scholarly journals The Role of sGC Stimulators and Activators in Heart Failure With Reduced Ejection Fraction

2021 ◽  
pp. 107424842110427
Author(s):  
David J. Cordwin ◽  
Theodore J. Berei ◽  
Kristen T. Pogue
Keyword(s):  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Ejection Fraction ◽  
Soluble Guanylate Cyclase ◽  
Guanosine Monophosphate ◽  
Current Guideline ◽  
Reduced Ejection Fraction ◽  
Cgmp Pathway ◽  
Sgc Activators ◽  
Sgc Stimulators

Over the past decade, soluble guanylate cyclase (sGC) activators and stimulators have been developed and studied to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The sGC enzyme plays an important role in the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, that has been largely untargeted by current guideline directed medical therapy (GDMT) for HFrEF. Disruption of the NO-sCG-cGMP pathway can be widely observed in patients with HFrEF leading to endothelial dysfunction. The disruption is caused by an oxidized state resulting in low bioavailability of NO and cGMP. The increase in reactive oxygen species can also result in an oxidized, and subsequently heme free, sGC enzyme that NO is unable to activate, furthering the endothelial dysfunction. The novel sGC stimulators enhance the sensitivity of sGC to NO, and independently stimulate sGC, while the sGC activators target the oxidized and heme free sGC to stimulate cGMP production. This review will discuss the pathophysiologic basis for sGC stimulator and activator use in HFrEF, review the pre-clinical and clinical data, and propose a place in the HFrEF armamentarium for this novel pharmacotherapeutic class.

scholarly journals Vericiguat for Heart Failure with Reduced Ejection Fraction

2021 ◽  
Vol 23 (10) ◽  
Author(s):  
Carlo Mario Lombardi ◽  
Giuliana Cimino ◽  
Matteo Pagnesi ◽  
Andrea Dell’Aquila ◽  
Daniela Tomasoni ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Soluble Guanylate Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Cgmp Signaling

Abstract Purpose of Review The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function, and it is disrupted in heart failure (HF), resulting in decreased protection against myocardial injury. Impaired NO-sGC-cGMP signaling in HF is secondary to reduced NO bioavailability and altered redox state of sGC, which becomes less responsive to NO. The sGC activator cinaciguat increases cGMP levels by direct NO-independent activation of sGC and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and therefore reduced NO levels, at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, thus exerting a more physiological action. Recent Findings Clinical trials have suggested the benefit of vericiguat in patients with high-risk HF; in particular, a lower incidence of death from cardiovascular causes or HF hospitalization. Summary Adding vericiguat may be considered in individual patients with HF, and reduced left ventricular ejection fraction (HFrEF) particularly those at higher risk of HF hospitalization.

scholarly journals Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Andreas B. Gevaert ◽  
Katrien Lemmens ◽  
Christiaan J. Vrints ◽  
Emeline M. Van Craenenbroeck
Keyword(s):  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Current Knowledge ◽  
Beta Blockers ◽  
Preserved Ejection Fraction ◽  
Cellular Mechanisms ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

Although the burden of heart failure with preserved ejection fraction (HFpEF) is increasing, there is no therapy available that improves prognosis. Clinical trials using beta blockers and angiotensin converting enzyme inhibitors, cardiac-targeting drugs that reduce mortality in heart failure with reduced ejection fraction (HFrEF), have had disappointing results in HFpEF patients. A new “whole-systems” approach has been proposed for designing future HFpEF therapies, moving focus from the cardiomyocyte to the endothelium. Indeed, dysfunction of endothelial cells throughout the entire cardiovascular system is suggested as a central mechanism in HFpEF pathophysiology. The objective of this review is to provide an overview of current knowledge regarding endothelial dysfunction in HFpEF. We discuss the molecular and cellular mechanisms leading to endothelial dysfunction and the extent, presence, and prognostic importance of clinical endothelial dysfunction in different vascular beds. We also consider implications towards exercise training, a promising therapy targeting system-wide endothelial dysfunction in HFpEF.

Heart failure with preserved ejection fraction

ESC CardioMed ◽  
2018 ◽  
pp. 1897-1902
Author(s):  
Maja Cikes ◽  
Scott D. Solomon
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Phase Ii ◽  
Soluble Guanylate Cyclase ◽  
Diuretic Therapy ◽  
Signs And Symptoms ◽  
Isosorbide Mononitrate ◽  
Preserved Ejection Fraction ◽  
Phase Ii Trials ◽  
Reduced Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a diverse syndrome characterized by signs and symptoms of heart failure with relatively preserved ejection fraction. Despite the established efficacy of numerous classes of drugs and devices in heart failure with reduced ejection fraction, no specific therapy has yet proven to reduce morbidity and mortality in HFpEF. Currently, treatment of HFpEF remains empiric, and includes diuretic therapy for decongestion, treatment of hypertension, diagnosis and treatment of ischaemia, rate control for atrial fibrillation, and treatment of co-morbidities. While outcomes trials in HFpEF have tested renin–angiotensin–aldosterone inhibitors, and none have met their primary endpoint, there is some evidence that in appropriate patients, the mineralocorticoid receptor antagonist spironolactone may be helpful to reduce heart failure hospitalizations. Several other medications have been tested in phase II trials. Sildenafil, isosorbide mononitrate, and the soluble guanylate cyclase stimulator vericiguat did not show benefit in phase II trials. In contrast, sacubitril/valsartan was associated with a significant decrease in N-terminal pro-B-type natriuretic peptide values and improvement in left atrial size in a phase II trial. A large phase III trial to confirm these findings is under way.

Soluble guanylate cyclase in NO signaling transduction

2013 ◽  
Vol 33 (4) ◽  
pp. 193-205
Author(s):  
Jie Pan ◽  
Fangfang Zhong ◽  
Xiangshi Tan
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Signaling Transduction ◽  
Function Mechanism ◽  
The Past ◽  
No Signaling ◽  
Sgc Activators ◽  
Sgc Stimulators

AbstractNitric oxide (NO), a signaling molecule in the cardiovascular system, has been receiving increasing attention since Furchgott, Ignarro, and Murad were awarded the Nobel Prize in Physiology and Medicine for the discovery in 1998. Soluble guanylate cyclase (sGC), as an NO receptor, is a key metalloprotein in mediating NO signaling transduction. sGC is activated by NO to catalyze the conversion of guanosine 5′-triphosphate (GTP) to cyclic guanylate monophosphate (cGMP). The dysfunction of NO signaling results in many pathological disorders, including several cardiovascular diseases, such as arterial hypertension, pulmonary hypertension, heart failure and so on. Significant advances in its structure, function, mechanism, and physiological and pathological roles have been made throughout the past 15 years. We herein review the progress of sGC on structural, functional investigations, as well as the proposed activation/deactivation mechanism. The heme-dependent sGC stimulators and heme-independent sGC activators have also been summarized briefly.

scholarly journals The dawn of the four-drug era? SGLT2 inhibition in heart failure with reduced ejection fraction

2021 ◽  
Vol 15 ◽  
pp. 175394472110026
Author(s):  
Michael V. Genuardi ◽  
Paul J. Mather
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Controlled Trial ◽  
Sglt2 Inhibitor ◽  
The United States ◽  
Sglt2 Inhibitors ◽  
Current Guideline ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic drug with salutary effects on glucose control, body weight, and blood pressure. Emerging evidence now indicates that these drugs may have a beneficial effect on outcomes in heart failure with reduced ejection fraction (HFrEF). Post-approval cardiovascular outcomes data for three of these agents (canagliflozin, empagliflozin, and dapagliflozin) showed an unexpected improvement in cardiovascular endpoints, including heart failure hospitalization and mortality, among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or risk factors. These studies were followed by a placebo controlled trial of dapagliflozin in patients with HFrEF both with and without T2DM, showing a reduction in all-cause mortality comparable to current guideline-directed HFrEF medical therapies such as angiotensin-converting enzyme inhibitors and beta-blockers. In this review, we discuss the current landscape of evidence, safety and adverse effects, and proposed mechanisms of action for use of these agents for patients with HFrEF. The United States (US) and European guidelines are reviewed, as are the current US federally approved indications for each SGLT2 inhibitor. Use of these agents in clinical practice may be limited by an uncertain insurance environment, especially in patients without T2DM. Finally, we discuss practical considerations for the cardiovascular clinician, including within-class differences of the SGLT2 inhibitors currently available on the US market (217/300).

Abstract 16824: Circulating Microvesicles in Heart Failure Patients Prior to, and Following LVAD Implantation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
William K Cornwell ◽  
Kelly A Stockelman ◽  
Noah DeSouza ◽  
Jared Greiner ◽  
chris desouza
Keyword(s):  
Heart Failure ◽  
Flow Cytometry ◽  
Endothelial Dysfunction ◽  
Ejection Fraction ◽  
Blood Samples ◽  
Reduced Ejection Fraction ◽  
Heart Failure Patients ◽  
Hemodynamic Assessment ◽  
Patients With Heart Failure ◽  
Inflammatory State

Introduction: Elevated levels of circulating endothelial and platelet (EMV and PMV) microvesicles are associated with endothelial dysfunction and thrombosis/inflammation, respectively. EMVs and PMVs are elevated in patients with heart failure with reduced ejection fraction (HFrEF) and are associated with clinical outcomes. We sought to characterize longitudinal changes in EMV and PMV following LVAD implantation in these patients. Methods: Blood samples were obtained from patients with advanced HFrEF (59±9years, N=9 males) during an invasive hemodynamic assessment with Swan-Ganz catheterization 2.7±4.1 and 4.3±1.3 months prior to, and following CF-LVAD implantation, respectively. Circulating concentrations of total MV, EMVs (CD31+) and PMVs (CD42b+) were determined by flow cytometry. Results: Demographics and hemodynamics pre- and post-LVAD implantation are displayed in the table . Prior to LVAD, four patients were on inotropes. Six patients received a Heartware VAD, and four patients received a Heartmate 3 VAD. As demonstrated in the figure , there was a significant reduction in total MV concentration, as well as EMVs and PMVs following LVAD implantation. Conclusion: Circulating concentrations EMVs and PMVs decline significantly in HFrEF patients following LVAD implantation. These findings are indicative of improvements in both endothelial function and thrombotic/inflammatory state associated with the heart-failure syndrome.

scholarly journals Current Treatment of Heart Failure with Preserved Ejection Fraction: Should We Add Life to the Remaining Years or Add Years to the Remaining Life?

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Jia Li ◽  
Peter Moritz Becher ◽  
Stefan Blankenberg ◽  
Dirk Westermann
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Current Treatment ◽  
Current Guideline ◽  
Preserved Ejection Fraction ◽  
Mortality And Morbidity ◽  
Pathophysiological Mechanisms ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
Novel Therapeutic Strategies

According to the ejection fraction, patients with heart failure may be divided into two different groups: heart failure with preserved or reduced ejection fraction. In recent years, accumulating studies showed that increased mortality and morbidity rates of these two groups are nearly equal. More importantly, despite decline in mortality after treatment in regard to current guideline in patients with heart failure with reduced ejection fraction, there are still no trials resulting in improved outcome in patients with heart failure with preserved ejection fraction so far. Thus, novel pathophysiological mechanisms are under development, and other new viewpoints, such as multiple comorbidities resulting in increased non-cardiac deaths in patients with heart failure and preserved ejection fraction, were presented recently. In this review, we will focus on the tested as well as the promising therapeutic options that are currently studied in patients with heart failure with preserved ejection fraction, along with a brief discussion of pathophysiological mechanisms and diagnostic options that are helpful to increase our understanding of novel therapeutic strategies.

scholarly journals Reliability of peripheral arterial tonometry in patients with heart failure, diabetic nephropathy and arterial hypertension

2017 ◽  
Vol 22 (4) ◽  
pp. 292-300 ◽  
Author(s):  
Fabian Weisrock ◽  
Max Fritschka ◽  
Sebastian Beckmann ◽  
Simon Litmeier ◽  
Josephine Wagner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diabetic Nephropathy ◽  
Endothelial Dysfunction ◽  
Ejection Fraction ◽  
Arterial Hypertension ◽  
Peripheral Arterial Tonometry ◽  
Clinical Trial Registration ◽  
Good Reliability ◽  
Reliable Technique ◽  
Reduced Ejection Fraction

Endothelial dysfunction plays a major role in cardiovascular diseases and pulse amplitude tonometry (PAT) offers a non-invasive way to assess endothelial dysfunction. However, data about the reliability of PAT in cardiovascular patient populations are scarce. Thus, we evaluated the test-retest reliability of PAT using the natural logarithmic transformed reactive hyperaemia index (LnRHI). Our cohort consisted of 91 patients (mean age: 65±9.7 years, 32% female), who were divided into four groups: those with heart failure with preserved ejection fraction (HFpEF) ( n=25), heart failure with reduced ejection fraction (HFrEF) ( n=22), diabetic nephropathy ( n=21), and arterial hypertension ( n=23). All subjects underwent two separate PAT measurements at a median interval of 7 days (range 4–14 days). LnRHI derived by PAT showed good reliability in subjects with diabetic nephropathy (intra-class correlation (ICC) = 0.863) and satisfactory reliability in patients with both HFpEF (ICC = 0.557) and HFrEF (ICC = 0.576). However, in subjects with arterial hypertension, reliability was poor (ICC = 0.125). We demonstrated that PAT is a reliable technique to assess endothelial dysfunction in adults with diabetic nephropathy, HFpEF or HFrEF. However, in subjects with arterial hypertension, we did not find sufficient reliability, which can possibly be attributed to variations in heart rate and the respective time of the assessments. Clinical Trial Registration Identifier: NCT02299960.

HFpEF treatment: pharmacological therapy

ESC CardioMed ◽  
2018 ◽  
pp. 1897-1902
Author(s):  
Maja Cikes ◽  
Scott D. Solomon
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Phase Ii ◽  
Soluble Guanylate Cyclase ◽  
Diuretic Therapy ◽  
Pharmacological Therapy ◽  
Isosorbide Mononitrate ◽  
Preserved Ejection Fraction ◽  
Phase Ii Trials ◽  
Reduced Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a diverse syndrome characterized by signs and symptoms of heart failure with relatively preserved ejection fraction. Despite the established efficacy of numerous classes of drugs and devices in heart failure with reduced ejection fraction, no specific therapy has yet proven to reduce morbidity and mortality in HFpEF. Currently, treatment of HFpEF remains empiric, and includes diuretic therapy for decongestion, treatment of hypertension, diagnosis and treatment of ischaemia, rate control for atrial fibrillation, and treatment of co-morbidities. While outcomes trials in HFpEF have tested renin–angiotensin–aldosterone inhibitors, and none have met their primary endpoint, there is some evidence that in appropriate patients, the mineralocorticoid receptor antagonist spironolactone may be helpful to reduce heart failure hospitalizations. Several other medications have been tested in phase II trials. Sildenafil, isosorbide mononitrate, and the soluble guanylate cyclase stimulator vericiguat did not show benefit in phase II trials. In contrast, sacubitril/valsartan was associated with a significant decrease in N-terminal pro-B-type natriuretic peptide values and improvement in left atrial size in a phase II trial. A large phase III trial to confirm these findings is under way.

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