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

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

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

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

S-Nitroso Human Serum Albumin Enhances Left Ventricle Hemodynamic Performance and Reduces Myocardial Damage after Local Ischemia–Reperfusion Injury

Endothelial nitric oxide (NO) production is crucial in maintaining vascular homeostasis. However, in the context of ischemia–reperfusion (I/R) injury, uncoupled endothelial nitric oxide synthase (eNOS) can exacerbate reactive oxygen species (ROS) generation. Supplementation with S-nitroso human serum albumin (S-NO-HSA) offers a potential solution by mitigating eNOS uncoupling, thereby enhancing NO bioavailability. In a study conducted at the University of Verona, male rats underwent thoracotomy followed by 30 min left anterior descendant coronary (LAD) occlusion and subsequent reperfusion. Hemodynamic parameters were meticulously assessed using a conductance catheter inserted via the carotid artery. The rats were stratified into two main groups based on reperfusion duration and the timing of drug infusion, with the effects of S-NO-HSA evaluated after 2 or 24 h. Remarkably, intravenous administration of S-NO-HSA, initiated before or during ischemia, exhibited notable benefits. It significantly improved left ventricular function, safeguarded energetic substrates such as phosphocreatine and ATP, and sustained glutathione levels akin to basal conditions, indicative of diminished oxidative stress. The data from this study strongly suggest a protective role for S-NO-HSA in mitigating I/R injury induced by LAD artery occlusion, a phenomenon observed at both 2 and 24 h post-reperfusion. These findings underscore the promising therapeutic potential of NO supplementation in alleviating myocardial damage subsequent to ischemic insult

Use of gelatin powder added to rifamycin versus bone wax in sternal wound hemostasis after cardiac surgery.

Bone wax is the substance which has been used for hemostasis in different surgical fields for up to one hundred years and historically used in our center to prevent sternal bleeding and subsequent complications. Recently, reabsorbable gelatin powder has come into use. Up to now there are no clinical studies that compare these two substances. Between 1st January and 31st December 2004, 1249 subsequent patients have been operated on for different cardiac surgical procedures in our center, of them 557 were enrolled in a randomized perspective monocentric study. They have been divided into two similar subgroups: one treated with swine gelatin plus rifamycin (group one) and the other with bone wax (group two). The two hemostatic products have been applied just after the sternotomy and before the chest closing. Each patient was evaluated for bleeding, sternal infections and was followed-up for two months for bone and wound healing. Postoperative bleeding at the tenth hour was 315 ml+/-269 (mean+/-S.D.) in the first group and 395 ml+/-265 in the second (P<0.001). In the 10th-20th hour interval time bleeding was 120 ml+/-74 and 205 ml+/-132, respectively (P<0.001). Total bleeding was 415 ml+/-87 in group one and 580 ml+/-150 in group two (P<0.001). Chest reopening for bleeding not due to surgical problems was carried out in 14 patients (4.7\%) (group one) and 19 (7.3\%) (group two) (n.s.). Superficial sternal wound infection occurred in two patients (0.7\%) in group one and three patients (1.1\%) in group two (n.s.). There were no deep sternal wound infections. Bleeding was significantly higher in patients treated with bone wax compared to those with absorbable gelatin plus rifamycin

Improved Outcome of Cardiac Extracorporeal Membrane Oxygenation in Infants and Children Using Magnetic Levitation Centrifugal Pumps.

Extracorporeal membrane oxygenation (ECMO) has traditionally been and, for the most part, still is being performed using roller pumps. Use of first-generation centrifugal pumps has yielded controversial outcomes, perhaps due to mechanical properties of the same and the ensuing risk of hemolysis and renal morbidity. Latest-generation centrifugal pumps, using magnetic levitation (ML), exhibit mechanical properties which may have overcome limitations of first-generation devices. This retrospective study aimed to assess the safety and efficacy of veno-arterial (V-A) ECMO for cardiac indications in neonates, infants, and children, using standard (SP) and latest-generation ML centrifugal pumps. Between 2002 and 2014, 33 consecutive neonates, infants, and young children were supported using V-A ECMO for cardiac indications. There were 21 males and 12 females, with median age of 29 days (4 days-5 years) and a median body weight of 3.2\u2009kg (1.9-18\u2009kg). Indication for V-A ECMO were acute circulatory collapse in ICU or ward after cardiac repair in 16 (49%) patients, failure to wean after repair of complex congenital heart disease in 9 (27%), fulminant myocarditis in 4 (12%), preoperative sepsis in 2 (6%), and refractory tachy-arrhythmias in 2 (6%). Central cannulation was used in 27 (81%) patients and peripheral in 6. Seven (21%) patients were supported with SP and 26 (79%) with ML centrifugal pumps. Median duration of support was 82\u2009h (range 24-672\u2009h), with 26 (79%) patients weaned from support. Three patients required a second ECMO run but died on support. Seventeen (51%) patients required peritoneal dialysis for acute renal failure. Overall survival to discharge was 39% (13/33 patients). All patients with fulminant myocarditis and with refractory arrhythmias were weaned, and five (83%) survived, whereas no patient supported for sepsis survived. Risk factors for hospital mortality included lower (<2.5\u2009kg) body weight (P\u2009=\u20090.02) and rescue ECMO after cardiac repair (P\u2009=\u20090.03). During a median follow-up of 34 months (range 4-62 months), there were three (23%) late deaths and two late survivors with neurological sequelae. Weaning rate (5/7 vs. 21/26, P\u2009=\u2009NS) and prevalence of renal failure requiring dialysis (4/7 vs. 13/26, P\u2009=\u2009NS) were comparable between SP and ML ECMO groups. Patients supported with ML had a trend toward higher hospital survival (1/7 vs. 12/26, P\u2009=\u20090.07) and significantly higher late survival (0/7 vs. 10/26, P\u2009=\u20090.05). The present experience shows that V-A ECMO for cardiac indications using centrifugal pumps in infants and children yields outcomes absolutely comparable to international registry (ELSO) data using mostly roller pumps. Although changes in practice may have contributed to these results, use of ML centrifugal pumps appears to further improve end-organ recovery and hospital and late survival