Antti Vento

Myocardial metabolism on off-pump surgery; a randomized study of 50 cases.

OBJECTIVE To study the inflammatory reaction and myocardial metabolism in off-pump and on-pump coronary artery bypass patients. DESIGN Fifty coronary artery bypass patients were randomized to off-pump or on-pump operations. Myocardial biopsies were taken to determine myocardial metabolism and inflammation (glutathione (GSH), superoxide dismutase (SOD) and myeloperoxidase (MP)) and plasma samples for indicators of oxidative stress (conjugated dienes (s-BDC), oxidative products of proteins (s-ox-Prot) and low-density lipoprotein (LDL)-total peroxyl radical trapping antioxidant potential (s-TRAP)). RESULTS s-ox-Prot 10 min was 2.11 +/- 0.75 vs 2.69 +/- 0.60 (p = 0.014), s-TRAP 5 min was 861 +/- 180 vs 969 +/- 192 (p = 0.032) and s-TRAP 10 min 857 +/- 176 vs 985 +/- 166 (p = 0.011), GSH 10 min 0.55 +/- 0.19 vs 0.72 +/- 1.16 (p = 0.007) (off-pump vs on-pump). The monobasic (MB) fraction of the creatinine kinase 24 h after the operation was significantly lower in the off-pump group, 20.5 +/- 24.2 vs 61.8 +/- 84.6 (p = 0.023). CONCLUSION GSH levels from the biopsies were increased in the perfusion group early in the reperfusion time showing that myocardial tissue was well protected and recovered more rapidly after cross-clamping than after the occlusion of the coronary arteries. However, release of creatinine kinase was lower in the off-pump group showing that cardiopulmonary bypass has more deleterious effects later after the operation.Objective --To study the inflammatory reaction and myocardial metabolism in off-pump and on-pump coronary artery bypass patients. Design --Fifty coronary artery bypass patients were randomized to off-pump or on-pump operations. Myocardial biopsies were taken to determine myocardial metabolism and inflammation (glutathione (GSH), superoxide dismutase (SOD) and myeloperoxidase (MP)) and plasma samples for indicators of oxidative stress (conjugated dienes (s-BDC), oxidative products of proteins (s-ox-Prot) and low-density lipoprotein (LDL)-total peroxyl radical trapping antioxidant potential (s-TRAP)). Results --s-ox-Prot 10 r min was 2.11 r - r 0.75 vs 2.69 r - 0.60 ( p r = r 0.014), s-TRAP 5 r min was 861 r - r 180 vs 969 r - r 192 ( p r = r 0.032) and s-TRAP 10 r min 857 r - r 176 vs 985 r - r 166 ( p r = r 0.011), GSH 10 r min 0.55 r - r 0.19 vs 0.72 r - r 1.16 ( p r = r 0.007) (off-pump vs on-pump). The monobasic (MB) fraction of the creatinine kinase 24 r h after the operation was significantly lower in the off-pump group, 20.5 r - r 24.2 vs 61.8 r - r 84.6 ( p r = r 0.023). Conclusion --GSH levels from the biopsies were increased in the perfusion group early in the reperfusion time showing that myocardial tissue was well protected and recovered more rapidly after cross-clamping than after the occlusion of the coronary arteries. However, release of creatinine kinase was lower in the off-pump group showing that cardiopulmonary bypass has more deleterious effects later after the operation.

Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: A prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass

BACKGROUND Bone marrow mononuclear cell (BMMC) transplantation for heart failure has shown inconsistent therapeutic efficacy. METHODS We enrolled 104 ischemic heart failure patients scheduled for coronary artery bypass surgery (CABG). After 4- to 12-week pharmacotherapy optimization, 39 patients with left ventricular ejection fraction (LVEF) of ≤45% received injections of BMMC or vehicle intra-operatively into the myocardial infarction border area in a randomized, double-blind manner. RESULTS The median number of cells injected was 8.4 × 10(8) (interquartile range [IQR]: 5.2 × 10(8) to 13.5 × 10(8)). We measured LV function and myocardial scar size by magnetic resonance imaging (MRI), and viability by positron emission tomography (PET) and single-photon emission computed tomography (SPECT), pre-operatively and after 1-year follow-up. LVEF, the pre-defined primary end-point measure, improved by a median of 5.6% in the control group (IQR 0.2 to 10.1) and by 4.8% in the BMMC group (IQR -0.5 to 8.2) (p = 0.59). Wall thickening in injected segments rose by a median of 4.5% among controls (IQR -18.1 to 23.9) and by 5.5% in the BMMC group (IQR -6.6 to 26.5) (p = 0.68). Changes in viability by PET and SPECT did not differ between groups. Myocardial scar size by MRI in injected segments rose by a median of 5.1% among controls (IQR -3.3 to 10.8), but fell by 13.1% in the BMMC group (IQR -21.4 to -6.5) (p = 0.0002). CONCLUSIONS BMMC therapy combined with CABG failed to improve LV systolic function, or viability, despite reducing myocardial scar size.

N‐Acetylcysteine as an additive to crystalloid cardioplegia increased oxidative stress capacity in CABG patients

Objective—This prospective, randomized study was designed to assess the effects of N‐acetylcysteine (NAC) in coronary artery bypass graft (CABG) patients. Design—Thirty‐five consenting CABG patients with normal myocardial function were randomly divided into control (C) patients (N = 20) who received crystalloid (Plegisol®) cardioplegia, and NAC patients receiving NAC in a 0.04 mol/l solution (N = 15) in Plegisol®. Simultaneous coronary sinus and aortic blood samples, and myocardial biopsies were taken 1, 5 and 10 min after declamping. Hemodynamics was measured invasively for 24 h. Results—There were no adverse effects observed. The myocardial glutathione content was significantly better preserved (p = 0.0001) and myeloperoxidase activity was over two times lower in the NAC group than in the C group (p = 0.03). The trap capacity gradient between the aorta and the coronary sinus increased significantly during the first minute of reperfusion in the treatment group (p = 0.001) when compared with the C group. In the first minute after reperfusion there were more leukocytes sequestered in the coronary circulation (p = 0.04) in the C group. The invasive hemodynamic data did not differ significantly between the groups. The incidence of arrhythmias was equal. Conclusion—NAC increased tissue capacity against oxidative stress and decreased inflammatory response in CABG patients with normal ejection fraction.

Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c‐Met/PI3K pathway

We previously showed cell–cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch‐wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase‐2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch‐wound healing in a concentration‐dependent manner. The HGF receptor, c‐Met, was rapidly phosphorylated in the nemosis‐stimulated keratinocytes. Nemosis‐induced in vitro scratch‐wound healing was inhibited by an HGF‐neutralizing antibody as well as the small molecule c‐Met inhibitor, SU11274. HGF‐induced in vitro scratch‐wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen‐activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF‐induced keratinocyte in vitro scratch‐wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch‐wound healing, and that in this effect signaling via HGF/c‐Met is involved.

Cardiopulmonary bypass and activation of antithrombotic plasma protein C.

OBJECTIVE We hypothesized that antithrombotic plasma-activated protein C plays a defensive antithrombotic role during coronary ischemia and postischemic reperfusion. METHODS AND RESULTS We evaluated protein C activation during cardiopulmonary bypass and coronary reperfusion in 20 patients undergoing coronary bypass surgery. During cardiopulmonary bypass and during the 10 minutes after aortic unclamping, the plasma levels of protein C (mean +/- standard error of the mean) decreased from 123% +/- 7% to 74% +/- 5% of normal mean. In contrast, the levels of activated protein C in plasma increased from 122% +/- 8% to 159% +/- 21%, and the activated protein C/protein C ratio increased from 1.04 +/- 0.08 to 2.29 +/- 0. 31 (P =.006, 2-tailed Wilcoxon signed rank test). Patients were stratified on the basis of the increase in activated protein C in the coronary sinus plasma at 10 minutes after reperfusion by means of the arbitrary value of 1.5 for the activated protein C/protein C ratio. Within 24 hours, the patients with low increases in activated protein C (ratio < 1.5, n = 8) had a significantly (P <.05) lower cardiac output and mean pulmonary artery pressure, as well as a higher systemic vascular resistance, than patients (n = 11) with high increases in activated protein C (ratio > 1.5). The rapid increase in activated protein C during the first 10 minutes after aortic unclamping indicated protein C activation in the reperfused vascular beds. CONCLUSIONS The antithrombotic protein C pathway was significantly activated during cardiopulmonary bypass mainly during the minutes after aortic unclamping in the ischemic vascular beds. Suboptimal protein C activation during ischemia may impair the postischemic recovery of human heart and circulation.

Antithrombin reduces pulmonary hypertension during reperfusion after cardiopulmonary bypass in a pig

Background:  Antithrombin (AT) may alleviate many cardiopulmonary bypass (CPB) and ischemia‐reperfusion (I/R)‐related adverse effects. Using a porcine model of clinical cardiac surgery on CPB, we tested the effects of supplementary AT on myocardial and lung I/R injury.

Nitecapone Reduces Cardiac Neutrophil Accumulation in Clinical Open Heart Surgery

BACKGROUND To study the effect of nitecapone, a novel antioxidant, on cardiac neutrophil activation during cardiopulmonary bypass in patients. METHODS In a double-blind, placebo controlled trial, 30 male patients undergoing coronary artery bypass grafting were randomly assigned to control (crystalloid cardioplegia, n = 15) and nitecapone groups (cardioplegia supplemented with nitecapone, n = 15). Leukocyte differential counts, neutrophil and monocyte CD11b and L-selectin expressions and neutrophil hydrogen peroxide production were measured in blood samples parallelly obtained from the coronary sinus and aorta before cardiopulmonary bypass and at 1, 5, and 10 min after aortic declamping. Myocardial myeloperoxidase activity was analyzed in biopsies taken at 1, 5, and 10 min after declamping. RESULTS Transcoronary neutrophil difference (i.e., aorta--sinus coronarius) at 1 min after aortic declamping was significantly lower in nitecapone-treated patients (0.41 [-0.42-0.98] x 10(9) cells/l) than in controls (0.68 [-0.28-2.47] x 10(9) cells/l; P = 0.032). At 5 min after aortic declamping, significant transcoronary reduction of neutrophil hydrogen peroxide production and CD11b expression were observed in controls but not in nitecapone patients. At 24 h postoperatively, left ventricular stroke volume was better in nitecapone-treated patients (94 [51-118] ml) than controls (66 [40-104] ml; P= 0.018). Data are median [range]. CONCLUSION Nitecapone added to cardioplegia solution reduces cardiac neutrophil accumulation and transcoronary neutrophil activation during clinical cardiopulmonary bypass. Reflected by better left ventricular stroke volume, nitecapone treatment may be an additional way of reducing the deleterious effects of neutrophil activation during cardiopulmonary bypass.

The effect of nitecapone, a new antioxidant, on myocardial function after aortic cross-clamping in experimental heart ischemia

During aortic cross-clamping, the myocardium suffers from global ischemia, which is followed by reperfusion after declamping. The generation of free oxygen radicals increases during reperfusion, resulting in arrhythmias and impaired cardiac function. This study was conducted to evaluate the effect of a novel antioxidant nitecapone (NC) on cardiac reperfusion injuryin vivo. Twelve pigs were anesthetized and after sternotomy the aorta and the right atrium were cannulated for cardiopulmonary bypass. The heart was arrested with either +4°C crystalloid cardioplegia alone in the control group (n=6) or cardioplegia with NC (50 µM) added in the NC group (n=6). Cardioplegia was added every 20 minutes. After 1 hour of aortic crossclamping, blood samples for oxidative stress analysis were taken, and hemodynamic profile surveillance continued for 90 minutes. Heart rate (p=0.04) and left ventricular end diastolic pressure (LVEDP) (p=0.04) were significantly lower in the NC group than in the C group after aortic declamping. Cardiac output and myocardial contractility (dP/dtmax) were also enhanced in the group receiving NC, but the difference was not statistically significant. At 30 minutes after reperfusion, the coronary production (coronary sinus-aorta) of thiobarbituric acid reactive substances correlated inversely with cardiac output (r=−0.90,p=0.001) and stroke volume (r=−0.82,p=0.007). The effect of NC on lipid peroxidation seems to be modest and therefore the target of NC is unclear. NC would appear, however, to be a beneficial additive in the crystalloid cardioplegia in terms of functional recovery.

Intramyocardial bone marrow mononuclear cell transplantation in ischemic heart failure: Long-term follow-up

BACKGROUND Long-term results regarding treatment of chronic ischemic heart failure with bone marrow mononuclear cells (BMMCs) have been few. We received encouraging results at the 1-year follow-up of patients treated with combined coronary artery bypass grafting (CABG) and BMMCs, so we decided to extend the follow-up. METHODS The study patients had received injections of BMMCs or vehicle into the myocardial infarction border area during CABG in a randomized and double-blind manner. We could contact 36 of the 39 patients recruited for the original study. Pre-operatively and after an extended follow-up period, we performed magnetic resonance imaging, measured pro-B-type amino-terminal natriuretic peptide, reviewed patient records from the follow-up period, and determined current quality of life with the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey. RESULTS The median follow-up time was 60.7 months (interquartile range [IQR], 45.1-72.6 months). No statistically significant difference was detected in change of pro-B-type amino-terminal natriuretic peptide values or in quality of life between groups. The median change in left ventricular ejection fraction was 4.9% (IQR, -2.1% to 12.3%) for controls and 3.9% (IQR, -5.2% to 10.2%) for the BMMC group (p = 0.647). Wall thickening in injected segments increased by a median of 17% (IQR, -5% to 30%) for controls and 15% (IQR, -12% to 19%) for BMMC patients (p = 0.434). Scar size in injected segments increased by a median of 2% (IQR, -7% to 19%) for controls but diminished for BMMC patients, with a median change of -17% (IQR, -30% to -6%; p = 0.011). CONCLUSIONS In the treatment of chronic ischemic heart failure, combining intramyocardial BMMC therapy with CABG fails to affect cardiac function but can sustainably reduce scar size, even in the long-term.

Advances in Cell Transplantation Therapy for Diseased Myocardium

The overall objective of cell transplantation is to repopulate postinfarction scar with contractile cells, thus improving systolic function, and to prevent or to regress the remodeling process. Direct implantation of isolated myoblasts, cardiomyocytes, and bone-marrow-derived cells has shown prospect for improved cardiac performance in several animal models and patients suffering from heart failure. However, direct implantation of cultured cells can lead to major cell loss by leakage and cell death, inappropriate integration and proliferation, and cardiac arrhythmia. To resolve these problems an approach using 3-dimensional tissue-engineered cell constructs has been investigated. Cell engineering technology has enabled scaffold-free sheet development including generation of communication between cell graft and host tissue, creation of organized microvascular network, and relatively long-term survival after in vivo transplantation.