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Transcriptomic and metabolomic signatures of an n-3 polyunsaturated fatty acids supplementation in a normolipidemic/normocholesterolemic Caucasian population.
Rudkowska, I, Paradis, AM, Thifault, E, Julien, P, Tchernof, A, Couture, P, Lemieux, S, Barbier, O, Vohl, MC
The Journal of nutritional biochemistry. 2013;(1):54-61
Abstract
OMIC technologies, including transcriptomics and metabolomics, may provide powerful tools for identifying the effects of nutrients on molecular functions and metabolic pathways. The objective was to investigate molecular and metabolic changes following n-3 polyunsaturated fatty acid (PUFA) supplementation in healthy subjects via traditional biomarkers as well as transcriptome and metabolome analyses. Thirteen men and 17 women followed a 2-week run-in period based on Canada's Food Guide and then underwent 6-week supplementation with n-3 PUFA (3 g/day). Traditional biochemical markers such as plasma lipids, inflammatory markers, glycemic parameters and erythrocyte fatty acid concentrations were measured. Changes in gene expression of peripheral blood mononuclear cells were assessed by microarrays, and metabolome profiles were assessed by mass spectrometry assay kit. After supplementation, plasma triglycerides decreased and erythrocyte n-3 PUFA concentrations increased to a similar extent in both genders. Further, plasma high-density lipoprotein cholesterol concentrations and fasting glucose levels increased in women after n-3 PUFA supplementation. N-3 PUFA supplementation changed the expression of 610 genes in men, whereas the expression of 250 genes was altered in women. Pathway analyses indicate changes in gene expression of the nuclear receptor peroxisome proliferator-activated receptor-alpha, nuclear transcription-factor kappaB, oxidative stress and activation of the oxidative stress response mediated by nuclear factor (erythroid-derived 2)-like 2. After n-3 PUFA supplementation, metabolomics profiles demonstrate an increase in acylcarnitines, hexose and leucine in men only and a decrease in saturation of glycerophosphatidylcholine and lysophosphatidylcholine concentrations in all subjects. Overall, traditional and novel biomarkers suggest that n-3 PUFA supplementation exerts cardioprotective effects.
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Levosimendan may improve weaning outcomes in venoarterial ECMO patients.
Affronti, A, di Bella, I, Carino, D, Ragni, T
ASAIO journal (American Society for Artificial Internal Organs : 1992). 2013;(6):554-7
Abstract
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides temporary mechanical circulatory support in patients with refractory cardiogenic shock, allowing time for cardiac recovery. Levosimendan is a calcium sensitizer with inotropic and vasodilatory effects used in the treatment of severe heart failure. It does not increase myocardial oxygen consumption. Its maximum hemodynamic response is seen 24-48 h after stopping infusion, but its effects can persist for 7-9 d owing to active metabolites. We sought to investigate whether the use of levosimendan improves weaning outcomes in patients on VA-ECMO. Six consecutive patients with cardiogenic shock were placed on femorofemoral VA-ECMO support and received levosimendan 24 h before the planned weaning (group A). As control group (group B), we retrospectively reviewed the VA-ECMO implanted at our institution before the introduction of the levosimendan protocol. These patients received only traditional inotropes. The weaning rate was 83.33% in group A and 27.3% in group B. The survival rate was 66.66% and 36.4%, respectively. In group A, three of six patients (50%) required inotropic/vasopressor support after ECMO cessation, while in group B 11 of 11 patients (100%) required support. In our case series, pretreatment with levosimendan seems to facilitate weaning from VA-ECMO, reducing the need for high-dose inotropes.
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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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Effect of serum sodium concentration and tolvaptan treatment on length of hospitalization in patients with heart failure.
Cyr, PL, Slawsky, KA, Olchanski, N, Krasa, HB, Goss, TF, Zimmer, C, Hauptman, PJ
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2011;(4):328-33
Abstract
PURPOSE The effect of serum sodium concentration and tolvaptan treatment on length of stay (LOS) in patients hospitalized with heart failure (HF) was evaluated. METHODS Data for this study were derived from a large, international, Phase III trial of patients hospitalized for HF. Two distinct post hoc analyses were performed, analyzing the association between serum sodium concentration and index hospitalization LOS in normonatremic patients and hyponatremic patients treated with placebo plus standard of care versus tolvaptan. Analysis of covariance models were constructed to adjust for potential variation in care delivery and adjusted for hyponatremia status or treatment. RESULTS Patients with a baseline serum sodium concentration of <135 meq/L who received placebo had an adjusted mean LOS that was 3.06 days longer than did normonatremic patients (p < 0.001). More severely hyponatremic patients had an adjusted mean LOS 5.18 days longer than did normonatremic patients (p < 0.001). In an analysis of all hyponatremic patients, those receiving tolvaptan had an adjusted mean LOS that was 1.72 days shorter than patients receiving placebo, though this difference was not significant. In more severely hyponatremic patients (serum sodium concentration of <130 meq/L), patients treated with tolvaptan had an adjusted mean LOS 2.12 days shorter than those receiving placebo, but this difference was not significant. CONCLUSION A secondary analysis of a large, international, Phase III trial of patients hospitalized for HF demonstrated that comorbid hyponatremia was associated with a significant increase in hospital LOS. Treatment of hyponatremia with tolvaptan was associated with reductions in LOS that were not significant.
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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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Should we give prophylactic renal-dose dopamine after coronary artery bypass surgery?
Gatot, I, Abramov, D, Tsodikov, V, Yeshayahu, M, Orman, S, Gavriel, A, Chorni, I, Tuvbin, D, Tager, S, Apelbom, A
Journal of cardiac surgery. 2004;(2):128-33
Abstract
OBJECTIVE A prospective double-blind randomized study undertaken to assess the effect of postoperative prophylactic "renal-dose" dopamine on post-coronary artery bypass grafting surgery's clinical outcome. METHODS Eighty-five consecutive patients undergoing CABG operation were randomized to receive either 3-5 microg/kg/min dopamine (group D, n = 41) or saline as placebo (group P, n = 45) for 48 postoperative hours. Clinical outcome parameters were collected for four postoperative days. RESULTS Preoperative and operative parameters were similar in both groups. Four patients from group P and none from group D reached an end-point of the study (oliguria, renal dysfunction) and received dopamine. Two patients from group P and none from group D needed an additional inotropic support. Mean arterial pressure values were similar during the first 24 hours after operation, but left atrial pressure values tended to be higher in group P (10 +/- 4 vs 7 +/- 3 mmH2O, p = 0.18). The mean pH was higher in group D at 8 hours after operation (7.38 +/- 0.2 vs 7.36 +/- 0.3, p = NS), due to higher bicarbonate levels (23 +/- 2 mmol/l vs 21 +/- 2, p = 0.49). The incidence of lung congestion in chest X-rays and CT scans was significantly higher in group P (50% vs 29%, p = 0.073 at 48 hours postoperatively). Room air blood O2 saturation and maximal expiratory volume tended to be higher in group D (at 72 hours after operation- 92 +/- 4 vs 90%+/- 5, p = 0.29 and 646 +/- 276 vs 485 ml +/- 206, p = 0.16, respectively). There was no statistical difference in urine output but the amount of furosemide given to patients in group P was significantly higher (during the first 8 hours 2.5 +/- 0.5 vs. 0.3 mg +/- 1.6, p = 0.07). Plasma creatinine levels were significantly lower in group D (at 24 hours 0.93 +/- 0.02 vs 1.05 mg/dL +/- 0.02, p = 0.02). Mobilization after surgery was faster in group D. CONCLUSIONS Prophylactic dopamine administration after coronary artery bypass grafting surgery improves patient hemodynamic and renal status, reduces the need for additional medical support (inotropes and furosemide) and thus, provides stable postoperative course.