Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

2013 ◽  
Vol 125 (9) ◽  
pp. 409-421 ◽  
Author(s):  
Laura A. Bienvenu ◽  
Melissa E. Reichelt ◽  
Lea M. D. Delbridge ◽  
Morag J. Young
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Sex Differences ◽  
Side Effects ◽  
Therapeutic Option ◽  
Cell Types ◽  
Receptor Activation ◽  
Cardiac Events ◽  
Cardiac Tissues ◽  
Targeted Interventions

MR (mineralocorticoid receptor) activation in the heart plays a central role in the development of cardiovascular disease, including heart failure. The MR is present in many cell types within the myocardium, including cardiomyocytes, macrophages and the coronary vasculature. The specific role of the MR in each of these cell types in the initiation and progression of cardiac pathophysiology is not fully understood. Cardiomyocyte MRs are increasingly recognized to play a role in regulating cardiac function, electrical conduction and fibrosis, through direct signal mediation and through paracrine MR-dependent activity. Although MR blockade in the heart is an attractive therapeutic option for the treatment of heart failure and other forms of heart disease, current antagonists are limited by side effects owing to MR inactivation in other tissues (including renal targets). This has led to increased efforts to develop therapeutics that are more selective for cardiac MRs and which may have reduced the occurrence of side effects in non-cardiac tissues. A major clinical consideration in the treatment of cardiovascular disease is of the differences between males and females in the incidence and outcomes of cardiac events. There is clinical evidence that female sensitivity to endogenous MRs is more pronounced, and experimentally that MR-targeted interventions may be more efficacious in females. Given that sex differences have been described in MR signalling in a range of experimental settings and that the MR and oestrogen receptor pathways share some common signalling intermediates, it is becoming increasingly apparent that the mechanisms of MRs need to be evaluated in a sex-selective manner. Further research targeted to identify sex differences in cardiomyocyte MR activation and signalling processes has the potential to provide the basis for the development of cardiac-specific MR therapies that may also be sex-specific.

scholarly journals β 1 -Adrenoreceptor Autoantibodies in Heart Failure

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Hans-Dirk Düngen ◽  
Aleksandar Dordevic ◽  
Stephan B. Felix ◽  
Burkert Pieske ◽  
Adriaan A. Voors ◽  
...  
Keyword(s):  
Heart Failure ◽  
Wide Spectrum ◽  
Therapeutic Option ◽  
Receptor Activation ◽  
Novel Approach ◽  
Treat Heart Failure ◽  
Patients With Heart Failure ◽  
Β Blocker ◽  
Potential Risks ◽  
Cellular Dysfunction

Antibodies that activate the β 1 -AR (β 1 -adrenoreceptor) can induce heart failure in animal models. These antibodies are often found in patients with heart failure secondary to varying etiologies. Their binding to the β 1 receptor leads to prolonged receptor activation with subsequent induction of cellular dysfunction, apoptosis, and arrhythmias. β-blocker therapy while highly effective for heart failure, may not be sufficient treatment for patients who have β 1 receptor autoantibodies. Removal of these autoantibodies by immunoadsorption has been shown to improve heart failure in small studies. However, immunoadsorption is costly, time consuming, and carries potential risks. An alternative to immunoadsorption is neutralization of autoantibodies through the intravenous application of small soluble molecules, such as peptides or aptamers, which specifically target and neutralize β 1 -AR autoantibodies. Peptides may induce immunogenicity. Animal as well as early phase human studies with aptamers have not shown safety concerns to date and have demonstrated effectiveness in reducing autoantibody levels. Novel aptamers have the potential advantage of having a wide spectrum of action, neutralizing a variety of known circulating G-protein coupled receptor autoantibodies. These aptamers, therefore, have the potential to be novel therapeutic option for patients with heart failure who have positive for β 1 -AR autoantibodies. However, clinical outcomes trials are needed to assess the clinical utility of this novel approach to treat heart failure.

scholarly journals Impairment of coronary endothelial cell ETB receptor function after short-term inhalation exposure to whole diesel emissions

2009 ◽  
Vol 297 (3) ◽  
pp. R640-R647 ◽  
Author(s):  
Tom W. Cherng ◽  
Matthew J. Campen ◽  
Travis L. Knuckles ◽  
Laura Gonzalez Bosc ◽  
Nancy L. Kanagy
Keyword(s):  
Cardiovascular Disease ◽  
Inhalation Exposure ◽  
Receptor Activation ◽  
Air Pollutant ◽  
Diesel Emissions ◽  
Acute Exposure ◽  
Cardiac Events ◽  
Pollution Levels ◽  
Etb Receptor ◽  
Oxide Synthase

Air pollutant levels positively correlate with increases in both acute and chronic cardiovascular disease. The pollutant diesel exhaust (DE) increases endothelin (ET) levels, suggesting that this peptide may contribute to DE-induced cardiovascular disease. We hypothesized that acute exposure to DE also enhances ET-1-mediated coronary artery constrictor sensitivity. Constrictor responses to KCl, U-46619, and ET-1 were recorded by videomicroscopy in pressurized intraseptal coronary arteries from rats exposed for 5 h to DE (300 μg/m3) or filtered air (Air). ET-1 constriction was augmented in arteries from DE-exposed rats. Nitric oxide synthase (NOS) inhibition [ Nω-nitro-l-arginine (l-NNA), 100 μM] and endothelium inactivation augmented ET-1 responses in arteries from Air but not DE rats so that after either treatment responses were not different between groups. DE exposure did not affect KCl and U-46619 constrictor responses, while NOS inhibition augmented KCl constriction equally in both groups. Thus basal NOS activity does not appear to be affected by DE exposure. The endothelin type B (ETB) receptor antagonist BQ-788 (10 μM) inhibited ET-1 constriction in DE but not Air arteries, and constriction in the presence of the antagonist was not different between groups. Cytokine levels were not different in plasma from DE and AIR rats, suggesting that acute exposure to DE does not cause an immediate inflammatory response. In summary, a 5-h DE exposure selectively increases constrictor sensitivity to ET-1. This augmentation is endothelium-, NOS-, and ETB receptor dependent. These data suggest that DE exposure diminishes ETB receptor activation of endothelial NOS and augments ETB-dependent vasoconstriction. This augmented coronary vasoreactivity to ET-1 after DE, coupled with previous reports that DE induces production of ET-1, suggests that ET-1 may contribute to the increased incidence of cardiac events during acute increases in air pollution levels.

scholarly journals Effectiveness of Intensive Cardiac Rehabilitation in High-Risk Patients with Cardiovascular Disease in Real-World Practice

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3883
Author(s):  
Iwona Świątkiewicz ◽  
Salvatore Di Somma ◽  
Ludovica De Fazio ◽  
Valerio Mazzilli ◽  
Pam R. Taub
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Cardiovascular Disease ◽  
High Risk ◽  
Cardiac Rehabilitation ◽  
Real World ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cardiac Events ◽  
Supervised Exercise

Structured lifestyle interventions through cardiac rehabilitation (CR) are critical to improving the outcome of patients with cardiovascular disease (CVD) and cardiometabolic risk factors. CR programs’ variability in real-world practice may impact CR effects. This study evaluates intensive CR (ICR) and standard CR (SCR) programs for improving cardiometabolic, psychosocial, and clinical outcomes in high-risk CVD patients undergoing guideline-based therapies. Both programs provided lifestyle counseling and the same supervised exercise component. ICR additionally included a specialized plant-based diet, stress management, and social support. Changes in body weight (BW), low-density lipoprotein cholesterol (LDL-C), and exercise capacity (EC) were primary outcomes. A total of 314 patients (101 ICR and 213 SCR, aged 66 ± 13 years, 75% overweight/obese, 90% coronary artery disease, 29% heart failure, 54% non-optimal LDL-C, 43% depressive symptoms) were included. Adherence to ICR was 96% vs. 68% for SCR. Only ICR resulted in a decrease in BW (3.4%), LDL-C (11.3%), other atherogenic lipids, glycated hemoglobin, and systolic blood pressure. Both ICR and SCR increased EC (52.2% and 48.7%, respectively) and improved adiposity indices, diastolic blood pressure, cholesterol intake, depression, and quality of life, but more for ICR. Within 12.6 ± 4.8 months post-CR, major adverse cardiac events were less likely in the ICR than SCR group (11% vs. 17%), especially heart failure hospitalizations (2% vs. 8%). A comprehensive ICR enhanced by a plant-based diet and psychosocial management is feasible and effective for improving the outcomes in high-risk CVD patients in real-world practice.

scholarly journals Cell-Based Therapies for Heart Failure

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonio Carlos Campos de Carvalho ◽  
Tais H. Kasai-Brunswick ◽  
Adriana Bastos Carvalho
Keyword(s):  
Heart Failure ◽  
Heart Diseases ◽  
Therapeutic Option ◽  
Cell Types ◽  
World Population ◽  
Future Perspectives ◽  
Cell Therapies ◽  
Ischemic Heart Diseases ◽  
Efficacious Treatment ◽  
Different Cell Types

Heart failure has reached epidemic proportions with the advances in cardiovascular therapies for ischemic heart diseases and the progressive aging of the world population. Efficient pharmacological therapies are available for treating heart failure, but unfortunately, even with optimized therapy, prognosis is often poor. Their last therapeutic option is, therefore, a heart transplantation with limited organ supply and complications related to immunosuppression. In this setting, cell therapies have emerged as an alternative. Many clinical trials have now been performed using different cell types and injection routes. In this perspective, we will analyze the results of such trials and discuss future perspectives for cell therapies as an efficacious treatment of heart failure.

scholarly journals P2X7

2020 ◽  
Author(s):  
Brandon G. Shokoples ◽  
Pierre Paradis ◽  
Ernesto L. Schiffrin
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Ischemia Reperfusion Injury ◽  
Purinergic Receptor ◽  
Ischemia Reperfusion ◽  
Low Grade ◽  
Cardiac Events ◽  
Blood Pressure Elevation ◽  
Pyrin Domain ◽  
Safety Margins

Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1β and IL-18. Increased P2X7 activation and IL-1β and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1β and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.

scholarly journals Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

2020 ◽  
Vol 9 (1) ◽  
pp. 241 ◽  
Author(s):  
Ruxandra Sava ◽  
Carl Pepine ◽  
Keith March
Keyword(s):  
Heart Failure ◽  
Immune Cell ◽  
Therapeutic Option ◽  
Cell Types ◽  
Immune Dysregulation ◽  
Tissue Healing ◽  
Inflammatory Phenotype ◽  
Stromal Stem Cells

Over 26 million people worldwide suffer from heart failure, a disease associated with a 1 year mortality rate of 22%. Half of these patients present heart failure with preserved ejection fraction (HFpEF), for which there is no available therapy to improve prognosis. HFpEF is strongly associated with aging, inflammation, and comorbid burden, which are thought to play causal roles in disease development. Mesenchymal stromal/stem cells (MSCs) have potent immunomodulatory actions and promote tissue healing, thus representing an attractive therapeutic option in HFpEF. In this review, we summarize recent data suggesting that a two-hit model of immune dysregulation lies at the heart of the HFpEF. A first hit is represented by genetic mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), which skew immune cells toward a pro-inflammatory phenotype, are associated with HFpEF development in animal models, and with immune dysregulation and risk of HF hospitalization in patients. A second hit is induced by cardiovascular risk factors, which cause subclinical cardiac dysfunction and production of danger signals. In mice, these attract proinflammatory macrophages, Th1 and Th17 cells into the myocardium, where they are required for the development of HFpEF. MSCs have been shown to reduce the pro-inflammatory activity of immune cell types involved in murine HFpEF in vitro, and to reduce myocardial fibrosis and improve diastolic function in vivo, thus they may efficiently target immune dysregulation in HFpEF and stop disease progression.

scholarly journals Spironolactone Versus Eplerenone as Adjunctive Treatment in Patients with Heart Failure

2019 ◽  
Vol 4 (2) ◽  
Keyword(s):  
Heart Failure ◽  
Side Effects ◽  
Adjunctive Therapy ◽  
Systolic Function ◽  
Clinical Status ◽  
The Other ◽  
Adjunctive Treatment ◽  
P Value ◽  
Cardiac Events ◽  
Patients With Heart Failure

Background: The goals of treatment in patients with heart failure (HF) are to improve their clinical status, functional capacity, and quality of life, prevent hospital admission and reduce mortality. Aim of the work: This work aims to evaluate spironolactone versus eplerenone as an adjunctive therapy regarding tolerability in patients with HF (NYHA II to IV) already on anti-failure treatment with beta Blockers (BB) and/or ivabradine and their effect on major adverse cardiac events. Study design: 100 patients were recruited and randomized into 2 groups (n=50/group); group 1 received spironolactone 25mg/d that was titrated to 100mg/d if tolerated, while group 2 received eplerenone 25mg/d that was titrated to 50mg/d if tolerated. Follow up of: symptoms, signs, potassium level, BNP, renal functions, systolic function and side effects was done over 3 months in 3 visits. Results: After 3 months it was found that 39 patients (78%) in each group showed good or marked improvement, with non significant P-value. Regarding side effects, the spironolactone group showed incidence of hyperkalemia in 6 patients (12%) in the spironolactone group; with 0% incidence in the other group with significant P-value (P<0.001). On the other hand 5 patients (10%) had gynecomastia in the spironolactone group with 0% incidence in the eplerenone group with significant P-value (P<0.001). Conclusion: spironolactone and eplerenone are both effective but the eplerenone is much more safer than spironolactone when added as an adjunctive therapy in patients with HF and are kept on full medical therapy including BBs.

scholarly journals Mineralocorticoid receptors in the heart: lessons from cell-selective transgenic animals

2014 ◽  
Vol 224 (1) ◽  
pp. R1-R13 ◽  
Author(s):  
Morag J Young ◽  
Amanda J Rickard
Keyword(s):  
Cardiovascular Disease ◽  
Cost Effective ◽  
Transgenic Animals ◽  
Receptor Activation ◽  
Ageing Population ◽  
Protective Effects ◽  
Negative Consequences ◽  
Cardiac Events ◽  
Tissue Inflammation ◽  
The Face

The clinical impact of cardiovascular disease cannot be underestimated. Equally, the importance of cost-effective management of cardiac failure is a pressing issue in the face of an ageing population and the increasing incidence of metabolic disorders worldwide. Targeting the mineralocorticoid receptor (MR) offers one approach for the treatment of heart failure with current strategies for novel MR therapeutics focusing on harnessing their cardio-protective benefits, but limiting the side effects of existing agents. It is now well accepted that activation of the MR in the cardiovascular system promotes tissue inflammation and fibrosis and has negative consequences for cardiac function and patient outcomes following cardiac events. Indeed, blockade of the MR using one of the two available antagonists (spironolactone and eplerenone) provides significant cardio-protective effects in the clinical and experimental setting. Although the pathways downstream of MR that translate receptor activation into tissue inflammation, fibrosis and dysfunction are still being elucidated, a series of recent studies using cell-selective MR (NR3C2)-null or MR-overexpressing mice have offered many new insights into the role of MR in cardiovascular disease and the control of blood pressure. Dissecting the cell-specific roles of MR signalling in the heart and vasculature to identify those pathways that are critical for MR-dependent responses is an important step towards achieving cardiac-selective therapeutics. The goal of this review is to discuss recent advances in this area that have emerged from the study of tissue-selective MR-null mice, and other targeted transgenic models and their relevance to clinical disease.

Abstract P011: ST2 As A Risk Predictor For Cardiovascular Disease, Heart Failure And Mortality In The Prospective Finrisk97 Population Cohort

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Maria F Hughes ◽  
Sebastian Appelbaum ◽  
Aki S Havulinna ◽  
Annika Jagodzinski ◽  
Francisco Ojeda ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Cardiovascular Disease ◽  
General Population ◽  
Significant Risk ◽  
Cox Proportional Hazards ◽  
Cardiac Events ◽  
Cvd Risk ◽  
Population Cohort ◽  
Framingham Risk

Introduction: ST2 is a receptor for the inflammatory cytokine IL33. The ST2-IL33 pathway has been associated with development of atherosclerosis and coronary artery disease in humans although the mechanism is not fully established. Increased ST2 levels have been associated with heart failure and death in patients with acute myocardial infarction and in the general population where it has also been associated with diabetes. We hypothesized that ST2 levels can identify people in the general population with elevated risk of subsequent cardiovascular disease (CVD) and add to existing risk prediction algorithms. Methods: We measured high sensitivity soluble ST2 (Presage) in 7,551 men and women (25-74 years) from the FINRISK97 prospective population cohort. Cox proportional hazards modeling using age as the time scale evaluated the ability of sST2 to predict cardiovascular endpoints including fatal and non-fatal cardiovascular disease (coronary heart disease, stroke, heart failure), incident diabetes and death over 14 years follow up. Missing data (~10%) was multiply imputed and participants with prevalent disease at baseline were excluded for corresponding endpoints of disease. Discrimination and reclassification statistics (c-index, NRI) for 10 year absolute risks were calculated with internal (10-fold) cross validation to compare the ability of ST2 to improve upon Framingham risk factors, N-terminal pro-brain natriuretic peptide (NTProBNP) and renal function (eGFR), established markers of CVD risk. Results: sST2 concentrations significantly predicted all-cause death (hazard ratio (HR) comparing the highest quartile with the lowest was 1.28 95% confidence interval (C.I.) 1.04-1.57 (1024 events), major adverse cardiac events (MACE) (HR 1.22 (95% C.I. 1.001-1.49) (1068 events) and stroke (1.44 (95% C.I. 0.99-2.1) (370 events) after adjustment for Framingham risk factors, NTProBNP and eGFR. sST2 showed suggestive but non-significant association with heart failure (HR 1.21 (95% C.I. 0.92-1.58) (577 events) after similar adjustment. Similarly, sST2 showed a trend toward elevated but non-significant risk for diabetes (HR 1.14 (95% C.I. 0.87-1.49) (377 events) after adjustment for age, area, sex, smoking, systolic blood pressure, antihypertensive medication, glucose and prevalent CVD. No improvement in the c-index was observed for models adding sST2 to Framingham and other risk factors. Clinical NRI was improved in fully adjusted models for death 9% ( p =1x10 -6 ) and stroke 4% ( p =0.028) with reclassification benefit mainly for non-cases. IDI was improved for MACE ( p =0.02) and stroke ( p =0.02). Conclusions: In a healthy general population from Finland (FINRISK97), sST2 improves prediction of death, MACE and stroke beyond Framingham covariates, NTProBNP and eGFR but does not improve prediction of heart failure.

scholarly journals Depression in Patients with Cardiovascular Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Dimos Mastrogiannis ◽  
Gregory Giamouzis ◽  
Efthimios Dardiotis ◽  
George Karayannis ◽  
Artemis Chroub-Papavaiou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Treatment Options ◽  
Medical Intervention ◽  
Lifestyle Changes ◽  
Screening Tools ◽  
Healthcare Personnel ◽  
Cardiac Events ◽  
Pathophysiological Mechanisms ◽  
Prevalence Of Depression

It has been widely suggested that depression negatively affects patients with cardiovascular disease. There are several pathophysiological mechanisms as well as behavioral processes linking depression and cardiac events. Improvements in nursing and medical care have prolonged survival of this patient population; however, this beneficial outcome has led to increased prevalence of depression. Since mortality rates in chronic heart failure patients remain extremely high, it might be as equally important to screen for depression and there are several valid and reliable screening tools that healthcare personnel could easily employ to identify patients at greater risk. Consultation should be provided by a multidisciplinary team, consisting of cardiologists, psychiatrists, and hospital or community nurses so as to carefully plan, execute, and evaluate medical intervention and implement lifestyle changes. We aim to systematically review the existing knowledge regarding current definitions, prognostic implications, pathophysiological mechanisms, and current and future treatment options in patients with depression and cardiovascular disease, specifically those with heart failure.

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