Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

Many conditions culminate in heart failure (HF), a multi-organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence-base supporting their use clinically. An established treatment paradigm now exists for the treatment of HF with reduced ejection fraction (HFrEF), but there have been very few notable developments in recent years. HF remains a significant health concern with an increasing incidence as the population ages. We may indeed be entering the surgical era for HF treatment, but these therapies remain expensive and inaccessible to many. Newer pharmacotherapeutic agents are slowly emerging, many targeting alternative therapeutic pathways, but with mixed results. Metabolic modulation and manipulation of the nitrate/nitrite/nitric oxide pathway have shown promise and could provide the answers to fill the therapeutic gap between medical interventions and surgery, but further definitive trials are warranted. We review the significant evidence base behind the current medical treatments for HFrEF, the physiology of metabolic impairment in HF, and discuss two promising novel agents, perhexiline and nitrite

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection.

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal

The effects of preconditioning coronary artery disease patients with hyperbaric oxygen prior to coronary artery bypass graft surgery & cardiopulmonary bypass

IntroductionCoronary artery bypass graft (CABG) is associated with periods of ischaemia and reperfusion, which may lead to myocardial dysfunction. In clinical studies, hyperbaric oxygen (HBO2) treatment following an acute myocardial infarction (AMI), has been shown to limit myocardial injury and improve myocardial function. The primary efficacy objective of this study was to determine if systemically preconditioning coronary artery disease (CAD) patients with HBO2, prior to first time elective on cardiopulmonary bypass (CPB) CABG surgery, leads to a remote preconditioning like effect that is capable of improving myocardial function following CABG. The main secondary objectives of this study were to assess the safety of HBO2 preconditioning and, its effects on myocardial injury and post operative intensive care unit (ICU) length of stay. The exploratory secondary objectives were to assess the effects of HBO2 preconditioning on surrogate serum biomarkers of endothelial and neutrophilic adhesiveness and, myocardial biomarkers of cardioprotection. Methods In this single centre, randomised control study, 81 patients, who were having first time elective on CPB CABG surgery, were recruited. 40 were randomised to the Control Group and 41 to the HBO2 Group. Treatment with HBO2 preconditioning was completed approximately 2 hours prior to CPB and consisted of two 30 minute sessions of 100% oxygen at 2.4 atmospheres (ATA) separated 5 minutes apart. Efficacy was measured by determining peri-operative haemodynamic measurements using a pulmonary artery (PA) catheter. Safety was measured by collecting peri-operative data on myocardial injury and adverse events (AEs) and, post operative days spent in ICU. Using collected peri-operative venous blood, myocardial injury was determined by measuring the concentration of serum Troponin-T. In these same venous blood samples, endothelial and neutrophilic adhesiveness was indirectly assessed by measuring the concentrations of sE-selectin, sP-Selectin and sICAM-1 and, sPSGL-1, respectively. Using intra-operative right atrial biopsies, the degree of cardioprotection provided by HBO2 preconditioning was determined by measuring the quantity of myocardial eNOS and Hsp72. Analysis of the serum and myocardial biomarkers were done by ELISA.Results Compared to the Control Group, the HBO2 Group demonstrated a significant improvement in left venticular stroke work (LVSW) 24 hours post CPB (p=0.005). While there were no significant safety findings, there were fewer cardiovascular, pulmonary, renal and neurological AEs in the HBO2 Group. This group also had a significantly shorter post operative ICU length of stay. 1 hour post HBO2 preconditioning, the concentration of sPSGL-1 increased significantly in the HBO2 Group. At all time points, the peri-oprative concentration of sPSGL-1 was higher in the HBO2 Group but none of the changes were significant. The latter was also the case for the peri-operative concentration of sP-Selectin, apart from following the period of ischaemic and reperfusion, when it was lower in the HBO2 Group. Intra-operatively, the concentration of sE-Selectin increased significantly in the HBO2 Group and was higher in this group throughout the peri-operative period. During this intra-operative period also, the concentration of sICAM-1 was higher in the HBO2 Group and the increase was particularly significant following the period of ischaemia and reperfusion. 24 hours post CPB, the concentrations of all the serum soluble adhesion molecules were higher in the HBO2 Group. No significant differences were observed between the groups with respect to the concentrations of serum Troponin-T and, the quantity of myocardial eNOS and Hsp72. However, in the HBO2 Group, the peri-operative concentrations of serum Tropinin-T, eNOS and Hsp72 were lower. Furthermore, while there was a pre-CPB reduction of both eNOS and Hsp72, following ischaemia and reperfusion, the quantity of both these myocardial biomarkers were increased. Conclusion From this study, it can be concluded that HBO2 preconditioning of patients with CAD prior to on CPB CABG, is capable of improving myocardial function 24 hours post CABG. Additionally, the data suggest that this may also be a safe modality of treatment as it did not lead to significant post operative AEs, limited peri-operative myocardial injury and reduced post operative ICU length of stay. It also led to increased post operative concentrations of the measured surrogate biomarkers of endothelial and neutrophilic adhesiveness, with a number of significant peri-operative changes. Finally, while HBO2 treatment did not lead to significant changes in the myocardial biomarkers of cardioprotection, the quantities of these increased in the HBO2 Group following ischaemia and reperfusion, suggesting that it may be capable of inducing endogenous cardioprotection following ischaemia and reperfusion

Supplementation With Hydrogen Sulfide Helps Mitigate The Effects Of Ischemia Reperfusion Injury In A Model Of Donation After Cardiac Death Renal Transplantation

Donation after cardiac death (DCD) grafts experience prolonged ischemia reperfusion injury (IRI) leading to higher rates of delayed graft function and failure. Recent studies have reported protective effects of hydrogen sulfide (H2S) against IRI. Our study aims at improving DCD renal graft outcomes by H2S supplementation in an in-vivo murine model of renal transplantation (RTx) and study the underlying mechanism in an in-vitro model using porcine kidney proximal-tubular-epithelial cells (LLC-PK1). H2S provided survival benefit, improved renal graft function and decreased renal injury in recipient rats. In our in-vitro model of LLC-PK1 cells, H2S demonstrated an important role mediated by mitochondria in the pathophysiological effects of IRI by reducing depolarization of the mitochondrial membrane and the amount of reactive oxygen species. In the long run, these findings would help bridge the gap between organ demand and supply by reducing the extent of renal IRI and delayed graft function in DCD donors

Renal Failure

The book "Renal Failure - The Facts" consists of some facts about diagnosis, etiopathogenis and treatment of acute and chronic renal failure. Acute, as well as chronic renal failure is great medical problems and their treatment is a burden for the budget of each government. The purpose of the chapters is to present some important issues of diagnosis and causes of AKI, as well as caused by snakes and arthropods, after cardiac surgery, as well as some therapeutic achievements in AKI. Well presented are the psychological condition in patients on haemodialysis, as well as the treatment of diabetic uremics. The book is aimed at clinicians with a special interest in nephrology, but it should also prove to be a valuable resource for any generalists who encounter a nephrological problems in their day-to-day practice

The role of endothelial enzymes NOS, VAP-1 and CD73 in acute lung injury

Acute lung injury (ALI) is a syndrome of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that is not caused by left atrial hypertension. Since there is no effective treatment available, this frequent clinical syndrome significantly contributes to mortality of both medical and surgical patients. Great majority of the patients with the syndrome suffers from indirect ALI caused by systemic inflammatory response syndrome (SIRS). Sepsis, trauma, major surgery and severe burns, which represent the most common triggers of SIRS, often induce an overwhelming inflammatory reaction leading to dysfunction of several vital organs. Studies of indirect ALI due to SIRS revealed that respiratory dysfunction results from increased permeability of endothelium. Disruption of endothelial barrier allows extravasation of protein-rich liquid and neutrophils to pulmonary parenchyma. Both under normal conditions and in inflammation, endothelial barrier function is regulated by numerous mechanisms. Endothelial enzymes represent one of the critical control points of vascular permeability and leukocyte trafficking. Some endothelial enzymes prevent disruption of endothelial barrier by production of anti-inflammatory substances. For instance, nitric oxide synthase (NOS) down-regulates leukocyte extravasation in inflammation by generation of nitric oxide. CD73 decreases vascular leakage and neutrophil emigration to inflamed tissues by generation of adenosine. On the other hand, vascular adhesion protein-1 (VAP-1) mediates leukocyte trafficking to the sites of inflammation both by generation of pro-inflammatory substances and by physically acting as an adhesion molecule. The aims of this study were to define the role of endothelial enzymes NOS, CD73 and VAP-1 in acute lung injury. Our data suggest that increasing substrate availability for NOS reduces both lung edema and neutrophil infiltration and this effect is not enhanced by concomitant administration of antioxidants. CD73 protects from vascular leakage in ALI and its up-regulation by interferon-β represents a novel therapeutic strategy for treatment of this syndrome. Enzymatic activity of VAP-1 mediates neutrophil infiltration in ALI and its inhibition represents an attractive approach to treat ALI.Siirretty Doriast

Ex Vivo Heart Perfusion

Heart transplantation offers the best prognostic results for patients with end stage heart failure. However, there is a much greater demand for donor hearts than there is adequate supply. Cold static storage (CSS) is the current standard protocol for donor heart procurement. CSS has excellent prognosis but subjects the organ to ischemic reperfusion injury (IRI) and induces tissue inflammation due to anoxic conditions and oxidative stress. Hearts from older donors or patients that have a history of previous heart disease can’t withstand the anoxic stressors and make for poor donor candidates with the CSS protocol since they are associated with worse prognostic outcomes, which restricts the donor pool for acceptable hearts. Ex vivo heart perfusion, a novel method for heart transport, is a potential solution to expanding the donor pool and reducing the IRI and anoxic insults. This protocol continuously perfuses the donor heart and has been shown to reduce ischemic injury, increase ex vivo viability time and improve the biochemical and cellular profile of the donor heart. These factors collectively open the door for the possibility of expanding the acceptable pool of donor hearts since this protocol places fewer stressors on the myocardial tissue. We review the limitations of the cold static storage protocol and evaluate the benefits, drawbacks and practicality of the ex vivo heart perfusion for use in clinical practice by examining both human and animal studies