Natsuki Nakamura

Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm.

We injected acetylcholine (ACh), the neurotransmitter of the parasympathetic nervous system, into the coronary arteries of 28 patients with variant angina. Injection of 10 to 80 micrograms ACh into the coronary artery responsible for the attack induced spasm together with chest pain and ST segment elevation or depression on the electrocardiogram in 30 of the 32 arteries of the 25 of the 27 patients. The injection of 20 to 100 micrograms ACh into the coronary artery not responsible for the attack in 18 patients resulted in various degrees of constriction in most of them, but no spasm in any of them. After intravenous injection of 1.0 to 1.5 mg atropine sulfate, the injection of ACh into the coronary artery responsible for the attack did not induce spasm or attack in any of the nine coronary arteries injected in eight patients. We conclude that the intracoronary injection of ACh induces coronary spasm and attack in patients with variant angina and that the activity of the parasympathetic nervous system may play a role in the pathogenesis of coronary spasm. We also conclude that the intracoronary injection of ACh is a useful test for provocation of coronary spasm.

Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials.

BACKGROUND Patients who have acute myocardial infarction remain at major risk of cardiovascular events. We aimed to assess the effects of either human atrial natriuretic peptide or nicorandil on infarct size and cardiovascular outcome. METHODS We enrolled 1216 patients who had acute myocardial infarction and were undergoing reperfusion treatment in two prospective, single-blind trials at 65 hospitals in Japan. We randomly assigned 277 patients to receive intravenous atrial natriuretic peptide (0.025 microg/kg per min for 3 days) and 292 the same dose of placebo. 276 patients were assigned to receive intravenous nicorandil (0.067 mg/kg as a bolus, followed by 1.67 microg/kg per min as a 24-h continuous infusion), and 269 the same dose of placebo. Median follow-up was 2.7 (IQR 1.5-3.6) years for patients in the atrial natriuretic peptide trial and 2.5 (1.5-3.7) years for those in the nicorandil trial. Primary endpoints were infarct size (estimated from creatine kinase) and left ventricular ejection fraction (gauged by angiography of the left ventricle). FINDINGS 43 patients withdrew consent after randomisation, and 59 did not have acute myocardial infarction. We did not assess infarct size in 50 patients for whom we had fewer than six samples of blood. We did not have angiographs of left ventricles in 383 patients. Total creatine kinase was 66,459.9 IU/mL per h in patients given atrial natriuretic peptide, compared with 77,878.9 IU/mL per h in controls, with a ratio of 0.85 between these groups (95% CI 0.75-0.97, p=0.016), which indicated a reduction of 14.7% in infarct size (95% CI 3.0-24.9%). The left ventricular ejection fraction at 6-12 months increased in the atrial natriuretic peptide group (ratio 1.05, 95% CI 1.01-1.10, p=0.024). Total activity of creatine kinase did not differ between patients given nicorandil (70 520.5 IU/mL per h) and controls (70 852.7 IU/mL per h) (ratio 0.995, 95% CI 0.878-1.138, p=0.94). Intravenous nicorandil did not affect the size of the left ventricular ejection fraction, although oral administration of nicorandil during follow-up increased the left ventricular ejection fraction between the chronic and acute phases. 29 patients in the atrial natriuretic peptide group had severe hypotension, compared with one in the corresponding placebo group. INTERPRETATION Patients with acute myocardial infarction who were given atrial natriuretic peptide had lower infarct size, fewer reperfusion injuries, and better outcomes than controls. We believe that atrial natriuretic peptide could be a safe and effective adjunctive treatment in patients with acute myocardial infarction who receive percutaneous coronary intervention.

Effects of intracoronary injection of acetylcholine on coronary arterial diameter

The effects of intracoronary injection of acetylcholine on coronary arterial diameter was examined by coronary arteriography in 30 adult patients (13 men, 17 women), aged 23 to 67 years (mean 51), with normal or almost normal coronary arteriographic findings. Patients with angina pectoris, myocardial infarction and other severe cardiac diseases were excluded. Two minutes after injection of 30 to 100 micrograms of acetylcholine into the left coronary artery, significant diffuse narrowing (more than 25% reduction in diameter) of the left main trunk, the proximal, mid- and distal left anterior descending artery, and the proximal, mid- and distal left circumflex artery occurred in 1 (4%), 5 (20%), 3 (12%), 9 (36%), 6 (24%), 8 (32%) and 3 (12%) of 25 patients, respectively. After injection of 30 to 50 micrograms of acetylcholine into the right coronary artery, significant diffuse narrowing of the proximal, mid- and distal right coronary artery occurred in 5 (25%), 7 (35%) and 10 (50%) of 20 patients, respectively. However, significant diffuse dilatation (more than 25% increment in diameter) appeared in the left main trunk, left anterior descending, left circumflex and right coronary arteries in a few patients. These results indicate that acetylcholine induces coronary vasoconstriction in a significant number and coronary vasodilatation in a small number of adult humans, and that response of the coronary artery to acetylcholine varies along the course of the coronary artery.

Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation – The Kumamoto Intervention Conference Study (KICS) Registry –

BACKGROUND The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. METHODS AND RESULTS This study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to-moderate CKD (30≤eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). CONCLUSIONS In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.

Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS Trial): Study protocol for a randomized controlled trial

BACKGROUND Although the positive association between achieved low-density lipoprotein cholesterol (LDL-C) level and the risk of coronary artery disease (CAD) has been confirmed by randomized studies with statins, many patients remain at high residual risk of events suggesting the necessity of novel pharmacologic strategies. The combination of ezetimibe/statin produces greater reductions in LDL-C compared to statin monotherapy. PURPOSE The Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS) trial was aimed at evaluating the effects of ezetimibe addition to atorvastatin, compared with atorvastatin monotherapy, on coronary plaque regression and change in lipid profile in patients with CAD. METHODS The study is a prospective, randomized, controlled, multicenter study. The eligible patients undergoing IVUS-guided percutaneous coronary intervention will be randomly assigned to receive either atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily using a web-based randomization software. The dosage of atorvastatin will be increased by titration within the usual dose range with a treatment goal of lowering LDL-C below 70 mg/dL based on consecutive measures of LDL-C at follow-up visits. IVUS will be performed at baseline and 9-12 months follow-up time point at participating cardiovascular centers. The primary endpoint will be the nominal change in percent coronary atheroma volume measured by volumetric IVUS analysis. CONCLUSION PRECISE-IVUS will assess whether the efficacy of combination of ezetimibe/atorvastatin is noninferior to atorvastatin monotherapy for coronary plaque reduction, and will translate into increased clinical benefit of dual lipid-lowering strategy in a Japanese population.

Synergistic effect of ezetimibe addition on coronary atheroma regression in patients with prior statin therapy: Subanalysis of PRECISE-IVUS trial.

Background The IMPROVE-IT trial showed that the clinical benefit of statin/ezetimibe combination appeared to be pronounced in patients with prior statin therapy. We hypothesized that the antiatherosclerotic effect of atorvastatin/ezetimibe combination was pronounced in patients with statin pretreatment. Methods In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound-guided percutaneous coronary intervention were randomized to atorvastatin/ezetimibe combination or atorvastatin alone. The dosage of atorvastatin was uptitrated with a treatment goal of lowering low-density lipoprotein cholesterol to below 70 mg/dl in both groups. Serial volumetric intravascular ultrasound was performed at baseline and 9–12 month follow-up to quantify the coronary plaque response in 202 patients. We compared the intravascular ultrasound endpoints in all subjects, stratified by the presence or absence of statin pretreatment. Results The baseline low-density lipoprotein cholesterol level (100.7 ± 23.1 mg/dl vs. 116.4 ± 25.9 mg/dl, p < 0.001) and lathosterol (55 (38 to 87)) µg/100 mg total cholesterol vs. 97 (57 to 149) µg/100 mg total cholesterol, p < 0.001) was significantly lower, and campesterol/lathosterol ratio (3.9 (2.4 to 7.4) vs. 2.6 (1.5 to 4.1), p < 0.001) was significantly increased in patients with statin pretreatment. Contrary to the patients without statin pretreatment (−1.3 (−3.1 to −0.1)% vs. −0.9 (−2.3 to 0.9)%, p = 0.12), the atorvastatin/ezetimibe combination showed a significantly stronger reduction in delta percent atheroma volume, compared with atorvastatin alone, in patients with statin pretreatment (−1.8 (−3.6 to −0.3)% vs. −0.1 (−1.6 to 0.8)%, p = 0.002). Conclusion Compensatory increase in cholesterol absorption observed in statin-treated patients might attenuate the inhibitory effects of statins on coronary plaque progression. A low-dose statin/ezetimibe combination might be a promising option in statin-hyporesponder.

Clinical outcomes of percutaneous coronary intervention (PCI) at hospital with or without onsite cardiac surgery backup.

Clinical outcomes of percutaneous coronary intervention (PCI) at hospital with or without onsite cardiac surgery backup Tomonori Akasaka , Seiji Hokimoto ⁎, Shuichi Oshima , Koichi Nakao , Kazuteru Fujimoto , Yuji Miyao , Hideki Shimomura , Ryusuke Tsunoda , Toyoki Hirose , Ichiro Kajiwara , Toshiyuki Matsumura , Natsuki Nakamura , Nobuyasu Yamamoto , Shunichi Koide , Hideki Oka , Yasuhiro Morikami , Naritsugu Sakaino , Koichi Kaikita , Sunao Nakamura , Kunihiko Matsui , Hisao Ogawa , on behalf of, Kumamoto Intervention Conference Study (KICS) Investigators

Clinical outcomes of percutaneous coronary intervention for acute coronary syndrome between hospitals with and without onsite cardiac surgery backup.

BACKGROUND Based on the 2011 American College of Cardiology/American Heart Association percutaneous coronary intervention (PCI) guideline, it is recommended that PCI should be performed at hospital with onsite cardiac surgery. But, data suggest that there is no significant difference in clinical outcomes following primary or elective PCI between the two groups. We examined the impact of with or without onsite cardiac surgery on clinical outcomes following PCI for acute coronary syndrome (ACS). METHODS AND RESULTS From August 2008 to March 2011, subjects (n=3241) were enrolled from the Kumamoto Intervention Conference Study (KICS). Patients were assigned to two groups treated in hospitals with (n=2764) or without (n=477) onsite cardiac surgery. Clinical events were followed up for 12 months. Primary endpoint was in-hospital death, cardiovascular death, myocardial infarction, and stroke. And we monitored in-hospital events, non-cardiovascular deaths, bleeding complications, revascularizations, and emergent coronary artery bypass grafting (CABG). There was no overall significant difference in primary endpoint between hospitals with and without onsite cardiac surgery [ACS, 7.6% vs. 8.0%, p=0.737; ST-segment elevation myocardial infarction (STEMI), 10.4% vs. 7.5%, p=0.200]. There was also no significant difference when events in primary endpoint were considered separately. In other events, revascularization was more frequently seen in hospitals with onsite surgery (ACS, 20.0% vs. 13.0%, p<0.001; STEMI, 21.9% vs. 14.5%, p=0.009). We performed propensity score matching analysis to correct for the disparate patient numbers between the two groups, and there was also no significant difference for primary endpoint (ACS, 8.6% vs. 7.5%, p=0.547; STEMI, 11.2% vs. 7.5%, p=0.210). CONCLUSIONS There is no significant difference in clinical outcomes following PCI for ACS between hospitals with and without onsite cardiac surgery backup in Japan.

Dose-dependent INhibitory effect of rosuVastatin In Japanese patienTs with Acute myocardial infarcTION on serum concentration of matrix metalloproteinases – INVITATION trial

BACKGROUND Acute myocardial infarction (AMI) is mainly characterized by the rupture of lipid-rich vulnerable atherosclerotic plaque. The matrix metalloproteinases (MMPs) have been shown to play a critical role in inflammatory processes underlying plaque rupture. Some reports suggested statins inhibit the increased MMP levels after AMI. However, there are a few comparison studies between the different dosages of the same statin and circulating levels of MMPs. PURPOSE This study will preliminarily investigate the potential effects of appropriate or low dose of rosuvastatin on circulating MMPs levels in AMI patients. Moreover, we will also obtain plasma from patients while undergoing diagnostic angiography to determine differences in various cardiac sites and peripheral vessels. METHODS This study is a multicenter, open-label, randomized, parallel-group study to be conducted to compare the appropriate or low dose of rosuvastatin in the effect on serum levels of inflammatory markers in AMI patients. The eligible patients undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive either appropriate or low-dose rosuvastatin daily using a web-based randomization software within 24h after PCI. The low-dose group will be treated with rosuvastatin 2.5mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5mg once daily, and the dose of rosuvastatin will be titrated to 10mg within 4 weeks. During administration of the study treatment, subjects will undergo laboratory testing including MMPs and be monitored for the occurrence of adverse events up to 24 weeks. The primary endpoint will be the change rate of MMPs at 24 weeks after administration. CONCLUSIONS INVITATION will compare the appropriate or low dose of rosuvastatin in the effects on serum levels of inflammatory markers including MMPs in AMI patients. This study will provide significant information on rosuvastatin as an anti-inflammatory agent for AMI.

Prognostic Value of the CHADS2 Score for Adverse Cardiovascular Events in Coronary Artery Disease Patients Without Atrial Fibrillation—A Multi‐Center Observational Cohort Study

Background The CHADS 2 score has mainly been used to predict the likelihood of cerebrovascular accidents in patients with atrial fibrillation. However, increasing attention is being paid to this scoring system for risk stratification of patients with coronary artery disease. We investigated the value of the CHADS 2 score in predicting cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. Methods and Results This was a multicenter, observational cohort study. The subjects had been admitted to one of the participating institutions with coronary artery disease requiring percutaneous coronary intervention. We calculated the CHADS 2 scores for 7082 patients (mean age, 69.7 years; males, 71.9%) without clinical evidence of atrial fibrillation. Subjects were subdivided into low‐ (0–1), intermediate‐ (2–3), and high‐score (4–6) groups and followed for 1 year. The end point was a composite of cardiovascular/cerebrovascular death, nonfatal myocardial infarction, and ischemic stroke at 1‐year follow‐up. Rates of triple‐vessel/left main trunk disease correlated positively with CHADS 2 score categories. CHADS 2 scores among single, double, and triple‐vessel/left main trunk groups were 2 (1–2), 2 (1–3), and 2 (2–3), respectively (P<0.001). A total of 194 patients (2.8%) had a cardiovascular/cerebrovascular event, and Kaplan–Meier analysis demonstrated a significantly higher probability of cardiovascular/cerebrovascular events in proportion to a higher CHADS 2 score (log‐rank test, P<0.001). Multivariate Cox hazard analysis identified CHADS 2 score (per 1 point) as an independent predictor of cardiovascular/cerebrovascular events (hazard ratio, 1.31; 95% CI, 1.17–1.47; P<0.001). Conclusions This large cohort study indicated that the CHADS 2 score is useful for the prediction of cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation.