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Based on the possible relation of atherosclerotic cardiovascular disease to the development of cancer, we examined whether polyvascular disease, as a surrogate marker of the severity of atherosclerosis, is associated with the incidence of cancer in patients with coronary artery disease (CAD).A total of 8,856 patients with CAD between January 2009 and July 2014 were eligible for this observational study. Two cohorts were established based on the presence or absence of polyvascular disease (i.e., polyvascular disease and CAD only) and tracked for the incidence of cancer and all causes of death. Polyvascular disease was defined when accompanied by diagnosed aortic and/or peripheral arterial disease or other arterial diseases at enrollment.With a median follow-up of 1,095 d, the incidence of cancer was markedly higher in the cohort of 716 patients with polyvascular disease than in the cohort of 8,140 patients with CAD only (8.8% vs. 4.9%,The presence of polyvascular disease may be associated with the incidence of cancer in patients with CAD, implying a pivotal role of the severity of atherosclerosis in cancer development (ClinicalTrials.gov. number: NCT04198896).

Background To address a clinical impact of atherosclerotic cardiovascular diseases (CVD) on cancer developments, we investigated an issue whether any difference in an incidence of cancers is present between patients with atherosclerotic CVD and those with non-atherosclerotic CVD. Methods Of a total of 32,095 consecutive patients with acquired CVD enrolled in the Sakakibara Health Integrative Profile cohort study, we segregated patients based on a presence of atherosclerotic or non-atherosclerotic CVD to investigate an incidence of cancers and mortality. We also evaluated an incidence of cancers in patients with a singular presence versus a plural presence of atherosclerotic CVD. Atherosclerotic CVD included coronary artery diseases, aortic diseases and peripheral artery diseases. Non-atherosclerotic CVD were any acquired CVD except atherosclerotic CVD. Results During a median follow-up of 1020 days (interquartile range, 665–1340 days), an incidence of cancers (5% vs. 2%, p = 0.0001) and overall mortality (6% vs. 3%, p = 0.0001) were more than two-fold higher in 10,592 patients with atherosclerotic CVD than in 21,503 patients with non-atherosclerotic CVD. A presence of atherosclerotic CVD (hazard ratio 1.372 with 95% confidence interval 1.199–1.569) was independently associated with an incidence of cancers. In patients with atherosclerotic CVD, 61 of 640 patients with a plural presence and 470 of 9932 patients with a singular presence developed cancers (9% vs. 5%, p = 0.0001). An incremental risk of death was found according to a presence of atherosclerotic CVD, cancers, and both of them (all p = 0.0001). Conclusions A presence of atherosclerotic CVD itself may have a potential risk for cancer developments. Trial registration ClinicalTrials.gov . number, NCT03005834

Patients are diagnosed as having chronic kidney disease (CKD) if estimated glomerular filtration rate (eGFR) is

Background: Recent studies have suggested that esmolol is the first choice for rate control in patients with postoperative atrial fibrillation (AF) after coronary artery bypass surgery, but side-effects of esmolol such as hypotension are problematic. To overcome this problem, landiolol, an ultra-short-acting β1-blocker with a less negative inotropic effect than esmolol, has been developed. The aim of the present study was to investigate whether landiolol was effective for both rate control and conversion to normal sinus rhythm (NSR). Methods and Results: A prospective, randomized, open-label comparison between i.v. landiolol and diltiazem in patients with postoperative AF was undertaken between January 2008 and June 2009 in Japan. Of 335 patients included in the analysis, 71 patients went into AF. Among these 71 patients, conversion to NSR within 8h after onset of AF occurred in 19 of 35 patients (54.3%) in the landiolol group vs. 11 of 36 patients (30.6%) in the diltiazem group (P

Aims To test whether angiotensin II receptor blockers (ARBs) therapy can reduce the incidence of cardiovascular events compared with non-ARB-based standard pharmacotherapy in coronary artery disease (CAD) patients with hypertension. Methods and results Angiographically documented CAD patients with hypertension were randomly assigned to receive either candesartan-based ( n = 1024) or non-ARB-based pharmacotherapy including angiotensin-converting enzyme-inhibitors ( n = 1025). The primary endpoint was the occurrence of a first major adverse cardiovascular event (MACE). There were 552 primary events during a median follow-up of 4.2 years: 264 (25.8%) in the candesartan group and 288 (28.1%) in the non-ARB group (hazard ratio, 0.89; 95% confidence interval, 0.76–1.06). No significant differences existed between groups in terms of cardiovascular death (2.7 vs. 2.4%, 1.14; 0.66–1.95), non-fatal myocardial infarction (2.8 vs. 2.5%, 1.12; 0.66–1.88), or heart failure (3.9 vs. 4.3%, 0.91; 0.59–1.40). New-onset diabetes was diagnosed significantly less frequently with candesartan than with non-ARBs (0.37; 0.16–0.89). Incidence of study drug discontinuation due to adverse events was lower with candesartan than with non-ARBs (5.7 vs. 12.2%, P < 0.001). Conclusion Although candesartan showed no significant differences in MACE compared with the non-ARB treatment group, the drug significantly reduced the incidence of new-onset diabetes and was better tolerated. This study is registered as International Standard Randomised Controlled Trial No. UMIN000000790.

Background The efficacy and safety of abciximab were investigated in Japanese patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) or unstable angina. Methods and Results The 973 patients were randomized into 3 groups: the low-dose group (L group) received bolus injection of 0.20 mg/kg followed by 12-h infusion; the high-dose group (H group) received bolus injection of 0.25 mg/kg followed by 12-h infusion; the placebo group (P group) received bolus and infusion of placebo. The incidence of the primary endpoint (30-day post-PCI coronary events: death, MI or urgent revascularization) was 3.6%, 1.6%, and 4.1% in the P, L, and H groups, respectively, with no significant difference between the P and L groups (P=0.104) or between the P and H groups (P=0.772). The incidence of bleeding tended to increase in a dose-dependent manner. Conclusion No significant difference in the incidence of coronary events was found between the placebo and abciximab groups, so the efficacy of abciximab in preventing post-PCI coronary events in Japanese patients was not confirmed. (Circ J 2009; 73: 145 - 151)

Background A multicenter study was conducted to assess the current medical management of unstable angina (UA) and non-ST-elevation acute coronary syndrome in Japan. Methods and Results This study presents the results of a nationwide questionnaire survey of 770 sites and a case report investigation performed at 20 sites. The questionnaire survey revealed that the number of acute myocardial infarction (AMI) patients treated annually was 1.56-fold greater than the number of UA patients. Non-ST-elevation AMI accounted for 17% of all patients with AMI. Analysis of case reports for 885 UA patients showed extensive use of invasive treatment. In the UA patients, the cumulative incidence of a composite endpoint (all-cause mortality, AMI, and urgent coronary revascularization) was 2% at 1 month and 9% at 6 months. Stratified analysis with respect to the composite endpoint through 6 months showed a significantly lower incidence in patients treated with a calcium-channel blocker than in patients not treated with a calcium-channel blocker. Conclusions In Japan, fewer patients are hospitalized annually for treatment of UA than for AMI. The largest percentage of UA patients had Braunwald class III disease. Non-ST-elevation AMI is managed in Japan according to the principle of early invasive treatment, resembling the treatment for ST-elevation AMI. The outcome of treatment is better for Japanese UA patients than for Japanese AMI patients. (Circ J 2007; 71: 1335 - 1347)

There is no consensus on lipids and restenosis after percutaneous transluminal coronary angioplasty (PTCA). We evaluated whether prevastatin could prevent restenosis after PTCA. In this study, pravastatin therapy was started one month before PTCA. The follow-up angiography was done three months later. Total cholesterol reduction rates [one index of reduction rate is calculated between 1 M (month) before PTCA and at PTCA, and another done between 1 M before PTCA and at follow-up angiography] proved to be good predictors of restenosis rate after PTCA; The greater the cholesterol reduction rate, the lower the rate of restenosis. The residual stenosis after PTCA correlated with the restenosis rate. The restenosis rate in the pravastatin group was lower than that in the control group, but the difference was not statistically significant. However, in the subgroup with pre-PTCA restenosis of 99% or more, the restenosis rate in the pravastatin group was significantly lower than that of the control group. Pravastatin seems to prevent intimal hyperplasia through the reduction of cholesterol level and to reduce restenosis. Many macrophages are present in the highly stenosed or occluded coronary arteries, and the reduction of the number and the activity of macrophages may prevent the restenosis. Pravastatin also has an antithrombotic action. In such regions, the occlusion by the thrombus formation is also considered to play a key role in restenosis in addition to the intimal hyperplasia. Thus, pravastatin may be useful especially for PTCA against highly stenosed or occluded coronary arteries.

Background Plasma catecholamines (CAs) are widely used as an index of sympathetic nervous system activity. In addition, CAs are known to be metabolized by catechol- O -methyltransferase (COMT) to produce their 3- O -methyl metabolites. We previously established a sensitive determination method of CAs and their 3- O -methyl metabolites using HPLC-peroxyoxalate chemiluminescence (POCL) reaction detection system. In this study, a microcolumn (100 × 1.0 mm I.D.) was used for separation to obtain higher sensitivity and shorter analysis time. Methods The system included automated precolumn ion-exchange extraction of amines, followed by separation on an ODS column, coulometric oxidation, fluorescence derivatization with ethylenediamine, and finally POCL reaction detection. Results The detection limits for CAs and their 3- O -methyl metabolites were 0.3–2.0 fmol. The analysis time was about 35 min, about half that of previously reported results. The method developed was used in monitoring changes in CAs and 3- O -methyl metabolite concentrations in human plasma during exercise. Conclusion The simultaneous determination method for concentrations of CAs and their 3- O -methyl metabolites in human plasma was developed using micro LC-peroxyoxalate chemiluminescence detection. We were successful in quantitating the changes in plasma CAs and their 3- O -methyl metabolites during exercise.

Aims To examine the impact of pre-operative atrial fibrillation (AF) on the outcome of mitral valve repair (MVR) for degenerative mitral regurgitation (MR). Methods and results Among 392 patients with moderate to severe MR who underwent MVR between 1991 and 2002, 283 patients with isolated degenerative MR were followed for 4.7+ 3.3 years. Of 27 deaths, nine were due to cardioembolic events and four were due to left ventricular (LV) dysfunction. When compared with patients with pre-operative AF, those with sinus rhythm (SR) had better survival (96 + 2.1 vs. 87+ 3.2% at 5 years, P ¼ 0.002) and higher cardiac event-free rates (96+ 2.0 vs. 75+ 4.4% at 5 years, P , 0.001). In patients with pre-operative SR, observed and expected survival were similar (P ¼ 0.811). Cox multivariable regression analysis confirmed AF [P ¼ 0.027, adjusted hazard ratio (AHR) 2.9] and age as independently predictive of survival, and AF (P ¼ 0.002, AHR 3.1), New York Heart Association Class, and LV fractional shortening as independently predictive of cardiac event. Conclusion Death due to LV dysfunction was not frequent and cardioembolic events due to AF were the leading cause for cardiac death. Pre-operative AF became a strong independent predictor of survival and morbidity. Patients with pre-operative SR had excellent prognosis. The benefits of preventing cardioembolic events due to AF validate the indication of MVR for patients with high risk for AF.

Background Although the anti-atherosclerotic effects of HMG-CoA reductase inhibitors are well known, their specific effect on saphenous vein grafts after coronary artery bypass graft (CABG) operation is not well documented and has not been studied in Japan, so the aim of the present prospective randomized controlled study involving 27 Japanese institutions was to investigate the effects of pravastatin on the progression of atherosclerosis in such grafts and native coronary arteries after CABG. Methods and Results A total of 303 patients who had undergone CABG were randomly assigned to either the pravastatin group (n=168) or the control group (n=167). Paired coronary angiograms were obtained at baseline and at the end of 5-year follow-up in 182 (60%) patients. The low-density lipoprotein cholesterol concentration significantly decreased in the pravastatin group from 141.4 mg/dl to 113.7 mg/dl (-19.6%), compared with 141.1 mg/dl to 133.7 mg/dl (-5.2%) in the control group (p

A 56-year-old man presented with sustained chest pain. Coronary angiography revealed total occlusion of the distal right coronary artery and left anterior descending branch. Left ventriculography depicted a mobile mass in the right sinus of Valsalva originating from the ostium of the right coronary artery. Transesophageal echocardiography (TEE) showed a mobile mass in the sinus of Valsalva and another mobile mass in the aortic arch. The mass at the right sinus of Valsalva was surgically resected, and histologic examination revealed an organized thrombus. Coagulation study showed protein S deficiency. This is the first case of acute myocardial infarction as a result of multiple coronary embolism caused by thrombosis in the right sinus of Valsalva with a second aortic arch thrombosis, contributed by protein S deficiency.

Background The efficacy and optimum dose of β-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a β-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF. Methods After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class. Results Carvedilol therapy achieved dose-dependent improvement of all end points ( P for linear trend, range .002 to P range, .024 to Conclusions In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.

We investigated adenylate cyclaserelated hormone actions induced by colforsin daropate hydrochloride (Adehl® Inj.: AD) injected by intravenous administration at 0.5 μg/kg/min for 3 hrs in 9 male healthy volunteers (age;21-32 y), compared with control administration of physiologic saline. Adenylate cyclaserelated parameters on serum chemistry, urine test and hormone secretion levels were measured at preadministration and, 1 and 3 hours after administration. [Statistics] As for statistic analysis to determine agent effects, we adopted both 95% confidence interval test (95%CI-test) and paired t-test. By 95%CI-test, we detected the discrepancy between 95% CI of each observed data and its standard value range, and by paired t-test we detected data changes between preadministration and post-administration. [Results] Adrenaline, insulin, ACTH, cortisol, NEFA, glycerol, and FT3, increased among glucose metabolism-or fat metabolism-related parameters. Concerning bone/Ca metabolism-related parameters, serum Ca, ALP, totalprotein, albumin, and serum cAMP increased while serum P and PTH-I decreased. And serum K decreased in water absorption-related parameters of kidney function. In sex hormones, FSH and testosterone in-creased. In the other hormones, noradrenaline and plasma renin activity increased. However, changes of all the detected parameters were transient within their normal ranges or standard limits, and were graded in minute or slight (plasma rennin activity only). [Discussion & Conclusion] We concluded that almost all the changes of these observed parameters were attributed to AD hemodynamic effects such as chronotropic action, inotropic action and vasodilating action, which were linked to hormonal secretion level changes (ACTH increase, adrenaline increase, noradrenaline increase) by way of cardiovascular homeostasismechanism or auto-regulation system. Concerning the slight increase of serum cAMP, it had no linkage to any hormonal secretions. The PTH-like action of AD such as PTH-I decrease reported in the precedent animal study was also observed.

The optimal timing of surgical correction of severe mitral regurgitation (MR) is important for improved morbidity and mortality. We utilized a scoring system to decide the timing of procedures. Based on clinical features and echocardiographic data, we hypothesized that preoperative semi-quantitation of MR using this scoring system may be useful for predicting prognosis after repair. The MR score was composed of 6 parameters associated with disease severity (i.e., history of heart failure, atrial fibrillation, pulmonary hypertension, left ventricular end-systolic dimension, fractional shortening, and left atrial dimension). The maximum score was 6. Of 267 patients who underwent mitral valve repair in the last 10 years, 191 patients with mitral valve prolapse were studied. Patients were categorized into 2 groups according to MR score (group low [L] : 0 to 2.5 and group high [H]: ≥3.0) irrespective of New York Heart Association functional class. A significant difference in postoperative event-free survival was observed between both groups (p = 0.0014); the adjusted risk ratio was 3.4 (95% confidence interval 1.6 to 7.2). Postoperative echocardiography showed larger left ventricular systolic dimensions (p

ObjectivesThis study sought to determine whether echocardiography before mitral valve repair (MVR) for mitral regurgitation (MR) was predictive of postoperative left ventricular (LV) dysfunction and useful for deciding the optimal timing of repair.BackgroundSome reports have shown that the preoperative echocardiographic data of left ventricular ejection fraction (LVEF) and left ventricular end-systolic diameter (LVDs) were good predictors of postoperative LV dysfunction. However, few reports were based on long-term follow-up data of large numbers of patients who underwent MVR in the last decade.MethodsA total of 274 patients with moderate or severe MR underwent MVR between October 1, 1991, and September 30, 2000. Among them, 171 patients who had both an operation for isolated MR due to degenerative pathology and a postoperative echocardiogram were studied. Postoperative echocardiograms were performed 3.9 ± 2.4 years after the operation.ResultsThe LVEF decreased from 66 ± 10% before surgery to 63 ± 11% after surgery (p < 0.0001). On univariate analysis, preoperative LVEF and LVDs correlated with postoperative LVEF (r = 0.41 and r = −0.39, respectively). Overall, postoperative LV dysfunction (defined as LVEF

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.

Perimyocarditis represents an inflammation of both the myocardium and pericardium. Although several causative agents have been recognized, pericarditis or myocarditis associated with rubella is an unusual complication. In a 29-year-old woman, left ventricular function transiently deteriorated accompanied by ongoing cardiac inflammation a few days after illness. The titer of rubella virus increased from seronegative to more than 32-fold during the admission, and a rise in specific antirubella virus antibody was present. The patient was suspected of having perimyocarditis associated with the rubella infection. The authors also present clinical features of rubella-associated perimyocarditis and myocarditis in the literature.

The relative importance of metabolic risk factors for coronary heart disease (CHD) in the Japanese is assessed by comparing their prevalence in patients with acute coronary syndrome (ACS) enrolled in the Asia-Pacific Collaboration on CHD Risk Factor Intervention (ASPAC) study to that obtained by a serum lipid survey carried out in 1990 and also by comparing them to the ASPAC data from other countries and regions in this area. Hypertension was the most prevalent risk factor among Japanese patients with ACS as in the other countries and regions. The prevalence of obesity with a body mass index (BMI) of 30 or more was several times higher than that in the general population, although the rate was still much lower than in New Zealand and Singapore. In addition to hypercholesterolemia, hypertriglyceridemia and diabetes mellitus were frequently found in Japanese patients with ACS. When the prevalence of metabolic risk factors was compared between people with and without hypertension in the general population, the most remarkable difference was seen in BMI, followed by triglyceride and total cholesterol. These results indicate that hypertriglyceridemia and diabetes mellitus may be more important CHD risk factors in the Japanese population than LDL-cholesterol.

Isolated ventricular noncompaction (IVNC) is an unusual congenital heart disease. The morphological features are trabeculations and intertrabecular recesses within the left ventricle. Important clinical considerations include the high mortality due to depressed cardiac function, and the instance of ventricular arrhythmia and systemic embolism. One of reasons for the high mortality is that there is still no effective therapy with the exception of the recommendation for anticoagulation therapy to prevent embolisms. Hence, we describe a 29-year-old man with IVNC presenting with chronic heart failure. Careful up-titration of carvedilol in this patient changed the parameters of cardiac diastolic performance.

A 58-year-old man with a 64-month history of unclassified cardiomyopathy developed congestive heart failure (CHF) and had been dependent on long-term intravenous positive inotropes. Combined pimobendan and carvedilol administration resulted in marked symptomatic improvement from New York Heart Association functional class IV to I. Echocardiograms showed improvement of left ventricular (LV) ejection fraction from 15 to 48%, and LV end-diastolic diameter from 6.7 to 4.9 cm. This mode of therapy not only improved LV contractile function but also normalized LV volume, which was an unusual clinical course compared with the general course of advanced CHF.

Two-dimensional echocardiography can provide intracardiac images. However, the cross-sectional images require mental reconstruction to understand a three-dimensional intracardiac structure. It is sometimes hard for inexperienced echocardiographers to engage in reconstruction. Thus, three-dimensional echocardiography is potentially beneficial because these images can provide extra information without mental reconstruction. Herein we demonstrate three-dimensional reconstruction using transesophageal echocardiography in a patient with a left atrial myxoma. It contributed to clarifying the surgical considerations, including whether the tumor was adhering to the left atrium or the mitral valve.

SummaryCX-397, a recombinant hirudin analog, is a potent and specific inhibitor of human α-thrombin. We conducted a comparative study of CX-397 and heparin in a canine model of left circumflex (LCX) coronary artery thrombosis to evaluate the anti-thrombotic efficacy of CX-397. Administration of drugs (i. v.; bolus + infusion) was commenced 10 min prior to the initiation of LCX coronary artery electrolytic injury (100 μA for 300 min). All saline-treated control animals (7/7) developed thrombotic occlusion during the experimental period, leaving a residual thrombus mass of 15.4 ± 3.8 mg. Treatment with CX-397 at three incremental dose levels reduced the incidence of occlusion (4/7, 2/5 and 0/7) and decreased thrombus weight (12.6 ± 2.5 mg, 6.3 ± 3.0 mg and 2.1 ± 1.3 mg, respectively) in a dose-dependent manner. At the in termediate dose (15,000 ATU/kg + 15,000 ATU/kg/h) or higher, CX-397 showed significant anti-thrombotic effects (p

A total of 502 patients presenting in Utsunomiya city and its suburbs during a 10-year period were studied to determine the clinical features of ischemic heart disease and to identify coronary risk factors. The male/female ratio was 1.21, but the ratio decreased with increasing age. The duration of chest pain showed a continuous spectrum between angina and infarction, with a short duration of chest pain not being useful for excluding the diagnosis of myocardial infarction. Hypertension was more common than hypercholesterolemia in this study, although the prevalence of the latter increased slightly with time, along with the shift towards a modernized occupational pattern. Smoking was a more important risk factor for ischemic heart disease in younger individuals than in the elderly, and diabetes mellitus was highly associated with the development of myocardial infarction. The incidence of radiologically diagnosed cardiac hypertrophy and aortic calcification decreased over time. These changes may have resulted in part from improved blood pressure control and the development of new antihypertensive and cholesterol-lowering agents. (Jpn Circ J 1998; 62: 675 - 679)

Developed by Bayer in Germany, nifedipine was shown to be effective in the treatment of patients with angina pectoris by Japanese investigators. Professor Kimura first reported the efficacy of nifedipine in patients with angina pectoris and those findings have been replicated in numerous trials conducted since then. Clinical trials found a low incidence of fixed coronary artery stenosis in Japanese patients with variant angina pectoris, and a complete antianginal response with Ca2+ channel antagonist such as nifedipine. It was hypothesised that the mechanism of this benefit with nifedipine was because of a strong coronary vasodilating action along with an inhibitory effect on coronary spasm. Recent evidence has established the tolerability and efficacy of once-daily dosage forms, which provide stable plasma nifedipine concentrations, in the management of coronary artery disorders.

The cyclic AMP (cAMP)-dependent chloride channel in the heart has been identified in various species as the cystic fibrosis transmembrane conductance regulator (CFTR). Although functional expression of the channel in the human atrium has been reported, we could not induce any cAMP-dependent chloride conductance in the atrial cells even with maximal cAMP stimulation, whereas the conductance could be induced in rabbit ventricular cells. To clarify the discrepancy between the results, we examined the level of CFTR mRNA expression in both conductance-positive (human colonic epithelium and rabbit ventricle) and -negative (human atrium) tissues. Total RNA samples prepared from these tissues were subjected to the reverse transcription-polymerase chain reaction (RT-PCR). While CFTR transcripts were amplified from the conductance-positive samples, no amplified products could be detected from the conductance-negative sample. A nested PCR performed on the RT-PCR products of the conductance-negative sample resulted in successful amplification of the transcripts, indicating that the level of the CFTR mRNA expression in human atrium is extremely low compared with that in colonic epithelium and rabbit ventricle. The same molecular results were observed in human ventricular tissues. A nucleotide sequencing of the amplified transcripts showed that exon 5 of the CFTR gene was not alternatively spliced in human atrium and ventricle, and both the exon 5 spliced and unspliced isoforms were expressed in rabbit ventricle, unlike the findings of previous reports. Our data suggest that the amount of CFTR expressed in human myocardium might be physiologically insufficient to activate detectable cAMP-dependent chloride conductance.

This study used body surface mapping to evaluate the ventricular repolarization process in the absence of delta waves in 13 patients with the intermittent Wolff-Parkinson-White (WPW) syndrome. The findings were compared with data from 30 normal individuals and 50 patients with the overt WPW syndrome. The QRST isointegral maps of patients with the overt WPW syndrome exhibited abnormal areas and the QRST departure maps showed a peculiar distribution to each accessory pathway site. The QRST isointegral map exhibited abnormal areas in 11 of the 13 cases (85%) of the intermittent WPW syndrome in the absence of delta waves. In 8 of these 11 cases (73%), the distribution of the departure map resembled that in the overt WPW syndrome. These findings suggest that abnormal ventricular repolarization due to cardiac memory is present in patients with the intermittent WPW syndrome even in the absence of delta waves.

Clinical manifestations of hypothyroidism, such as bradycardia, suggest decreased sympathetic tone. However, previous studies in patients with hypothyroidism have suggested that increased plasma noradrenaline (NA) levels represent enhanced general sympathetic activity. As yet, cardiac sympathetic activity (CSA) in hypothyroidism has not been clarified. To evaluate CSA in patients with hypothyroidism, iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed in eight patients with hypothyroidism before therapy and in ten normal control patients. Planar images were obtained at 15 min and 4 h after injection of MIBG. The ratio of early myocardial uptake to the total injected dose (MU) and myocardial clearance of MIBG within 4 h p.i. (MC) were calculated. Plasma NA was also measured, and echocardiography was performed in all patients. Those patients with hypothyroidism in the euthyroid state after medical therapy were also evaluated in a similar manner. Left ventricular ejection fraction, measured by echocardiography, did not differ significantly between the groups. NA, MU and MC were significantly higher in patients with hypothyroidism than in controls, and all parameters were decreased after therapy. MC was well correlated with NA in hypothyroidism (r=0.86) before therapy. We conclude that CSA is increased in patients with hypothyroidism, in parallel with the enhanced general sympathetic activity.

1. To determine the contribution of the various phosphodiesterase (PDE) isozymes to the regulation of the L-type calcium current (ICa(L)) in the human myocardium, we investigated the effect of selective and non-selective PDE inhibitors on ICa(L) in single human atrial cells by use of the whole-cell patch-clamp method. We repeated some experiments in rabbit atrial myocytes, to make a species comparison. 2. In human atrial cells, 100 microM pimobendan increased ICa(L) (evoked by depolarization to +10 mV from a holding potential of -40 mV) by 250.4 +/- 45.0% (n = 15), with the concentration for half-maximal stimulation (EC50) being 1.13 microM. ICa(L) was increased by 100 microM UD-CG 212 by 174.5 +/- 30.2% (n = 10) with an EC50 value of 1.78 microM in human atrial cells. These two agents inhibit PDE III selectively. 3. A selective PDE IV inhibitor, rolipram (1-100 microM), did not itself affect ICa(L) in human atrial cells. However, 100 microM rolipram significantly enhanced the effect of 100 microM UD-CG 212 on ICa(L) (increase with UD-CG 212 alone, 167.9 +/- 33.9, n = 5; increase with the two agents together, 270.0 +/- 52.2%; n = 5, P < 0.05). Rolipram also enhanced isoprenaline (5 nM)-stimulated ICa(L) by 52.9 +/- 9.3% (n = 5) in human atrial cells. 4. In rabbit atrial cells, ICa(L) at +10 mV was increased by 22.1 +/- 9.0% by UD-CG 212 (n = 10) and by 67.4 +/- 12.0% (n = 10) by pimobendan (each at 100 microM). These values were significantly lower than those obtained in human atrial cells (P < 0.0001). Rolipram (1-100 microM) did not itself affect ICa(L) in rabbit atrial cells. However, ICa(L) was increased by 215.7 +/- 65.2% (n = 10) by the combination of 100 microM UD-CG 212 and 100 microM rolipram. This value was almost 10 times larger than that obtained for the effect of 100 microM UD-CG 212 alone. 5. These results imply a species difference: in the human atrium, the PDE III isoform seems dominant, whereas PDE IV may be more important in the rabbit atrium for regulating ICa(L). However, PDE IV might contribute significantly to the regulation of intracellular cyclic AMP in human myocardium when PDE III is already inhibited or when the myocardium is under beta-adrenoceptor-mediated stimulation.

We studied the influence of early coronary reperfusion on QT interval dispersion in patients with acute myocardial infarction (MI). There were 54 males and 18 females with a mean age of 60 +/- 10 years. Of the 51 patients with recanalization of the infarct related vessel in the recovery phase, 28 (group A) had early coronary reperfusion (5.5 +/- 2.7 hours), 23 other patients (group B) were not confirmed with early coronary reperfusion. Twenty-one patients (group C) did not undergo recanalization of the infarct related vessel in the recovery phase. Corrected QT (QTc) maximum, QTc minimum, and QTc dispersion calculated as the difference between the maximum and minimum QTc intervals, were compared among these three groups at both acute and recovery phase. At the acute phase after MI, there were no significant differences in the QTc maximum, QTc minimum, QT dispersion, and QTc dispersion among these three groups. At the recovery phase after MI, there were also no significant differences in the QTc maximum and QTc minimum. However, there were significant differences in the QT dispersion (0.035 +/- 0.010 in group A, 0.049 +/- 0.015 in group B, and 0.061 +/- 0.031 s in group C, respectively; P = 0.0001), and QTc dispersion (0.038 +/- 0.012 in group A, 0.050 +/- 0.015 in group B, and 0.063 +/- 0.032 s in group C, respectively; P = 0.0003) among the three groups. Comparison of QTc dispersion between acute and recovery phase revealed significant reduction from acute to recovery phase in group A. The number of premature ventricular contraction was lower in group A and B than group C. In summary, early coronary reperfusion may reduce electrophysiological instability by reducing QT dispersion in the recovery phase after acute MI.

Objectives. This prospective, randomized, double-blind multicenter trial evaluated the efficacy and safety of a single bolus injection of the novel modified tissue-type plasminogen activator (t-PA) E6010 in the treatment of acute myocardial infarction compared with that of native t-PA. Background. E6010 is a novel modified t-PA with a prolonged half-life (t1/2alpha ≥23 min) compared with native t-PA (t1/2alpha = 4 min). E6010 can be administered in patients as a single intravenous bolus injection, and early recanalization can be expected. Methods. The efficacy of E6010 was compared with that of native t-PA in 199 patients with acute myocardial infarction who were treated within 6 h of onset in a prospective, randomized, double-blind multicenter trial. Patients were given either 0.22 mg/kg body weight of E6010 intravenously over 2 min or native t-PA (tisokinase) 28.8 mg or 14.4 million IU (10% of the total dose over 1 to 2 min, the remainder infused over 60 min). Results. The primary end point was the recanalization rate of the infarct-related coronary artery at 60 min after the start of treatment. Time to reperfusion was shorter in the E6010 group than in the native t-PA group. Thrombolysis in Myocardial Infarction flow grade 2 or 3 recanalization at 15, 30, 45 and 60 min after administration was observed in 37%, 62%, 74% and 79% (95% confidence interval [CI] 70% to 87%) of the E6010-treated patients and in 14%, 32%, 50% and 65% (95% CI 55% to 74%) of native t-PA-treated patients, respectively (p = 0.032 at 60 min). Conclusions. The present study indicates that, compared with native t-PA, a single bolus injection of E6010 over 2 min produces a higher rate of early recanalization of the infarct-related coronary artery without fatal bleeding complications. (J Am Coll Cardiol 1997;29:1447–53)

We evaluated the effects of disopyramide in terms of the balance between myocardial oxygen supply and demand in patients with hypertrophic obstructive cardiomyopathy (HOCM). The myocardial oxygen supply was evaluated by measuring coronary flow velocity and the myocardial oxygen demand was assessed by the pressure-volume area (PVA). The time velocity integral of coronary flow did not change significantly (20 +/- 6 to 21 +/- 8 cm), but the peak left ventricular pressure and left ventricular external work decreased significantly (206 +/- 44 to 157 +/- 37 mmHg, P0.001; 1.09 +/- 0.33 to 0.80 +/- 0.23 J/beat, P0.001) after disopyramide administration. From theoretical analysis using these data, we concluded that disopyramide improves the myocardial oxygen supply-demand balance in patients with HOCM.

The electrophysiological effect of extracellular ATP was investigated in voltage-clamped single cells from the rabbit sino-atrial node. External 0.5 mM ATP consistently activated a time-independent, weakly inwardly rectifying current (2.26 +/- 0.14 pA/pF at -100 mV, n = 23). This external ATP-activated current increased in a dose-dependent manner over the concentration range 0.01 to 1 mM ATP. However, non-hydrolysable ATP analogs (a, beta-methylene ATP and beta,r-methylene ATP) failed to activate this current. Moreover, adenosine, adenosine monophosphate and adenosine diphosphate were all ineffective in eliciting the ATP-activated current over the concentration range 0.5 to 1 mM, suggesting that it is regulated via the P2-purinoreceptor. The permeability sequence for the ATP-activated current among different cations (determined from reversal potential measurements) was 1.09: 1: 1: 0.24: 0.22 for K+, Na+, Cs+, Tris and N-methyl-D-glucamine. The current component was not affected by substitution of external Cl- by aspartate or by the application of a stilbene-derivative Cl- channel blocker. Thus, the ATP-activated current in rabbit sino-atrial node cells was non-selective for monovalent cations, and could be carried by large molecular ions, such as N-methyl-D-glucamine or Tris. We suggest that it might make some contribution to the chronotropic effects seen on release of transmitters from autonomic nerve endings in the heart.

We conducted a multi-center two-stage randomized double-blind placebo-controlled study to assess the efficacy and safety of NKH477. This drug, a newly synthesized water-soluble forskolin derivative, has been previously shown to improve hemodynamics and subjective symptoms in patients with acute heart failure.In the first stage (study 1), 78 patients with acute heart failure were randomly assigned to receive either NKH477 by intravenous administration at 0.5μg/kg/min for 30 min or a lower dose of NKH477 as a “substitute” placebo, namely 0.2μg/kg/min for 30 min. The second stage (study 2) began within 10 min after the end of dosing in study 1. Forty-seven patients were randomly assigned to either continue treatment with NKH477 at 0.5 μg/kg/min for 1 hr or toreceive matching vehicle placebo.In study 1, the percentage improvement in hemodynamic and subjective and objec tive conditions in the control group as judged by attending physicians was 34.3 %. In contrast, improvement in the NKH477 group was 71.4 %, this difference being significant (p

To evaluate the efficacy and safety of NKH 477, a water soluble forskolin derivative, a multicenter group study was conducted in 62 patients with severe heart failure.Patients were intravenously administered NKH477 at a rate of 0.25μg/kg/min (low) initially and the dose was increased hourly to 0.5μg/kg/min (intermediate) and finally to 0.75μg/kg/min (high).NKH477 improved the hemodynamics in the patients with severe heart failure, since this agent directly activates adenylate cyclase. The cardiac index (CI) increased significantly and pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance (SVR) were significantly decreased.In the principal physicians' assessment of the global improvement, the percentage of patients judged as “improved” or higher was 19.0% in the low-dose group, 49.1% in the intermediate-dose group and 70.6% in the high-dose group.Adverse events occurred in 6.5% in the low-dose group, 19.7% in the intermediatedose group and 37.0% in the high-dose group, increasing with dose. The most common symptoms were palpitation, flush and headache. It is important to also note an increment of arrhythmias.In the evaluation of usefulness based on the grobal improvement and overall safety, the percentage of patients in which the treatment was assessed as “useful” or higher was 22.4% in the low-dose group, 52.6% in the intermediate-dose group which showed significant increase and 70.6% in the high-dose group.In conclusion, the clinical optimal dose of NKH 477 is thought to be 0.5μg/kg/min.

Patients are diagnosed as having chronic kidney disease (CKD) if estimated glomerular filtration rate (eGFR) is

We compared the post-hospital prognosis after an acute coronary event (acute myocardial infarction and unstable angina) in 106 patients in Japan vs. 789 patients in North America who were prospectively enrolled in the Multicenter Study of Myocardial Ischemia and were followed-up for an average of 26 months per patients. Risk factors more frequent in Japan were older age, males and smoking at enrollment, but the rest of many risk factors were similar. After adjusting for differences in clinical and medication variables, Cox analyses indicated patients in North America had a significantly greater risk of experiencing a primary end-point (cardiac death, non-fatal myocardial infarction or unstable angina) than patients in Japan (hazard ratio [North America:Japan] = 3.1, P = 0.003). There was a non-significant trend in the restricted end-points (cardiac death or non-fatal myocardial infarction) with North America having more frequent events than Japan (hazard ratio = 2.2, P = 0.12). The long-term outcome after recovery from an acute coronary event is more favorable in Japan than in North America, mostly due to a reduction in subsequent hospitalization for unstable angina. The reason for these findings cannot be explained by differences in the measured risk factors or medications.

Abstract Anion conductance is known to be activated by mechanical stimulation, such as osmotic cell swelling or cell inflation via the patch pipette, of canine or rabbit cardiac myocytes. The effects of mechanical stimulation on time-dependent currents, however, remain unsettled. Using the whole-cell voltage-clamp method, we have found that mechanical stimuli enhance the L-type Ca 2+ current (I Ca,L ) in rabbit cardiac myocytes. At every membrane potential, I Ca,L was reversibly increased by osmotic cell swelling and by cell inflation caused by applying a positive pressure of 10 to 15 cm H 2 O via the patch pipette. I Ca,L was increased during cell inflation by 37±21% (mean±SD, n=17) in atrial cells and by 37±8% (n=7) in sinoatrial node cells in solution containing 2 mmol/L Ca 2+ . The current-voltage relationship, the inactivation time constant, the steady state inactivation curve, and the conductance properties of I Ca,L were all virtually unaffected by mechanical stimulation except for the open probability, which appears to increase. The increase in I Ca,L was not dependent on protein kinase A, since an inhibitor peptide of cAMP-dependent protein kinase failed to prevent the increase in I Ca,L during mechanical stimuli (n=5). The increase in I Ca,L caused by cell inflation was unaffected by the chelation of intracellular Ca 2+ by the addition of 10 mmol/L EGTA or 10 mmol/L BAPTA to the pipette solution, suggesting that the effect was not mediated by changes in intracellular Ca 2+ . Thus, mechanical stimulation due to cell swelling or inflation may itself directly increase I Ca,L in rabbit cardiac myocytes.

Objectives.We investigated the role of endogenous endothelin-1 in the development of cardiac hypertrophy in vivo under pressure overload conditions.Background.Endothelin-1, a potent vasoconstrictor peptide, has recently been shown to act as a growth factor of myocardial cells in culture.Methods.We examined the effect of an endothelin-A receptor antagonist (FR139317) on the development of right ventricular hypertrophy in rats with monocrotaline-induced pulmonary hypertension. Three groups of rats were studied: those given monocrotaline alone or monocrotaline plus FR139317 and those given vehicle alone (control group).Results.The ratio of right ventricular systolic pressure to aortic systolic pressure was similarly elevated in rats treated with monocrotaline and monocrotaline plus FR139317. The right ventricular/left ventricular weight ratio was increased in monocrotaline-treated rats but lower in rats treated with monocrotaline plus FR139317 than in those treated with monocrotaline alone (p < 0.01). As a biochemical marker of hypertrophy, the isoform ratio of beta-myosin heavy chain protein was determined for the right ventricular tissue samples. This ratio was increased in all monocrotaline-treated rats but was lower (p < 0.01) in rats given monocrotaline plus FR139317 than in those given monocrotaline alone. The isoform ratio of beta-myosin heavy chain messenger ribonucleic acid quantitated by S1 nuclease mapping also was lower (p < 0.025) in rats receiving monocrotaline plus FR139317 than in those receiving monocrotaline alone.Conclusions.These data suggest that blocking the action of endothelin-1 with a receptor antagonist ameliorates cardiac hypertrophy in this model system, and that this action is not mediated by ameliorating hemodynamic changes.

Overdrive suppression test (OST) におけるSRTの反応から, 洞不全症候群 (SSS) をlow-rate反応群, high-rate反応群, 正常反応群, atrial standstill群の4群に分類し, OSTによるSSSの分類の意義を検討した.臨床所見および電気生理学的から, SSSの病変は, low-rate反応群では, 洞結節を含む心房筋にあり, high-rate反応群では洞房接合部に限局し, 正常反応群では洞結節に限局し, atrial standstill群では洞結節・洞房接合部・心房筋・His-PurkinJe系と広範に存在することが推測された.さらにSSSのOSTに対する反応の経時変化からは, 正常反応群→high-rate反応群, high-rate反応群→low-rate反応群, low-rate反応群→atrial standstill群への移行する症例がみられた.即ち, SSSでは, 洞結節から心房筋への連続性かつ進行性の病態を示す症例が存在し, SSSを洞結節, 洞房接合部に限局した病態から, 高度の心房筋病変を伴うatrial standstillに至る連続した病態として捉えることが可能と考えられた.

Histologic, ultrastructural and nick end labeling studies were made of the process of apoptosis in the bulbus cordis of rat embryos. Apoptosis was observed between the 14th and 16th days of gestational age, at which time the bulbus cordis undergoes extensive remodeling. Three types of mesenchymal cells were identified in this region: cells undergoing apoptosis, cells engaging in the phagocytic removal of apoptotic cells, and cells not involved in either of these two processes. Fragmentation of DNA, demonstrated by nick end labeling, was found only in the apoptotic cells. The combined use of morphologic and labeling techniques is extremely useful in the evaluation of the contribution of apoptosis to cardiac morphogenesis.

To elucidate the clinical features of acute myocardial infarction (AMI) and post-MI silent myocardial ischemia (SMI) in the elderly, and efficacy of therapy in an era of coronary intervention, a total of 10,607 patients with AMI who were enrolled in a multicenter survey between 1982 and 1992 were examined. The elderly had a higher ratio of females, noncardiac illness, atypical symptoms at the onset of AMI, severe pump failure at admission, cardiac rupture and multivessel disease. Hospital mortality was markedly higher in patients > or = 75 years, and it was 4-fold compared with patients < 65 years. In the last 5 years, the rate of application of coronary angiography and primary PTCA significantly increased even in the very elderly. In contrast, use of thrombolysis highly diminished. Hospital mortality declined (14.6 vs 11.9%, p < 0.001) in every age group compared with the first 5 years, although it was higher in the elderly even in the last 5 years. Investigation of 642 survivors after AMI admitted to one hospital showed that the elderly had a higher incidence of SMI and post-MI angina compared with the non-elderly. Clinical features of SMI were similar in both groups. However, medical treatment was more prevalent and recurrence of MI and cardiac death during follow-up (average 27 months) were more frequent in the elderly. In this retrospective study, characteristics of AMI and SMI, and effectiveness and limitation of therapy in the elderly were clearly demonstrated. It was evident that hospital mortality of the elderly had improved, although it was still higher than the non-elderly.

The calcium concentration in papillary muscles was measured by X-ray microanalysis in order to clarify the role played by mitochondria in intracellular calcium regulation during ischemia and reperfusion. Rat hearts perfused by the Langendorff method were rapidly frozen prior to and during ischemia, as well as following reperfusion. Sections prepared by cryoultramicrotomy were freeze-dried, carbon-coated, and analyzed in an electron microscope. A new freeze-drying procedure was developed, in which the ultrastructure was well-preserved, with sarcomeres, triads, and mitochondria easily recognized. Calcium accumulation into the mitochondria occurred during 30-min ischemia (29.7 +/- 17.0 mmol/kg dry weight) and increased further after 15-min reperfusion (157.1 +/- 104.5), the calcium concentration decreased after 60-min reperfusion (58.1 +/- 29.0). However, the calcium concentration in the cytosol did not change significantly. It is thought that mitochondrial calcium accumulation is reversible, to a certain degree, and that the mitochondria play a part in intracellular calcium regulation in pathological states.