Use of Sodium-Glucose Cotransporter-2 Inhibitors and Angiotensin Receptor-Neprilysin Inhibitors in Patients With Atrial Fibrillation and Heart Failure From 2021 to 2022: An Analysis of Real-World Data.

BACKGROUND: Contemporary use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF) has not been described. METHODS AND RESULTS: We analyzed the MarketScan databases for the period January 1, 2021 to July 30, 2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower use, including demographics and comorbidities. The study population included 60 927 patients (mean age, 75 years; 43% women) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), whereas the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (22%-29% in HFrEF, 6%-8% in HFpEF), and SGLT2i from 3% to 9% (6%-16% in HFrEF, 2%-7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower use of these 2 medication types overall and by HF type. CONCLUSIONS: Use of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among women and older individuals, though use is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence-based therapies among patients with comorbid AF and HF.

Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

PURPOSE: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. METHODS: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. RESULTS: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. CONCLUSION: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

Angiotensin Receptor-Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle-Aged Mice.

BACKGROUND: Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age-related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age-related arterial fibrotic remodeling and stiffening in 1-year-old mice. METHODS AND RESULTS: Treatment of in 1-year-old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse-wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. CONCLUSIONS: This study provides preclinical mechanistic evidence indicating that ARNI-based interventions may counteract age-related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly.

Angiotensin Receptor-Neprilysin Inhibition in Patients With STEMI vs NSTEMI.

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).

Effect of angiotensin receptor neprilysin inhibitor on physical activity in patients with heart failure with reduced ejection fraction, monitored by implantable electronic device home monitoring.

AIMS: Angiotensin receptor neprilysin inhibitor (ARNI) therapy is a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF), with significant improvement in mortality as well as morbidity and quality of life. However, maximal ARNI doses often result in hypotension. Recent studies with 'real world' experience suggest that lower doses of ARNI are as effective as higher doses.In order to evaluate the symptomatic effect of low-dose ARNI in HFrEF patients, we analyzed physical activity data obtained via home monitoring of patients with cardiac implantable electronic devices (CIEDs). METHODS: We retrospectively analyzed physical activity data obtained from HFrEF patients with CIED-active home monitoring during the years 2021-2022. Patients with ARNI therapy were further divided into subgroups according to the administered dose. Low-dose ARNI included doses of up to 24/26 mg sacubitril/valsartan daily. Intermediate dose and high dose included doses of 72/78-120/130 mg/day, and 144/156-194/206 mg/day, respectively. RESULTS: A total of 122 patients had home monitoring-compatible CIEDs and HFrEF during the study period. Sixty-four of these patients were treated with ARNI. Administration of low-dose ARNI resulted in a 20% increase in daily activity when compared with patients without ARNI treatment ( P  = 0.038). Change in physical activity of patients in the intermediate-dose and high-dose groups was not significant. Younger patients, patients with cardiac resynchronization therapy, and patients without diabetes mellitus were more physically active. CONCLUSION: Low-dose ARNI had a beneficial effect on physical activity in HFrEF patients. MH via CIED provided real-life objective data for patients' follow-up.

Estimating the clinical and budgetary impact of using angiotensin receptor neprilysin inhibitor as first line therapy in patients with HFrEF.

AIMS: Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first-line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom. METHODS AND RESULTS: A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10 years. The model included treatment specific all-cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000-12 300 life years gained and 2600-4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112-195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population. CONCLUSIONS: Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first-line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom.

The antihypertensive action of C-phycocyanin is related to the prevention of angiotensin II-caused vascular dysfunction in chronic kidney disease.

C-phycocyanin (CPC) is a photosynthetic protein found in Arthrospira maxima with a nephroprotective and antihypertensive activity that can prevent the development of hemodynamic alterations caused by chronic kidney disease (CKD). However, the complete nutraceutical activities are still unknown. This study aims to determine if the antihypertensive effect of CPC is associated with preventing the impairment of hemodynamic variables through delaying vascular dysfunction. Twenty-four normotensive male Wistar rats were divided into four groups: (1) sham + 4 mL/kg/d vehicle (100 mM of phosphate buffer, PBS) administered by oral gavage (og), (2) sham + 100 mg/kg/d og of CPC, (3) CKD induced by 5/6 nephrectomy (CKD) + vehicle, (4) CKD + CPC. One week after surgery, the CPC treatment began and was administrated daily for four weeks. At the end treatment, animals were euthanized, and their thoracic aorta was used to determine the vascular function and expression of AT1, AT2, and Mas receptors. CKD-induced systemic arterial hypertension (SAH) and vascular dysfunction by reducing the vasorelaxant response of angiotensin 1-7 and increasing the contractile response to angiotensin II. Also, CKD increased the expression of the AT1 and AT2 receptors and reduced the Mas receptor expression. Remarkably, the treatment with CPC prevented SAH, renal function impairment, and vascular dysfunction in the angiotensin system. In conclusion, the antihypertensive activity of CPC is associated with avoiding changes in the expression of AT1, AT2, and Mas receptors, preventing vascular dysfunction development and SAH in rats with CKD.

Pulmonary pressure-flow responses to exercise in heart failure treated with angiotensin receptor neprilysin inhibitor.

BACKGROUND: The role of the angiotensin receptor neprilysin inhibitor (ARNI) in cardiac function, particularly its impact on pulmonary circulation, remains underexplored. Recent studies have described abnormal mean pulmonary artery pressure (mPAP)-cardiac output (CO) responses as having the potential to assess the disease state. The aim of this study was to assess the effects of ARNI on pulmonary circulation in heart failure. We measured echocardiographic parameters post 6-min walk (6 MW) and compared the changes with baseline and follow-up. Our hypothesis was that pulmonary pressure-flow relationship of the pulmonary circulation obtained by 6 MW stress echocardiography would be improved with treatment. METHODS: We prospectively enrolled 39 heart failure patients and conducted the 6 MW test indoors. Post-6 MW echocardiography measured echocardiographic variables, and CO was derived from electric cardiometry. Individualized ARNI doses were optimized, with follow-up echocardiographic evaluations after 1 year. RESULTS: Left ventricular (LV) volume were significantly reduced (160.7 ± 49.6 mL vs 136.0 ± 54.3 mL, P < 0.001), and LV ejection fraction was significantly improved (37.6 ± 11.3% vs 44.9 ± 11.5%, P < 0.001). Among the 31 patients who underwent 6 MW stress echocardiographic study at baseline and 1 year later, 6 MW distance increased after treatment (380 m vs 430 m, P = 0.003). The ΔmPAP/ΔCO by 6 MW stress decreased with treatment (6.9 mmHg/L/min vs 2.8 mmHg/L/min, P = 0.002). The left atrial volume index was associated with the response group receiving ARNI treatment for pulmonary circulation. CONCLUSIONS: Initiation of ARNI was associated with improvement of left ventricular size and LVEF. Additionally, the 6 MW distance increased and the ΔmPAP/ΔCO was improved to within normal range with treatment.

Protective effect of novel angiotensin receptor neprilysin inhibitor S086 on target organ injury in spontaneously hypertensive rats.

BACKGROUND: Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure associated with injury to the heart, kidney, brain, and other organs. Angiotensin receptor neprilysin inhibitors (ARNi), including angiotensin receptor blockers (ARBs) and neprilysin inhibitors (NEPi), have been shown to be safe and effective at reducing blood pressure and alleviating development of target organ injury. This study was used to develop S086 as a novel ARNi and conducted preclinical studies in animal models to evaluate the protective effects of S086 on target organs. METHODS: This study used a 14-month-old spontaneously hypertensive rat (SHR) model to evaluate the protective effects of S086 on the cardiovascular system and organs such as heart and kidney by blood pressure monitoring, urine and blood examination, pathological examination, and immunological index detection. RESULTS: After administering S086 orally to the SHR, their blood pressure and levels of renal injury indicators such as serum creatinine and urinary microalbumin were reduced, and myocardial cell necrosis and cardiac fibrosis of the heart were significantly improved. In addition, there were also significantly improvements in the histological lesions of blood vessels and the kidneys. CONCLUSIONS: The findings showed that S086 effectively reduced the blood pressure of SHR and had effects on alleviating development of heart, blood vessels and kidney.

Patient-Centered Heart Failure Therapy.

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.

Catch your breath: The protective role of the angiotensin AT2 receptor for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease whereby excessive deposition of extracellular matrix proteins (ECM) ultimately leads to respiratory failure. While there have been advances in pharmacotherapies for pulmonary fibrosis, IPF remains an incurable and irreversible disease. There remains an unmet clinical need for treatments that reverse fibrosis, or at the very least have a more tolerable side effect profile than currently available treatments. Transforming growth factor ß1(TGFß1) is considered the main driver of fibrosis in IPF. However, as our understanding of the role of the pulmonary renin-angiotensin system (PRAS) in the pathogenesis of IPF increases, it is becoming clear that targeting angiotensin receptors represents a potential novel treatment strategy for IPF - in particular, via activation of the anti-fibrotic angiotensin type 2 receptor (AT2R). This review describes the current understanding of the pathophysiology of IPF and the mediators implicated in its pathogenesis; focusing on TGFß1, angiotensin II and related peptides in the PRAS and their contribution to fibrotic processes in the lung. Preclinical and clinical assessment of currently available AT2R agonists and the development of novel, highly selective ligands for this receptor will also be described, with a focus on compound 21, currently in clinical trials for IPF. Collectively, this review provides evidence of the potential of AT2R as a novel therapeutic target for IPF.

Geographic Variation in the Quality of Heart Failure Care Among U.S. Veterans.

BACKGROUND: The burden of heart failure is growing. Guideline-directed medical therapies (GDMT) reduce adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Whether there is geographic variation in HFrEF quality of care is not well described. OBJECTIVES: This study evaluated variation nationally for prescription of GDMT within the Veterans Health Administration. METHODS: A cohort of Veterans with HFrEF had their address linked to hospital referral regions (HRRs). GDMT prescription was defined using pharmacy data between July 1, 2020, and July 1, 2021. Within HRRs, we calculated the percentage of Veterans prescribed GDMT and a composite GDMT z-score. National choropleth maps were created to evaluate prescription variation. Associations between GDMT performance and demographic characteristics were evaluated using linear regression. RESULTS: Maps demonstrated significant variation in the HRR composite score and GDMT prescriptions. Within HRRs, the prescription of beta-blockers to Veterans was highest with a median of 80% (IQR: 77.3%-82.2%) followed by angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (69.3%; IQR: 66.4%-72.1%), sodium-glucose cotransporter-2 inhibitors (10.3%; IQR: 7.7%-12.8%), mineralocorticoid receptor antagonists (29.2%; IQR: 25.8%-33.9%), and angiotensin receptor-neprilysin inhibitors (12.2%; IQR: 8.6%-15.3%). HRR composite GDMT z-scores were inversely associated with the HRR median Gini coefficient (R = -0.13; P = 0.0218) and the percentage of low-income residents (R = -0.117; P = 0.0413). CONCLUSIONS: Wide geographic differences exist for HFrEF care. Targeted strategies may be required to increase GDMT prescription for Veterans in lower-performing regions, including those affected by income inequality and poverty.

Clinical Response and Safety of Angiotensin Receptor and Neprilysin Inhibitor Combination in Advanced Chronic Kidney Disease and Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Though the combination of an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (ARNi) has been shown to be useful in heart failure with reduced ejection fraction (HFrEF), its use has mostly been restricted to chronic kidney disease (CKD) patients with an estimated glomerular filtration rate (eGFR) >30 mL/minute/1.73 m2 . We studied the role of ARNi in advanced CKD. MATERIALS AND METHODS: Patients with HFrEF and advanced CKD with an eGFR of <30 mL/ minute/1.73 m2 were given ARNi (sacubitril with valsartan) and prospectively studied for changes in hospitalization rate for HF, clinical symptoms, levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), eGFR, and potassium. RESULTS: Of 34 patients who received ARNi, five were excluded due to hyperkalemia and three due to a decrease in eGFR >30% occurring within 1 month. The remaining 26 patients included 17 with diabetes mellitus (DM) and 23 with underlying coronary artery disease. A total of eight patients had stage 4 and 18 stage 5 CKDs, amongst which eight required hemodialysis. Following ARNi, there was a significant decrease in the need for hospitalization for breathlessness (2.04 ± 1.03-0.23 ± 0.51; p < 0,05), New York Heart Association (NYHA) and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores (3.77 ± 0.43-2.19 ± 0.56 and 28.58 ± 9.04-64.81 ± 14.3, respectively, p < 0.001) and NT-pro-BNP levels (24761 ± 12157.51-20149.92 ± 13555.269, p < 0.05) without significant change in eGFR after 6 months. There were no significant differences in the need for hospitalization, changes in NT proBNP levels and eGFR between stages 4 and 5. CONCLUSION: Neprilysin inhibitor (ARNi) is effective and can be used with care even in patients with CKD stages 4 and 5 having HFrEF with monitoring of eGFR and potassium.

Dual angiotensin receptor and neprilysin inhibitor reduced portal pressure through peripheral vasodilatation and decreasing systemic arterial pressure in cirrhotic rats.

BACKGROUND: Portal hypertension develops along with the progression of liver cirrhosis. Natriuretic peptides have been shown to reduce portal pressure but concomitantly activate the renin-angiotensin-aldosterone system (RAAS). Angiotensin receptor-neprilysin inhibitors (ARNIs) upregulate natriuretic peptides and avoid the adverse effects of RAAS activation. ARNIs have been shown to reduce portal pressure in rats with pre-hepatic portal hypertension, which involves relatively little liver injury. This study aimed to evaluate the relevant effects of an ARNI in rats with both liver cirrhosis and portal hypertension. METHODS: Male Sprague-Dawley rats received common bile duct ligation to induce liver cirrhosis and portal hypertension. Sham-operated rats served as surgical controls. All rats were randomly allocated into three groups to receive distilled water (vehicle), LCZ696 (an ARNI), or valsartan for 4 weeks. Portal hypertension and relevant derangements were assessed after treatment. RESULTS: Portal hypertension and hyperdynamic circulation developed in the cirrhotic rats. In the rats with cirrhosis and portal hypertension, both LCZ696 and valsartan reduced portal hypertension, mean arterial pressure, and systemic vascular resistance. The decrease in portal pressure was highly associated with the reduction in arterial pressure and systemic vascular resistance. Blood flow in hepatic, splanchnic, and portosystemic collateral systems was not altered. LCZ696 did not significantly influence liver injury or plasma cytokine levels. Liver fibrosis and splanchnic angiogenesis were not affected. CONCLUSION: ARNI treatment exerted portal pressure lowering effects via peripheral vasodilatation and decreasing systemic arterial pressure in the rats with liver cirrhosis and portal hypertension. Caution should be taken when using ARNIs in liver cirrhosis.

Interaction of Angiotensin II AT1 Receptors with Purinergic P2X Receptors in Regulating Renal Afferent Arterioles in Angiotensin II-Dependent Hypertension.

In angiotensin II (Ang II)-dependent hypertension, Ang II activates angiotensin II type 1 receptors (AT1R) on renal vascular smooth muscle cells, leading to renal vasoconstriction with eventual glomerular and tubular injury and interstitial inflammation. While afferent arteriolar vasoconstriction is initiated by the increased intrarenal levels of Ang II activating AT1R, the progressive increases in arterial pressure stimulate the paracrine secretion of adenosine triphosphate (ATP), leading to the purinergic P2X receptor (P2XR)-mediated constriction of afferent arterioles. Thus, the afferent arteriolar tone is maintained by two powerful systems eliciting the co-existing activation of P2XR and AT1R. This raises the conundrum of how the AT1R and P2XR can both be responsible for most of the increased renal afferent vascular resistance existing in angiotensin-dependent hypertension. Its resolution implies that AT1R and P2XR share common receptor or post receptor signaling mechanisms which converge to maintain renal vasoconstriction in Ang II-dependent hypertension. In this review, we briefly discuss (1) the regulation of renal afferent arterioles in Ang II-dependent hypertension, (2) the interaction of AT1R and P2XR activation in regulating renal afferent arterioles in a setting of hypertension, (3) mechanisms regulating ATP release and effect of angiotensin II on ATP release, and (4) the possible intracellular pathways involved in AT1R and P2XR interactions. Emerging evidence supports the hypothesis that P2X1R, P2X7R, and AT1R actions converge at receptor or post-receptor signaling pathways but that P2XR exerts a dominant influence abrogating the actions of AT1R on renal afferent arterioles in Ang II-dependent hypertension. This finding raises clinical implications for the design of therapeutic interventions that will prevent the impairment of kidney function and subsequent tissue injury.

Efficacy and safety analysis of angiotensin receptor neprilysin inhibition(ARNI)in patients with heart failure: a real-world retrospective study.

BACKGROUND: In a large randomized controlled trial (PARADIGM-HF), ARNI has been shown to significantly reduce cardiovascular mortality and hospitalization for patients with reduced ejection fraction in heart failure. This study analyzed the efficacy and safety of ARNI on the basis of various types of heart failure patients in southwestern Sichuan Province. METHODS: This study included patients with heart failure who were treated at the Affiliated Hospital of North Sichuan Medical College from July 2017 to June 2021. This study analyzed the efficacy and safety of ARNI in the treatment of heart failure, and analyzed the risk factors for readmission after ARNI treatment. RESULTS: After propensity score matching, a total of 778 patients were included in the study. The readmission rate for heart failure in patients treated with ARNI (8.7%) was significantly lower than that in the standard treatment group (14.5%) (P = 0.023). Both the proportion of patients with increased LVEF and with decreased LVEF were higher in the ARNI treatment group than in the conventional therapy group. Compared with receiving standard medical treatment, combined ARNI treatment resulted in a greater reduction in SBP (-10.00, 95%CI: -24.00-1.50 vs. -7.00, 95%CI: -20.00-4.14; P = 0.016) in HF patients. Combination ARNI therapy did not increase the risk of adverse events. The study found that age (> 65 vs. ≤65 years) (OR = 4.038, 95%CI: 1.360-13.641, P = 0.013) and HFrEF (OR = 3.162, 95%CI: 1.028-9.724, P = 0.045) were independent predictors of readmission in HF patients treated with ARNI. CONCLUSION: Patients with heart failure treated with ARNI can improve clinical symptoms and reduce the risk of readmitted hospital admission. Age > ~ 65 years and HFrEF were independent predictors of readmission in HF patients treated in ARNI group.