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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Background The high mortality of acute myocardial infarction (AMI) with cardiogenic shock (i.e., Killip class IV AMI) remains a challenge in emergency cardiovascular care. This study aimed to examine institutional factors, including the number of JCS board-certified members, that are independently associated with the prognosis of Killip class IV AMI patients.Methods and Results:In the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (years 2012-2016), the 30-day mortality of Killip class IV AMI patients (n=21,823) was 42.3%. Multivariate analysis identified age, female sex, admission by ambulance, deep coma, and cardiac arrest as patient factors that were independently associated with higher 30-day mortality, and the numbers of JCS board-certified members and of intra-aortic balloon pumping (IABP) cases per year as institutional factors that were independently associated with lower mortality in Killip class IV patients, although IABP was associated with higher mortality in Killip classes I-III patients. Among hospitals with the highest quartile (≥9 JCS board-certified members), the 30-day mortality of Killip class IV patients was 37.4%. Conclusions A higher numbers of JCS board-certified members was associated with better survival of Killip class IV AMI patients. This finding may provide a clue to optimizing local emergency medical services for better management of AMI patients in Japan.

International audience; Purpose: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocar-ditis) may present similarly and/or overlap with other cardiac pathology including acute cor-onary syndrome presenting a challenge for prompt clinical diagnosis.Methods: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery steno-sis >70% in patients undergoing coronary angiogram.Results: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coro-nary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coro-nary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revas-cularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was margin-ally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057).Conclusion: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diag-nosis and treatment or more severe presentation of ICB-myocarditis.

Cardiogenic shock frequently leads to death even with intensive treatment. Although the leading cause of cardiogenic shock is acute coronary syndrome (ACS), the clinical characteristics and the prognosis of ACS with cardiogenic shock in the present era still remain to be elucidated. We analyzed clinical characteristics and predictors of 30-day mortality in ACS with cardiogenic shock in Japan. The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multicenter, cohort study. Between May 2012 and June 2014, 495 ACS patients with cardiogenic shock were analyzed. The primary endpoint was 30-day all-cause mortality. The median [interquartile range; IQR] age was 71.0 [63.0, 80.0] years. The median [IQR] value of systolic blood pressure (SBP) and heart rate were 75.0 [50.0, 86.5] mm Hg and 65.0 [38.0, 98.0] bpm, respectively. Multivariable analysis showed an odds ratio (OR) of 4.76 (confidence intervals; CI 1.97–11.5, p

Capnocytophaga canimorsus and Capnocytophaga cynodegmi, both commensal bacteria in the oral cavities of dogs and cats, are zoonotic pathogens. In particular, C. canimorsus causes sepsis and fatal septic shock. Recently, a novel Capnocytophaga species, C. canis, was isolated from the oral cavities of healthy dogs. It is reportedly oxidase-negative and therefore considered avirulent in humans. In the present study, three strains of C. canis were isolated from Japanese patients with sepsis. All three strains, HP20001, HP33001 and HP40001, were oxidase-positive. Nucleotide sequence identities of the 16S rRNA gene of the three strains to the C. canimorsus type strain ATCC35979, C. cynodegmi type strain ATCC49044 and C. canis type strain LMG29146 were 96.9-97.0%, 96.9-97.0% and 99.7-99.8%, respectively. Multi-locus sequence analysis based on seven house-keeping genes, dnaJ, fumC, glyA, gyrB, murG, trpB and tuf, revealed that the oxidase-positive C. canis strains isolated in Japan and oxidase-negative strains of C. canis from canine oral cavities in Switzerland were clustered in different genetic subgroups. These results indicate that the virulence of C. canis strains in humans is associated with oxidase activity.

Objective It is recommended that middle-aged and elderly individuals reduce their salt intake because of the high prevalence of hypertension. The consumption of miso soup is associated with salt intake, and the reduced consumption of miso soup has been recommended. Recent studies have demonstrated that the consumption of miso soup can attenuate an autonomic imbalance in animal models. However, it is unclear whether these results are applicable to humans. This study examined the cross-sectional association between the frequency of miso soup consumption and the blood pressure and heart rate of human subjects. Methods A total of 527 subjects of 50 to 81 years of age who participated in our hospital health examination were enrolled in the present study and divided into four groups based on the frequency of their miso soup consumption ([bowl(s) of miso soup/week] Group 1

BACKGROUND Consciousness disturbance is one of the major clinical signs associated with shock state, but its prognostic value has not been previously evaluated in cardiovascular shock patients. We aimed to evaluate the prognostic value of neurological status for 30-day mortality in cardiovascular shock patients without out-of-hospital cardiac arrest (OHCA). Methods and Results: Patients with out-of-hospital onset cardiovascular shock were recruited from the Japanese Circulation Society Shock Registry. Neurological status upon hospital arrival was evaluated using the Japan Coma Scale (JCS). Patients were divided into 4 groups according to the JCS: alert, JCS 0; awake, JCS 1-3 (not fully alert but awake without any stimuli); arousable, JCS 10-30 (arousable with stimulation); and coma JCS 100-300 (unarousable). The primary endpoint was 30-day all-cause death. In total, 700 cardiovascular shock patients without OHCA were assessed. The coma group was associated with a higher incidence of 30-day all-cause death compared with other groups (alert, 15.3%; awake, 24.4%; arousable, 36.8%; coma, 48.5%, P

Background There are little data about cardiovascular shock caused by various diseases. We evaluated the characteristics and predictors of 30-day mortality in patients with cardiovascular shock in Japan. Methods and results The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multicenter, cohort study. Between May 2012 and June 2014, 979 patients with cardiovascular shock were analyzed. The primary endpoint was 30-day all-cause mortality. The mean systolic blood pressure on hospital arrival was 78±18 mmHg. The main causes of shock were acute coronary syndrome (51.0%), non-ischemic arrhythmia (16.4%), and aortic disease (14.9%). The 30-day all-cause mortality was 34.3%. After adjustment for independent predictors of 30-day mortality, the odds ratios for systolic blood pressure (per 10-mmHg decrease), consciousness disturbance, congestive heart failure, out-of-hospital cardiac arrest, estimated glomerular filtration rate (per 10-ml/min/1.73 m(2)decrease), and causes of shock (non-ischemic arrhythmia, aortic disease, and myocarditis) were 1.15 (95% confidence interval [CI], 1.08-1.22), 2.62 (95% CI, 1.80-3.82), 2.58 (95% CI, 1.67-3.99), 1.62 (95% CI, 1.05-2.51), 1.20 (95% CI, 1.10-1.30), and 0.48 (95% CI, 0.30-0.77), 3.98 (95% CI, 2.32-6.81), and 3.25 (95% CI, 1.20-8.84), respectively. Conclusions The 30-day mortality for cardiovascular shock was still high at 34%. Primary predictors of mortality were cardiorenal function on hospital arrival and shock etiology.

Capnocytophaga canimorsus and Capnocytophaga cynodegmi, both commensal bacteria in the oral cavities of dogs and cats, are zoonotic pathogens. In particular, C. canimorsus causes sepsis and fatal septic shock. Recently, a novel Capnocytophaga species, C. canis, was isolated from the oral cavities of healthy dogs. It is reportedly oxidase-negative and therefore considered avirulent in humans. In the present study, three strains of C. canis were isolated from Japanese patients with sepsis. All three strains, HP20001, HP33001 and HP40001, were oxidase-positive. Nucleotide sequence identities of the 16S rRNA gene of the three strains to the C. canimorsus type strain ATCC35979, C. cynodegmi type strain ATCC49044 and C. canis type strain LMG29146 were 96.9-97.0%, 96.9-97.0% and 99.7-99.8%, respectively. Multi-locus sequence analysis based on seven house-keeping genes, dnaJ, fumC, glyA, gyrB, murG, trpB and tuf, revealed that the oxidase-positive C. canis strains isolated in Japan and oxidase-negative strains of C. canis from canine oral cavities in Switzerland were clustered in different genetic subgroups. These results indicate that the virulence of C. canis strains in humans is associated with oxidase activity.

Objective We aimed to elucidate clinical characteristics, contemporary practice and outcomes of patients with takotsubo syndrome who were hospitalized in an emergency general hospital with angiography capabilities. Methods This retrospective study included a total of 42 consecutive patients who were admitted between January 2010 and August 2014. Results The study population included 11 men (26%) and 31 women (74%) [median age 76 years (interquartile range, 66-83)]. Physical stress and emotional stress were identified as triggers in 28 (67%) patients and 5 (12%) patients, respectively. Electrocardiographic changes were observed in 41 (98%) patients, with ST-segment elevation being the most common (71%) finding. In-hospital complications occurred in 24 (57%) patients, and acute pulmonary congestion or cardiogenic shock was seen in 21 (50%) patients. Five patients died during hospitalization (in-hospital mortality: 12%). Conclusion Takotsubo syndrome was associated with significant morbidity and mortality among elderly patients who were treated at an emergency general hospital. Physicians and surgeons in all departments should be aware of the condition, especially in acutely ill subjects.

An early invasive strategy for patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) has been recommended. However, patients at greater risk including the elderly are more often managed conservatively. We aimed to elucidate contemporary practice and outcomes of patients with NSTE-ACS who were referred to our hospital located in Kitakyushu City, one of the most aging metropolises in Japan.A total of 270 consecutive NSTE-ACS patients hospitalized between January 2012 and December 2014 were retrospectively studied.Median [interquartile range] age was 73 [64, 80]years. Coronary angiography was performed in 264 (98%) patients. Importantly, 75% and 89% underwent angiography within 24h and 72h after admission, respectively. Revascularization was done in 124 (79%). The all-cause, in-hospital mortality was 3.7% and was higher in patients aged ≥80years (8.5% vs. 2.0% in those aged80years, p0.0001). No patient developed major bleeding or stroke during hospitalization. Killip class IV at presentation (odds ratio [OR] 8.77, 95% confidence intervals [CI] 1.64-47.6) and left main trunk disease (OR 7.58, 95% CI 1.28-45.5) were independently associated with in-hospital death. These two variables and a high (≥140) GRACE score were associated with a higher 1-year mortality by Kaplan-Meier survival analysis (p0.0001).An early invasive strategy was safely done in an elderly cohort of Japanese patients with NSTE-ACS. In addition to early invasive approach, a further therapeutic strategy, most probably targeting a shock status, is needed to improve both short- and long-term survival.

A 73-year-old woman presented with diarrhea, leg edema, and exertional dyspnea. Six years before admission, she had been hospitalized for heart failure with moderate-to-severe tricuspid regurgitation because of incomplete leaflet coaptation (Figure 1A; Movie I in the Data Supplement). She was treated with furosemide and has remained on this therapy since then. In the same period of time, an ovarian tumor was detected after total hysterectomy and unilateral salpingo-oophorectomy for uterine myoma. Although the surgeons tried to resect the tumor, it was inoperable and could not be diagnosed definitively at that time because of postoperative adhesion. Figure 1. The time-course of changes in the echocardiograms of the right-sided heart valves. A and C , Tricuspid and pulmonary valves recorded 6 years earlier (arrows). B and D , Tricuspid and pulmonary valves recorded on admission (arrows). Left , The B-mode image; and right , the color Doppler image. Ao indicates aorta; PA, pulmonary artery; RA, right atrium; and RV, right ventricle. On admission, physical examination revealed jugular venous distention, hepatomegaly, and ascites. Compared with the echocardiogram at the previous hospitalization (Figure 1A), the tricuspid valve leaflets were further retracted with severe regurgitation (Figure 1B; Movie II in the Data Supplement). The pulmonary valve was also retracted with moderate regurgitation (Figure 1C and 1D; Movies III and IV in the Data Supplement). It was noteworthy that the aortic and mitral valves became thickened and moderately regurgitant (Figure 2A through 2D; Movies …

Background— Recently, there has been increasing concern about adverse health effects of exposure to desert dust events. However, the association between dust and the incidence of ischemic heart diseases is unknown. The aim of the present study was to elucidate whether Asian dust (AD), a windblown sand dust originating from mineral soil in China and Mongolia, is associated with the incidence of acute myocardial infarction (AMI). Methods and Results— We investigated the data regarding hospitalization because of AMI among 3068 consecutive patients from 4 AMI centers in Fukuoka, Japan, and data for AD from April 2003 to December 2010. We applied a time-stratified case-crossover design to examine the association between AD and the incidence of AMI. Using a conditional logistic regression analysis, we estimated the odds ratios of AMI associated with AD after controlling for ambient temperature and relative humidity. The occurrence of AD events 0 to 4 days before the day of admission was significantly associated with the incidence of AMI. In particular, the occurrence of AD 4 days before admission was significantly associated with the onset of AMI. Conclusions— These data suggest that exposure to AD a few days before symptom onset is associated with the incidence of AMI.

Red cell distribution width (RDW) is a measure of variation in the volume of circulating erythrocytes and has recently emerged as a powerful prognostic marker in heart failure. We studied the effect of 5-month, home-based cardiac rehabilitation on RDW.Sixty-two patients (age: median 67 years, IQR 63-74) with chronic heart failure caused by reduced left ventricular systolic function were enrolled. Exercise time and physical activity levels out of the hospital were determined by a single-axial accelerometer. Baseline RDW values were: median 13.6, IQR 12.8-14.4%, with 13 patients (21.0%) showing values above the upper normal limit. RDW values were decreased significantly after training in the 13 patients with elevated baseline RDW values (P0.01), but not in the remaining 49 patients with normal baseline RDW values. There was a highly significant correlation between baseline RDW and changes in RDW after exercise training (P = 0.0001, r2 = 0.628, n = 62). The time spent for moderate (3 METs) exercise was: median 9.0, IQR 3.0-18.8 minutes per day.Relatively low intensity, home-based cardiac rehabilitation was associated with decreased RDW in heart failure patients with abnormal RDW.

In late December 2015, a 69-year-old woman presented with general malaise and palpitation lasting a few days. She had choroidal malignant melanoma with liver and bone metastases and had undergone 3 cycles of anticancer treatment with an anti-PD-1 (programmed cell death protein 1) antibody nivolumab (2 mg/kg of body weight every 3 weeks) from October 2015 to early December 2015. Two weeks had elapsed since the last treatment with nivolumab. On physical examination, blood pressure was 121/83 mm Hg and heart rate 110 beats per minute. ECG showed ST-segment elevation in leads II, III, and aVF. A bedside rapid assay for cardiac troponin T was positive, and the concentrations of creatine kinase and creatine kinase MB-isozyme were increased to be 728 IU/L and 48.7 U/L, respectively. Echocardiography …

An 85-year-old woman with chronic kidney disease was referred to us for the examination of a tumour in the left ventricle that was not observed 2 years earlier. She was afebrile associated with negative blood cultures. Transthoracic and transoesophageal echocardiography revealed mitral annular calcification (MAC) and a highly mobile, hyperechoic, and spindle-shaped tumour …

SummaryA 26-year-old pregnant woman who was an intravenous drug user (IDU) was admitted to our hospital for the treatment of tricuspid valve infective endocarditis (IE) and lung abscesses due to methicillin-resistant Staphylococcus aureus (MRSA). We started to treat her with vancomycin (VCM) alone and then in combination with rifampicin (RFP), but her condition did not improve. Then we added sulfamethoxazole/trimethoprim (SMZ/TMP) to VCM and RFP. After that, she improved rapidly. In Japan, there are very few reports about tricuspid valve IE caused by MRSA in IDUs. This case suggests that the combination of VCM, RFP, and SMZ/TMP may be effective for the treatment of severe MRSA infections.

Sleep-disordered breathing (SDB) is common in patients with heart failure and carries an independent risk for poor long-term prognosis. We aimed to study the effects of supervised, aerobic exercise training for 6 months on SDB in patients with chronic heart failure.We enrolled 18 patients having both systolic dysfunction (left ventricular ejection fraction45%) and SDB (apnea-hypopnea index [AHI]10). The exercise group comprised 10 patients who participated in our cardiac rehabilitation program for 6 months, and the remaining 8 patients served as control. AHI (median [interquartile range]) was unchanged in the control group patients at 6-month intervals (30.4 [19.9-36.3] versus 36.6 [8.6-39.4], NS). In contrast, AHI was significantly decreased in the exercise group from 24.9 [19.2-37.1] to 8.8 [5.3-10.1] (P.01). In the exercise group, the numbers of central sleep apnea per night was significantly decreased (152 [124-244] versus 50 [24-67], P.01) after exercise training, but those of obstructive apnea/hypopnea were unchanged (42 [7-94] versus 18 [7-54], NS). In addition, exercise training significantly increased peak oxygen consumption and decreased minute ventilation to carbon dioxide production slope (both P.01).Six-month, aerobic exercise training increased exercise capacity and improved central sleep apnea in patients with chronic heart failure from systolic dysfunction.

Objectives. The purpose of this study was to determine whether the assessment of mitral annulus displacement (MAD) using Doppler-tissue image (DTI) could provide a useful marker of heart failure severity.[Methods] In seventy-five subjects with heart diseases, we measured MAD by tissue-tracking method with DTI. MAD was evaluated in both septal and lateral corners of the mitral annulus in the apical 4-chamber view, and the degree of MAD in postsystolic phase was estimated as a ratio of displacement at aortic valve closure and peak point (P/A ratio). We divided subjects into three groups (group A: subjects with preserved MAD, group B: subjects with reduced MAD without increasing P/A ratio, group C: subjects with reduced MAD with increasing P/A ratio) and compared NYHA functional class and left ventricular ejection fraction (LVEF).Results. NYHA functional class and LVEF were significantly different among the three groups (NYHA functional class; group A: 1.2±0.4, group B: 2.3±0.9, group C: 3.1±0.8, LVEF; group A: 58±12 %, group B: 42±15 %, group C: 25±8 %). These results indicated that MAD which represents mainly LV longitudinal function is decreased in the first place, and then, post-systolic displacement is exaggerated according to the severity of heart failure.Conclusions. The classification of the degree and timing of peak MAD (P/A ratio) is well correlated with NYHA functional class and LVEF and becomes one of the useful indexes of heart failure severity.

Introduction: Despite the advances in the treatment of cardiogenic shock, mortality in these patients remains high. Data on the actual state of cardiovascular shock treatment and outcomes in Japan are scarce. In this study, we aimed to investigate the baseline characteristics and outcomes of patients with cardiovascular shock and identify the predictors of 30-day mortality. Methods: The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multi-center, cohort study. Between May 2012 and June 2014, a total of 980 patients with cardiovascular shock were enrolled from 82 centers in Japan. The median (interquartile range) age of the enrolled patients was 72 (63, 81) years, and 66% of the patients were male. The primary endpoint was all-cause death at 30 days. Results: The causes of shock included acute coronary syndrome (50.6%), non-ischemic arrhythmia (15.9%), aortic disease (14.9%), myocarditis (2.2%), cardiomyopathy (3.4%), pulmonary embolism (4.4%), valvular heart disease (1.3%), infective endocarditis (0.5%) and cardiac tamponade (1.4%). The all-cause mortality was 34.3%. On multivariate analysis, systolic blood pressure (odds ratio [OR], 0.986; 95% confidence interval [CI], 0.98-0.99, p Conclusion: Patients with non-ischemic arrhythmia had better prognosis, whereas those with aortic disease and myocarditis had poor prognosis. Blood pressure, neurological status, and renal function were also independent predictors of 30-day mortality.

Angina caused by spasm of the large epicardial coronary artery has been extensively investigated for >50 years, and its risk factors, diagnostic procedures, treatments, and prognosis are well established. In 1998, we proposed coronary microvascular spasm as a possible pathogenic mechanism of myocardial ischemia in Japanese patients with chest pain and normal epicardial coronary arteries (microvascular angina),1 which was later confirmed by others.2 In the cardiac catheterization laboratory, the occurrence of coronary microvascular spasm is suspected when patient’s symptoms are reproduced in association with ischemic electrocardiographic changes after intracoronary injection of acetylcholine or ergonovine without large epicardial artery hyperconstriction/spasm. Coronary …

BACKGROUND: Hypertension is an important risk factor of coronary heart disease. A new guidelines for hypertension prevention and management in The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in the United States recommended lifestyle modification or medical treatment for subjects with prehypertension. However, whether prehypertension increases the risk of coronary atherosclerosis in the Japanese population is still unknown. METHODS: A cross-sectional study in a clinical setting was conducted. The subjects were 705 patients (417 males and 288 females) aged 30 years and older who underwent a first-time coronary angiography for suspected or known coronary heart disease at 5 major cardiology departments in the Fukuoka metropolitan area between September 1996 and August 1997. RESULTS: Compared to subjects with normal blood pressure, those with prehypertension had an increased risk of coronary atherosclerosis even after adjusting for other factors. CONCLUSION: Prehypertension may be an important clinical entity which requires treatment in the Japanese population.

Dual-chamber pacing reportedly improves the quality of life by reducing the frequency of anginal episodes in selected patients with the obstructive form of hypertrophic cardiomyopathy (HCM), although the underlying mechanism or coronary effect is poorly understood. We report 3 patients with obstructive HCM, in whom the effects of atrial vs. dual-chamber tachypacing on systemic hemodynamics and myocardial lactate metabolism were studied. In all patients myocardial lactate production, objective evidence of myocardial ischemia, was demonstrated during atrial pacing, whereas no patient developed myocardial ischemia during dual-chamber pacing. By contrast, the responses of pressure gradient to pacing varied among the patients. These observations demonstrate for the first time that dual-chamber pacing exerted an anti-ischemic effect in obstructive HCM, which may contribute, at least partly, to the beneficial effects of chronic AV pacing on angina status and/or LV function.

OBJECTIVES We sought to determine whether a potent Rho-kinase inhibitor fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm. BACKGROUND Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction. METHODS We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or fasudil (4.5 mg intracoronarily, n = 13). RESULTS Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125). CONCLUSIONS Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.

This study examined the relation of Type A behavior pattern and its components to angiographically documented coronary atherosclerosis in 198 Japanese women. A questionnaire-based interview elicited psychosocial and other factors. Type A behavior pattern was measured by 12 questions. Significant coronary stenosis was defined when a 75% or greater luminal narrowing occurred at one or more major coronary arteries or 50% or greater narrowing occurred at the left main artery. Gensini's score also was calculated. Logistic regression analysis was used to calculate odds ratios and 95% confidence intervals with adjustment for traditional coronary risk factors and the presence of a job. Global Type A behavior pattern showed no material association with the severity of coronary atherosclerosis assessed by both Gensini's score and the presence of significant coronary stenosis. However, its subcomponents, enthusiasm and competitiveness, were positively related to the severity of coronary atherosclerosis, whereas self-confidence and perfectionism were negatively related. These findings suggest overall a null association between global Type A and coronary atherosclerosis as well as the presence of toxic or beneficial components of Type A behaviors in Japanese women.

Left ventricular hypertrophy (LVH) caused by chronic pressure overload is associated with increased risk of myocardial ischemia without epicardial coronary artery disease. We aimed to test the hypothesis that endogenous nitric oxide (NO) prevents myocardial ischemia in patients with LVH.Epicardial coronary blood flow (Doppler wire and quantitative coronary arteriography) and myocardial lactate metabolism (paired arterial and coronary sinus blood sampling) were measured in 12 patients with hypertension, LVH, and angiographically normal epicardial coronary arteries and in 7 control subjects. Measurements were done under 3 pacing protocols: with no treatment (control), with intracoronary N(G)-monomethyl-L-arginine (L-NMMA; NO synthesis inhibitor), and with intracoronary L-arginine (NO substrate).In control subjects the myocardial lactate extraction ratio was normal and stable during the 3 pacing protocols. In contrast, lactate uptake was significantly decreased from 0.21 +/- 0.05 to 0.10 +/- 0.06 (P.05) during L-NMMA pacing in patients with LVH; in 6 of them, lactate production was demonstrated. After L-arginine administration, the lactate extraction ratio during pacing was normalized (0.18 +/- 0.04) and lactate production was not observed in any patient. The level of myocardial lactate uptake at peak pacing after L-NMMA was correlated with that under untreated condition (P.0001).In patients with hypertension, LVH, and angiographically normal coronary arteries, inhibition of endogenous NO synthesis in the coronary circulation unmasked myocardial ischemia during tachycardia, and L-arginine reversed the adverse effects of L-NMMA. Although the precise mechanism remains to be determined, our results suggest that constitutive NO in the coronary circulation plays an anti-ischemic role in this population.

We aimed to test the hypothesis that coronary microvascular spasm (MVS) alone causes myocardial ischemia in patients with angina attributable to epicardial coronary spasm, and to determine whether there is a difference in clinical characteristics between those with and without microvascular spasm.Patients with "vasospastic angina" have epicardial coronary artery spasm, but it is unknown whether coronary microvessel disease also contributes to the occurrence of angina in these patients.We studied 55 consecutive patients with angina in whom epicardial coronary spasm was provoked by intracoronary acetylcholine (ACH).In 14 patients (25.5%, Group 1), submaximal dose of ACH induced myocardial ischemia (chest pain, ischemic electrocardiogram changes, lactate production) without large epicardial spasm, suggesting the occurrence of coronary microvascular spasm. By contrast, the remaining 41 patients (Group 2) had evidence of myocardial ischemia only when epicardial spasm was angiographically demonstrated. The Group 1 patients were predominantly women (p0.05) and had a history of prolonged (30 min) chest pain (p0.05), whereas the Group 2 patients were more likely men and smokers (p0.01).Myocardial ischemia most probably due to coronary MVS was demonstrated in a sizable portion of patients with epicardial vasospasm, preferentially in women having both typical and prolonged anginal pain. The result suggests that coronary microvascular disease may also contribute to angina in patients with "vasospastic angina."

Introduction: Several studies have shown that patients with acute coronary syndrome (ACS) presenting during off-hours have higher mortality, however, the impact of off-hour presentation on short-term mortality in patients with cardiogenic shock complicating ACS is uncertain. Hypothesis: Off-hour presentation may affect the short-term mortality in ACS patients with cardiogenic shock. Methods: We investigated consecutive 499 patients with cardiogenic shock complicating ACS from prospective and national-wide multicenter registry (JCS Shock Registry) database from March 2012 to April 2014. The primary outcomes of the present study were 30-day mortality among patients presenting either during regular-hours (defined as week-day from 8:00 AM to 8:00 PM) and off-hour (defined as weekdays from 8:01 PM to 7:59 AM, weekends and holidays). Results: Fifty-three percent of patients were presented in off-hour. Baseline characteristics were comparable including symptom onset to presentation time (off-hour; 65 min, interquartile range 39 to 180 vs. regular hour; 59 min, interquartile range 38 to 143, p = 0.22). Eighty percent of patients underwent urgent percutaneous coronary intervention and door to balloon time was also comparable between groups (off-hour; 86 min, interquartile range 60 to 110 vs. regular hour; 80 min, interquartile range 60 to 110, p = 0.74). The rate of 30-day mortality were comparable (off-hour; 35.1 % vs. regular hour 31.7 %, log-rank p = 0.48). In multivariate cox regression analysis, off-hours presentation did not affect the 30-day mortality (age- and gender-adjusted HR 1.12, 95% CI 0.82-1.52, p = 0.46). Conclusions: The clinical impact of either off-hours or regular-hours presentation is comparable in patients with cardiogenic shock complicating acute coronary syndrome (ACS) in Japan.

Background: We recently reported that coronary microvascular spasm could cause angina in patients with chest pain and normal coronary arteriograms. However, the long-term prognosis of these patients or the effect of calcium channel blockers is not known. Methods: Of consecutive 283 patients who underwent acetylcholine testing for the evaluation of chest pain, we identified 68 patients with microvascular angina attributable to coronary microvascular spasm. All patients were discharged on calcium channel blockers and followed up for an average period of 3.3 years. Results: As compared with those having epicardial spasm (n=169), there was a female predominance in the microvascular spasm group (P

Reasearch Institute of Angiocardiology and Cardiovascular Clinic,Faculty of Medicine Kyushu University, Fukuoka, JapanOBJECTIVE: To investigate the relation of the obesity and body-fat distribution with angiographically defined coronaryatherosclerosis.DESIGN: Cross-sectional study in a clinical setting.SUBJECTS: Three hundred and twenty men (median age, 59y) and 212 women (median age, 67y) who underwent coronaryangiography for suspected or known coronary heart disease at 5 cardiology departments between September 1996 and August1997. Patients with disease duration >1y were excluded.MEASUREMENTS: The body mass index (BMI) and the waist to hip circumference ratio (WHR) were used as main exposurevariables, and either the presence of significant coronary stenosis or the Gensini’s score ( 10 vs

The present study evaluated the effect of hypertension (HT), dyslipidemia and diabetes mellitus (DM) on the development of coronary atherosclerosis in the Japanese population, using a cross-sectional study of 433 patients (254 men and 179 women) aged 30 years or older who underwent coronary angiography for suspected or known coronary heart disease angina at 5 cardiology departments in the Fukuoka area between September 1996 and August 1997. Patients with a disease duration of 6 months or more were excluded. The main outcome measure was angiographically defined coronary artery stenosis and was found to a significant degree in 146 patients (33.7%). HT, DM, low levels of high-density lipoprotein cholesterol (HDL-C) and hypertriglyceridemia remained as significant coronary artery disease (CAD) risk factors even after controlling for age, sex, hospital, smoking, alcohol use, body mass index and leisure time physical activity. However, hypercholesterolemia was not a significant risk factor after adjusting for these variables. After controlling for these variables, DM, low HDL-C and hypertriglyceridemia were significant CAD risk factors for men, but only DM was a significant CAD risk factor in women. These results indicate that in Japan DM, low HDL-C and hypertriglyceridemia may be more important CAD risk factors than hypercholesterolemia.

Coronary flow reserve is reduced in patients with idiopathic dilated cardiomyopathy (DCM). We examined acute effects of intracoronary enalaprilat on metabolic coronary vasodilation during pacing tachycardia in patients. Coronary blood flow (Doppler guidewire) and diameter (quantitative angiography) were measured in seven patients with DCM and seven control subjects. In the DCM group, tachypacing increased coronary blood flow by 37 +/- 22% from the baseline before enalaprilat and by 65 +/- 22% (p < 0.01 vs. before treatment) after enalaprilat (0.5 microg/kg/min for 5 min, i.c.) at comparable double product. Pacing-induced dilation of the epicardial coronary artery also was greater after enalaprilat (p < 0.05). Effects of enalaprilat on coronary blood flow and diameter during pacing tachycardia were abolished by pretreatment with intracoronary administration of the nitric oxide (NO) synthesis inhibitor, N(G)-monomethyl-L-arginine. These beneficial effects of enalaprilat on large and small coronary vasodilation were not observed in control patients. Thus, intracoronary enalaprilat acutely augmented dilator responses of the large and small coronary arteries to pacing tachycardia in patients with DCM, and NO appeared to play an important role in mediating the effects of enalaprilat. These favorable effects of enalaprilat on the coronary circulation may be of clinical significance in patients with heart failure due to nonischemic DCM. Further long-term studies of the effects of angiotensin-converting enzyme inhibition on coronary vasodilation will be needed in this population.

Myocardial perfusion abnormalities occur in the absence of epicardial coronary artery disease in patients with a wide spectrum of cardiovascular disorders including microvascular angina, hypertension and left ventricular hypertrophy, coronary atherosclerosis, hypercholesterolemia, and non-ischemic left ventricular dysfunction. These patients have limited coronary microvascular dilator reserve which occasionally is associated with evidence of myocardial ischemia. Primary microvascular hyperconstriction (spasm) is also proposed to cause myocardial ischemia in a subset of patients with rest angina. There is ample evidence suggesting that endothelial dysfunction contributes to microvascular dysfunction, but the precise mechanism of endothelial dysfunction is not known. Nitric oxide is one of the key molecules which control microvascular tone and therefore coronary blood flow, and its decreased availability appears to be involved under certain conditions. This hypothesis has attracted considerable interest as a new therapeutic strategy for these patients having coronary microvascular derangements caused by divergent cardiovascular diseases.

Microvascular angina can occur during exercise and at rest. Reduced vasodilator capacity of the coronary microvessels is implicated as a cause of angina during exercise, but the mechanism of angina at rest is not known. Our aim was to test the hypothesis that primary hyperconstriction (spasm) of coronary microvessels causes myocardial ischaemia at rest.Acetylcholine induces coronary artery spasm in patients with variant angina. We tested the effects of intracoronary acetylcholine at graded doses in 117 consecutive patients with chest pain (at rest, during exertion, or both) and no flow-limiting (50%) organic stenosis in the large epicardial coronary arteries. We also assessed the metabolism of myocardial lactate during acetylcholine administration in 36 of the patients by measurement of lactate in paired blood samples from the coronary artery and coronary sinus vein.Of the 117 patients, 63 (54%) had large-artery spasm, 29 (25%) had microvascular spasm, and 25 (21%) had atypical chest pain. The 29 patients with microvascular spasm developed angina-like chest pain, ischaemic electrocardiogram (ECG) changes, or both spontaneously (two patients) or after administration of acetylcholine (27 patients) without spasm of the large epicardial coronary arteries. Testing of paired samples of arterial and coronary sinus venous blood showed that lactate was produced during angina attack in nine of 11 patients with microvascular spasm. There was more women (p0.01) and fewer coronary risk factors (p0.01) in patients with microvascular spasm than in those with large-artery spasm.Coronary microvascular spasm and resultant myocardial ischaemia may be the cause of chest pain in a subgroup of patients with microvascular angina.

Background: Controversy exists concerning the duration of infarct size reduction with ischemic preconditioning in different species. In the present study, we (a) evaluated the time course of protection with preconditioning and (b) sought to determine whether late protec tion (the "second window") after 24 hours is manifest in the open-chest pig model.Methods and Results: Six groups of pentobarbital-anesthetized pigs underwent 1 hour of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Group 1 served as control, and pigs in group 2 received two 10-minute episodes of preconditioning ischemia followed by 30 minutes of reperfusion before the sustained 1-hour occlusion. In groups 3-6, the period of intervening reperfusion between the preconditioning stimulus and the index ischemia was extended to 60, 90, and 300 minutes and 24 hours, respectively. The area at risk was determined by fluorescein dye injection, and infarct size was measured by incubation in p-nitrobluetetrazolium and expressed as percent of the risk area. Infarct size in preconditioned pigs (group 2) was significantly reduced compared with controls (25.6 ± 3.9% v 71.3 ± 5.9%, P < .001). Extension of the intervening reperfusion to 60, 90, and 300 minutes and 24 hours resulted in infarct sizes of 64.5 ± 5.5%, 67.2 ± 8%, 62.6 ± 6.1%, and 75.3 ± 7%, respectively ( P = NS v control).Conclusions: The infarct size-limiting effects of ischemic preconditioning last less than 1 hour in the pig model. Moreover, in contrast to other species, a late protection at 24 hours after the preconditioning stimulus was not detected. These results indicate that precondi tioning-induced reduction of infarct size is monophasic in anesthetized pigs.

Objectives. The present study aimed to determine the role of nitric oxide (NO) and angiotensin-converting enzyme (ACE) in bradykinin (BK)-induced dilation of human coronary arteries in vivo.Background. BK, produced by way of the kinin-kallikrein system, causes endothelium-dependent vasodilation. However, little is known about the mechanism of BK-induced dilation of coronary arteries in humans in vivo.Methods. The effects of an inhibitor of NO synthesis and of an ACE inhibitor on BK-induced coronary vasodilation were examined in 20 patients who had no significant atherosclerotic stenosis in the artery under study. Lumen diameters of the large epicardial coronary arteries and coronary blood flow (CBF) were measured by quantitative coronary arteriography and intracoronary Doppler technique.Results. Intracoronary infusion of BK (0.6 and 2.0 μg/min) increased coronary artery diameter and CBF with no change in arterial pressure or heart rate. The BK-induced increases in coronary artery diameter and CBF were significantly reduced (p < 0.01) after pretreatment with NG-monomethyl-l-arginine (200 μmol) and were significantly increased (p < 0.01) after pretreatment with enalaprilat (50 μg).Conclusions. BK-induced dilation of human large epicardial and resistance coronary arteries is mediated by NO and increased by prior ACE inhibition.(J Am Coll Cardiol 1997;30:108–12)

It has been shown that substance P causes endothelium-dependent vasodilation in the human coronary and forearm vessels. However, the precise mechanism whereby substance P dilates the coronary and peripheral vasculatures is unknown in humans. The aim of this study was to examine whether the vasodilator effect of substance P is mediated by nitric oxide in the human coronary and forearm vessels. Eight patients with normal coronary angiograms were studied for the measurements of coronary blood flow (intracoronary Doppler guide wire and quantitative coronary arteriography) and forearm blood flow (strain-gauge plethysmograph). Intracoronary acetylcholine (10 micrograms/min for 2 min) and substance P (30 and 90 ng/min for 2 min) increased coronary blood flow from the baseline value. Intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA) at 200 mumol significantly attenuated the magnitudes of increase in coronary blood flow induced by both acetylcholine (p < 0.01) and substance P (p < 0.01). Acetylcholine (4, 8, and 16 micrograms/min for 2 min) and substance P (0.8, 1.6, and 3.2 ng/min for 2 min) also increased forearm blood flow in a dose-dependent manner. Intraarterial L-NMMA (8 mumol/min for 5 min) decreased the magnitudes of increase in forearm blood flow induced by acetylcholine (p < 0.01). L-NMMA at the same dosage decreased the increase in forearm blood flow induced by substance P, but the magnitude of the inhibitory effect of L-NMMA on blood-flow responses to substance P was significantly smaller in the forearm than in coronary vessels. It is suggested that endothelium-derived nitric oxide contributes to substance P-induced vasodilation, and that the contribution of nitric oxide to substance P-induced vasodilation is smaller in the forearm than in coronary circulation.

Objectives: Coronary microembolisation in the pig heart induces angiogenesis in a model of sterile inflammation due to focal necrosis. We have recently shown in this model that insulin-like growth factor I (IGF-I) is involved in inflammation-linked angiogenic processes due to its enhanced transcription after 72 h of ischaemia by infiltrating monocytes in areas of microsphere-induced focal necrosis where capillary sprouting could be detected. To obtain further insights into this process we studied by means of Northern blot analysis and in situ hybridisation the gene expression of other members of the IGF family, i.e. the six IGF binding proteins (IGFBPs), the insulin receptor, and the type I IGF receptor. Methods: Myocardial injury was induced by injection of 25 μ m non-radioactive microspheres into the left circumflex artery (LCx) in pigs that were killed after 3–24, 72, or 168 h of microembolisation. Tissue was collected from a non-ischaemic control area and the LCx region of the same heart for further analysis. Results: We found decreased IGFBP-5 (2.7-fold; P

Supervised cardiac rehabilitation provided at dedicated centres ameliorates exercise intolerance in patients with chronic heart failure.To correlate the amount of physical activity outside the hospital with improved exercise tolerance in patients with limited access to centre-based programs.Forty patients (median age 69 years) with stable heart failure due to systolic left ventricular dysfunction participated in cardiac rehabilitation once per week for five months. Using a validated single-axial accelerometer, the number of steps and physical activity-related energy expenditures on nonrehabilitation days were determined.Median (interquartile range) peak oxygen consumption was increased from 14.4 mL/kg/min (range 12.9 mL/kg/min to 17.8 mL/kg/min) to 16.4 mL/kg/min (range 13.9 mL/kg/min to 19.1 mL/kg/min); P0.0001, in association with a decreased slope of the minute ventilation to carbon dioxide production plot (34.2 [range 31.3 to 38.1] versus 32.7 [range 30.3 to 36.5]; P0.0001). Changes in peak oxygen consumption were correlated with the daily number of steps (P0.01) and physical activity-related energy expenditures (P0.05). Furthermore, these changes were significantly correlated with total exercise time per day and time spent for light (≤3 metabolic equivalents) exercise, but not with time spent for moderate/vigorous (3 metabolic equivalents) exercise.The number of steps and energy expenditures outside the hospital were correlated with improved exercise capacity. An accelerometer may be useful for guiding home-based cardiac rehabilitation.

Endothelium-derived NO contributes to the control of coronary perfusion. We investigated the roles of NO in the metabolic coronary vasodilatation induced by rapid pacing in humans. We evaluated the dilatation of large epicardial and resistance coronary arteries during rapid atrial pacing before and after intracoronary infusion of N G -monomethyl- l -arginine (L-NMMA), an inhibitor of NO synthesis, in 19 patients without significant coronary artery disease. The diameter of the large epicardial coronary artery and coronary blood flow (CBF) were assessed by quantitative coronary arteriography and by a Doppler flow velocity measurement. An increase in the heart rate increased CBF ( P P P P P

Background The pathogenesis of impaired endothelium-dependent coronary vasodilation in angina pectoris and normal coronary arteriograms (microvascular angina pectoris) is not known. We examined whether supplementation with l -arginine, a precursor of endothelium-derived nitric oxide, improves endothelium-dependent coronary vasodilation in patients with microvascular angina. Methods and Results The effect of intracoronary infusion of l -arginine (50 mg/min) on acetylcholine-induced coronary vasomotion was studied in eight patients with microvascular angina and eight control subjects. The responses of the large epicardial coronary artery diameter and coronary blood flow were measured with coronary arteriography and an intracoronary Doppler catheter, respectively. Acetylcholine increased coronary blood flow with modest vasoconstriction of the large coronary artery without altering arterial pressure and heart rate. The acetylcholine-induced increases in coronary blood flow were significantly less ( P l -Arginine significantly augmented the coronary blood flow responses to acetylcholine in patients, but not in control subjects. l -Arginine did not alter responses of the large coronary artery in either group. Conclusions Study results suggest that l -arginine improved endothelium-dependent vasodilation of coronary microcirculation in patients with microvascular angina pectoris.

Objectives.The aim of this study was to investigate the basal release of nitric oxide at spastic sites in patients with variant angina. Background.We previously reported that endothelium-dependent dilator responses to acetylcholine, substance P and bradykinin are preserved at the site of coronary artery spasm. However, it is not known whether the basal release of endothelium- derived nitric oxide is altered at the spastic site. Methods.The effects of intracoronary NG-monomethyl-l-arginine (l-NMMA, an inhibitor of nitric oxide synthesis) at cumulative doses of 50, 100 and 200 μmol on basal coronary artery tone were investigated in eight patients with variant angina and normal coronary angiograms and in eight control subjects. The lumen diameters of large epicardial coronary arteries were assessed by quantitative coronary arteriography. Results.Coronary spasm was provoked by the intracoronary administration of acetylcholine in all patients with variant angina. l-NMMA did not alter the arterial pressure and heart rate but significantly decreased the coronary artery diameter at spastic and nonspastic sites. Constrictive responses to l-NMMA were significantly greater (p < 0.01) at the spastic site (constriction by 200 μmol, 22 ± 7%, mean ± SD) than at the nonspastic site (10 ± 7%). Constrictive responses to l-NNMA at the nonspastic site in patients with variant angina were comparable to those in the control subjects. Conclusions.These findings support the hypothesis that the basal release of nitric oxide may not be decreased at the spastic site in patients with variant angina.

We report a case of a patient with vasovagal syncope, in whom isoproterenol infusion provoked vasovagal response without upright tilting. We subjected the patient, who had had two previous syncopal and several presyncopal episodes, to upright tilting with isoproterenol infusion. Before a control tilt was performed for 10 min (80 degrees), the patient was placed in the supine position for 5 min. The control tilt did not provoke a vasovagal response. With isoproterenol being infused at a dose of 1 mu g/min, the sequence of positioning in the supine position for 5 min and upright tilting for 10 min was repeated. This dose of isoproterenol infusion did not provoke any vasovagal response in the patient, either in the supine or in the upright position. When the dose of isoproterenol infusion was then increased to 2 mu g/min, the heart rate increased to 121/min, but then suddenly dropped to 74/min; systemic arterial pressure simultaneously fell from 148/80 to 108/80 mmHg. The patient complained of palpitation and anxiety, and showed profound cold sweating. The drop in the heart rate and the fall in blood pressure occurred when the patient was in the supine position, indicating that, unlike upright tilting with isoproterenol infusion, venous return was not decreased at the beginning of vasovagal response in this setting. This observation suggests that isoproterenol infusion, even without upright tilting, may provoke the vasovagal response in some patients.