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JAMA Network Open Sep 2022In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still insufficient evidence for drug therapy for HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).
OBJECTIVE
To compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF.
DATA SOURCES
A search of the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies published from inception to October 9, 2021.
STUDY SELECTION
Randomized clinical trials on the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), β-blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with HFpEF or HFmrEF.
DATA EXTRACTION AND SYNTHESIS
Data extraction and bias assessment were independently performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All data for 3 outcomes were pooled with a fixed-effect model.
MAIN OUTCOMES AND MEASURES
The main outcomes were first hospitalization for HF, all-cause mortality, and cardiovascular mortality. Hazard ratios (HRs) and 95% credible intervals (CrIs) were evaluated using a bayesian network meta-analysis model.
RESULTS
In this analysis, 19 randomized clinical trials, including 20 633 patients with HF and an ejection fraction of 40% or more, without a remarkable risk of bias were included. Compared with placebo, no treatments were associated with a significant reduction in the risk of all-cause death or cardiovascular death. SGLT2 inhibitors, ARNIs, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared with placebo (SGLT2 inhibitors: HR, 0.71 [95% CrI, 0.60-0.83]; ARNIs: HR, 0.76 [95% CrI, 0.61-0.95]; MRAs: HR, 0.83 [95% CrI, 0.69-0.99]), and SGLT2 inhibitors were the optimal drug class in terms of reducing the risk for HF admission. Sensitivity analysis results demonstrated a progressive decrease in the risk of HF admission and an advance in mean rank associated with the increasing use of drug classes.
CONCLUSIONS AND RELEVANCE
The findings of this study suggest that SGLT2 inhibitors were the optimal drug class for HFpEF and HFmrEF, consistent with the most recent guideline recommendation. The incremental use of combinations of SGLT2 inhibitors, ACE inhibitors or ARBs, and β-blockers may be associated with accumulative benefits in HF hospitalization rather than all-cause death among patients with HFpEF and HFmrEF.
Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Bayes Theorem; Glucose; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Neprilysin; Receptors, Angiotensin; Sodium; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 36125813
DOI: 10.1001/jamanetworkopen.2022.31963 -
The American Journal of Medicine Jan 2024Simultaneous initiation of quadruple therapy with angiotensin receptor-neprilysin inhibitor, beta-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and... (Review)
Review
Simultaneous initiation of quadruple therapy with angiotensin receptor-neprilysin inhibitor, beta-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor aims at prompt improvement and prevention of readmission in patients hospitalized for heart failure with reduced ejection fraction. However, titration of quadruple therapy is time consuming. Lengthy up-titration of quadruple therapy may negate the benefit of early initiation. Quadruple therapy should start with a sodium glucose cotransporter 2 inhibition and a mineralocorticoid antagonist, as both enable safe decongestion and require minimal or no titration. Depending on the level of decongestion and clinical characteristics, patients receive an angiotensin receptor-neprilysin inhibitor or a beta-adrenergic receptor blocker to be titrated after hospital discharge. Outpatient addition of an angiotensin receptor-neprilysin inhibitor to a beta-adrenergic receptor blocker or vice versa completes the quadruple therapy scheme. By focusing on decongestion and matching intervention to patients' profile, the present therapeutic sequence allows rapid implementation of quadruple therapy at fully recommended doses.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Neprilysin; Stroke Volume; Angiotensin Receptor Antagonists; Heart Failure; Anti-Arrhythmia Agents; Adrenergic beta-Antagonists; Enzyme Inhibitors; Receptors, Adrenergic, beta; Receptors, Angiotensin; Patient-Centered Care; Mineralocorticoid Receptor Antagonists
PubMed: 37838238
DOI: 10.1016/j.amjmed.2023.09.018 -
Proceedings of the National Academy of... Aug 2020There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research...
There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine receptor group. GPCRs are challenging targets for conventional antibody discovery methods, as many are highly conserved across species, are biochemically unstable upon purification, and possess deeply buried ligand-binding sites. Here, we describe a selection methodology to enrich for functionally modulatory antibodies using a yeast-displayed library of synthetic camelid antibody fragments called "nanobodies." Using this platform, we discovered multiple nanobodies that act as antagonists of the angiotensin II type 1 receptor (AT1R). Following angiotensin II infusion in mice, we found that an affinity matured nanobody antagonist has comparable antihypertensive activity to the angiotensin receptor blocker (ARB) losartan. The unique pharmacology and restricted biodistribution of nanobody antagonists may provide a path for treating hypertensive disorders when small-molecule drugs targeting the AT1R are contraindicated, for example, in pregnancy.
Topics: Angiotensin Receptor Antagonists; Animals; Antibody Affinity; Blood Pressure; Cell Line; Humans; Mice; Receptors, Angiotensin; Single-Domain Antibodies
PubMed: 32753386
DOI: 10.1073/pnas.2009029117 -
International Journal of Molecular... Aug 2021The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and... (Review)
Review
The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.
Topics: Angiotensin Receptor Antagonists; Antihypertensive Agents; Arrhythmias, Cardiac; Cardiovascular Diseases; Heart Failure; Humans; Hypertension; Natriuretic Peptides; Neprilysin; Receptors, Angiotensin; Renin-Angiotensin System; Sympathetic Nervous System; Tetrazoles
PubMed: 34445698
DOI: 10.3390/ijms22168994 -
American Journal of Physiology. Heart... Apr 2018It has become clear that the vasoactive peptide angiotensin II, like other so-called intracrines, can act in the intracellular space. Evidence has accumulated indicating... (Review)
Review
It has become clear that the vasoactive peptide angiotensin II, like other so-called intracrines, can act in the intracellular space. Evidence has accumulated indicating that such angiotensin II activity can be upregulated in disease states and cause pathology. Indeed, other intracrines appear to be involved in disease pathogenesis as well. At the same time, nitric oxide, potentially a cell protective factor, has been shown to be upregulated by intracellular angiotensin II. Recently data have been developed indicating that other potentially protective factors are directly upregulated at neuronal nuclei by angiotensin II. This led to the suggestion that intracellular angiotensin II is cell protective and not pathological. Here, the data on both sides of this issue and a possible resolution are discussed. In summary, there is evidence for both protective and pathological actions of intracellular angiotensin, just as there is abundant evidence derived from whole animal physiology to indicate that angiotensin-driven signaling cascades, including angiotensin II type 2 receptor- and Mas receptor-mediated events, can mitigate the effects of the angiotensin II/angiotensin II type 1 receptor axis (25). This mitigation does not negate the physiological and pathological importance of angiotensin II/angiotensin II type 1 receptor action but does expand our understanding of the workings of both intracellular and extracellular angiotensin II.
Topics: Angiotensin II; Animals; Cell Nucleus; Humans; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction
PubMed: 29351452
DOI: 10.1152/ajpheart.00632.2017 -
The EMBO Journal Jun 2023The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT R and its downstream signaling proteins G and...
The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT R and its downstream signaling proteins G and β-arrestin. AT R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT R β-arrestin-biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo-electron microscopy (cryo-EM) structure of the human AT R in complex with a balanced agonist, Sar -AngII, and G protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT R signal transduction from the ligand-binding pocket to both G and β-arrestin pathways. Specifically, we found that the MHN mutations N111 A and N294 A induce biased signaling to G and β-arrestin, respectively. These insights should facilitate AT R structure-based drug discovery for the treatment of cardiovascular diseases.
Topics: Humans; Cryoelectron Microscopy; Signal Transduction; beta-Arrestins; Angiotensin II; Receptors, Angiotensin
PubMed: 37038975
DOI: 10.15252/embj.2022112940 -
Hypertension Research : Official... Jul 2022Angiotensin receptor-neprilysin inhibitors have multiple beneficial effects on the cardiovascular system. The angiotensin receptor-neprilysin inhibitor... (Review)
Review
Angiotensin receptor-neprilysin inhibitors have multiple beneficial effects on the cardiovascular system. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to effectively reduce ambulatory 24-h blood pressure in patients with hypertension, and improvements in many aspects of hemodynamic function have also been reported. Overall hemodynamic effects on arterial stiffness and nocturnal blood pressure play an important role in the pathogenesis of hypertensive heart disease. Therefore, these could represent mechanistic targets underlying the effects of angiotensin receptor-neprilysin inhibitors on the continuum of cardiovascular disease from hypertension to heart failure. Other potential mechanisms include reductions in circulating volume and sympathetic activity, both of which contribute to the protection against target organ damage and positive changes in cardiac biomarkers seen during angiotensin receptor-neprilysin inhibitor therapy. The mechanisms of action and beneficial effects of angiotensin receptor-neprilysin inhibitors are complementary to those of a number of other treatment options for hypertension, suggesting the possibility of additive or even synergistic benefits. Based on available data, there are a number of patient groups who will benefit from antihypertensive treatment with an angiotensin receptor-neprilysin inhibitor, including those with salt-sensitive hypertension, structural hypertension, resistant hypertension, and hypertension in the presence of heart failure. Overall, angiotensin receptor-neprilysin inhibitors regulate blood pressure and pulse pressure via multiple mechanisms and provide cardiovascular protection. This provides an option for effective intervention early in the vicious cycle of elevated blood pressure and central pressures with progression toward heart failure that should help to address the growing worldwide heart failure epidemic.
Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Drug Combinations; Heart Failure; Hemodynamics; Humans; Hypertension; Neprilysin; Receptors, Angiotensin; Tetrazoles; Valsartan
PubMed: 35501475
DOI: 10.1038/s41440-022-00923-2 -
Frontiers in Endocrinology 2022In conjunction with the endothelin (ET) type A (ETR) and type B (ETR) receptors, angiotensin (AT) type 1 (ATR) and type 2 (ATR) receptors, are peptide-binding class A... (Review)
Review
In conjunction with the endothelin (ET) type A (ETR) and type B (ETR) receptors, angiotensin (AT) type 1 (ATR) and type 2 (ATR) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the ATR and ETR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the ATR, ATR, and ETR to provide an improved molecular understanding.
Topics: Angiotensins; Ligands; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; Signal Transduction
PubMed: 35518926
DOI: 10.3389/fendo.2022.880002 -
The FEBS Journal Mar 2020Obesity is often associated with high systemic and local renin-angiotensin system (RAS) activity in adipose tissue. Adipose-derived mesenchymal stem/stromal cells... (Review)
Review
Obesity is often associated with high systemic and local renin-angiotensin system (RAS) activity in adipose tissue. Adipose-derived mesenchymal stem/stromal cells (ADSCs), responsible for adipose tissue growth upon high-fat diet, express multiple angiotensin II receptor isoforms, including angiotensin II type 1 receptor (AT R), angiotensin II type 2 receptor (AT R), Mas and Mas-related G protein-coupled receptor D. Although AT R is expressed on most ADSCs, other angiotensin receptors are co-expressed on a small subpopulation of the cells, a phenomenon that results in a complex response pattern. Following AT R activation, the effects are transient due to rapid receptor internalisation. This short-lived effect can be prevented by heteromerisation with AT R, a particularly important strategy for the regulation of ADSC differentiation and secretory activity. Heteromeric AT R might be especially important for the generation of thermogenic beige adipocytes. This review summarises current data regarding the regulation of adipose tissue renewal and particularly ADSC adipogenic differentiation and secretory activity by RAS, with an emphasis on AT R and its effects. We reveal a new scheme that implicates AT R into the regulation of ADSC hormonal sensitivity.
Topics: Adipose Tissue; Animals; Cell Proliferation; Humans; Receptor, Angiotensin, Type 2
PubMed: 31899581
DOI: 10.1111/febs.15200 -
Clinical Science (London, England :... Feb 2015The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue... (Review)
Review
The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking similarities. Moreover, in some instances, antagonists for one receptor are able to inhibit the action of agonists for the respective other receptor. These observations suggest that there may be a functional or even physical interaction of both receptors. This article discusses potential mechanisms underlying the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1-7) metabolite alamandine and its receptor MrgD in the observed effects. We conclude that evidence for a functional interaction of both receptors is strong, but that such an interaction may be species- and/or tissue-specific and that elucidation of the precise nature of the interaction is only at the very beginning.
Topics: Animals; Humans; Ligands; Protein Binding; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled
PubMed: 25328009
DOI: 10.1042/CS20130515