coronary spasm (CS). Interactions between hemoglobin and high-sensitivity C-reactive protein (hs-crp) in patients with CS have not been

Transcription

1 1

2 2 Background The benefit of modest anemia, although well known in cerebral spasm, is unclear in coronary spasm (CS). Interactions between hemoglobin and high-sensitivity C-reactive protein (hs-crp) in patients with CS have not been evaluated. Methods Patients undergoing diagnostic coronary angiography with proven CS but without coronary stenosis >50% were evaluated. A total of 869 subjects were analyzed. The levels of hs-crp measured immediately before coronary angiography were examined in a subset of 526 patients.

3 3 Results In 337 women, patients with CS were likely to have high levels of hemoglobin, hematocrit and hs-crp. In 532 men, patients with CS were likely to be older, current smokers and have high levels of hs-crp. In women, hemoglobin and hs-crp level were associated with CS, with hs-crp level being the most significant factor (odds ratio [OR]=1.15, 95% confidence interval [CI]= , p=0.001). In men, age and smoking were independently associated with CS. Among women with high hemoglobin level, the ORs from the lowest to the highest tertiles of hs-crp were 1.21, 2.15, and 5.93 (CI= , p=0.009). In women with low hemoglobin level, an elevated risk was found from the middle to the highest tertiles

4 4 of hs-crp; OR from 0.59 to 3.85 (CI= , p=0.004). This relationship was not observed in men. Conclusions Hemoglobin is a potent modifier in the development of CS in women, but not in men. There is a positive interaction between hemoglobin and hs-crp in women with this disease. Recurrent episodes of angina are frequently observed in CS patients whereas complications such as death and myocardial infarction are rare.

5 5 Coronary spasm (CS), caused by an increase in vascular tone, is an important cause not only of variant angina but also of ischemic heart disease, including effort angina, acute coronary syndrome and sudden death (1,2). Through oxygen-dependent release of the vasodilator adenosine 5 triphosphate, red blood cells have been suggested to be a regulator of vascular tone (3). However, because of their high hemoglobin content, red blood cells were thought to exert scavenging activity towards nitric oxide produced by endothelial cells (4), which diffuses into the flowing blood, where it is destroyed by oxyhemoglobin in red

6 6 blood cells (5). Being one of the determinants of blood flow and viscosity, red blood cells are the component of blood necessary for cerebral spasm to develop, leading to the demonstration that spasm-induced cerebral ischemia could be treated with hypervolemia and hemodilution (6). The benefit of modest anemia to reduce blood viscosity by hemodilution, although well established in cerebral spasm (6), is unclear in CS. Although previous studies show that anemia is associated with mortality in patients with coronary artery disease (CAD) (7), high hemoglobin is also associated with poor prognosis, giving a J-shaped relationship between hemoglobin and prognosis (8). While the interaction between hemoglobin and gender

7 7 has been demonstrated to be insignificant among patients with CAD (8), this association has not been investigated in CS. CS is reported to be an inflammatory disease, as indicated by the presence of elevated high-sensitivity C-reactive protein (hs-crp) (9), a biomarker of inflammation. We have previously demonstrated that the relationship between hs-crp and CS differed between women and men, in which the interaction between men and hs-crp was positively linear and monotonic; in women, however, we found that hs-crp had a threshold effect (9). Little is known, however, about the effect of the relationship among gender, hemoglobin and hs-crp on risk and prognosis for CS. Therefore, we retrospectively enrolled more

8 8 patients with and without CS to determine whether there are interactions among gender, hemoglobin and hs-crp that influence the development of CS in patients without obstructive CAD.

9 9 Study population. From January 1999 to December 2010, 869 patients with suspected ischemic heart disease who underwent diagnostic coronary angiography and, thus, had no obstructive CAD were subjected to intracoronary methylergonovine testing. Inclusion criteria for CS included spontaneous chest pain at rest associated with ST-segment elevation or depression on electrocardiogram and relieved by sublingual administration of nitroglycerin, no obstructive CAD after intracoronary nitroglycerin administration on coronary angiography, and/or positive intracoronary

10 10 methylergonovine provocation testing. The control group consisted of patients who presented with atypical chest pain, had no obstructive CAD, and had negative intracoronary methylergonovine provocation tests (no CS). Exclusion criteria were obstructive CAD, inflammatory manifestations probably associated with noncardiac diseases (e.g., infections and autoimmune disorders), associated liver disease/renal failure (serum creatinine level >2.5 mg/dl), collagen disease, or malignancy and loss of blood samples. Clinical data. Current smoking was defined as having smoked a cigarette within 3 weeks of the cardiac catheterization.

11 11 Diabetes mellitus was defined from dietary treatment and/or medical therapy and hypertension as receiving the appropriate medical therapy or blood pressure of >140/90 mmhg. Hypercholesterolemia was defined where serum total cholesterol was >200 mg/dl. Laboratory analysis. Blood specimens were collected immediately before coronary angiography. Coronary angiography and intracoronary methylergonovine testing. Nitrates and calcium antagonists were withdrawn for 24 hours before coronary angiography. The left ventricular ejection fraction (LVEF) was calculated using Simpson s method. Obstructive CAD was

12 12 defined as 50% diameter reduction in lumen caliber after administration of intracoronary nitroglycerin (100 g) (10). Intracoronary methylergonovine provocation testing was performed in succession if no obstructive CAD was found. Methylergonovine was administered stepwise (1, 5, 10, 30 g) first into the right coronary artery and subsequently into the left coronary artery. Provocation testing for CS was considered positive where there was a 70% reduction in luminal diameter compared to post intracoronary nitroglycerin and there was associated angina and/or ST depression or elevation (11). After CS diagnosis, the intracoronary methylergonovine

13 13 administration was stopped with intracoronary nitroglycerin g administration for reversal. Spontaneous CS was defined as the relief of >70% diameter stenosis after intracoronary nitroglycerin g administration. Follow-up. Patient follow-up data were obtained using medical records of outpatient visits and hospital readmissions or telephone interviews for whom none of these data were available. All information was obtained between January 1999 and December 2010, 12 years after study entry. The study end point was the occurrence of major adverse cardiovascular event (MACE), a composite of death, nonfatal myocardial infarction, and recurrent

14 14 angina pectoris requiring repeat coronary angiography. All deaths were considered cardiac unless an unequivocal noncardiac cause could be identified. Coronary events were defined as nonfatal myocardial infarction and recurrent angina pectoris requiring repeat coronary angiography. Of all 869 patients from the initial study, follow-up data were available in 783 patients (90.1%) of whom 293 were women (86.9% follow-up) and 490 were men (92.1% follow-up). Statistical analysis. Continuous variables were expressed as mean ± SD, while log transformation was performed for variables with positive skewness for the subsequent Student s t tests between two groups. Categorical variables were

15 15 analysed using the chi-square test. Tertiles of hs-crp were categorized as lowest (<1 mg/l), middle (1-3 mg/l), or highest (>3 mg/l) (12). Multiple logistic regression with adjusted odds ratios (OR) and 95% confidence intervals (CI) was used to identify risk factors. Stratified analyses were performed on a subset of 526 patients whose hs-crp measurements were available to examine the interaction of hs-crp tertiles and hemoglobin (cutoff point determined by the mean concentration of 13.6 g/dl) on CS. The difference in incidence of MACE as well as freedom from coronary events between groups during the follow-up period was assessed by the Kaplan-Meier method with the log-rank test. Differences in hemoglobin levels across

16 16 the age groups were analyzed with 1-way ANOVA, and post hoc analysis for significant results were performed using Scheffe correction. Data management and statistical analyses were performed using SPSS 15.0 for Windows. The level of significance was set at p <0.05 (2-sided).

17 17 Baseline characteristics. Among the 869 patients o mean age was 57 ± 12 years, and 39% were women. None of the patients had angiographic evidence of obstructive CAD. o A total of 495 patients had CS (CS group) and 374 did not have CS (control group). o Age, the number of men, the number of current smokers, hemoglobin, hematocrit and hs-crp levels were significantly greater in the CS group than in the control group (Table 1). o Single-vessel CS was the most common finding in CS patients, and spasm was provoked mostly in the right coronary artery. o The use of β-blockers and calcium channel blockers were significantly greater in the control group than in the CS group, while the distribution of other concomitant medications was fairly even between groups.

18 18 o Among women, hemoglobin, hematocrit and hs-crp levels were positively associated with CS. o Among men, age, current smoking status, and hs-crp level were positively associated with CS (Table 2). Among CS patients, women tended to have a higher LVEF than men. In addition, the prevalence of current smokers was higher among men than women. There were no statistical differences in age, body mass index, the prevalence of diabetes mellitus, hypertension, level of cholesterol, hemoglobin, hematocrit or level of hs-crp between genders (Table 2). Variables associated with CS in women or men with hs-crp measurements. Multivariable analysis of women revealed that the level of hs-crp was independently associated with CS (Table 3). Multivariable analysis of men showed that age and current smoking status were independently

19 associated with CS. Gender-specific stratified analyses of hs-crp tertiles and hemoglobin. In women, high hemoglobin levels were significant risk factors for CS. In men, however, high hemoglobin levels were not significant risk factors for CS (Table 4). Significant interactions were demonstrated between hs-crp tertiles and hemoglobin for CS risk. In the analysis of women: o patients with high hemoglobin levels in the highest tertile of hs-crp had a 5.9-fold higher risk for CS than those with low hemoglobin levels in the lowest hs-crp tertile. o patients with low hemoglobin levels in the highest tertile of hs-crp had a 3.9-fold higher risk for CS than those with low hemoglobin levels in the lowest hs-crp tertile. o This relationship was not observed in men (Fig 1). This interaction between hemoglobin and hs-crp in the development of CS was linear 19

20 20 and monotonic in women with high hemoglobin levels. In women with low hemoglobin levels, however, hs-crp had a threshold effect on CS development. o The prevalence of smoking in women with CS did not differ between those with hs-crp levels >3 mg/l and those with hs-crp levels <3 mg/l (7% versus 11%, p = 0.34) or between those with low hemoglobin levels and high hemoglobin levels (8% versus 18%, p = 0.15). Hemoglobin distribution by gender. Hemoglobin concentration varies substantially according to age and sex. o Hemoglobin levels, on average, decreased with advancing age in men throughout adulthood, while a more modest decline occurred in women after the age of 50 (p < and p = 0.018, respectively). o In women, the patients with spasm had higher hemoglobin levels in any age group compared with the patients without spasm. However, this

21 pattern is less clear in men (Fig. 2). Follow-up. 5 patients in the control group died during follow-up (1%), all of which were due to a noncardiac cause (septic shock [n = 4], cancer [n = 1]). 3 deaths occurred in the CS group (0.6%), 2 due to sudden cardiac deaths and 1 due to cancer. Coronary events were noted in patients from the control (n = 7, 2%) and CS groups (n = 40, 8%); with nonfatal myocardial infarction identified only in the CS group (n = 3, 0.6%). Survival curves. The frequency of MACE-free survival was significantly lower in the control group than in the group of spasm in women (p = ) and men (p = ) (Fig. 3A). As compared with the control, both groups of spasm in women (p = ) and men (p < ) were associated with a significant increased risk for coronary events (Fig. 3B). 21

22 22 However, no difference was observed in terms of coronary events between the patients with high and low hemoglobin levels in the groups of spasm in women and men (p = 0.54 and 0.46, respectively) (Fig. 3C, 3D).

23 23 We conclude that 1. Hemoglobin is a potent modifier in the development of CS in women. 2. The relationship between hemoglobin and hs-crp in CS differed between women and men. We found that the interaction between women with high hemoglobin and hs-crp was positively linear and monotonic; in women with low hemoglobin, however, we found that hs-crp had a threshold effect. 3. There is a positive interaction between hemoglobin and hs-crp in women with this disease. This relationship was not observed in men. 4. Compared with patients with normal coronary arteries, recurrent episodes of angina are frequently observed in CS patients whereas complications such as death and myocardial infarction are rare.

24 24 1. Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U. Coronary artery spasm as a frequent cause of acute coronary syndrome: The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) Study. J Am Coll Cardiol 2008 Aug 12;52(7): Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y. Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment. J Cardiol 2008;51: Ellsworth ML, Ellis CG, Goldman D, Stephenson AH, Dietrich HH, Sprague RS. Erythrocytes: oxygen sensors and modulators of vascular tone. Physiology 2009;24: Lancaster JR Jr. Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci U S A 1994 Aug 16;91(17): Schechter AN, Gladwin MT. Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 2003 Apr 10;348(15): Tummala RP, Sheth RN, Heros RC. Hemodilution and fluid management in neurosurgery. Clin Neurosurg 2006;53: Arant CB, Wessel TR, Olson MB, Bairey Merz CN, Sopko G, Rogers WJ, Sharaf BL, Reis SE, Smith KM, Johnson BD, Handberg E, Mankad S, Pepine CJ; National Heart, Lung, and Blood Institute Women's Ischemia Syndrome Evaluation Study. Hemoglobin level is an independent predictor for adverse cardiovascular outcomes in women undergoing evaluation for chest pain: results from the National Heart, Lung, and Blood Institute Women's Ischemia Syndrome Evaluation Study. J Am Coll Cardiol 2004 Jun 2;43(11): Shah AD, Nicholas O, Timmis AD, Feder G, Abrams KR, Chen R, Hingorani AD, Hemingway H. Threshold haemoglobin levels and the prognosis of stable coronary disease: two new cohorts and a systematic review and meta-analysis. PLoS Med 2011 May;8(5):e Hung MY, Hsu KH, Hung MJ, Cheng CW, Cherng WJ. Interactions among gender, age, hypertension and C-reactive protein in coronary vasospasm. Eur J Clin Invest 2010 Dec;40(12): Sharaf BL, Williams DO, Miele NJ, McMahon RP, Stone PH, Bjerregaard P et al. A detailed angiographic analysis of patients with ambulatory electrocardiographic ischemia: results from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study angiographic core laboratory. J Am Coll Cardiol 1997;29: Miyao Y, Kugiyama K, Kawano H, Motoyama T, Ogawa H, Yoshimura M et al. Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol 2000;36: Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M et al. Centers for Disease Control and Prevention. American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:

25 Table 1 Baseline Clinical Characteristics 25 Characteristic Controls (n = 374) CS (n = 495) p Value Age (yrs) 56 ± ± Male 185 (50) 347 (70) <0.001 Body mass index (kg/m 2 ) 26.0 ± ± Current smoker 84 (23) 223 (45) <0.001 Diabetes mellitus 68 (18) 95 (19) 0.70 Hypertension 172 (46) 217 (44) 0.51 LVEF (%) 67 ± ± Cholesterol (mg/dl) 204 ± ± LDL-cholesterol (mg/dl) 141 ± ± HDL-cholesterol (mg/dl) 37 ± ± Hemoglobin (g/dl) 13.2 ± ± 1.6 <0.001 Hematocrit (%) 39.2 ± ± 4.2 <0.001 hs-crp (mg/l) * 1.24 ( ) 2.28 ( ) <0.001 Provoked coronary artery Left main artery Left anterior descending artery Left circumflex artery Right coronary artery 4 (0.8) 145 (29) 109 (22) 328 (66) Number of provoked spastic artery 1-vessel spasm 2-vessel spasm 3-vessel spasm 389 (79) 26 (5) 56 (11)

26 Medications before coronary angiography 26 Beta-blockers Calcium-channel blockers ACE inhibitors Angiotensin receptor blocker Nitrates Statins Aspirin Diuretics 67 (18) 45 (9) < (45) 139 (28) < (9) 46 (9) (15) 69 (14) (38) 198 (40) (10) 59 (12) (70) 332 (67) (22) 89 (18) 0.15 ACE = angiotensin-converting enzyme; CS = coronary spasm; LVEF = left ventricular ejection fraction; hs-crp = high sensitivity C-reactive protein. Data are presented as n (%), mean ± SD or median (interquartile range). * hs-crp samples were collected in a subset of 526 patients, with 210 and 316 in the control and CS groups, respectively. Log-transformed values were used in analyses.

27 Table 2 Gender-Specific Baseline Characteristics Between Study Groups Women (n = 337) Men (n = 532) 27 p p p Value Characteristic Controls (n = 189) CS (n = 148) Value Controls (n = 185) CS (n = 347) Value * Age (years) mean ± SD 58 ± ± ± ± 13 < Body mass index (kg/m 2 ) mean ± SD 25.7 ± ± ± ± Current smoker, n (%) 11 (6) 15 (10) (40) 208 (60) <0.001 <0.001 Diabetes mellitus, n (%) 40 (21) 28 (19) (15) 67 (19) Hypertension, n (%) 87 (46) 71 (48) (46) 146 (42) LVEF (%) mean ± SD 69 ± ± ± ± Cholesterol mean ± SD (mg/dl) 207 ± ± ± ± Hemoglobin (g/dl) 12.2 ± ± ± ± <0.001 Hematocrit (%) 36.6 ± ± ± ± <0.001 hs-crp (mg/l) median (25 th -75 th percentile) 1.49 ( ) 1.98 ( ) ( ) 2.42 ( ) < Abbreviations as in Table 1. * Comparison between women and men among CS patients. hs-crp samples were collected in a subset of 526 patients, with 99 and 93 in the control and CS groups in women, and 111 and 223 in the control and CS groups in men, respectively. Log-transformed values were used in analyses.

28 Table 3 Gender-Specific Univariate and Multivariate Analysis of Variables Associated With CS Women (n = 337) Men (n = 532) 28 Univariate Multivariate * Univariate Multivariate * Variable OR (95% CI) p Value OR (95% CI) p Value OR (95% CI) p Value OR (95% CI) p Value Age (yr) 1.01 ( ) ( ) ( ) < ( ) Body mass index (kg/m 2 ) 1.03 ( ) ( ) ( ) ( ) 0.37 Current smoker 1.83 ( ) ( ) ( ) < ( ) Diabetes mellitus 0.87 ( ) ( ) ( ) ( ) 0.60 Hypertension 1.08 ( ) ( ) ( ) ( ) 0.93 Left ventricular ejection fraction (% ) 1.00 ( ) ( ) ( ) ( ) 0.99 Cholesterol (mg/dl) 1.00 ( ) ( ) ( ) ( ) 0.60 Hemoglobin (g/dl) 1.31 ( ) ( ) ( ) ( ) 1.00 Hematocrit (%) 1.08 ( ) ( ) ( ) ( ) 0.94 * hs-crp (mg/l) 1.09 ( ) ( ) ( ) ( ) 0.12 CS indicates coronary spasm; hs-crp, high sensitivity C-reactive protein; OR (95% CI), Odds Ratio (95% Confidence Interval). * Multivariate analysis was performed in a subset of 526 patients with hs-crp measurements, with 192 in women, and 334 in men, respectively.

29 Table 4 Stratified analysis of multivariate-adjusted odds ratios for CS with tertiles of hs-crp and hemoglobin Women (n = 192) Men (n = 334) 29 Tertile of hs-crp Tertile of hs-crp Model <1 mg/l 1-3 mg/l >3 mg/l <1 mg/l 1-3 mg/l >3 mg/l Hemoglob in (g/dl) < (reference) 0.59 ( ) 3.85 ( ) 1.0 (reference) 0.81 ( ) 1.50 ( ) ( ) 2.15 ( ) 5.93 ( ) 0.43 ( ) 0.47 ( ) 1.19 ( ) Abbreviations as in Tables 1 & 3. Data are presented as multivariate-adjusted OR (95% CI), with adjusted variables including age, body mass index, smoking, diabetes mellitus, hypertension, LVEF, cholesterol and hematocrit other than the stratified variable per se.

30 Figure 1. Interaction exists between hemoglobin and hs-crp in patients with coronary spasm (CS). In the analysis of women, patients with high hemoglobin levels in the highest tertile of hs-crp had a 5.9-fold higher risk for CS than those with low hemoglobin levels in the lowest hs-crp tertile. In patients with low hemoglobin levels in the highest tertile of hs-crp had a 3.9-fold higher risk for CS than those with low hemoglobin levels in the lowest hs-crp tertile. This relationship was not observed in men. 30

31 Figure 2. Mean Hemoglobin Concentration by Age and Gender. Values are mean ± 95% confidence interval. The mean decreased with advancing age in men, while a more modest decline occurred in women after the age of 50. A. Hemoglobin distribution in different age groups in 337 women. 31

32 B. Hemoglobin distribution in different age groups in 532 men. 32

33 Figure 3. A. Kaplan-Meier Event-Free Survival Curves for MACE. Kaplan-Meier event-free survival curves for MACE comparing the control with the groups of spasm in women (p = ) and men (p = ). MACE = major adverse cardiovascular event. 33

34 B. Kaplan-Meier Event-Free Survival Curves for Coronary Events. Kaplan-Meier event-free survival curves for coronary events showing significantly more events in the groups of spasm in women (p = ) and men (p < ) than the control group. 34

35 C. Kaplan-Meier Event-Free Survival Curves for Coronary Events. 35 Kaplan-Meier event-free survival curves for coronary events comparing the groups of spasm in women with high or low hemoglobin levels.

36 D. Kaplan-Meier Event-Free Survival Curves for Coronary Events. 36 Kaplan-Meier event-free survival curves for coronary events comparing the groups of spasm in men with high or low hemoglobin levels.

37 37 A 59-year-old woman with diabetes mellitus presented at the emergency department with a sudden onset of chest pain radiating to her neck, jaw, and bilateral shoulders for 6 hours. The blood pressure was 100/48 mm Hg and the pulse 52 bpm. An electrocardiogram showed sinus rhythm at 42 bpm. The level of troponin I was elevated (3.71 ng/ml; reference, <0.5). She was diagnosed as acute non-st-segment elevation myocardial infarction. Emergency coronary angiography revealed a 60% stenosis in the mid (Figure 1A) and a total occlusion in the distal right coronary artery (RCA). Other coronary arteries were normal. A guidewire could be advanced without difficulty. A control injection showed a free jet of contrast into the pericardium through an exit hole, a localized contrast

38 blush in the mid RCA and a linear deposit of contrast outlining the inferior pericardial sac in the distal RCA (Figure 1B). Coronary spasm developed in the mid RCA (Figure 1C). Simultaneous electrocardiograms demonstrated ST-segment elevation at the same time. Ventricular fibrillation followed for 62 seconds and recovered with cardioversion (Figure 2). A good result was obtained after immediate implantation of one stent (Titan 2, Hexacath, France) in the mid and delayed implantation of the other stent (Titan 2, Hexacath, France) one week later in the distal RCA (Figure 1D), when complete angiographic sealing appeared at the site of coronary perforation. 38

39 39

40 The more likely cause of ST-segment elevation in this case was coronary spasm. The catheter-induced coronary spasm was unlikely because the patency of ostial RCA was spared and the spasm was located quite far away from the catheter tip. Coronary spasm may be related to hemopericardium as hemoglobin may interfere with nitric oxide action and inhibit endothelium-dependent relaxation. To the best of our knowledge, this is the first to illustrate that blood-bathed coronary artery could develop spasm in hemopericardium. 40