Shinji Tayama

Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, on coronary spasm after withdrawal of calcium-channel blockers.

OBJECTIVES The purpose of this study was to determine whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) suppresses coronary spasm. BACKGROUND Coronary spasm is associated with endothelial dysfunction. Statins have been shown to improve endothelial function. METHODS This was a prospective, randomized, open-label, end point study. Sixty-four patients who had no significant organic coronary stenosis and in whom coronary spasm was induced by intracoronary injection of acetylcholine (ACh) were randomly assigned to fluvastatin 30 mg/day plus the conventional calcium-channel blocker (CCB) therapy (31 patients, statin group) or the conventional CCB therapy (33 patients, nonstatin group). After 6 months of treatment, the intracoronary injection of ACh was repeated and the coronary spasm was assessed. RESULTS Coronary spasm was suppressed in 16 of the 31 patients (51.5%, p < 0.0001) of the statin group and in 7 of the 33 patients (21.2%, p = 0.0110) of the nonstatin group after 6 months of treatment. Thus, the number of patients with ACh-induced coronary spasm was significantly reduced in the statin group as compared with the nonstatin group (51.6% vs. 21.2%, p = 0.0231) after 6 months of treatment. CONCLUSIONS The addition of fluvastatin 30 mg/day to the conventional CCB therapy for 6 months significantly reduced the number of patients with ACh-induced coronary spasm as compared with the conventional CCB therapy. Thus, a statin (fluvastatin) may possibly be a novel therapeutic drug for coronary spasm.

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

Background The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection, clinical features, and long‐term prognosis in patients with vasospastic angina (VSA). Methods and Results This is a retrospective, observational, single‐center study of 1877 consecutive patients who underwent ACh‐provocation test between January 1991 and December 2010. ACh‐provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis. ACh‐positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were ACh‐negative patients. ACh‐positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the ACh‐provoked diffuse spasm pattern in patients with VSA. Kaplan–Meier survival curve indicated better 5‐year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (P=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with VSA. Conclusions ACh‐induced diffuse coronary spasm was frequently observed in female VSA patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the ACh‐provoked coronary spasm subtypes in patients with VSA.

Impairment of coronary blood flow regulation by endothelium-derived nitric oxide in dogs with alloxan-induced diabetes

Diabetes mellitus is a major cause of ischemic coronary artery disease. Endothelial dysfunction is implicated in the pathogenesis of diabetic vascular disease. To examine coronary blood flow (CBF) regulation with endothelium-derived nitric oxide (EDNO) in the diabetic state, we compared the effects of both acetylcholine (ACh) and adenosine (Ado) on left circumflex coronary artery (LCX) blood flow in 12 vehicle-treated and 21 dogs made diabetic with alloxan anesthetized with pentobarbital. All dogs were pretreated with aspirin to inhibit endogenous prostaglandins. None of the hemodynamic parameters were significantly different in the two groups. The percent change in coronary vascular resistance (CVR) after ACh (100 ng/kg) infusion was significantly attenuated in diabetic dogs (-56.5 +/- 1.4%) as compared with vehicle-treated dogs (-64.5 +/- 1.2%) (p < 0.01), whereas the effect of Ado (1 microgram/kg) was not different between the two groups (-71.1 +/- 1.5% in vehicle, -67.0 +/- 1.3% in diabetes). After infusion of incremental doses of NG-nitro-L-arginine methyl ester (L-NAME) 10(-5)-10(-3)M, the effect of ACh was progressively inhibited in both groups and was different no longer between the two groups after the maximal dose. L-Arginine (L-ARG), but not D-ARG, significantly restored the effect of ACh in diabetic dogs but did not affect vehicle-treated dogs. The effect of Ado did not change after L- and D-ARG administration. Cu, Zn-superoxide dismutase (Cu, Zn-SOD) had no effect on any of the effects of ACh and Ado in diabetic dogs. Regulation of CBF with EDNO is impaired in dogs with alloxan-induced diabetes, and this impairment is partially restored by L-ARG.

Microvascular coronary artery spasm presents distinctive clinical features with endothelial dysfunction as nonobstructive coronary artery disease.

Background Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers. Methods and Results Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor–borderline ischemic electrocardiogram findings at rest, limited–baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate–induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months. Conclusions Microvascular CAS causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided. Clinical Trial Registration URL: www.umin.ac.jp/ctr. Unique identifier: UMIN000003839.

Growth differentiation factor-15 is a useful prognostic marker in patients with heart failure with preserved ejection fraction.

BACKGROUND Circulating growth differentiation factor 15 (GDF-15) levels correlate with heart mass and fibrosis; however, little is known about its value in predicting the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS We measured serum GDF-15 levels in 149 consecutive patients with left ventricular diastolic dysfunction (LVDD) and normal LV ejection fraction (>50%) and followed them for cardiovascular events. LVDD was defined according to the European Society of Cardiology guidelines. RESULTS The New York Heart Association functional class and circulating B-type natriuretic peptide (BNP) levels were significantly higher in the high-GDF-15 group (n = 75; greater than or equal to the median value [3694 pg/mL]) than in the low-GDF-15 group (n = 74). Patients were divided into HFpEF and LVDD groups according to the presence or absence of HF. Serum GDF-15 levels were significantly higher in the HFpEF group (n = 73) than in the LVDD group (n = 76) (median, 4215 [interquartile range, 3382-5287] vs 3091 [interquartile range, 2487-4217 pg/mL]; P < 0.0001). Kaplan-Meier curve analysis showed a significantly higher probability of cardiovascular events in the high-GDF-15 group than in the low-GDF-15 group for data of all patients (log-rank test P = 0.006) and data of patients in the HFpEF group only (P = 0.014). Multivariate Cox hazard analysis identified age (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.87-0.98; P = 0.008), atrial fibrillation (HR, 7.95; 95% CI, 1.98-31.85, P = 0.003), lnBNP (HR, 3.37; 95% CI, 1.73-6.55; P < 0.0001), and GDF-15 (ln[GDF-15]) (HR, 4.74; 95% CI, 1.26-17.88, P = 0.022) as independent predictors of primary end points. CONCLUSIONS GDF-15 is a potentially useful prognostic biomarker in patients with HFpEF.

Determination of cut-off levels for on-clopidogrel platelet aggregation based on functional CYP2C19 gene variants in patients undergoing elective percutaneous coronary intervention

INTRODUCTION Carriers of reduced-function CYP2C19 allele on antiplatelet therapy show diminished platelet inhibition and higher rate of clinical risk. The purpose of this study was to determine cut-off levels of VerifyNow P2Y12 system associated with effective inhibition of on-clopidogrel platelet aggregation to predict carriers of CYP2C19 reduced-function allele among patients undergoing percutaneous coronary intervention (PCI). MATERIALS AND METHODS We enrolled 202 consecutive patients with stable coronary artery disease (CAD) undergoing PCI and treated with clopidogrel. All patients underwent CYP2C19 genotyping and measurement of residual platelet aggregation by VerifyNow system. RESULTS Carriers of CYP2C19 reduced-function allele constituted 131 (65%) of 202 CAD patients. Platelet inhibition measured by P2Y12 reaction units (PRU) and %inhibition was diminished in carriers compared with noncarriers (PRU: 290.0±81.2 vs 217.6±82.4, p<0.001, %inhibition: 17.9±17.8 vs 35.5±22.8, p<0.001, respectively). Multiple logistic regression analysis identified PRU and %inhibition as significant predictors of carrier state [odds ratio (OR) 4.95; 95% confidence interval (95%CI): 2.49 to 9.85; p<0.001, OR 5.55; 95%CI: 2.80 to 10.99; p<0.001, respectively]. Receiver-operating characteristic analysis showed that PRU and %inhibition were significant predictors of carrier state [area under the curve (AUC) 0.736 (95%CI: 0.664 to 0.808; p<0.001), AUC 0.727 (95%CI: 0.651 to 0.803; p<0.001), respectively]. The cut-off levels of PRU and %inhibition were 256 and 26.5% for the identification of carriers. CONCLUSIONS Our results suggested that the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentially useful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI.

Coronary plaque component in patients with vasospastic angina: A virtual histology intravascular ultrasound study

BACKGROUND Coronary spasm plays an important role in the pathogenesis of ischemic heart disease. However, tissue components of coronary plaque in patients with vasospastic angina (VSA) have been unknown. This study used virtual histology (VH)-intravascular ultrasound (IVUS) to elucidate the tissue component of spastic coronary arteries and its gender differences in patients with VSA. METHODS According to acetylcholine provocation tests, the study subjects (42 patients [19 men, 23 women, 61 ± 13 years]) were divided into 2 groups: the VSA group of 26 patients and the non-VSA group of 16 patients. After nitrate injection, IVUS volumetric analysis was done, and the parameters were compared between the groups. RESULTS Although clinical demographics were almost identical between the groups, VSA group had lower plasma adiponectin level (5.9 ± 3.3 μg/ml vs. 11.2 ± 7.6 μg/ml, p=0.007) and tended to have higher high-sensitivity C-reactive protein (0.15 ± 0.24 mg/dl vs. 0.06 ± 0.04 mg/dl, p=0.1) than non-VSA group. VSA group had diffusely thickened intima (% plaque volume, 34 ± 11% vs. 27 ± 7%, p=0.01) compared with non-VSA group. However, plaque components of patients with VSA were similar with that of non-VSA patients (dense calcium, 4 ± 6% vs. 3 ± 4%; necrotic core, 10 ± 9% vs. 8 ± 6%; fibrofatty, 19 ± 16% vs. 22 ± 11%; and fibrous, 67 ± 16% vs. 67 ± 9%). Although male patients with VSA had atherogenic lipid and metabolic profiles than female VSA patients, there were no significant gender differences in the volumetric IVUS parameters and plaque components. CONCLUSIONS Compared with non-VSA patients, VSA patients had diffusely thickened fibrous-dominant coronary plaque without gender difference, and that might suggest the role of vasospasm in the development of atherosclerosis.

Combination Treatment of Rosuvastatin or Atorvastatin, with Regular Exercise Improves Arterial Wall Stiffness in Patients with Coronary Artery Disease

Objective Statin- and exercise-therapy are both clinically beneficial by preventing cardiovascular events in patients with coronary artery disease (CAD). However, there is no information on the vascular effects of the combination of statins and exercise on arterial wall stiffness in CAD patients. Methods The present study is a sub-analysis of PRESET study that determined the effects of 20-week treatment with statins (rosuvastatin, n = 14, atorvastatin, n = 14) combined with regular exercise on arterial wall stiffness assessed by measurement of brachial and ankle pulse wave velocity (baPWV) in CAD patients. Results The combination of statins and regular exercise significantly improved exercise capacity, lipid profile, including low- and high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hs-CRP), baPWV (baseline: 1747±355, at 20 weeks of treatment: 1627±271 cm/s, p = 0.008), and basophil count (baseline: 42±32, 20 weeks: 26±15 cells/µL, p = 0.007), but had no effect on blood pressure (baseline: 125±22, 20 weeks: 121±16 mmHg). Changes in baPWV correlated significantly with changes in basophil count (r = 0.488, p = 0.008), but not with age, lipids profile, exercise capacity, or hs-CRP. Conclusion In CAD patients, the combination treatment with statins and exercise resulted in significant amelioration of arterial wall stiffness, at least in part, through reduction of circulating basophils.

Comparison of pitavastatin with atorvastatin in increasing HDL-cholesterol and adiponectin in patients with dyslipidemia and coronary artery disease: The COMPACT-CAD study

BACKGROUND Many large-scale clinical trials have confirmed that statins are effective in reducing low-density lipoprotein cholesterol (LDL-C) level, resulting in reducing cardiovascular events. Recent studies have focused on the effects of statins on high-density lipoprotein cholesterol (HDL-C). Here we compared the effects of two statins on lipid profile and other metabolic parameters. METHODS The study population included 129 patients with stable coronary artery disease, hypercholesterolemia, and hypo-HDL-cholesterolemia (HDL-C<50mg/dl). They were randomly allocated to treatment by pitavastatin 2-4 mg/day or atorvastatin 10-20mg/day and followed-up for 30 months. The primary endpoint was percent changes in HDL-C and adiponectin during the study. The secondary endpoints were percent and absolute changes in markers of glucose metabolism, serum lipids, and apolipoproteins. RESULTS The effects of 30-month treatment with pitavastatin on HDL-C were significantly greater than those of atorvastatin (%change: pitavastatin: 20.1 ± 25.7%, atorvastatin: 6.3 ± 19.8%, p=0.01; absolute change: pitavastatin: 7.3 ± 9.1mg/dl, atorvastatin: 2.3 ± 8.0mg/dl, p=0.02). A similar trend was seen with regard to apolipoprotein-AI (ApoAI) (%change: pitavastatin: 20.8 ± 19.3%, atorvastatin: 11.4 ± 17.6%, p=0.03; absolute change: pitavastatin: 23.1 ± 20.2mg/dl, atorvastatin: 12.1 ± 19.4 mg/dl, p=0.02). Treatment with pitavastatin, but not atorvastatin, significantly increased adiponectin levels. Neither statin had a significant effect on hemoglobin A1c. No severe adverse events were registered during the study. CONCLUSION Long-term treatment with pitavastatin resulted in significantly greater increases in serum HDL-C and ApoAI levels without adverse effects on glucose metabolism, compared with atorvastatin.

Clinical features and prognosis of patients with coronary spasm-induced non-ST-segment elevation acute coronary syndrome.

Background The prevalence, clinical features, and long‐term outcome of patients with non–ST‐segment elevation acute coronary syndrome (NSTE ACS) associated with coronary spasm are not fully investigated. Methods and Results This observational multicenter study enrolled 1601 consecutive patients with suspected NSTE‐ACS who underwent cardiac catheterization between January 2001 and December 2010. A culprit lesion was found in 1152 (72%) patients. In patients without a culprit lesion, the acetylcholine provocation test was performed in 221 patients and was positive in 175 patients. In the other patients, coronary spasm was verified in 145 patients during spontaneous attack. Spasm‐induced NSTE‐ACS was diagnosed in 320 (20%) patients. Multivariable analysis identified age <70 years (odds ratio [OR] 2.19, 95% CI 1.58 to 3.04), estimated glomerular filtration rate >60 mL/min per 1.73 m2 (OR 1.72, 95% CI 1.16 to 2.56), and lack of hypertension (OR 2.55, 95% CI 1.90 to 3.41), dyslipidemia (OR 2.76, 95% CI 2.05 to 3.73), diabetes mellitus (OR 2.49, 95% CI 1.78 to 3.48), previous myocardial infarction (OR 5.37, 95% CI 2.89 to 10.0), and elevated cardiac biomarkers (OR 2.84, 95% CI 2.11 to 3.83) as significant correlates of spasm‐induced NSTE‐ACS (P<0.01 for all variables). Transient ST‐segment elevation during spontaneous attack (variant angina) was observed in 119 patients with spasm‐induced NSTE‐ACS. Variant angina was more common in nondyslipidemic men among patients with spasm‐induced NSTE‐ACS. Conclusions The study showed frequent involvement of coronary spasm in the pathogenesis of NSTE‐ACS. Variant angina was observed in one third of patients with spasm‐induced NSTE‐ACS. Coronary spasm should be considered even in patients with less coronary risk factors and nonobstructive coronary arteries.