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Journal of the American College of... Mar 2024Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients.
OBJECTIVES
The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI.
METHODS
The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type.
RESULTS
Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53).
CONCLUSIONS
Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727).
Topics: Humans; Neprilysin; Ramipril; ST Elevation Myocardial Infarction; Non-ST Elevated Myocardial Infarction; Angiotensins; Receptors, Angiotensin; Prospective Studies; Tetrazoles; Treatment Outcome; Valsartan; Heart Failure; Aminobutyrates; Biphenyl Compounds; Angiotensin-Converting Enzyme Inhibitors; Myocardial Infarction; Ventricular Dysfunction, Left; Angiotensin Receptor Antagonists
PubMed: 38418004
DOI: 10.1016/j.jacc.2024.01.002 -
International Journal of Molecular... Oct 2023In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine... (Review)
Review
In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated.
Topics: Humans; Neprilysin; Tetrazoles; Angiotensin Receptor Antagonists; Heart Failure; Angiotensin-Converting Enzyme Inhibitors; Drug Combinations; Renin-Angiotensin System; Natriuretic Peptides; Aminobutyrates; Biphenyl Compounds
PubMed: 37895150
DOI: 10.3390/ijms242015472 -
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 -
International Journal of Molecular... Jul 2023Bradykinin (BK) metabolism and its receptors play a central role in drug-induced angioedema (AE) without urticaria through increased vascular permeability. Many... (Review)
Review
Bradykinin (BK) metabolism and its receptors play a central role in drug-induced angioedema (AE) without urticaria through increased vascular permeability. Many cardiovascular and diabetic drugs may cause BK-mediated AE. Angiotensin-converting enzyme inhibitors (ACEIs) and neprilysin inhibitors impair BK catabolism. Dipeptidyl peptidase-IV (DPP-IV) inhibitors reduce the breakdown of BK and substance P (SP). Moreover, angiotensin receptor blockers, thrombolytic agents, and statins may also induce BK-mediated AE. Understanding pathophysiological mechanisms is crucial for preventing and treating drug-induced AE.
Topics: Humans; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Dipeptidyl-Peptidase IV Inhibitors; Fibrinolytic Agents
PubMed: 37511409
DOI: 10.3390/ijms241411649 -
Frontiers in Bioscience (Landmark... Jul 2023Pharmacotherapy is the cornerstone treatment for patients with heart failure (HF) that uses drugs targeting the renin-angiotensin-aldosterone system (RAAS), including... (Review)
Review
Pharmacotherapy is the cornerstone treatment for patients with heart failure (HF) that uses drugs targeting the renin-angiotensin-aldosterone system (RAAS), including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan. This article reviews the pathophysiology of the RAAS and the neurohormonal changes seen in patients with HF as well as the targets and the mode of action of these drugs. We also assess the role of ACE in ventricular remodeling and summarize the main evidence for the use of ACE-related drugs in HF patients.
PubMed: 37525924
DOI: 10.31083/j.fbl2807150 -
BioRxiv : the Preprint Server For... Aug 2023G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While...
G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue, and cellular level. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays, and structural studies, we develop maternally selective heavy chain-only antibody ("nanobody") antagonists against the angiotensin II type I receptor (AT1R) and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to AT1R with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and pharmacology, attesting to their potential as next-generation GPCR modulators.
PubMed: 37662341
DOI: 10.1101/2023.08.23.554128 -
Current Opinion in Cell Biology Oct 2023As a universal mechanical cue, shear stress plays essential roles in many physiological processes, ranging from vascular morphogenesis and remodeling to renal transport... (Review)
Review
As a universal mechanical cue, shear stress plays essential roles in many physiological processes, ranging from vascular morphogenesis and remodeling to renal transport and airway barrier function. Disrupted shear stress is commonly regarded as a major contributor to various human diseases such as atherosclerosis, hypertension, and chronic kidney disease. Despite the importance of shear stress in physiology and pathophysiology, our current understanding of mechanosensors that sense shear stress is far from complete. An increasing number of candidate mechanosensors have been proposed to mediate shear stress sensing in distinct cell types, including G protein-coupled receptors (GPCRs), G proteins, receptor tyrosine kinases, ion channels, glycocalyx proteins, and junctional proteins. Although multiple types of mechanosensors might be able to convert shear stress into downstream biochemical signaling events, in this review, we will focus on discussing the mechanosensitive GPCRs (angiotensin II type 1 receptor, GPR68, histamine H1 receptor, adhesion GPCRs) and ion channels (Piezo, TRP) that have been reported to be directly activated by shear stress.
Topics: Humans; Signal Transduction; Receptor Protein-Tyrosine Kinases; Receptors, G-Protein-Coupled
PubMed: 37595342
DOI: 10.1016/j.ceb.2023.102216 -
Autoimmunity Reviews Sep 2023There are an increasing number of reports of autoantibodies (AAbs) against host proteins such as G-protein coupled receptors (GPCRs) and the renin-angiotensin system... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
There are an increasing number of reports of autoantibodies (AAbs) against host proteins such as G-protein coupled receptors (GPCRs) and the renin-angiotensin system (RAS) in COVID-19 disease. Here we have undertaken a systematic review and meta-analysis of all reports of AAbs against GPCRs and RAS in COVID-19 patients including those with long-COVID or post-COVID symptoms.
METHODS
PubMed, Embase, Web of Science, and Scopus databases were searched to find papers on the role of GPCR and RAS AAbs in the presence and severity of COVID-19 or post- COVID symptoms available through March 21, 2023. Data on the prevalence of AngII or ACE, comparing AngII or ACE between COVID-19 and non-COVID-19, or comparing AngII or ACE between COVID-19 patients with different disease stages were pooled and a meta-analysed using random- or fixed-effects models were undertaken.
RESULTS
The search yielded a total of 1042 articles, of which 68 studies were included in this systematic review and nine in the meta-analysis. Among 18 studies that investigated GPCRs and COVID-19 severity, 18 distinct AAbs were detected. In addition, nine AAbs were found in case reports that assessed post- COVID, and 19 AAbs were found in other studies that assessed post- COVID or long- COVID symptoms. Meta-analysis revealed a significantly higher number of seropositive ACE2 AAbs in COVID-19 patients (odds ratio = 7.766 [2.056, 29.208], p = 0.002) and particularly in severe disease (odds ratio = 11.49 [1.04, 126.86], p = 0.046), whereas AngII-AAbs seropositivity was no different between COVID-19 and control subjects (odds ratio = 2.890 [0.546-15.283], p = 0.21).
CONCLUSIONS
GPCR and RAS AAbs may play an important role in COVID-19 severity, the development of disease progression, long-term symptoms COVID and post- COVID symptoms.
Topics: Humans; Renin-Angiotensin System; Autoantibodies; COVID-19; Post-Acute COVID-19 Syndrome; Receptors, G-Protein-Coupled
PubMed: 37490975
DOI: 10.1016/j.autrev.2023.103402 -
Current Hypertension Reports Jan 2024To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes.
RECENT FINDINGS
ARBs have previously shown greater neuroprotection compared to other anti-hypertensive classes. The benefits are primarily attributed to the ARB's effect on modulating the renin-angiotensin system via inhibiting the Ang II/AT1R pathway and activating the Ang II/AT2R, Ang IV/AT4R, and Ang-(1-7)/MasR pathways. These interactions are associated with pleiotropic neurocognitive benefits, including reduced β-amyloid accumulation and abnormal hyperphosphorylation of tau, ameliorated brain hypo-fusion, reduced neuroinflammation and synaptic dysfunction, better neurotoxin clearing, and blood-brain barrier function restoration. While ACEis also inhibit AT1R, they simultaneously lower Ang II and block the Ang II/AT2R and Ang IV/AT4R pathways that counterbalance the potential benefits. ARBs may be considered an adjunctive approach for neuroprotection. This preliminary evidence, coupled with their underlying mechanistic pathways, emphasizes the need for future long-term randomized trials to yield more definitive results.
Topics: Humans; Angiotensin Receptor Antagonists; Hypertension; Angiotensin-Converting Enzyme Inhibitors; Renin-Angiotensin System; Cognition
PubMed: 37733162
DOI: 10.1007/s11906-023-01266-0 -
Frontiers in Immunology 2023Increased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated...
BACKGROUND
Increased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated with severe coronavirus disease 2019 (COVID-19) infection. The aim of this study was to determine whether 1) these antibodies are specifically related to COVID-19 disease pathogenesis or increased during any severe respiratory illness, 2) if they are formed during illness, and 3) if they correlate with inflammatory markers or long-term symptoms.
METHODS
Antibodies against AT1R, ETAR, and antinuclear antibodies (ANAs) were measured in n=40 prospectively enrolled COVID-19 patients and n=207 COVID-19 patients included in a biobank. Clinical and laboratory findings were prospectively and retrospectively assessed in both cohorts, and results were combined for analysis. The presence of auto-antibodies against AT1R or ETAR in peripheral blood was compared between hospitalized patients with COVID-19 and controls (n=39). Additionally, AT1R and ETAR titers were compared between patients with an unfavorable disease course, defined as intensive care admission and/or death during hospital admission (n=121), to those with a favorable disease course (n=126). A subset of intubated patients with severe COVID-19 were compared to intubated patients with acute respiratory distress syndrome (ARDS) due to any other cause.
RESULTS
Significantly increased AT1R and ETAR antibody titers were found in COVID-19 patients compared to controls, while titers were equal between favorable and unfavorable COVID-19 disease course groups. On ICU, intubated patients with COVID-19 had significantly increased AT1R and ETAR titers compared to patients with ARDS due to any other cause. The titers did not correlate with baseline inflammatory markers during admission or with diffusion capacity, cognitive impairment, or fatigue measured at 3 months follow-up.
CONCLUSIONS
In patients hospitalized for COVID-19, antibodies against AT1R and ETAR are increased compared to controls and patients with ARDS due to other causes than COVID-19. The baseline antibody titers do not correlate with inflammatory markers or long-term symptoms in this study.
Topics: Humans; Receptor, Endothelin A; Receptor, Angiotensin, Type 1; Retrospective Studies; COVID-19; Autoantibodies; Respiratory Distress Syndrome
PubMed: 37622126
DOI: 10.3389/fimmu.2023.1204433