Ming Jui Hung

Coronary Artery Spasm: Review and Update

Coronary artery spasm (CAS), an intense vasoconstriction of coronary arteries that causes total or subtotal vessel occlusion, plays an important role in myocardial ischemic syndromes including stable and unstable angina, acute myocardial infarction, and sudden cardiac death. Coronary angiography and provocative testing usually is required to establish a definitive diagnosis. While the mechanisms underlying the development of CAS are still poorly understood, CAS appears to be a multifactorial disease but is not associated with the traditional risk factors for coronary artery disease. The diagnosis of CAS has important therapeutic implications, as calcium antagonists, not β-blockers, are the cornerstone of medical treatment. The prognosis is generally considered benign; however, recurrent episodes of angina are frequently observed. We provide a review of the literature and summarize the current state of knowledge regarding the pathogenesis of CAS.

Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells

Objective We hypothesized a possible mechanism for atherosclerosis in which interleukin-6 (IL-6) might affect the endothelial nitric oxide synthase (eNOS)–caveolin-1 interaction and result in decreased nitric oxide bioavailability in the setting of low-grade inflammation. Methods Because eNOS and caveolin-1 are crucial for vascular tone control, we studied the effects of IL-6 on the expression and activation of eNOS and caveolin-1 in human vascular endothelial cells. Results IL-6 inhibited the phosphorylation of eNOS at Ser1177 and the bradykinin-stimulated nitric oxide production; however, eNOS protein expression was not changed. In addition, IL-6 inhibited bradykinin-stimulated Akt phosphorylation at Ser473 and Thr 308 without affecting the Akt protein expression. IL-6 did not alter the mRNA level of caveolin-1; however, the caveolin-1 protein level was significantly increased dose-dependently. The binding of eNOS and caveolin-1 in endothelial cells, as demonstrated by coimmunoprecipitation assay, was increased by IL-6 treatment. IL-6 treatment was found to stabilize caveolin-1 protein and its half-life was estimated to prolong from 7.5 h to longer than 12 h. Furthermore, treatment with PD98059 and short interference RNA of extracellular signal-regulated kinase gene reversed the effects of IL-6 on eNOS and caveolin-1. Conclusion In addition to decreasing Akt phosphorylation, the results of this study demonstrate, for the first time, the molecular mechanism underlying the effect of IL-6 to decrease the nitric oxide bioavailability by increasing the half-life and, therefore, the protein levels of caveolin-1. The increased caveolin-1 proteins bind more eNOS and consequently decrease eNOS activation by reducing the Ser1177 phosphorylation.

Increased leukocyte Rho-associated coiled-coil containing protein kinase activity predicts the presence and severity of coronary vasospastic angina

OBJECTIVE Although inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) has been shown to prevent coronary vasospastic angina (CVA), direct evidence linking ROCK activity and CVA is lacking. Accordingly, we investigated whether ROCK activity is an independent marker for CVA and is altered after treatment with antispastic medications. METHODS AND RESULTS We prospectively studied 31 Taiwanese patients who were diagnosed with CVA and 33 control subjects. Subject demographics were recorded, and blood samples were obtained at baseline in all participants and in CVA patients after 3 months of antispastic treatment. Compared with control subjects, leukocyte ROCK activity was greater in CVA patients (136% versus 91%, P<0.001). A cutoff value for leukocyte ROCK activity of 104% predicted the presence of CVA with specificity and sensitivity rates of 88% and 84%, respectively. ROCK activity increased with the severity of CVA (P for trend<0.001). Following 3-month treatment of antispastic agents, leukocyte ROCK activity, high-sensitivity C-reactive protein, and interleukin-6 levels were reduced by 43%, 42% and 27%, respectively (P<0.05 for all). CONCLUSIONS Increased levels of leukocyte ROCK activity independently predicted the presence of CVA and correlated with CVA severity. Treatment with antispastic agents substantially reduced the level of leukocyte ROCK activity.

Interactions among gender, age, hypertension and C‐reactive protein in coronary vasospasm

Eur J Clin Invest 2010; 40 (12): 1094–1103

C-Reactive Protein for Predicting Prognosis and Its Gender-Specific Associations with Diabetes Mellitus and Hypertension in the Development of Coronary Artery Spasm

Background While hypertension is negatively associated with coronary artery spasm (CAS), scarce data are available on diabetes mellitus in relation to CAS. In addition, outcome prediction in patients with CAS is challenging due to the lack of appropriate biomarkers. Therefore, we sought to identify the roles that gender, high-sensitivity C-reactive protein (hs-CRP), diabetes mellitus and hypertension play in CAS development and prognosis. Methodology/Prinicpal Findings Patients (350 women and 547 men) undergoing diagnostic coronary angiography with or without proven CAS but without obstructive stenosis were evaluated at long-term follow-up (median 102 months). Diabetic women and diabetic men with low hs-CRP levels had a low and high risk of CAS (odds ratio [OR]: 0.16, 95% confidence interval [CI]: 0.01–1.88 and OR: 5.02, 95% CI: 1.03–24.54, respectively). The ORs of CAS in both women and men with the highest hs-CRP tertile (>3 mg/L) reduced from 4.41 to 1.45 and 2.98 to 1.52, respectively, if they had diabetes mellitus, and from 9.68 to 2.43 and 2.60 to 1.75, respectively, if they had hypertension. Hypertension had a more negative effect on CAS development in diabetic than non-diabetic women, which was not observed in men. The highest hs-CRP tertile was an independent predictor of adverse outcomes. Patients with the highest hs-CRP tertile had more coronary events than patients with the lowest hs-CRP tertitle (p = 0.021, log-rank test). Conclusions Diabetes mellitus contributes to CAS development in men with low hs-CRP levels, but not in women. There are negative effects of diabetes mellitus and hypertension on CAS development in patients with high hs-CRP levels and especially in women. Elevated hs-CRP level independently predicts adverse outcomes.

Pulsation, Systolic Thrill and Murmur in Femoral Veins Secondary to Severe Tricuspid Regurgitation

We report on a case of pulsatile femoral veins with a systolic thrill and murmur in a 26-year-old patient who exhibited severe tricuspid regurgitation. The pulsatile nature of the veins may result from the ‘ventricularization’ of venous pressure with each pressure pulse. The observed systolic thrill and murmur may be due to the systolic reversal of substantial regurgitant flow in the venous system of the lower limbs. This case also demonstrates that severe tricuspid regurgitation can have far-reaching manifestations.

Impact of Asthma on the Development of Coronary Vasospastic Angina: A Population-Based Cohort Study.

Abstract Although asthma increases the risk of cardiovascular disease, little is known about the relation of asthma and its severity to coronary vasospastic angina (CVsA). We hypothesized that asthma contributed to the development of CVsA. Patients in this population-based cohort study were retrospectively collected from the Taiwan National Health Insurance database. Using propensity score matching, subjects were stratified at a 1 : 4 ratio into a study group comprising 3087 patients with a diagnosis of CVsA, and a control group consisting of 12,348 patients who underwent coronary intervention for obstructive coronary artery disease (CAD) during the period 2000 to 2011. Asthma significantly increased the risk of new-onset CVsA independent of other comorbidities [adjusted odds ratio (OR) = 1.85, 95% confidence interval (95% CI) = 1.47–2.32, P < 0.001]. In addition, the risk of new-onset CVsA was significantly higher in previous users of oral or inhaled corticosteroids (oral corticosteroids: OR = 1.22, 95% CI = 1.01–1.49, P = 0.04; inhaled corticosteroids: OR = 1.89, 95% CI = 1.28–2.79, P = 0.001). In addition, the prevalence of asthma was highest among patients with CVsA alone, followed by patients with CAD and CVsA and patients who underwent coronary intervention for CAD alone (P trend < 0.001). Our study suggests that asthma is independently associated with CVsA and prior steroid use increases the risk of CVsA development.

Gender-Specific Prognosis and Risk Impact of C-Reactive Protein, Hemoglobin and Platelet in the Development of Coronary Spasm

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 (<1 mg/l) to the highest tertiles (>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 myocardial 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.

Effect of dialysis dependence and duration on post-coronary artery bypass grafting outcomes in patients with chronic kidney disease: A nationwide cohort study in Asia.

BACKGROUND Chronic kidney disease (CKD) is associated with adverse outcomes in patients who undergo coronary artery bypass grafting (CABG). However, the impact of preoperative dialysis dependence and duration in CKD patients on outcomes after CABG has limited research. OBJECTIVES To evaluate the effect of preoperative dialysis dependence and duration on CABG outcomes in patients with CKD. METHODS A total of 33,920 patients without CKD and 2573 patients with CKD, all of whom underwent isolated CABG between 1998 and 2009, were identified using the Taiwan National Health Insurance Research Database. The patients with CKD were divided into non-dialysis (N=1167), dialysis<3years (N=749), and dialysis≥3years (N=657) groups. The primary outcomes were cumulative incidence of all-cause mortality, cardiovascular (CV) death, and myocardial infarction (MI) or repeat revascularization. RESULTS After adjustment of all covariates, a higher all-cause mortality was associated with dialysis≥3years than with dialysis<3years (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.35-1.80; P<0.001) and with non-dialysis (HR, 1.41; 95% CI, 1.20-1.66; P<0.001) after 2years of follow-up. Similar results were observed for CV death. In addition, both the dialysis groups had a higher risk of MI or revascularization than the non-dialysis group. Furthermore, subgroup analysis revealed that longer duration was associated with a higher risk of 30-day mortality (P for linear trend <0.001). CONCLUSIONS Among the CABG recipients, dialysis dependence is associated with a higher incidence of MI or repeat revascularization, and longer dialysis duration is associated with a higher risk of mortality.

Research update for articles published in EJCI in 2012

Department of Cardiology and Coronary Unit, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain, Biomarkers Research Program, Biochemistry Department, College of Science, , Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia, Cardiovascular Research Center (CSIC-ICCC), Barcelona, Spain, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain, Cardiovascular Research Chair, UAB, Barcelona, Spain, Cardiology Department, Hospital Clinico Universitario, INCLIVA, University of Valencia, Valencia, Spain, First Clinical of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy, Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China, Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, Health Research Institute, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain, Liver Research Unit, Santa