The effect of Del Nido versus custodiol cardioplegia on clinical outcomes and troponin-I changes among pediatrics with tetralogy of fallot undergoing cardiopulmonary bypass.

BACKGROUND: Myocardial protection during operations with cardiopulmonary bypass (CPB) and aortic cross clamping is vital. For this purpose, Del Nido (DN) and Custodiol cardioplegia (CC) solutions are used for single-dose cardioplegia in cardiac surgical procedures with CPB. Present study aimed to compare the effects of DN and CC on peri-operative clinical outcomes in pediatrics with Tetralogy of Fallot (TF) undergoing cardiopulmonary bypass. METHODS: Present randomized clinical trial was performed in two trial groups with parallel design. One group received DN and another group received CC. We assessed circulatory Troponin-I (cTnI) and coronary sinus lactate level as primary outcomes. Secondary outcomes were ventilation time, electrolytes levels, pump time, cross-clamp time and other clinical parameters. RESULTS: Duration of CPB and cross-clamp were the same in both groups. There were no significant differences in hemodynamic parameters, left ventricular ejection fraction after the surgery and discharge time between the two trial groups. Ventilation time (8.5 vs. 18; p = 0.001), ICU stay, Troponin-I in ICU admission and Coronary sinus lactate level (p = 0.001) were significantly higher among patients of Custodiol group compared to other trial group. Electrolytes Na, Cl and K levels, during CPB, were significantly less in Custodiol group. CONCLUSION: When used for inducing cardiac arrest during CPB, DN solution offers better maintenance of the electrolyte balance during CPB, and is associated with less circulatory cTnI and coronary sinus lactate level compared with the CC.

Human mesenchymal stem cells derived from amniotic membrane attenuate isoproterenol (ISO)-induced myocardial injury by targeting apoptosis.

Background: Currently, stem cell therapy has been proposed as an efficient strategy to prevent or treat myocardial injuries. The current study was conducted to examine cardioprotective effects of human mesenchymal stem cells derived from amniotic membrane (hAMSCs) against isoproterenol (ISO)-induced myocardial injury and explore its potential mechanisms. Methods: The hAMSCs were injected intramyocardially in male Wistar rats 28 days after last injection of ISO (170 mg/kg body weight for 4 consecutive days). The echocardiography was performed to confirm induction of myocardial damage and cardiac function 28 days after last injection of ISO and 4 weeks hAMSCs transplantation after HF induction. The expression of apoptotic markers such as Bcl-2, Bax and P53 was evaluated using Western blotting assay. Masson's trichrome staining was used to determine fibrosis. The cytoarchitecture of myocardial wall and morphology of cells were investigated using hematoxylin and eosin (H&E) staining. Results: As compared to ISO group, hAMSCs transplantation after heart failure (HF) induction significantly blunted the increasing of cardiac dimensions and restored ejection fraction (EF) and fractional shortening (FS) parameters (p<0.05). Moreover, hAMSCs transplantation after HF induction increased the expression of antiapoptotic markers such as Bcl-2 and decreased the expression of pro-apoptotic markers such as P53 and Bax (p<0.05). As compared to ISO group, hAMSCs transplantation after HF induction markedly reduced interstitial myocardial fibrosis and contributed to maintain of normal cytoarchitecture of myocardial wall and morphology of cells. Conclusion: Collectively, the results of current study suggest that transplantation of hAMSCs confers cardioprotection by targeting ISO-induced mitochondria-dependent (intrinsic) pathway of apoptosis.

Amniotic Membrane-Derived Mesenchymal Stem Cells for Heart Failure: A Systematic Review and Meta-Analysis of the Published Preclinical Studies.

Background: Ischemic cardiomyopathies are the leading causes of mortality and morbidity. Stem cell therapy using amniotic membrane mesenchymal stem cells have emerged as a promising cardiac regeneration modality. They have shown great immunological advantage when used in allogeneic or xenogeneic transplantation. The aim of the current study is to accumulate evidence from published preclinical studies on the application of amniotic membrane derived mesenchymal stem cells (AMSCs) in the treatment of ischemic cardiomyopathies including myocardial ischemia and heart failure. The aim is to define if there is enough high-quality current evidence to support starting the use of these cells in clinical trials. Methods: PubMed, SCOPUS, EMBASE, and ISI Web of Science databases were searched without temporal and language restrictions. Data were extracted from selected studies. The primary outcomes were left ventricular ejection fraction (LVEF) and LV fibrosis. The risk of bias (ROB) assessment was performed using SYRCLE's ROB tool. After qualitative synthesis, provided that data meets the criteria for quantitative analysis, a meta-analysis was performed using Stata software V12 to investigate the heterogeneity of the data and to get an overall estimate of the effect size of the treatment on each outcome. Results: On primary search, 438 citations were retrieved. After screening, three studies were selected for quantitative analysis of each of the outcomes LVEF and LV fibrosis. Their administration in acute and chronic MI alleviates heart failure and improves LVEF (SMD=3.56, 95% CI: 2.24-4.87, I-squared=83.1%, p=0.003) and reduces infarct size (SMD= -4.41, 95% CI: (-5.68)-(-3.14), I-squared=79.0%, p=0.009). These observations were achieved in the acute MI model, HF following ischemia due to coronary artery stenosis and coronary artery occlusion with the early restoration of the perfusion. Conclusion: Present low and medium quality evidence from preclinical studies confirm the efficacy of the AMSCs in the preclinical models of acute MI and HF following ischemia due to coronary artery stenosis and permanent/temporary coronary artery occlusion. High-quality preclinical studies are indicated to bridge the gaps in translation of the current findings of AMSCs research for the treatment of patients with acute and chronic myocardial ischemia and heart failure.

Serum levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α, renal function biochemical parameters and clinical outcomes in pediatric cardiopulmonary bypass surgery.

BACKGROUND: Cardiopulmonary bypass causes detrimental effects on remote organs due to inflammatory response. One of these organs is kidney that is frequently affected by cardiac surgery. Acute kidney injury is a post-cardiopulmonary bypass complication, which may result in increased post-operative morbidity and mortality. Post-cardiopulmonary bypass inflammatory response may contribute to remote organ dysfunction. In the present study, we investigated the relation between cytokines including interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α, and renal function tests such as creatinine and blood urea nitrogen (BUN). METHODS: In total, 91 patients between the ages of 4 and 60 months were enrolled for elective cardiac surgery with cardiopulmonary bypass after informed consent. Data regarding renal function tests and clinical outcomes were carefully recorded until 24 hours after admission to intensive care unit and analyzed. RESULTS: Our findings support that there is a direct correlation between cytokines including interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α and cardiopulmonary bypass time, duration of operation, and intensive care unit stay. Longer cardiopulmonary bypass time was associated with higher interleukin-8 at cross-clamp removal and 24 hours post- intensive care unit as well as higher interleukin-10 at declamp time. Higher interleukin-6 at declamp time was directly correlated with higher post-operative BUN. Interleukin-8 level after anesthesia induction was directly correlated with intensive care unit stay duration. Higher blood interleukin-6 and tumor necrosis factor-α levels following 24 hours of admission to intensive care unit were associated with longer mechanical ventilation time. CONCLUSION: Higher circulatory pro-inflammatory cytokine level is associated with adverse outcomes such as increased intensive care unit stay and longer mechanical ventilation time in pediatric patients. It is also correlated with unfavorable biochemical parameter of renal function, BUN. Findings hint that proper control of the inflammatory response is vital for the control of unfavorable clinical and pathological outcomes.

Irisin Peptide Protects Brain Against Ischemic Injury Through Reducing Apoptosis and Enhancing BDNF in a Rodent Model of Stroke.

Evidence has shown therapeutic potential of irisin in cerebral stroke. The present study aimed to assess the effects of recombinant irisin on the infarct size, neurological outcomes, blood-brain barrier (BBB) permeability, apoptosis and brain-derived neurotrophic factor (BDNF) expression in a mouse model of stroke. Transient focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 45 min and followed reperfusion for 23 h in mice. Recombinant irisin was administrated at doses of 0.1, 0.5, 2.5, 7.5, and 15 µg/kg, intracerebroventricularly (ICV), on the MCAO beginning. Neurological outcomes, infarct size, brain edema and BBB permeability were evaluated by modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride (TTC) staining and Evans blue (EB) extravasation methods, respectively, at 24 h after ischemia. Apoptotic cells and BDNF protein were detected by TUNEL assay and immunohistochemistry techniques. The levels of Bcl-2, Bax and caspase-3 proteins were measured by immunoblotting technique. ICV irisin administration at doses of 0.5, 2.5, 7.5 and 15 µg/kg, significantly reduced infarct size, whereas only in 7.5 and 15 µg/kg improved neurological outcome (P < 0.001). Treatment with irisin (7.5 µg/kg) reduced brain edema (P < 0.001) without changing BBB permeability (P > 0.05). Additionally, irisin (7.5 µg/kg) significantly diminished apoptotic cells and increased BDNF immunoreactivity in the ischemic brain cortex (P < 0.004). Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein. The present study indicated that irisin attenuates brain damage via reducing apoptosis and increasing BDNF protein of brain cortex in the experimental model of stroke in mice.

Inflammatory cytokine response and cardiac troponin I changes in cardiopulmonary bypass using two cardioplegia solutions; del Nido and modified St. Thomas': a randomized controlled trial.

BACKGROUND: Long intervals of del Nido (DN) solution administration, 90 minutes, may result in rewarming of the myocardial tissue and elevate metabolic demand and hypoxia. This will potentially increase inflammatory response due to ischemia-reperfusion injury. We conducted this study to compare the inflammatory response between patients receiving DN and multi-dose St Thomas' cardioplegia solution (MST) in cardiopulmonary bypass (CPB) surgery for the correction of tetralogy of Fallot (TF). METHODS: Fifty-nine pediatric patients undergoing TF total correction surgery were randomly assigned into two groups: DN and MST. The patients' demographic data, blood chemistry parameters, hemodynamics and other clinical variables were recorded. TNF-a, IL-6, IL-8, IL-10 and cTnI were measured after anesthesia induction (before skin incision), immediately after cross-clamp removal and 24 hours after admission to the intensive care unit (ICU). RESULTS: Thirty-two patients of a mean age of 28.0±16.4 months received DN and 27 patients of a mean age of 24.2±15.9 months received MST. Perioperative clinical parameters were not significantly different between the two groups. Cytokine levels for all patients were significantly increased after surgery. Inter-group comparisons of cytokine levels demonstrated no significant differences in TNF-α, IL-6 and IL-8 cytokines levels. IL-10 level showed a moderately significant increase in the MST group compared to the DN group after surgery (2.94±0.9 vs. 2.46±0.61 log10 pg/mL, respectively; p=0.039). Postoperative lactate level was significantly different between two groups (2.475±1.29 vs 1.63±0.82 mg/dL in DN and MST groups, respectively; p=0.007). CTnI levels increased after surgery and remained constant until 24 hours after surgery. Significant differences between the MST and DN groups, at all times, were not detected. CONCLUSIONS: The anti-inflammatory cytokine response in the MST group is significantly better than in the DN group. This may be due to shorter intervals of the MST cardioplegia solution administration, which prevents rewarming of the myocardium, increased metabolic demand and hypoxia. Decreasing the intervals of DN administration may improve its cardioprotective properties.

A new design for electrospinner collecting device facilitates the removal of small diameter tubular scaffolds and paves the way for tissue engineering of capillaries.

Electrospinning is a technique widely used for tissue engineering. Despite hurdles, electrospun vascular tissue scaffolds has shown great promise in in vitro studies. One problem is the removal of tubular scaffolds from a electrospinning collection device with no unwanted crumpling or tearing, especially for small diameter scaffolds. To tackle this problem we designed a collection device for simple removal of the scaffold from the collector while no chemical pretreatment was required. The scaffolds fabricated on this collecting device maintained their tubular structure and showed favorable surface properties, mechanical strength and biocompatibility. The device offers a new opportunity for tissue engineering researchers to fabricate tubular scaffolds from materials which have not been possible to date and help them improve the quality of synthesized scaffolds.

Conjugated linoleic acid rat pretreatment reduces renal damage in ischemia/reperfusion injury: Unraveling antiapoptotic mechanisms and regulation of phosphorylated mammalian target of rapamycin.

SCOPE: Conjugated linoleic acids (CLAs) are dietary components with beneficial effects on human health. The aim of this study was to evaluate the potential benefits of CLA pretreatment in a rat model of renal ischemia/reperfusion injury (IRI). METHODS AND RESULTS: Animals were treated with CLAs (200 mg/kg/day) or water for two weeks prior to sham surgery or to surgery to induce IRI. Renal function, oxidative stress, apoptosis, and cell proliferation markers, were evaluated. Moreover, kidney sections were submitted to histological evaluation. IRI induced increased serum creatinine, blood urea nitrogen, fractional sodium excretion, malondialdehyde, Bax, and phosphorylated mammalian target of rapamycin (P-mTOR), and decreased clearance of creatine, superoxide dismutase and catalase activities, and Bax in comparison with control groups. CLA prefeeding restored, at least in part, the above reported markers to normal levels, increased the anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2), and reduce the histological damage. CONCLUSION: The results suggest that the decreased renal tissue damage and improved renal function and oxidative stress, in rats pretreated with CLAs before renal IRI induction, could be associated with downregulation of Bax and P-mTOR, and upregulation of Bcl-2. CLAs pretreatment resulted to protect against IRI through the regulation of signaling pathways involved in apoptosis.

Improvement of tissue survival of skin flaps by 5α-reductase inhibitors: possible involvement of nitric oxide and inducible nitric oxide synthase.

BACKGROUND: Skin flap grafting is a popular approach for reconstruction of critical skin and underlying soft tissue injuries. In a previous study, we demonstrated the beneficial effects of two 5α-reductase inhibitors, azelaic acid and finasteride, on tissue survival in a rat model of skin flap grafting. In the current study, we investigated the involvement of nitric oxide and inducible nitric oxide synthase (iNOS) in graft survival mediated by these agents. METHODS: A number of 42 male rats were randomly allocated into six groups: 1, normal saline topical application; 2, azelaic acid (100 mg/flap); 3, finasteride (1 mg/flap); 4, injection of L-NG-nitroarginine methyl ester (L-NAME) (i.p., 20 mg/kg); 5, L-NAME (20 mg/kg, i.p.) + azelaic acid (100 mg/flap, topical); 6, L-NAME (20 mg/kg, i.p.) + finasteride (1 mg/flap, topical). Tissue survival, level of nitric oxide, and iNOS expression in groups were measured. RESULTS: Our data revealed that azelaic acid and finasteride significantly increased the expression of iNOS protein and nitric oxide (NO) levels in graft tissue (P < 0.05). These increases in iNOS expression and NO level were associated with higher survival of the graft tissue. CONCLUSION: It appears that alterations of the NO metabolism are implicated in the azelaic acid- and finasteride-mediated survival of the skin flaps.