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Rationale and design of the 'MITOCARE' Study: a phase II, multicenter, randomized, double-blind, placebo-controlled study to assess the safety and efficacy of TRO40303 for the reduction of reperfusion injury in patients undergoing percutaneous coronary intervention for acute myocardial infarction.
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Cardiology. 2012;(4):201-7
Abstract
Treatment of acute ST-elevation myocardial infarction (STEMI) by reperfusion using percutaneous coronary intervention (PCI) or thrombolysis has provided clinical benefits; however, it also induces considerable cell death. This process is called reperfusion injury. The continuing high rates of mortality and heart failure after acute myocardial infarction (AMI) emphasize the need for improved strategies to limit reperfusion injury and improve clinical outcomes. The objective of this study is to assess safety and efficacy of TRO40303 in limiting reperfusion injury in patients treated for STEMI. TRO40303 targets the mitochondrial permeability transition pore, a promising target for the prevention of reperfusion injury. This multicenter, double-blind study will randomize patients with STEMI to TRO40303 or placebo administered just before balloon inflation or thromboaspiration during PCI. The primary outcome measure will be reduction in infarct size (assessed as plasma creatine kinase and troponin I area under the curve over 3 days). The main secondary endpoint will be infarct size normalized to the myocardium at risk (expressed by the myocardial salvage index assessed by cardiac magnetic resonance). The study is being financed under an EU-FP7 grant and conducted under the auspices of the MITOCARE research consortium, which includes experts from clinical and basic research centers, as well as commercial enterprises, throughout Europe. Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present paper describes the rationale, design and the methods of the trial.
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Effects of nicorandil on cardiovascular events in patients with coronary artery disease in the Japanese Coronary Artery Disease (JCAD) study.
Horinaka, S, Yabe, A, Yagi, H, Ishimitsu, T, Yamazaki, T, Suzuki, S, Kohro, T, Nagai, R, ,
Circulation journal : official journal of the Japanese Circulation Society. 2010;(3):503-9
Abstract
BACKGROUND Nicorandil has cardioprotective effects in the ischemic myocardium, mimicking ischemic preconditioning, and is thus expected to improve the prognosis of ischemic heart disease (IHD). As part of the Japanese Coronary Artery Disease (JCAD) Study, a multicenter collaborative prospective observational study of a large cohort of coronary artery disease patients, the effect of nicorandil on outcome was examined. METHODS AND RESULTS In total, 2,558 patients with nicorandil treatment and controls subjected to propensity score matching were eligible among 13,812 patients registered in the JCAD study. The mean follow-up interval was 2.7 years. The primary endpoint, death from all causes, was significantly lower, by 35% (hazard ratio 0.65, P=0.0008), in the nicorandil group than in the control group. There were also significant reductions in secondary endpoints, including cardiac death (56%), fatal myocardial infarction (56%), cerebral or vascular death (71%), and congestive heart failure (33%) in the nicorandil group, with no excess of deaths from other non-cardiovascular causes. Treatment with nicorandil reduced the number of deaths from all causes to a similar extent with or without treatment with sulfonylureas. CONCLUSIONS The reduction in cardiovascular death with nicorandil was large in patients with IHD, which has important implications for treatment.
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Effects of levosimendan on left ventricular functional remodelling and exercise intolerance: a tissue Doppler study.
Kasikcioglu, HA, Unal, S, Tartan, Z, Uyarel, H, Okmen, E, Kasikcioglu, E, Cam, N
The Journal of international medical research. 2005;(4):397-405
Abstract
Levosimendan is a calcium sensitizer that demonstrates enhanced myocardial contractility. There is little information concerning the effect of levosimendan on left ventricular tissue parameters and exercise capacity. We evaluated the effects of a 24-h course of levosimendan therapy on cardiac tissue parameters in 30 patients, aged 48 - 70 years, admitted to our hospital for the management of decompensated heart failure. All patients underwent echocardiographic examination using tissue Doppler imaging (TDI) and a 6-min walk test. Systolic myocardial velocity of the mitral annulus (Sm) was significantly increased in levosimendan-treated patients compared with placebo-treated patients. There was a positive correlation between Sm and exercise capacity. Levosimendan might be expected to increase cardiac contractile force, especially Sm velocity, in parallel with exercise tolerance. The study has also shown that the progress of ventricular function after levosimendan treatment in patients with exercise intolerance could be monitored effectively by Sm velocity measurements using TDI.
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Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress.
Zern, TL, Wood, RJ, Greene, C, West, KL, Liu, Y, Aggarwal, D, Shachter, NS, Fernandez, ML
The Journal of nutrition. 2005;(8):1911-7
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Abstract
To evaluate the effects of grape polyphenols on plasma lipids, inflammatory cytokines, and oxidative stress, 24 pre- and 20 postmenopausal women were randomly assigned to consume 36 g of a lyophilized grape powder (LGP) or a placebo for 4 wk. The LGP consisted of 92% carbohydrate and was rich in flavans, anthocyanins, quercetin, myricetin, kaempferol, and resveratrol. After a 3-wk washout period, subjects were assigned to the alternate treatment for an additional 4 wk. The placebo consisted of an equal ratio of fructose and dextrose and was similar in appearance and energy content (554 kJ) to LGP. Plasma triglyceride concentrations were reduced by 15 and 6% in pre- and postmenopausal women, respectively (P < 0.01) after LGP supplementation. In addition, plasma LDL cholesterol and apolipoproteins B and E were lower due to LGP treatment (P < 0.05). Further, cholesterol ester transfer protein activity was decreased by approximately 15% with intake of LGP (P < 0.05). In contrast to these beneficial effects on plasma lipids, LDL oxidation was not modified by LGP treatment. However, whole-body oxidative stress as measured by urinary F(2)-isoprostanes was significantly reduced after LGP supplementation. LGP also decreased the levels of plasma tumor necrosis factor-alpha, which plays a major role in the inflammation process. Through alterations in lipoprotein metabolism, oxidative stress, and inflammatory markers, LGP intake beneficially affected key risk factors for coronary heart disease in both pre- and postmenopausal women.
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Myocardial protective effects of nicorandil during percutaneous coronary intervention in patients with unstable angina.
Kim, JH, Jeong, MH, Yun, KH, Kim, KH, Kang, DK, Hong, SN, Lim, SY, Lee, SH, Lee, YS, Hong, YJ, et al
Circulation journal : official journal of the Japanese Circulation Society. 2005;(3):306-10
Abstract
BACKGROUND The purpose of the study was to prospectively evaluate the protective effect of nicorandil during percutaneous coronary intervention (PCI) in patients with unstable angina (UAP). METHODS AND RESULTS Two hundred patients (61+/-10 year-old, male 143) diagnosed with UAP at an emergency medical center were randomly assigned to 2 groups: intravenous isosorbide dinitrate, Group I (n=100), or intravenous nicorandil, Group II (n=100). PCI was performed 12-48 h after infusion of each agent. Serum concentrations of creatine kinase-MB (CK-MB), cardiac troponin T (cTnT), and I (cTnI) were measured before and 6, 12, 24 h after PCI. Patients with non-coronary chest pain, requiring emergency coronary angiogram, temporary pacemaker or glycoprotein IIb/IIIa receptor blocker were excluded. PCI was successfully performed in 96 patients (Group I=54, 61.7+/-8.2 years, 32 males; Group II=42, 60.4+/-11.7 years, 27 males). No significant differences in clinical or coronary angiographic characteristics were observed between the 2 groups. The concentration of CK-MB was elevated in 9 patients (17%) of Group I and 6 (14%) of Group II, cTnT in 16 (30%), 6 (14%) and cTnI in 25 (46%), 9 (21%) after PCI. Elevation of any troponin was less frequent in Group II [28/54 (52%) vs 10/42 (24%) patients, p=0.01]. Major adverse coronary events during the 6-month clinical follow-up occurred in 9 (17%) of Group I and 5 patients of Group II (12%, p=NS). Follow-up echocardiography revealed lower left ventricular ejection fraction in Group I than in Group II (65.4+/-7.2% vs 71.0+/-6.7%, p=0.03). CONCLUSION Nicorandil has a myocardial protective effect during PCI in patients with UAP.
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The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia.
Sonntag, S, Sundberg, S, Lehtonen, LA, Kleber, FX
Journal of the American College of Cardiology. 2004;(12):2177-82
Abstract
OBJECTIVES We assessed the effects of levosimendan on left ventricular (LV) function in patients with acute myocardial ischemia and after coronary angioplasty. BACKGROUND The calcium sensitizer levosimendan improves the function of myocardium in experimental stunning. METHODS Twenty-four patients with an acute coronary syndrome underwent angioplasty followed by double-blinded, randomized treatment with 24 microg/kg of levosimendan (n = 16) or placebo (n = 8). Left ventricular pressures and volumes were recorded by cineventriculography and micromanometer-tipped catheters 10 min after angioplasty before drug administration (baseline) and 20 min after drug administration. Left ventricular function was assessed by the pressure-volume loop, and regional function analysis by the Slager method. RESULTS The number of hypokinetic segments decreased with levosimendan, from 8.9 +/- 0.9 to 6.5 +/- 1.1 (mean +/- SEM), as compared with an increase from 7.8 +/- 1.0 to 8.5 +/- 1.1 with placebo (p = 0.016). A leftward and/or upward shift of the systolic part of the pressure-volume loop, indicating improved systolic function, was observed in eight of 16 of the levosimendan-treated and one of eight of the placebo patients (p = 0.178). In addition, the single-beat elastance was increased by levosimendan (p = 0.045). The pressure-volume area (p = 0.001), end-systolic pressure (p = 0.002), and volume index (p < 0.001) were decreased by levosimendan, but there was no change in the end-systolic pressure-volume ratio. End-diastolic pressure remained unchanged, whereas the end-diastolic volume index was decreased by levosimendan (p = 0.002). The time constant of isovolumic LV pressure fall decreased with levosimendan (p = 0.001). CONCLUSIONS Levosimendan improved the function of stunned myocardium without obvious impairment of diastolic function.
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Cardioprotective effects of magnesium sulfate in patients undergoing primary coronary angioplasty for acute myocardial infarction.
Nakashima, H, Katayama, T, Honda, Y, Suzuki, S, Yano, K
Circulation journal : official journal of the Japanese Circulation Society. 2004;(1):23-8
Abstract
BACKGROUND Experimental evidence indicates that magnesium sulfate may have potential cardioprotective properties as an adjunct to coronary reperfusion. The present study was designed to examine the hypothesis that magnesium might have beneficial effects on left ventricular (LV) function and coronary microvascular function in patients with acute myocardial infarction (AMI). METHODS AND RESULTS The study population of 180 consecutive patients with a first AMI (anterior or inferior) underwent successful primary coronary intervention. Patients were randomized to treatment with either intravenous magnesium (magnesium group, n=89) or normal saline (control group, n=91). Pre-discharge left ventriculograms were used to assess LV ejection fraction (LVEF), regional wall motion (RWM) within the infarct-zone and LV end-diastolic volume index. The Doppler guidewire was used to assess coronary flow velocity reserve (CFVR) as an index of coronary microvascular function. Magnesium group subjects showed significantly better LV systolic function (LVEF 63+/-9% vs 55+/-13%, p<0.001; RWM: -1.01+/-1.29 SD/chord vs -1.65+/-1.11 SD/chord, p=0.004), significantly smaller LV end-diastolic volume index (63+/-17 ml/m(2) vs 76+/-20 ml/m(2), p<0.001), and significantly higher CFVR (2.95+/-0.76 vs 2.50+/-0.99, p=0.023) than controls. CONCLUSION Magnesium sulfate as an adjunct to primary coronary intervention shows favorable functional outcomes in patients with AMI.
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Comparison between nicorandil and magnesium as an adjunct cardioprotective agent to percutaneous coronary intervention in acute anterior myocardial infarction.
Nameki, M, Ishibashi, I, Miyazaki, Y, Sakai, Y, Namikawa, S, Kuriyama, N, Komiyama, N, Tsunoda, K, Masuda, Y, Komuro, I
Circulation journal : official journal of the Japanese Circulation Society. 2004;(3):192-7
Abstract
BACKGROUND It has been reported that both nicorandil and magnesium have a cardioprotective effect in experimental ischemia - reperfusion models. In the present study, the cardioprotective effects of nicorandil and magnesium as an adjunct to reperfusion therapy in patients with acute myocardial infarction (AMI) were compared. METHODS AND RESULTS Forty consecutive patients with AMI caused by occlusion of anterior descending coronary artery were randomized into 3 groups: (1) Group N: nicorandil was given as 4 mg iv and 4 mg ic before reperfusion, followed by continuous infusion at 4 mg/h for 24 h; (2) Group M: magnesium was administered at 10 mmol iv before reperfusion, followed by continuous infusion at 0.4 mmol/h for 24 h; and (3) Group C: neither nicorandil nor magnesium was given. Left ventriculography was performed immediately after reperfusion and 3 months later. There was no significant change in regional wall motion (RWM) in either Group C or M, whereas that of group N improved significantly. The change in RWM in Group N was significantly greater than in Group C (Group N: 0.92+/-0.92, Group M: 0.44+/-0.80, Group C: -0.01+/-0.65, p<0.05). CONCLUSIONS The early administration of nicorandil as an adjunct to reperfusion is useful for cardioprotection in AMI, but magnesium is not.
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Coenzyme Q10 in patients with end-stage heart failure awaiting cardiac transplantation: a randomized, placebo-controlled study.
Berman, M, Erman, A, Ben-Gal, T, Dvir, D, Georghiou, GP, Stamler, A, Vered, Y, Vidne, BA, Aravot, D
Clinical cardiology. 2004;(5):295-9
Abstract
BACKGROUND The number of patients awaiting heart transplantation is increasing in proportion to the waiting period for a donor. Studies have shown that coenzyme Q10 (CoQ10) has a beneficial effect on patients with heart failure. HYPOTHESIS The purpose of the present double-blind, placebo-controlled, randomized study was to assess the effect of CoQ10 on patients with end-stage heart failure and to determine if CoQ10 can improve the pharmacological bridge to heart transplantation. METHODS A prospective double-blind design was used. Thirty-two patients with end-stage heart failure awaiting heart transplantation were randomly allocated to receive either 60 mg U/day of Ultrasome--CoQ10 (special preparation to increase intestinal absorption) or placebo for 3 months. All patients continued their regular medication regimen. Assessments included anamnesis with an extended questionnaire based partially on the Minnesota Living with Heart Failure Questionnaire, 6-min walk test, blood tests for atrial natriuretic factor (ANF) and tumor necrosis factor (TNF), and echocardiography. RESULTS Twenty-seven patients completed the study. The study group showed significant improvement in the 6-min walk test and a decrease in dyspnea, New York Heart Association (NYHA) classification, nocturia, and fatigue. No significant changes were noted after 3 months of treatment in echocardiography parameters (dimensions and contractility of cardiac chambers) or ANF and TNF blood levels. CONCLUSIONS The administration of CoQ10 to heart transplant candidates led to a significant improvement in functional status, clinical symptoms, and quality of life. However, there were no objective changes in echo measurements or ANF and TNF blood levels. Coenzyme Q10 may serve as an optional addition to the pharmacologic armamentarium of patients with end-stage heart failure. The apparent discrepancy between significant clinical improvement and unchanged cardiac status requires further investigation.
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Hemodynamics and renal function during administration of low-dose dopamine in severely ill patients.
Pereira, CN, Machado, FR, GuimarĂ£es, HP, Senna, AP, do Amaral, JL
Sao Paulo medical journal = Revista paulista de medicina. 2004;(4):141-6
Abstract
CONTEXT Although a large number of studies have been performed regarding the renal and hemodynamic effects of the infusion of low-dose dopamine (LDD) in severely ill patients, there is still controversy on this subject. OBJECTIVE To evaluate the effects of dopamine (2 microg/kg/min) on systemic hemodynamics (lowest mean arterial pressure, MAP, highest heart rate, HR, central venous pressure, CVP), creatinine clearance (CLcr), diuresis and fractional sodium excretion (FENa+). TYPE OF STUDY A non-randomized, open, prospective clinical trial. SETTING An intensive care unit in a tertiary university hospital. PARTICIPANTS 22 patients with hemodynamic stability admitted to the intensive care unit. PROCEDURES Patients were submitted to three two-hour periods: without dopamine (P1), with dopamine (P2) and without dopamine (P3). MAIN MEASUREMENTS The above mentioned variables were measured during each period. CLcr was assessed based upon the formula U x V/P, where U is urinary creatinine (mg/dl), V is diuresis in ml/min and P is serum creatinine (mg/dl). FENa+ was calculated based upon the formula: urinary sodium (mEq/l) x P/plasma sodium (mEq/l) x U) x 100. Results were presented as mean and standard deviation. The Student t test was used and results were considered significant if p was less than 0.05. RESULTS Twelve patients (seven males and five females) were included, with a mean age of 55.45 years. There was no significant variation in MAP, HR, CVP, CLcr or FENa+ with a dopamine dose of 2 microg/kg/min. On the other hand, diuresis significantly increased during P2, from 225.4 to 333.9 ml. CONCLUSION Infusion of 2 microg/kg/min of dopamine for 2 hours increases diuresis. At the doses studied, dopamine does not induce significant alterations in MAP, HR, CVP, CLcr and FENa+.