Role of calcium desensitization in the treatment of myocardial dysfunction after deep hypothermic circulatory arrest

Abstract Introduction Rewarming from deep hypothermic circulatory arrest (DHCA) produces calcium desensitization by troponin I (cTnI) phosphorylation which results in myocardial dysfunction. This study investigated the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan, a calcium sensitizer, on myocardial function after rewarming from DHCA. Methods Forty male Wistar rats (400 to 500 g) underwent cardiopulmonary bypass (CPB) through central cannulation and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After DHCA (20 minutes) and CPB-assisted rewarming (60 minutes) rats were randomly assigned to 60 minute intravenous infusion with levosimendan (0.2 μg/kg/min; n = 15), epinephrine (0.1 μg/kg/min; n = 15) or saline (control; n = 10). Systolic and diastolic functions were evaluated at different preloads with a conductance catheter. Results The slope of left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) recovered significantly better with levosimendan compared to epinephrine (Ees: 85 ± 9% vs 51 ± 11%, P\u3c0.003 and PRSW: 78 ± 5% vs 48 ± 8%, P\u3c0.005; baseline: 100%). Levosimendan but not epinephrine reduced left ventricular stiffness shown by the end-diastolic pressure-volume relationship and improved ventricular relaxation (Tau). Levosimendan preserved ATP myocardial content as well as energy charge and reduced plasma lactate concentrations. In normothermia experiments epinephrine in contrast to Levosimendan increased cTnI phosphorylation 3.5-fold. After rewarming from DHCA, cTnI phosphorylation increased 4.5-fold in the saline and epinephrine group compared to normothermia but remained unchanged with levosimendan. Conclusions Levosimendan due to prevention of calcium desensitization by cTnI phosphorylation is more effective than epinephrine for treatment of myocardial dysfunction after rewarming from DHCA

Fingolimod plays role in attenuation of myocardial injury related to experimental model of cardiac arrest and extracorporeal life support resuscitation

Background: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia-reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation.Methods: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated with fingolimod (Group A, n = 30) or saline (Group B, n = 30). Half of the animals in each group (Group A1 and B1, n = 15 each) were sacrificed after 1 h, and the remaining animals (Group A2 and B2) after 24 h of reperfusion. Blood and myocardial tissues were collected for analysis of cardiac features, inflammatory biomarkers, and cell signaling pathways.Results: Treatment with fingolimod resulted in activation of survival pathways resulting into reduced inflammation, myocardial oxidative stress and apoptosis of cardiomyocytes. This led to significant improvement in systolic and diastolic functions of the left ventricle and improved contractility index.Conclusions: Sphingosine1phosphate receptor activation with fingolimod improved cardiac function after cardiac arrest supported with ECLS. Present study findings strongly support a cardioprotective role of fingolimod through sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest

Cardioprotective effects of sphingosine-1-phosphate receptor immunomodulator fty720 in a clinically relevant model of cardioplegic arrest and cardiopulmonary bypass

Objective: FTY720, an immunomodulator derived from sphingosine-1-phosphate, has recently demonstrated its immunomodulatory, anti-inflammatory, anti-oxidant, anti-apoptotic and anti-inflammatory properties. Furthermore, FTY720 might be a key pharmacological target for preconditioning. In this preclinical model, we have investigated the effects of FTY720 on myocardium during reperfusion in an experimental model of cardioplegic arrest (CPA) and cardiopulmonary bypass. Methods: 30 Sprague-Dawley rats (300-350 g) were randomized into two groups: Group-A, treated with FTY720 1 mg/kg via intravenous cannulation, and Group-B, as control. After 15 min of treatment, rats underwent CPA for 30 min followed by initiation of extracorporeal life support for 2 h. Support weaning was done, and blood and myocardial tissues were collected for analysis. Hemodynamic parameters, inflammatory mediators, nitro-oxidative stress, neutrophil infiltration, immunoblotting analysis, and immunohistochemical staining were analyzed and compared between groups. Results: FTY720 treatment activated the Akt/Erk1/2 signaling pathways, reduced the level of inflammatory mediators, activated antiapoptotic proteins, and inhibited proapoptotic proteins, leading to reduced nitro-oxidative stress and cardiomyocyte apoptosis. Moreover, significant preservation of high-energy phosphates were observed in the FTY720-treated group. This resulted in improved recovery of left ventricular systolic and diastolic functions. Conclusion: The cardioprotective mechanism in CPA is associated with activation of prosurvival cell signaling pathways that prevents myocardial damage. FTY720 preserves high-energy phosphates attenuates myocardial inflammation and oxidative stress, and improves cardiac function

Planeamiento estratégico de la Provincia de Castrovirreyna

El Plan Estratégico de la provincia de Castrovirreyna se realizó con base en el Modelo Secuencial del Proceso Estratégico, el cual desarrolló el Dr. Fernando D’Alessio Ipinza, quien partió de un análisis de la situación actual, para llegar a una situación futura deseada, por medio del establecimiento de la visión, misión, valores, objetivos de largo plazo, corto plazo y estrategias asociadas al entorno y sus fortalezas, debilidades, oportunidades y amenazas. Castrovirreyna es una provincia que se conforma de 13 distritos, es predominantemente rural y tiene un alto grado de pobreza y pobreza extrema, posee abundantes recursos que podrían permitirle mejorar su posición, debido a que no tiene la promoción e inversión necesaria para capitalizar la riqueza de su patrimonio en actividades productivas que le permitan desarrollarse y crecer. La propuesta del Plan se basa en el desarrollo de la infraestructura (vial y de comunicaciones) y de los servicios básicos (salud, educación e internet) que sirva de soporte e incremente el nivel de vida y la competitividad de la provincia; el desarrollo de sectores económicos como agropecuario, acuícola y turismo, a través de la mejora de la tecnología de producción de especies propias de la provincia y los beneficios tributarios, otorgados desde el Estado y las capacitaciones e incentivos a la generación de clústeres, también la participación de la población en todos los procesos de la búsqueda del desarrollo provincial. Asimismo, se orienta a motivar a las nuevas generaciones al emprendimiento teniendo en cuenta las potencialidades de la provincia, y de esta manera poder reducir las brechas de pobreza y desigualdad existentesThe Strategic Plan of the province of Castrovirreyna has been made based on the sequential model of the Strategic Process developed by Dr. Fernando D’Alessio Ipinza, based on an analysis of the current situation, to reach a desired future situation, through the establishment of vision, mission, values, long-term goals, short-term and related to the environment and their strategies strengths, weaknesses, opportunities and threats. Castrovirreyna is a province that is composed of 13 districts, it’s predominantly rural and has a high degree of poverty and extreme poverty, it has abundant resources that could enable it to improve its position because it does not have the promotion and investment needed to capitalize on the wealth of its assets in activities productive that allow develop and grow. Plan’s proposal is based on the development of the infrastructure (roads and communications) and of the basic services (health, education and internet) to serve as a support and increase the standard of living and competitiveness of the province; the development of economic sectors such as agriculture, aquaculture and tourism through improved production technology of species native of the province and the tax benefits granted from the State and trainings and incentives to generate clusters, also participation of the population in all processes of the search for provincial development. Additional aims to encourage new generations to entrepreneurship taking into account the potential of the province, and thus to reduce the gaps existing poverty and inequalityTesi

Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) Attenuates Myocardial Fibrosis in Post-heterotopic Heart Transplantation

Background and Objective: Sphingosine 1-phosphate (S1P), and S1P receptor modulator fingolimod have been suggested to play important cardioprotective role in animal models of myocardial ischemia/reperfusion injuries. To understand the cardioprotective function of S1P and its mechanism in vivo, we analyzed apoptotic, inflammatory biomarkers, and myocardial fibrosis in an in vivo heterotopic rat heart transplantation model.Methods: Heterotopic heart transplantation is performed in 60 Sprague–Dawley (SD) rats (350–400 g). The heart transplant recipients (n = 60) are categorized into Group A (control) and Group B (fingolimod treated 1 mg/kg intravenous). At baseline with 24 h after heart transplantation, blood and myocardial tissue are collected for analysis of myocardial biomarkers, apoptosis, inflammatory markers, oxidative stress, and phosphorylation of Akt/Erk/STAT-3 signaling pathways. Myocardial fibrosis was investigated using Masson’s trichrome staining and L-hydroxyline.Results: Fingolimod treatment activates both Reperfusion Injury Salvage Kinase (RISK) and Survivor Activating Factor Enhancement (SAFE) pathways as evident from activation of anti-apoptotic and anti-inflammatory pathways. Fingolimod treatment caused a reduction in myocardial oxidative stress and hence cardiomyocyte apoptosis resulting in a decrease in myocardial reperfusion injury. Moreover, a significant (p < 0.001) reduction in collagen staining and hydroxyproline content was observed in fingolimod treated animals 30 days after transplantation demonstrating a reduction in cardiac fibrosis.Conclusion: S1P receptor activation with fingolimod activates anti-apoptotic and anti-inflammatory pathways, leading to improved myocardial salvage causing a reduction in cardiac fibrosis

Cardioprotective role of S-Nitroso Human Serum Albuminduring regional myocardial ischemia-reperfusion.

BACKGROUND: The early period of reperfusion after myocardial ischemia is critical for endothelial dysfunction and the impairment of nitric oxide synthesis plays a critical role. We investigated the cardioprotective effect of S-NO-HSA in a regional myocardial ischemia/reperfusion rat model reproducing clinical scenarios. METHODS AND RESULTS: Male Wistar rats (n: 120) underwent reversible occlusion of the left anterior descending artery for 30 minutes and subsequent reperfusion for 24 hours. The animals were randomly treated with S-NO-HSA (0.3 \u3bcmol/kg/h) or human serum albumin (HSA) infusion. The infusion started 15 minutes before the beginning of ischemia in a group (Pre-I) whereas it starter 15 min after the initiation of ischemia in the other group (Post-I). The infusion continued until the first 30 minutes of reperfusion in both groups. Ventricular systolic and diastolic function was evaluated during early and late reperfusion (120 min and 24 h) in vivo at different preloads by a Millar microtip P-V conductance catheter. Hearts were excised after reperfusion to determine infarct size (IS) and area at risk (AR). Biopsies were obtained to measure high-energy phosphates, the expression of endothelial nitric oxide synthase (eNOS) and inducile nitric oxide synthase (iNOS) and the production of NFkB. Treatment with S-NO-HSA had a significative effect in reducing IS (42.2% +/-3.5 vs. 65.3 +/-4.2; p<0.05), the maximum effect is produced when the drug is administered before ischemia. S-NO-HSA effect on LV systolic function is evident considering the preload independent contractility parameters: maximal slope of the systolic pressure increment end diastolic volume relationship (dP/dtMAX-EDV), the slope EMAX of the end-systolic P-V relationship and the preload recruitable stroke work (PRSW) were significantly increased during reperfusion in all treated animals and after ischemia only in the pre-treated group (Pre-I). The LV diastolic function was improved by S-NO-HSA treatment. Tau-Weiss (index of ventricular relaxation), LV end-diastolic pressure (LVEDP) and end-diastolic P-V relationship (EDPVR) (indexes of ventricular stiffness) were significantly decreased with S-NO-HSA both in Pre-I and Post-I group after ischemia and during the 24 h reperfusion. NO supplementation by S-NO-HSA led to partial and in Pre-I group to total preservation of high energy phosphates. Phosphocreatine (CrP) content was preserved in Pre-I group (5.25 +/- 1.65 vs. 1.53 +/- 1.29 \u3bcmol/g protein; p < 0.05) and in Post-I group (3.85 +/- 1.12 vs. 1.53 +/- 1.29 \u3bcmol/g protein; p < 0.05) after 24 h reperfusion. Indeed energy charge was significantly higher only in the Pre-I group (0.62 +/- 0.07 vs 0.30 +/- 0.07). S-NO-HSA did not change the constitutive eNOS expression (measured by immunohistochemistry), instead it prevent the NFkB activation (quantified by EMSA) and therefore the iNOS mRNA expression (measured by Northern Blot). CONCLUSIONS: S-NO-HSA limits the infarct size, improves diastolic and systolic function and the energetic reserve of the heart after regional myocardial ischemia/reperfusion. These results suggest that S- NO-HSA might be an interesting option for patients undergoing regional myocardial ischemia reperfusion.BACKGROUND: The early period of reperfusion after myocardial ischemia is critical for endothelial dysfunction and the impairment of nitric oxide synthesis plays a critical role. We investigated the cardioprotective effect of S-NO-HSA in a regional myocardial ischemia/reperfusion rat model reproducing clinical scenarios. METHODS AND RESULTS: Male Wistar rats (n: 120) underwent reversible occlusion of the left anterior descending artery for 30 minutes and subsequent reperfusion for 24 hours. The animals were randomly treated with S-NO-HSA (0.3 \u3bcmol/kg/h) or human serum albumin (HSA) infusion. The infusion started 15 minutes before the beginning of ischemia in a group (Pre-I) whereas it starter 15 min after the initiation of ischemia in the other group (Post-I). The infusion continued until the first 30 minutes of reperfusion in both groups. Ventricular systolic and diastolic function was evaluated during early and late reperfusion (120 min and 24 h) in vivo at different preloads by a Millar microtip P-V conductance catheter. Hearts were excised after reperfusion to determine infarct size (IS) and area at risk (AR). Biopsies were obtained to measure high-energy phosphates, the expression of endothelial nitric oxide synthase (eNOS) and inducile nitric oxide synthase (iNOS) and the production of NFkB. Treatment with S-NO-HSA had a significative effect in reducing IS (42.2% +/-3.5 vs. 65.3 +/-4.2; p<0.05), the maximum effect is produced when the drug is administered before ischemia. S-NO-HSA effect on LV systolic function is evident considering the preload independent contractility parameters: maximal slope of the systolic pressure increment end diastolic volume relationship (dP/dtMAX-EDV), the slope EMAX of the end-systolic P-V relationship and the preload recruitable stroke work (PRSW) were significantly increased during reperfusion in all treated animals and after ischemia only in the pre-treated group (Pre-I). The LV diastolic function was improved by S-NO-HSA treatment. Tau-Weiss (index of ventricular relaxation), LV end-diastolic pressure (LVEDP) and end-diastolic P-V relationship (EDPVR) (indexes of ventricular stiffness) were significantly decreased with S-NO-HSA both in Pre-I and Post-I group after ischemia and during the 24 h reperfusion. NO supplementation by S-NO-HSA led to partial and in Pre-I group to total preservation of high energy phosphates. Phosphocreatine (CrP) content was preserved in Pre-I group (5.25 +/- 1.65 vs. 1.53 +/- 1.29 \u3bcmol/g protein; p < 0.05) and in Post-I group (3.85 +/- 1.12 vs. 1.53 +/- 1.29 \u3bcmol/g protein; p < 0.05) after 24 h reperfusion. Indeed energy charge was significantly higher only in the Pre-I group (0.62 +/- 0.07 vs 0.30 +/- 0.07). S-NO-HSA did not change the constitutive eNOS expression (measured by immunohistochemistry), instead it prevent the NFkB activation (quantified by EMSA) and therefore the iNOS mRNA expression (measured by Northern Blot). CONCLUSIONS: S-NO-HSA limits the infarct size, improves diastolic and systolic function and the energetic reserve of the heart after regional myocardial ischemia/reperfusion. These results suggest that S- NO-HSA might be an interesting option for patients undergoing regional myocardial ischemia reperfusion

Temperature Management During Circulatory Arrest in Cardiac Surgery

Surgery for complex aortic pathologies, such as acute dissections and aneurysms involving the aortic arch, remains one of the most technically and strategically challenging intervention in aortic surgery, requiring thorough understanding not only of cardiovascular physiology but also of neurophysiology (cerebral and spinal cord), and is still associated with significant mortality and morbidity. The introduction of deep hypothermia in the mid 1970s, allowing defined periods of circulatory arrest, has made possible the advent of modern aortic surgery requiring prolonged ischemic tolerance of central nervous system. In the late 1980s, when deep hypothermic circulatory arrest was the standard operative strategy for aortic surgery, selective cerebral perfusion, as an adjunct to deep hypothermia, made possible excellent neuroprotection and improved overall outcome. This encouraged the use of selective cerebral perfusion in combination with steadily increasing body core temperatures, a trend culminating in progressive promotion of moderate to mild hypothermia and even normothermia. The motivation for progressive temperature elevation was the limitation of adverse effects of deep hypothermia, in particular, reduction of systemic inflammatory response (and organ dysfunctions) and diminution of the risk of severe postoperative bleeding. However, adverse outcomes due to inappropriate temperature management (core temperatures too high for the required duration of circulatory arrest) are probably underreported. Indeed, complications historically associated with hypothermia are possibly overestimated