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  • Int. J. Med. Sci. 2013, Vol. 10


    IInntteerrnnaattiioonnaall JJoouurrnnaall ooff MMeeddiiccaall SScciieenncceess 2013; 10(3):255-264. doi: 10.7150/ijms.5383

    Research Paper

    Gender-Specific Prognosis and Risk Impact of C-Reactive Protein, Hemoglobin and Platelet in the Development of Coronary Spasm Ming-Yow Hung1,2,3, Kuang-Hung Hsu4, Wei-Syun Hu2, Nen-Chung Chang1,5, Chun-Yao Huang1,5, Ming-Jui Hung6

    1. Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 2. Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 3. Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan 4. Laboratory for Epidemiology, Department of Health Care Management, Chang Gung University, Taoyuan, Taiwan 5. Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan 6. Department of Cardiology, Chang Gung Memorial Hospital, Keelung, Chang Gung University College of Medicine, Taiwan

    Corresponding author: Ming-Jui Hung, MD, PhD, Department of Cardiology, Chang Gung Memorial Hospital at Keelung, 222 Maijin Road, Keelung 20401, Taiwan. Tel:+886-2-24313131 ext 3168; Fax: +886-2-24335342; e-mail:

    Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License ( licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.

    Received: 2012.10.14; Accepted: 2013.01.09; Published: 2013.01.22


    Background: Scarce data are available on hemoglobin and platelet in relation to coronary artery spasm (CAS) development. We sought to determine the roles that high-sensitivity C-reactive protein (hs-CRP), hemoglobin and platelet play in CAS patients. Methods: Patients (337 women and 532 men) undergoing coronary angiography with or without CAS but without obstructive coronary artery disease were evaluated during a 12-year period. Results: Among women with high hemoglobin levels, the odds ratios (OR) from the lowest (3 mg/l) of hs-CRP were 1.21, 2.15, and 5.93 (p=0.009). In women with low hemoglobin levels, an elevated risk was found from the middle to the highest tertiles of hs-CRP (OR 0.59 to 3.85) (p=0.004). This relationship was not observed in men. In men, platelet count was the most significant risk factor for CAS (p=0.004). The highest likelihood of developing CAS was found among women with the highest hs-CRP tertile and low platelet counts (OR 8.77; 95% confidence interval [CI] 2.20-35.01) and among men with the highest hs-CRP tertile and high platelet counts (OR 4.58; 95% CI 0.48-43.97). Neither hemoglobin level nor platelet count was associated with frequent recurrent angina in both genders with CAS whereas death and myo-cardial infarction were rare. Conclusions: There are positive interactions among hs-CRP, hemoglobin and platelet in women with this disease, but not in men. While hemoglobin is a modifier in CAS development in women, platelet count is an independent risk factor for men. Both women and men have good prognosis of CAS.

    Key words: gender, hemoglobin, platelets, C-reactive protein, coronary spasm

    Introduction Coronary artery spasm (CAS), of which the

    mechanism is not fully understood, is an important cause of variant angina and ischemic heart disease

    [1-2]. While smoking and inflammation, characterized by elevated high-sensitivity C-reactive protein (hs-CRP) levels [2, 3], may predispose to CAS, they


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  • Int. J. Med. Sci. 2013, Vol. 10


    are unlikely to constitute major direct causes of CAS in the whole population of patients with this disease [2]. CAS has been even purportedly associated with bitter orange (Citrus aurantium)-containing products [4]. Thus, elucidating other potential triggers could represent elusive therapeutic targets. It has long been recognized that red blood cells are vasoactive [5-7]. While the benefit of modest anemia to reduce blood viscosity is well established in cerebral spasm [7, 8], it is unclear in CAS. A J-shaped relationship has been observed between hemoglobin (Hb) levels and prog-nosis, indicating that low and high Hb levels are as-sociated with poor prognosis of patients with coro-nary artery disease (CAD) [9]. Such an association, however, has never been investigated in patients with CAS.

    A dynamic interaction has been demonstrated between platelet aggregates and CAS in myocardial infarction [1]. Transient increases in platelet counts are observed in many inflammatory diseases [10]. Although there is evidence that women have higher platelet counts and reactivity than men with CAD [11], it is unclear whether there is a similar gender disparity in CAS. We previously demonstrated that the relationship between hs-CRP and CAS in patients without obstructive CAD differed between women and men and that age contributed to CAS develop-ment in men [4]. Little is known, however, about the effect of the relationship among hs-CRP, Hb and platelet on risk and prognosis for CAS. Therefore, we enrolled more patients with and without CAS to de-termine whether there are interactions among gender, hs-CRP, Hb and platelet that influence CAS devel-opment in patients without obstructive CAD. Fur-thermore, we determined the long-term prognosis of CAS in these patients.

    Methods Study population

    From January 1999 to December 2010, 869 pa-tients with suspected ischemic heart disease and no angiographic evidence of obstructive CAD were sub-jected to intracoronary methylergonovine testing. Inclusion criteria for patients with CAS included spontaneous chest pain at rest associated with elec-trocardiographic evidence of ST-segment elevation or depression, subsequently relieved by sublingual ad-ministration of nitroglycerin, no angiographic evi-dence of obstructive CAD after intracoronary nitro-glycerin administration, and/or a positive result on intracoronary methylergonovine provocation tests. The control group consisted of patients who pre-sented with atypical chest pain, no angiographic evi-

    dence of obstructive CAD, and negative results on intracoronary methylergonovine provocation tests (no CAS). Exclusion criteria included evidence of ob-structive CAD, inflammatory manifestations probably associated with noncardiac diseases (e.g., infections and autoimmune disorders), liver disease/renal fail-ure (serum creatinine level >2.5 mg/dl), collagen disease, or malignancy, and loss of blood samples. This study was approved by the Chang Gung Memo-rial Hospital Institutional Review Board (96-1069B) and the Taipei Medical University-Joint Institutional Review Board (201011004). All patients gave written informed consent.

    Definition of terms Current smoking was defined as having smoked

    a cigarette within 3 weeks of the cardiac catheteriza-tion. Diabetes mellitus was defined from dietary treatment and/or medical therapy. Baseline seated blood pressure is the mean of 6 readings obtained during the first 2 office visits performed 2 weeks apart. Hypertension is defined as blood pressure of >140/90 mmHg or receiving antihypertensive treat-ment. Hypercholesterolemia was defined where se-rum total cholesterol was >200 mg/dl.

    Laboratory analysis Blood specimens were collected after an over-

    night fast immediately before coronary angiography. Serum hs-CRP was measured in duplicate by an en-zyme-linked immunosorbent assay (IMMULITE hs-CRP, Diagnostic Products Corp., Los Angeles, California). The lower limit of this assay was 0.10 mg/l and coefficients of variation were 5% at 0.20 mg/l of C-reactive protein.

    Provocative protocol Coronary angiography was performed using the

    standard Judkins technique. Nitrates and calcium antagonists were withdrawn for 24 hours before the procedure. Left ventricular ejection fraction (LVEF) was calculated using Simpsons method. Obstructive coronary stenosis was defined as a 50% reduction in luminal diameter after administration of intracoro-nary nitroglycerin [12]. If no obstructive coronary stenosis was found, intracoronary methylergonovine (Methergin; Novartis, Basel, Switzerland) was ad-ministered stepwise (1, 5, 10, 30 g) first into the right coronary artery and subsequently into the left coro-nary artery. CAS was defined as a >70% reduction in luminal diameter compared with postintracoronary nitroglycerin, with associated angina and or ST de-pression or elevation [13]. Provocation testing was stopped with an intracoronary injection of 50-200 g

  • Int. J. Med. Sci. 2013, Vol. 10


    of nitroglycerin (Millisrol; G. Pohl-Boskamp, Ho-henlockstedt, Germany). Reversal in coronary artery diameter confirmed the diagnosis of CAS. Spontane-ous CAS was defined as the relief of >70% diameter stenosis after intracoronary nitroglycerin 50-200 g administration.

    Follow-up Patient follow-up data were obtained from

    medical records of outpatient visits and hospital re-admissions or telephone interviews. All patients with the exception of those who died were followed up for at least 12 months. The study end point was the oc-currence of a major adverse cardiovascular event (MACE), which is a composite of death, nonfatal myocardial infarction, and recurrent angina pectoris requiring repeat coronary angiography. All deaths were considered cardiac-related deaths unless an unequivocal noncardiac cause could be identified. Coronary events were defined as nonfatal myocardial infarction an