsiveness in Patients With Coronary Spastic Angina Relationship Between Coronary Spasticity and Airway Responsiveness

Several reports have suggested a possible link between bronchial asthma and coronary spasm, but the possibility of a relationship in coronary spastic angina (CSA) has not been clarified. Airway responsiveness to methacholine and coronary spasticity to acetylcholine were examined in 42 patients with CSA and 36 patients with chest pain syndrome (CP). Furthermore, 18 control subjects were examined and their airway responsiveness compared with that of the CSA and CP patients. The incidence of airway hyperresponsiveness was significantly higher in the CSA group (74%) than in the CP (19%) and control (17%) groups (p<0.0001). The geometric mean of the log minimum dose (Dmin), defined as the cumulative dose at the point at which respiratory conductance began to decrease, was significantly lower in the CSA group (0.75 log units) than in the CP (1.20 log units) and control (1.38 log units) groups (p=0.004). These results demonstrate that acetylcholine-induced coronary spasticity is significantly related to methacholine-induced airway responsiveness in patients with CSA. A generalized hyperresponsiveness of the vascular and nonvascular smooth muscles, including that through cholinergic mechanisms, may exist in patients with CSA.

Impact of Paraoxonase Polymorphism (Q192R) on Endothelial Function in Intact Coronary Circulation

Paraoxonase-1 (PON1) can protect endothelial function by preventing the oxidation of low-density lipoprotein (LDL) cholesterol and retarding the development of atherosclerosis. We examined whether PON1 polymorphism influences endothelium-dependent coronary vasomotor responses. Sixty-seven patients underwent diagnostic cardiac catheterization, but showed no significant coronary artery stenosis. In all patients, PON1 genotypes (Q/Q, Q/R and R/R) were determined, and provocative testing was performed by the intracoronary administration of graded doses of bradykinin (BK; 0.2, 0.6 and 2.0 mug/min) and acetylcholine (ACh; 3, 10 and 30 mug/min). Coronary blood flow (CBF) was evaluated by a Doppler guide wire. The patients were divided into 2 groups on the basis of ACh testing: one with coronary spastic angina (CSA) and one with non-CSA. The frequencies of the PON1 genotype in the CSA group did not differ significantly from those in the non-CSA group. In the non-CSA group, the patients were subdivided into 2 groups: a group with the Q/Q or Q/R genotypes and a group with the R/R genotype. The vasoconstrictive responses of the epicardial coronary artery to ACh were comparable between the Q/Q + Q/R and R/R groups. Also, the coronary vasodilations induced by BK in the R/R group were similar to those in the QR + QQ group. There were no significant differences in the CBF responses induced by BK or ACh between the Q/Q + Q/R and R/R groups. In conclusion, as estimated by BK and ACh testing, our findings suggest that PON1 genotypes may not play a critical role in the modulation of endothelial vasomotor function in the intact coronary circulation.

Plasma fibrinogen level is related to intimal pathology in coronary spastic angina

Fibrinogen promotes atherosclerosis and thrombosis. To evaluate the possibility that plasma fibrinogen levels represent a marker of atherosclerosis or are a predictor of cardiac events in coronary spastic angina, we studied the relation between plasma fibrinogen values and coronary angioscopic findings. We measured plasma fibrinogen in 20 patients with coronary spastic angina, 19 patients with chronic stable angina and 22 control subjects. Percutaneous angioscopic examination was performed in the patients with coronary spastic angina at the site of vasospasm induced by acetylcholine and in those with chronic stable angina at the site of organic coronary stenosis. Fibrinogen levels were significantly higher in those with coronary spastic angina (308.4 ± 83.0 mg/dl) and chronic stable angina (289.4 ± 69.3 mg/dl) than in the controls (239.5 ± 49.9 mg/dl) (p<0.01, coronary spastic angina vs control;p<0.05 chronic stable angina vs control). Angioscopy showed intimal injuries (hemorrhage, flap, thrombus and/or ulcer) in 9 of the 20 (45%) coronary spastic angina patients, and flap or ulcer in 2 of the 19 (11%) chronic stable angina patients. Hemorrhage and/or thrombus were shown in 6 of the 20 coronary spastic angina patients. In the coronary spastic angina group fibrinogen levels were significantly higher (p<0.05) in those with than without hemorrhage and/or thrombus (365.3 ± 97.4 mg/dl vs. 238.9 ± 65.4 mg/dl). These results suggest that elevated fibrinogen levels in patients with coronary spastic angina are associated with atherosclerosis and thrombus formation.

Coronary vasomotor responses to bradykinin and acetylcholine in patients with coronary spastic angina.

It is unclear whether coronary endothelial function is linked to the pathogenesis of coronary spastic angina (CSA), so the present study examined the coronary vasomotor responses to acetylcholine (ACh) and bradykinin (BK) in 23 patients with CSA, 26 patients with CSA+coronary artery disease (CAD), and 21 control patients. Acetylcholine induced vasospasm of the left coronary artery in all of the patients with CSA, but not in any of the control patients. The changes in dilatation of the left coronary artery in response to bradykinin at doses of 0.2, 0.6 and 2.0 microg/min in the CSA group were significantly greater than those in the other 2 groups. The ratio of epicardial coronary vasodilations induced by BK to those induced by nitroglycerin did not differ among any of the groups. Bradykinin caused a similar increase in coronary blood flow in the control group and CSA group, but had less of an effect in the CSA+CAD group. In conclusion, the vasorelaxing effect of BK was preserved not only in epicardial spasm coronary arteries induced by ACh, but also in resistance coronary arteries distal to the spasm arteries in patients with CSA. The coronary vasodilation response induced by BK may not deteriorate until coronary atherosclerosis advances in patients with CSA.

Is inflammation related to the clinical severity of unstable angina?

The present study determined the white blood cell (WBC) count and the serum C-reactive protein (CRP) level in 27 patients with coronary spastic angina, 16 with Braunwald class IB unstable angina (UA) and 13 with Braunwald class IIIB. The relationship between the clinical presentation of UA and the requirement for emergency percutaneous transluminal coronary angioplasty (PTCA) was examined, and in patients with medically refractory angina, the determining factor among the clinical manifestations of angina was also investigated. In the acute phase, the WBC count and the serum CRP level were significantly higher in patients with Braunwald class IIIB than in those with coronary spastic angina or Braunwald class IB UA (p<0.001). In the Braunwald class IIIB group, a significantly higher rate of patients required emergency PTCA than that of the coronary spastic angina group (p<0.01). Patients with medically refractory angina had a significantly higher WBC count and higher serum CRP level on admission, and the WBC count on admission was independently associated with medically refractory angina by multivariate analysis (p<0.05). Inflammation may play a major pathological role in the rapid development of acute coronary syndrome.

Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: Possible role of reactive oxygen species

OBJECTIVESThis study was designed to examine the effect of antioxidant supplementation on the endothelial function and insulin sensitivity in patients with coronary spastic angina (CSA).BACKGROUNDInsulin resistance may play a key role in coronary heart disease, and there is a possible link between acetylcholine-induced coronary vasoconstriction and hyperinsulinemia in patients with CSA. Endothelial dysfunction is present in the systemic arteries in CSA patients, and reactive oxygen species may cause inactivation of nitric oxide in these patients.METHODSWe measured flow-mediated dilation of the brachial artery using ultrasound technique in 22 patients with CSA and 20 control subjects. We also evaluated glucose tolerance using a 75-g oral glucose tolerance test and insulin sensitivity using steady-state plasma glucose (SSPG) methods in the same patients.RESULTSThe incidence of impaired glucose tolerance was higher in the CSA group than in the control group. Vitamin C infusion augmented flow-mediated dilation and decreased SSPG levels in the CSA group (from 3.27 ± 0.77% to 7.00 ± 0.59% [p < 0.001 by analysis of variance (ANOVA)] and from 177.3 ± 13.3 to 143.1 ± 14.9 mg/dl [p = 0.047 by ANOVA], respectively) but not in the control group (from 6.47 ± 0.66% to 6.80 ± 0.60% and from 119.8 ± 11.7 mg/dl to 118.1 ± 11.3 mg/dl, respectively). The steady-state plasma insulin levels were not affected by vitamin C infusion in either group.CONCLUSIONSVitamin C improves both endothelial function and insulin sensitivity in patients with CSA. Thus, reactive oxygen species and/or decreased nitric oxide bioactivity may play an important role in the genesis of both endothelial dysfunction and insulin resistance in patients with CSA.

Heparin-Releasable Endothelial Cell-Associated Tissue Factor Pathway Inhibitor (Tfpi) is Increased in the Coronary Circulation After Coronary Spasm in Patients with Coronary Spastic Angina

Tissue factor pathway inhibitor (TFPI) is a physiological regulator of the extrinsic coagulation cascade. Coronary spasm can alter endothelial cell properties in the coronary artery with resultant thrombosis. To determine whether coronary spasm affects plasma TFPI level, we measured the heparin-releasable endothelial cell-associated TFPI (heparin-releasable TFPI) (ng/ml) in the coronary sinus and the aortic root before and after coronary spasm induced by an injection of acetylcholine in 18 patients with coronary spastic angina, and before and after myocardial ischemia induced by rapid atrial pacing in 18 patients with stable exertional angina, and in 17 control subjects with normal coronary arteries and no coronary spasm. Heparin-releasable TFPI level in the coronary spastic angina group significantly increased in the coronary sinus (122±46 to 147±63, p<0.001) after the ischemic event but not in the aortic root (113±44 to 121±58). The level in the coronary sinus and the aortic root remained unchanged after the ischemic event in the stable exertional angina group and after the injection of acetylcholine in the control group. The coronary sinus-arterial difference in the amount of the heparin-releasable TFPI significantly increased after the ischemic event only in the coronary spastic angina group (10±18 to 26 ±18, p<0.002). Our result suggested that heparin-releasable TFPI is increased in the coronary circulation after coronary spasm.

Soluble P-Selectin Is Released Into the Coronary Circulation After Coronary Spasm

The glycoprotein P-selectin is an adhesion molecule involved in the property change of leukocytes at the initiation of the inflammatory process. The purpose of the present study was to determine whether acute myocardial ischemia induced by coronary spasm causes an acute inflammatory response in the coronary circulation. We examined plasma soluble P-selectin levels in the coronary sinus and the aortic root simultaneously in 16 patients with coronary spastic angina before and after left coronary artery spasm induced by intracoronary injection of acetylcholine and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid atrial pacing. Ten control patients with chest pain but normal coronary arteries and no coronary spasm also received intracoronary acetylcholine. Plasma soluble P-selectin levels were increased significantly in the coronary sinus (32.8 +/- 3.6 to 52.8 +/- 5.9 ng/mL, P < .001) and in the aortic root (34.6 +/- 3.7 to 41.9 +/- 4.4 ng/mL, P < .05) after the attacks in the coronary spastic angina group but remained unchanged in the stable exertional angina group after the attacks and in the control group after the administration of acetylcholine. Furthermore, the coronary sinus-arterial difference of soluble P-selectin increased significantly after the attacks in the coronary spastic angina group (-1.8 +/- 2.2 to 10.9 +/- 2.7 ng/mL, P < .001). Our data indicate that soluble P-selectin is released into the coronary circulation after coronary artery spasm. We conclude that coronary artery spasm may induce the leukocyte adhesion in the coronary circulation and may lead to myocardial damage.

Fibrinopeptide A is released into the coronary circulation after coronary spasm.

To examine whether acute myocardial ischemia activates the coagulation system and platelet activation in the coronary circulation, we measured plasma levels of fibrinopeptide A and beta-thromboglobulin in the coronary sinus and the aortic root simultaneously in 15 patients with coronary spastic angina before and after the left coronary spasm induced by intracoronary injection of acetylcholine and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid atrial pacing. Fifteen patients with chest pain but normal coronary arteries and no coronary spasm served as controls. The coronary sinus-arterial difference of fibrinopeptide A increased markedly (p less than 0.001) from 0.1 +/- 0.2 to 4.3 +/- 0.7 ng/ml after the anginal attacks in the coronary spastic angina group. However, fibrinopeptide A levels remained unchanged after the attacks in the stable exertional angina group and after intracoronary injection of acetylcholine in the control group. Plasma beta-thromboglobulin levels remained unchanged after the attacks in both patient groups and after acetylcholine in the control group. Our data indicate that coronary spasm induces thrombin generation and may lead to thrombus formation in the coronary artery involved, but pacing-induced ischemia does not activate the coagulation system.