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In recent years, transthyretin amyloid cardiomyopathy (ATTR-CM) has received increasing attention; however, the epidemiology of ATTR-CM in Japan is not yet understood. In the Kumamoto Cardiac Amyloid Survey, we evaluated the current incidence, clinical characteristics, diagnostic approaches, and treatment strategies for ATTR-CM and compared tafamidis-prescription hospitals with regional hospitals.We conducted a retrospective multicenter observational cohort study. The registry included patients with ATTR-CM diagnosed in two tafamidis-prescription hospital institutes [Japanese Circulation Society (JCS)-certified facilities] and 15 regional cardiovascular facilities in Kumamoto between January 2018 and December 2020.In total, 174 patients were diagnosed with ATTR-CM. The incidence of ATTR-CM was estimated to be approximately 1 per 10,000 person-years in the elderly population (65 years old) in Kumamoto. Compared with that in the JCS-certified facilities cohort (n=115), age at diagnosis was significantly older (84.5 ± 5.6 vs. 77.5 ± 6.3 years old; p0.01) in the regional hospitals cohort (n=59). Histological (25% vs. 81%; p0.01) and genetic diagnosis (7% vs. 82%) were also less frequently performed. Probable (as indicated by positive bone scintigraphy findings with confirmation of monoclonal protein absence) and possible (as indicated by positive bone scintigraphy findings without confirmation of monoclonal protein absence) ATTR-CM accounted for the majority of cases (75% vs. 19%; p0.01) in the regional hospitals cohort compared to the JCS-certified facilities cohort. There were no cases of hereditary ATTR-CM among the patients who underwent TTR genetic testing (n=98).We confirmed the incidence of ATTR-CM in Kumamoto and the diagnostic approach used in patients with ATTR-CM. Further prospective studies with a larger sample are needed to validate our results and to further shed light on the epidemiology of ATTR-CM in Japan.

Aim Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. Methods This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. Results Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. Conclusions This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

Cardiovascular and cerebrovascular diseases are considered the principal cause of morbidity and mortality worldwide; the effect of stroke-induced cardiac manifestations is well recognized; however, not enough clinical data have been found about the impact of stroke with underlying cardiac disease. This study's objective is to assess the impact of stroke on the prognosis of patients with underlying IHD, who underwent PCI treatment. This was a multicenter, 1-year observational study in patients undergoing PCI in one of the 17 participating centers across Japan. 18,495 patients were registered on the PCI list; 2481 patients had a prior stroke experience, whereas 15,979 were stroke-free. Our study revealed that stroke patients were significantly older (mean age 73.5 ± 9.6, 69.7(± 11.5), respectively), and suffered from more comorbidities (diabetes, hypertension, and chronic kidney disease, p 0.0001). During the 1-year period, subjects with stroke showed higher incidence of clinical events compared to those without stroke; to illustrate, all-cause death accounted for 6.2% in patients with stroke, in contrast to only 2.8% in stroke-free patients (p 0.0001), cardiac death amounted for 2.2 and 1.2%, respectively (p 0.0001), recurrent stroke for 3.1% and 1.2% (p 0.0001), non-cardiac death for 3.6 and 1.54% (p 0.0001), and finally, hemorrhagic complications with 2.6 and 1.3% (p 0.0001). Kaplan-Meier analysis revealed that stroke patients had a higher probability of all-cause mortality, cardiac death, and recurrent stroke (log-rank p 0.0001). Cox hazard analysis also showed that the presence of stroke is a significant indicator in determining the outcome of cardiac death (HR = 1.457, 95% CI 1.036-2.051, p = 0.031); hence, proving it to be a crucial predictor on cardiac prognosis. History of prior stroke was common in PCI patients, and independently associated with a higher rate of subsequent cardiovascular and cerebrovascular events recurrence. Thus, highlighting an urgent need for comprehensive prevention of cardiac and cerebrovascular diseases.

Aim: Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM. Methods: The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9–12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL. Results: In DM patients, the monotherapy group (n = 13) and the DLLT group (n = 12) showed a similar prevalence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: −2.77 ± 3.47% vs. −0.77 ± 2.51%, P = 0.11; non-DM: −2.01 ± 3.36% vs. −0.08 ± 2.66%, P = 0.008). The change in LDL-C level was not correlated with ΔPAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r = 0.52, P = 0.008). Conclusions: ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.

An autonomic nervous disorder is an important characteristic of cardiac amyloidosis; however, the prevalence of autonomic dysfunction in wild-type transthyretin amyloidosis (ATTRThis is a single-center, retrospective, case-control study. Fifty patients with heart failure (HF) were studied. The etiologies of HF were as follows: ATTRThere was no difference in the CVR-ROur data suggested autonomic dysfunction in patients with ATTR

Graphical abstract, Highlights • Additional apical obstruction may lower LV obstruction flow velocity. • LV systole may last to the end of IVRT. • PSS may cause intraventricular flow. • Isovolumic relaxation flow does not always imply the presence of apical aneurysm.

The paradoxical association of obesity with mortality, named the "obesity paradox", has been inconsistent, possibly due to a difference between body mass index (BMI) and central obesity, estimated by waist circumference (WC) as patterns of adiposity.We enrolled 8513 participants from the Kumamoto Intervention Conference Study, a multicenter registry that included consecutive patients undergoing percutaneous coronary intervention (PCI) at 18 centers between 2008 and 2017 in Japan. Patients were divided into quartiles in ascending order of the BMI or WC. The primary endpoints were all-cause mortality and cardiovascular death within a year.There were 186 deaths (case fatality rate, 22.1/1000 person-years) during the follow-up period. The lowest group (1st quartile) of BMI or WC had the worst prognosis among the quartiles (1st quartile, 4.2%; 2nd quartile, 1.9%; 3rd quartile, 1.5%; 4th quartile, 1.1%; P 0.001 (χThe obesity paradox was observed in patients after PCI, and single-use of BMI (or WC) was sufficient to predict the prognosis of patients after PCI.

Percutaneous coronary intervention (PCI) has significantly advanced over the last 40 years, but it is not clear whether there have been any changes in prognosis in recent years. The Kumamoto Intervention Conference Study Real-World Registry is a multi-center registry that enrolls consecutive patients undergoing PCI in 17 centers in Kyushu, Japan. To elucidate the clinical impact of recent changes in treatment strategies, 8841 consecutive participants (historical PCI: n = 4038, enrolled between January 2013 and December 2014, and current PCI: n = 4803, between January 2015 and March 2017) with 1-year follow-up data were analyzed. The incidences of major adverse cardiovascular and other clinical events were comparable between historical PCI and current PCI, even though complex lesions were more frequent during the more recent period. During this period, the use of radial approaches, drug eluting stents, and coronary imaging was greater. The use of prasugrel was more frequent (P

Although there is accumulating evidence for the usefulness of imaging-guided percutaneous coronary intervention (PCI), there are few studies for acute coronary syndrome (ACS), and the impact of the frequency of use has not been well addressed. From the Kumamoto Intervention Conference Study; a Japanese registry comprising 17 institutions, consecutive patients undergoing successful PCI from April 2008 through March 2014 were enrolled. Subjects were divided into two groups: imaging-guided PCI and angiography-guided PCI. Clinical outcome was a composite of cardiac death, non-fatal myocardial infarction, and stent thrombosis within 1 year. A total of 6025 ACS patients were enrolled: 3613 and 2412 patients with imaging- and angiography-guided PCI, respectively. Adverse cardiac events were significantly lower in the imaging-guided PCI group (long-rank P P = 0.004). To assess the effects of frequency of imaging usage, we divided the 17 institutions into six low-, six moderate-, and five high-frequency groups. The event rates decreased depending on the frequency, seemingly driven by stepwise event suppression in angiography-guided PCI. In Japanese ACS patients, the incidence of adverse clinical events in patients treated with imaging-guided PCI were significantly lower than that in patients with angiography-guided PCI. Better clinical result was found in the institutions using intravascular imaging more frequently. University Hospital Medical Information Network (UMIN)-CTR (http://www.umin.ac.jp/ctr/). Identifier: KICS (UMIN000015397).

In patients with suspected coronary artery disease (CAD), coexisting extracardiac abnormalities have a major impact on the patient management. This study aimed to evaluate the image quality of whole-body computed tomography (CT) immediately after the coronary computed tomography angiography (CTA) and investigate the incidence of extracardiac findings in patients with suspected CAD. We enrolled 450 patients undergoing whole-body CT at 100 kVp and model-based iterative reconstruction immediately after the coronary CTA (Group A) and retrospectively reviewed 144 control patients who underwent conventional contrast-enhanced CT (120 kVp) with filtered back projection (Group B). We compared the signal-to-noise ratio (SNR) of the aorta and liver and radiation dose between the two groups. Then, we evaluated the prevalence of extracardiac findings in Group A. Compared with Group B, Group A demonstrated significantly higher aorta and liver SNR and lower radiation dose. In Group A, whole-body CT revealed 229 coexisting lesions in 165 patients, including 32 and 106 cases of oncologic and vascular diseases, respectively. Additional whole-body CT after coronary CTA may provide adequate image quality. Using additional whole-body CT, 36% of patients with suspected CAD had clinically relevant coexisting findings, including malignancy.

To compare the objective and subjective image qualities between single-energy computed tomography (CT) at 70 kVp and virtual monoenergetic imaging (VMI) of dual-source dual-energy CT for CT angiography with 180 mgI/kg.Total 63 patients scanned with 180 mgI/kg were randomly divided into two groups: Group A (32 patients) underwent CT angiography at 70-kVp, and Group B (31 patients) underwent dual-energy CT. VMI sets were generated at 10-keV increments between 40 and 100 keV. We calculated aortic attenuation, contrast-to-noise-ratio (CNR), signal-to-noise-ratio, figure of merit of CNR, and effective dose for each protocol. Three radiologists scored overall image quality and various arteries' visibility using a four-point scale. Quantitative and qualitative comparisons between 70 kVp and VMI with the highest CNR were performed with the two-tailed t test or Kruskal-Wallis test.The 40-keV images offered the highest CNR among VMIs. Aortic attenuation at 70 kVp was significantly lower than that at 40 keV (p0.001). However, the signal-to-noise-ratio, CNR, and figure of merit of CNR were significantly higher at 70 kVp than those at 40-keV (p0.001, p0.05, and p0.05, respectively). The effective dose of each group was almost equal. The qualitative visibility scores for various arteries, except the ascending and upper-abdominal aorta, were also better at 70 kVp than those at 40 keV.Aortic attenuation at 70 kVp with 180 mg I/kg was lower than that of VMI at 40 keV, and the objective and subjective image qualities were higher at 70 kVp than those at 40 keV.

Rationale and Objectives The purpose of this study was to evaluate the noise and image quality of images reconstructed with a knowledge-based iterative model reconstruction (knowledge-based IMR) in ultra-low dose cardiac computed tomography (CT). Materials and Methods We performed submillisievert radiation dose coronary CT angiography on 43 patients. We also performed a phantom study to evaluate the influence of object size with the automatic exposure control phantom. We reconstructed clinical and phantom studies with filtered back projection (FBP), hybrid iterative reconstruction (hybrid IR), and knowledge-based IMR. We measured effective dose of patients and compared CT number, image noise, and contrast noise ratio in ascending aorta of each reconstruction technique. We compared the relationship between image noise and body mass index for the clinical study, and object size for phantom study. Results The mean effective dose was 0.98 ± 0.25 mSv. The image noise of knowledge-based IMR images was significantly lower than those of FBP and hybrid IR images (knowledge-based IMR: 19.4 ± 2.8; FBP: 126.7 ± 35.0; hybrid IR: 48.8 ± 12.8, respectively) ( P P P P P Conclusion Compared to FBP and hybrid IR, the knowledge-based IMR offers significant noise reduction and improvement in image quality in submillisievert radiation dose cardiac CT.

Background and aims Although dual low-density lipoprotein cholesterol (LDL-C)-lowering therapy (DLLT) with statin-ezetimibe combination showed clinical benefit in patients with acute coronary syndrome (ACS) confirming "the lower, the better," the underlying mechanisms of DLLT are still unknown. Methods PRECISE-IVUS trial evaluated the effects of DLLT on IVUS-derived coronary atherosclerosis and lipid profile, compared with atorvastatin monotherapy, quantifying the coronary plaque response in 100 ACS patients. We explored the potential predictors of plaque regression. Results Lower total cholesterol, LDL-C, triglyceride, remnant-like particles cholesterol, and stronger reduction of small dense LDL-C and cholesterol absorption markers were observed in patients with plaque regression compared to those with progression. Multivariate analysis revealed that achieved LDL-C was the strongest predictor for coronary plaque regression (95% CI: 0.944–1.000, p = 0.05), followed by age (95% CI: 0.994–1.096, p = 0.09). Conclusions Incremental LDL-C lowering by DLLT was associated with stronger coronary plaque regression, reconfirming that lowering LDL-C to levels below previous targets provided additional clinical benefit.

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.

Background Despite standard statin therapy, a majority of patients retain a high “residual risk” of cardiovascular events. Objectives The aim of this study was to evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention (PCI). Methods This trial was a prospective, randomized, controlled, multicenter study. Eligible patients who underwent PCI were randomly assigned to atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily. Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol (LDL-C) Results The combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 ± 16.3 mg/dl vs. 73.3 ± 20.3 mg/dl; p Conclusions Compared with standard statin monotherapy, the combination of statin plus ezetimibe showed greater coronary plaque regression, which might be attributed to cholesterol absorption inhibition–induced aggressive lipid lowering. (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound [PRECISE-IVUS]; NCT01043380 )

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 24 h after PCI. The low-dose group will be treated with rosuvastatin 2.5 mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5 mg once daily, and the dose of rosuvastatin will be titrated to 10 mg 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.

Background The use of the smallest contrast dose is highly desirable in performing cardiac computed tomography (CT), especially for patients with cardiovascular diseases to prevent contrast-induced nephropathy. Purpose To evaluate the feasibility of 20% reduced contrast dose protocol in cardiac CT using 100 kVp and high-tube-current-time product setting. Material and Methods Fifty patients were scanned with our conventional 120 kVp protocol, and the other 50 patients underwent scans using a tube voltage of 100 kVp, a high-tube-current-time product, and a 20% reduced contrast dose. We evaluated estimated effective dose (ED), CT attenuation, image noise, and contrast-to-noise ratio (CNR) of the ascending aorta. We also evaluated CT attenuation of the coronary arteries. Two radiologists independently assessed image quality of coronary arteries. Results There was no significant difference in the ED between the 100 kVp and 120 kVp protocols (21.7 mSv ± 1.6 vs. 21.8 mSv ± 1.1, P = 0.65). There was no significant difference in the CNR of the ascending aorta between the 100 kVp and 120 kVp protocols (18.8 ± 3.5 vs. 18.7 ± 3.8, P = 0.98). Mean CT attenuation of the coronary arteries of the 100 kVp protocols was significantly higher than that of 120 kVp protocols ( P Conclusion For cardiac CT a voltage setting of 100 kVp and a high-tube-current-time product enable 20% reduction in the contrast dose without affecting the quality of coronary artery images compared with a 120 kVp and standard-contrast-dose CT protocol.

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.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.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).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.

We compared the fixed injection rate protocol (P2) with the fixed injection duration protocol (P1) for coronary CT angiography using the test bolus technique. We randomly assigned 100 patients to one of two protocols. In P1, they received 0.7 mL/kg Iohexol-350 in an injection duration of 9 s, and we selected a delay of 3 s after peak enhancement of test bolus scan. In P2, they received 0.7 mL/kg Iohexol-350 at an injection rate of 5 mL/s, and we selected a delay after peak enhancement of test bolus scan using the following formula: TID/2-2 s, where TID is the injection duration of full bolus. We compared attenuation values in the ascending aorta and coronary arteries and patient-to-patient enhancement variability at each segment. At all segments, CT attenuations of P2 were significantly greater than those of P1 (ascending aorta 400 ± 64 vs. 368 ± 60, P = 0.01; left main trunk 399 ± 67 vs. 369 ± 55, P = 0.02; proximal-RCA 393 ± 66 vs. 363 ± 56, P = 0.01). There was no significant difference in patient-to-patient enhancement variability at all segments between the two groups (P > 0.05). P2 yielded superior vessel enhancement and comparable patient-to-patient enhancement variability compared with P1 in thin patients.

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

Previous studies have showed that the intensive lipid lowering therapy (ILLT) with statins could decrease coronary atheroma plaque, but the effect is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We conducted to evaluate whether ILLT by ezetimibe combined with statin

Background Randomized trials have established statins as an agent for prevention of coronary heart disease (CHD). The purpose of this study was to assess the hypothesis that standard-dose statin therapy has a beneficial effect in normocholesterolemic diabetic patients with CHD. Methods and results A prospective, randomized, open, blinded-endpoint trial was conducted from 2002 to 2004 at 55 hospitals in Japan to evaluate the effect of statins on subsequent cardiovascular events. A total number of 1,016 CHD patients (301 patients with type 2 diabetes mellitus [DM] and 715 non-DM patients) with serum total cholesterol levels of 180-240 mg/dl were randomly divided into non-statin and statin treatments. Clinical parameters were comparable between DM and non-DM groups. Serum low-density lipoprotein (LDL)-cholesterol levels were equally decreased after statin treatment in the 2 groups. Statin treatment improved prognosis in both the DM and non-DM groups; however, the number needed to treat (NNT) and relative risk reduction (RRR) were remarkable especially in the DM group (NNT=8, RRR=67%) compared with the non-DM group (NNT=30, RRR=24%). Conclusions Standard-dose statin therapy provides incremental clinical benefits in DM patients with normal cholesterol levels compared with non-DM patients. The data suggest that DM patients may enjoy the pleiotropic effects of statins, independent of the LDL-cholesterol lowering effects of these agents.

Background Statins are widely used to reduce blood levels of low-density lipoprotein-cholesterol (LDL-C). Each statin has unique pharmacokinetic properties; lipophilicity is one such property and relates to tissue selectivity. Methods and Results The Multicenter Study for Aggressive Lipid-lowering Strategy by HMG-CoA Reductase Inhibitors in Patients with Acute Myocardial Infarction (MUSASHI-AMI) trial evaluated the effect of discretional statin treatment initiated within 96 h after onset of acute myocardial infarction (AMI) in Japanese patients. To clarify whether statin lipophilicity affects prognosis, a post hoc analysis of the MUSASHI-AMI database was performed. Patients who were assigned to receive statin were separated into 2 groups according to the lipophilicity of the statins they were administered: lipophilic statins (atorvastatin, fluvastatin, pitavastatin and simvastatin; LS group; n=131) or hydrophilic statins (pravastatin; HS group; n=110). There was no difference in baseline LDL-C concentrations between the 2 groups. Although LDL-C was decreased more potently in the LS than HS groups (-34% vs -19%; p=0.0069), acute coronary syndrome events tended to occur less frequently (3.6% vs 9.9%; p=0.0530) and the incidence of new Q-wave appearance in electrocardiogram was significantly lower (75% vs 89%; p=0.0056) in the HS than LS groups. Conclusions In normocholesterolemic Japanese patients after AMI, hydrophilic pravastatin could be superior to lipophilic statins at preventing new Q-wave appearance and reducing cardiovascular events. (Circ J 2007; 71: 1348 - 1353)

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 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.

The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants.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≤eGFR60, n=1,956) and severe CKD (eGFR30, 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).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.

Statins have been shown to prevent coronary artery disease and to preserve left ventricular function in dilated cardiomyopathy. We hypothesized that early use of statins would decrease cardiovascular events, including heart failure in patients with acute myocardial infarction (AMI). To examine the effect of statins in Japanese patients with AMI, a prospective, randomized, open-label trial was conducted in 486 patients with normal total cholesterol levels. Patients were randomly assigned to receive any available statin (n = 241) within 96 hours of AMI onset or no statin (n = 245) and were followed for up to 24 months. The primary end point was a composite of cardiovascular death, nonfatal AMI, recurrent symptomatic myocardial ischemia, congestive heart failure, and stroke. Event rate for the primary end point was lower in the statin group than in the nonstatin group (6.1% vs 11.4%, p = 0.0433). The statin group had a lower risk of congestive heart failure and symptomatic myocardial ischemia (p = 0.0154 and 0.0264, respectively). In conclusion, early lipid-lowering therapy with statins decreases recurrent cardiovascular events, in particular, congestive heart failure.

Background The purpose of this study was to investigate the feasibility of single-breath-hold whole-heart MRA with a 3-T system. Ten healthy male volunteers underwent single-breath-hold whole-heart coronary MRA at 3 T. We assessed acquisition time, scores of image quality of coronary artery (RCA: proximal, middle and distal, LAD: main, proximal, middle and distal, LCX: proximal and distal) and the visualized vessel length of RCA, LAD and LCX. Findings Mean acquisition time was 37.7 ± 5.2 sec. Coronary branch was successfully depicted in 67/80 branches (84%) in the 10 healthy volunteers with diagnostic image quality. And, the average visible RCA, LAD and LCX vessel length were 83.4 ± 22 mm and 59.6 ± 24 mm. Conclusions 3-T MRI with single-breath-hold 3D whole-heart coronary MRA can yield adequate image quality. Further study is needed to evaluate the clinical benefit of this technique.

The aim of this study was to determine whether isolated coronary arteries from patients with variant angina show hyperreactivity and/or supersensitivity to acetylcholine in vitro. Coronary arterial rings were obtained at autopsy within 3 h after death from six coronary arteries having spasm in four patients with variant angina and from 22 coronary arteries in 14 control patients with non-cardiac death. The coronary rings were suspended in the organ chamber filled with Krebs Henseleit solution bubbled with 95% O 2 + 5% CO 2 , and their isometric tensions were monitered. Arterial rings isolated from both the patients with variant angina and the controls contracted dose-dependently in response to acetylcholine (10 −9 – 10 −5 mol/l). EC 50 of acetylcholine (i.e. concentration producing 50% of maximum contraction) was not significantly different between the coronary arteries from patients with variant angina and those from controls, but maximum contraction elicited by acetylcholine (expressed as a percentage of the contraction elicited by 60 mmol/l KCl) was significantly greater in the coronary arteries from patients with variant angina than those from controls. In conclusion, the isolated coronary arteries from patients with variant angina have hypercontractile reactivity to acetylcholine. This intrinsic alteration of the coronary reactivity to acetylcholine may play a role in the genesis of coronary spasm occurring in the situations of enhanced parasympathetic nervous discharge.

Coronary recanalization rate and infarct size were compared between 2 different methods of intravenously administering recombinant tissue-type plasminogen activator (rt-PA) 41.4 mg; 1) an initial bolus dose of 30% followed by infusion of the remainder over 60 min (30% group), and an initial bolus dose of 10% followed by infusion of the remainder over 60 min (10% group). Thirty min after beginning rt-PA infusion, the coronary recanalization rate was higher in the 30% group than in the 10% group (82.9% (34/41) vs 53.7% (22/41), p < 0.01). The peak creatine kinase and peak creatine kinase-MB levels were lower in the 30% group than in the 10% group. We conclude that a higher initial bolus dose of rt-PA gives a higher rate of recanalization of the infarct-related artery at the very early phase, and probably leads to a smaller infarct size.

To evaluate the radiation dose and image quality of 100 kVp cardiac CT, and the effects of display setting optimization. We randomly assigned 100 patients undergoing cardiac CT to one of following two protocols. Fifty patients underwent our conventional protocol with 120 kVp, and the other 50 patients underwent our low radiation dose protocol with 100 kVp. We compared effective dose (ED); CT number, image noise, and contrast noise ratio (CNR) of ascending aorta at 120 and 100 kVp protocol. We also performed quantitative analysis and qualitative analysis for bitmap image of 120, 100 kVp, and display preset optimization for 100 kVp images. The estimated ED was 48 % lower with the 100 kVp protocol than the 120 kVp protocol (2.8 vs. 5.5 mSv, p0.01). There is no significant difference in the CNR between 100 and 120 kVp protocol (18.5 ± 3.6 vs. 18.6 ± 3.8, p = 0.84). Display preset optimization significantly improved image quality of 100 kVp cardiac CT, and there is no significant difference in qualitative analysis and quantitative analysis between 100 kVp scan with optimized display preset and 120 kVp scan (p0.05). The 100 kVp scanning with optimized display preset offers almost same image quality at cardiac CT of thin adults under 48 % decreased radiation dose.

To evaluate the effect on image quality of a low contrast and radiation dose protocol for cardiac computed tomography (CT) using a low tube voltage, the hybrid-iterative reconstruction algorithm, and a 256-row CT scanner. Before clinical study, we performed phantom experiments to evaluate the hybrid iterative reconstruction technique. We randomly assigned 68 patients undergoing cardiac CT to one of two protocols; 33 were scanned with our conventional 120 kVp protocol, the contrast material (370 mgI/kg body weight) was delivered over 15 s. The other 35 patients underwent scanning at a tube voltage of 80 kVp; the contrast dose, reduced by 50 % (185 mgI/kg), was delivered at the same fractional dose (24.7 mgI/kg/s). The 80 kVp images were post-processed with the 60 % hybrid-iterative reconstruction technique. We evaluated the effective dose (ED), image noise, mean attenuation, and contrast-to-noise ratio (CNR) of each protocol. The hybrid-iterative reconstruction technique offers almost same spatial resolution and noise-power-spectrum curve as compared with filtered back projection reconstruction. There were no decrease in spatial resolution and no shift of spatial frequency in noise power spectrum. The average ED was 74 % lower with the 80- than the 120 kVp protocol (1.4 vs 5.4 mSv). Dunnett's test showed that there were no significant differences in the image noise, mean attenuation, and CNR between hybrid-iterative-reconstructed 80 kVp scans and 120 kVp scans (28.6 ± 6.5 vs 25.3 ± 4.5, p = 0.18; 475.0 HU ± 87.0 vs 445.3 HU ± 67.7, p = 0.20; 17.1 HU ± 3.5 vs 17.8 HU ± 3.1, p = 0.53). The low kVp scan and hybrid-iterative reconstruction algorithm can dramatically decrease the radiation dose and contrast dose with adequate image quality at cardiac CT of thin adults using a 256-row CT scanner.

Objective: The aim was to examine differences in the vascular response to α adrenoceptor stimulation on both smooth muscle and endothelium among large arteries perfusing various organs. Methods: In ring preparations of coronary, carotid, iliac, mesenteric, and renal arteries from pigs (n=24), the magnitudes of contraction to noradrenaline (with β blocker), with or without endothelium, and endothelium dependent relaxation to noradrenaline (with α1 and β blocker) were compared in vitro. Results: In both endothelium-intact and denuded groups, the contractions to noradrenaline were significantly smaller in coronary and carotid arteries than in iliac, mesenteric, and renal arteries. The presence of endothelium significantly suppressed the contractions in coronary and carotid arteries, but did not affect the contractions in iliac, mesenteric, and renal arteries. The endothelium dependent relaxations to noradrenaline, which were abolished by LNMMA, were more prominent in coronary and carotid arteries than in iliac, mesenteric, and renal arteries. Conclusions: The contractions via α adrenoceptors were small, and endothelium dependent relaxations via α2 adrenoceptors were large, in the coronary and carotid arteries, which perfuse the vital organs (heart and brain), as compared with those in iliac, mesenteric, and renal arteries. These results suggest that in the state of activation of the sympathetic nervous system, arterial tone in response to α adrenoceptor stimulation may be regulated not only by α adrenoceptors on vascular smooth muscle but also by those on endothelium, through release of endothelium derived relaxing factor (EDRF) via α2 adrenoceptors. Cardiovascular Research 1993; 27 :779-784

To examine the constrictor response of the infarct-related stenotic coronary artery in comparison with that of noninfarct-related stenotic arteries, acetylcholine in maximal doses of 100 μg for the left and 50 μg for the right coronary artery was injected into the 16 infarct-related coronary arteries of 16 patients with previous myocardial infarction (group 1) and into 19 stenotic coronary arteries of 16 patients with stable angina without myocardial infarction (group 2). Acetylcholine's effects on lumen diameter and area were quantitatively analyzed at the stenotic segment and its proximal segment without significant stenosis.Acetylcholine decreased lumen diameter and area at the stenotic segments from 0.72 ± 0.18 to 0.18 ± 0.33 mm and from 0.45 ± 0.22 to 0.10 ± 0.22 mm2, respectively, in group 1 (both p < 0.01) and from 0.75 ± 0.22 to 0.49 ± 0.30 mm and 0.48 ± 0.29 to 0.26 ± 0.23 mm2, respectively, in group 2 (both p < 0.01). Acetylcholine decreased the diameter and area at the proximal segment from 2.71 ± 0.75 to 2.38 ± 0.6 mm and from 6.18 ± 3.4 to 4.71 ± 2.23 mm2, respectively, in group 1 (both p < 0.01) and from 2.31 ± 0.67 to 1.95 ± 0.59 mm and from 4.5 ± 2.97 to 3.22 ± 1.96 mm2, respectively, in group 2 (both p < 0.01). The changes in diameter and area at the stenotic segment in group 1 were significantly greater than those in group 2 (both p < 0.01); there were no significant differences between groups in the changes at the proximal segment. Total or subtotal occlusion of the stenotic artery was induced in 11 (69%) patients in group 1 compared with 4 (21%) patients in group 2 (p < 0.01 group 1 vs. group 2).It is concluded that the constrictor response to acetylcholine of the stenotic segment of the infarct-related coronary artery is enhanced as compared with that of noninfarct-related arteries.

Study objective — The aim was to investigate the relationship between vascular aging and endothelial regulation of the vascular tone by various agonists in isolated pig coronary arteries. Experimental materials and design — Coronary artery rings from young (4-6 month old) and aged (3-4 years old) Yorkshire pigs were studied under isometric tension by organ chamber experiments. Cumulative concentration-response curves were obtained for vasorelaxing agents including noradrenaline (with β blocker), substance P, bradykinin, and glyceryl trinitrate in rings precontracted with prostaglandin F2α (PGF2α). The degree of atherosclerosis of the coronary arteries was examined by light microscopy after the pharmacological experiments. Measurements and main results — In the presence of propranolol (3 × 10−6M), noradrenaline (10−8−10−5 M) caused endothelium dependent relaxation. The maximum relaxation was significantly greater in the young [45.4(SEM 2.5)% of the magnitude of precontraction induced by PGF2α] than in the aged group \[26.9(3.0)%\] (p

BACKGROUND This study was designed to examine the hemodynamic, renal, and hormonal effects of brain natriuretic peptide (BNP) infusion in patients with congestive heart failure (CHF) and in control subjects. METHODS AND RESULTS We infused synthetic human BNP at a rate of 0.1 micrograms/kg/min. BNP infusion decreased pulmonary capillary wedge pressure (control, from 5 +/- 1 to 2 +/- 1 mm Hg, p less than 0.01; CHF, from 21 +/- 3 to 14 +/- 4 mm Hg, p less than 0.05) and systemic vascular resistance (control, from 1,264 +/- 75 to 934 +/- 52 dyne.sec.cm-5; CHF, from 2,485 +/- 379 to 1,771 +/- 195 dyne.sec.cm-5; p less than 0.01, respectively) and increased stroke volume index (control, from 49.9 +/- 2.7 to 51.5 +/- 2.3 ml/m2, p = NS; CHF, from 25.6 +/- 3.8 to 32.0 +/- 3.9 ml/m2, p less than 0.01). BNP infusion significantly increased urine volume (control, from 2.3 +/- 0.7 to 7.5 +/- 1.9 ml/min; CHF, from 0.8 +/- 0.2 to 5.3 +/- 1.0 ml/min; p less than 0.01, respectively), excretion of sodium (control, from 79.2 +/- 21.6 to 332.8 +/- 70.9 microEq/min; CHF, from 77.4 +/- 20.8 to 753.5 +/- 108.0 microEq/min; p less than 0.01, respectively), and excretion of chloride (control, from 72.5 +/- 18.4 to 256.0 +/- 43.3 microEq/min; CHF, from 74.0 +/- 19.6 to 708.8 +/- 103.3 microEq/min; p less than 0.01, respectively). Urinary excretion of sodium and of chloride in response to BNP infusion was higher in patients with CHF than in control subjects (p less than 0.01, respectively). BNP infusion increased the levels of plasma atrial natriuretic peptide (control, from 65 +/- 11 to 84 +/- 14 pg/ml; CHF, from 262 +/- 65 to 301 +/- 62 pg/ml; p less than 0.05, respectively) and decreased plasma aldosterone concentrations in both groups (control, from 43.3 +/- 12.1 to 27.3 +/- 7.1 pg/ml; CHF, from 91.1 +/- 34.3 to 66.3 +/- 27.2 pg/ml; p less than 0.05, respectively). CONCLUSIONS We conclude that BNP infusion improves left ventricular function in patients with CHF by vasodilation and prominent natriuretic action.

To study the effects of magnesium (Mg2+) on human coronary arteries and to compare those effects with those of diltiazem and nitroglycerin, we measured the tension of ring segments from isolated human coronary arteries obtained at autopsy within 5 hours after death. Precontracted segments with 3 x 10(-6) M prostaglandin F2 alpha were studied after adding cumulative concentrations of these agents (1.0-8.0 mM, 10(-9)-10(-5) M, and 10(-10)-10(-6) M, respectively). Mg2+ significantly inhibited the tonic contraction compared with the time-matched controls at 1.0 and 2.0 mM (48.7 +/- 5.6% vs. 88.6 +/- 2.2%, p less than 0.01, 36.2 +/- 6.1% vs. 78.9 +/- 3.0%, p less than 0.01, respectively). 1.0 and 2.0 mM Mg2+ did not suppress, but actually increased, the amplitude of periodic contraction, but 8.0 mM Mg2+ reduced the amplitude compared with the controls (6.6 +/- 5.2% vs. 73.3 +/- 10.7%, p less than 0.01). Diltiazem at a concentration of 10(-5) M moderately inhibited the tonic contraction, and reduced the amplitude of periodic contraction almost completely. Nitroglycerin reduced the tonic contraction almost completely at a concentration of 10(-6) M but did not reduce the amplitude of periodic contraction at any concentration. We conclude that 1.0 and 2.0 mM Mg2+ inhibits the tonic contraction and that 8.0 mM Mg2+ inhibits the periodic as well as the tonic contraction of isolated human coronary arteries. Diltiazem inhibits the periodic contraction, whereas nitroglycerin suppresses tonic contraction without affecting the periodic contraction.

Constriction of epicardial coronary arteries induces severe flow reduction causing myocardial ischaemia in patients with vasospastic angina. Whether such constriction is inherent in coronary arteries in general was determined by perfusing isolated epicardial coronary segments of humans and pigs at a constant perfusion pressure. Mean flow reduction after perfusion with potassium chloride (60 mmol.litre-1), acetylcholine (10(-9)-10(-5) mol.litre-1), and histamine (10(-8)-10(-4) mol.litre-1) was not different between humans and pigs. Prostaglandin F2 alpha (PGF2 alpha; 3 X 10(-6) mol.litre-1) decreased the flow more substantially in humans (by 74(9)%) than in pigs (by 6(1)%) (p less than 0.01). A pronounced flow reduction to 0 ml.min-1 was observed in eight of 17 human coronary arteries after potassium chloride, histamine, or PGF2 alpha perfusion but in none of the pigs. Histological examination of the coronary arteries showed no atherosclerotic lesions in the pigs but various lesions in humans, ranging from intimal thickening to 96% luminal stenosis in cross sectional area. Flow reduction after PGF2 alpha was significantly greater in human coronary arteries with stenoses greater than 50% (94(4)%) than in those with stenoses less than 25% (55(14)%) (p less than 0.05). Complete cessation of flow was observed more often in the stenotic arteries (greater than 50% stenosis) than in others (p less than 0.05). A substantial reduction in flow, which may cause myocardial ischaemia in vivo, was not seen in normal pig coronary arteries even after strong vasoconstrictor stimuli but was present in human coronary arteries with atherosclerosis.

We examined the longitudinal propagation of contraction in isolated human and pig coronary arteries. Epicardial coronary arteries of about 2 cm were cut open longitudinally, and the tension development of circular muscles was measured simultaneously at three sites (both cut ends and the midportion of the segment). Cyclic tension changes arising at one site of human coronary artery propagated smoothly to the other sites, and the whole length of segment worked as a single unit. Contraction induced by locally applied prostaglandin F2 alpha or histamine also propagated in four of seven preparations. The remaining three human and all seven pig coronary arteries showed propagation of such drug-induced contraction after treatment with 10 mM tetraethylammonium (TEA). In pig coronary arteries treated with TEA, electrical stimulation evoked a reproducible local contraction and its propagation. Propagation velocity was 9.0 +/- 0.7 at 0.8 mM calcium concentration and increased to 11.1 +/- 0.9 and 13.1 +/- 1.4 mm/sec as calcium concentration rose to 1.8 mM and 7.2 mM, respectively. Local contraction did not propagate at calcium concentrations of 0.2 mM or less. The calcium antagonist diltiazem decreased the propagation velocity dose dependently and blocked propagation of contraction at 0.3 microM without significant effects on the magnitude of local contraction. We conclude that smooth propagation of contraction develops in epicardial coronary arteries of humans and pigs and that the propagation may depend on calcium influx.

The effect of perivascular nerve stimulation on coronary contraction was examined by perfusing the isolated epicardial coronary artery of pigs. Coronary flow decreased in a frequency-dependent manner after electrical stimulation, with a maximum percent flow reduction of 23.8±1.1% (n = 10) at 20 Hz. The reduction in flow rate was not inhibited by phentolamine nor propranolol but was inhibited by atropine. Neostigmine enhanced the flow reduction induced by nerve stimulation. Acetylcholine reduced the flow rate dose dependently but norepinephrine showed no effect. We conclude that perivascular nerve stimulation of the epicardial coronary artery of pigs causes a modest flow reduction through activation of a cholinergic mechanism.