Angiotensin Receptor Research Articles

Efficacy of Olmesartan/Amlodipine Single-Pill Combination on 24-h Mean Systolic Blood Pressure Measured by Ambulatory Monitoring in Non-Responders to Valsartan or Candesartan Monotherapy.

The aim of this study was to evaluate the efficacy of olmesartan/amlodipine (OLM/AML) single-pill combination (SPC) therapy using ambulatory blood pressure monitoring (ABPM) in non-responders to valsartan or candesartan monotherapy. Isolated systolic hypertension (ISH) is the most prevalent form of hypertension in middle-aged and elderly individuals. Patients aged over 55 years who did not achieve the target systolic blood pressure (SBP < 140mmHg) with valsartan 80mg or candesartan 8mg for at least 4 weeks were included. Doses were escalated from 20/5mg to 40/5mg and finally to 40/10mg of OLM/AML SPC until patients reached the target SBP. Efficacy was assessed via ABPM by comparing baseline values with those in the 12th week. Office blood pressure (OBP) and brachial-ankle pulse wave velocity (baPWV) were assessed at baseline, weeks 4, 8, and 12. Fifty-four patients (average age 64 ± 6 years; 33 males) participated. The 24-h mean BPs decreased significantly from an average of 146.2 ± 12.7/93.3 ± 9.2mmHg to 129.7 ± 14.3/83.4 ± 10.7mmHg (p < 0.001), and pulse pressures (PPs) from ABPM were reduced (p < 0.001). Additionally, significant reductions in night-time SBP standard deviations (SDs) (14.7 ± 4.7vs. 12.5 ± 3.9, p = 0.029) were observed at 12 weeks compared to baseline. OBPs significantly dropped from 151.1 ± 9.7/89.3 ± 8.3mmHg to 125.5 ± 13.8/77.8 ± 8.8mmHg after 12 weeks of SPC therapy (p < 0.001). Reductions in PPs of OBP and baPWVs were also observed. OLM/AML SPC therapy effectively reduced the 24-h mean BP, as measured by ABPM, in hypertensive patients over 55 years old who failed to achieve a target SBP (< 140mmHg) with angiotensin receptor blocker (ARB) monotherapy using valsartan 80mg or candesartan 8mg. Trial Registration: ClinicalTrials.gov identifier: NCT01713920.

Patterns and factors associated with electrolyte abnormalities among patients with heart failure in Uganda.

Electrolyte abnormalities (EAs) worsen the clinical course of patients with heart failure (HF). The patterns of EAs vary among patients with HF. This study investigated patterns and factors associated with EAs among patients with HF admitted to Hoima Regional Referral Hospital (HRRH) in western Uganda. This hospital-based cross-sectional study used quantitative data of 384 HF patients admitted at HRRH between 21st February and 15th May 2023. Data on sociodemographic, lifestyle, and medical characteristics were collected and presented as descriptive statistics. EAs were considered electrolyte values below or above the reference normal ranges. Bivariate and multiple logistic regression analyses were conducted to establish associations. An association with a p < 0.05 is considered statistically significant. Of 384 HF patients, 342 (89.1%) had EAs. Hypocalcemia was the most common EA, 165 (43.0%). Among the patients, 69 (18.0%) were on diuretics, 185 (48.2%) were on angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), and 105 (27.3%) were on calcium channel blockers (CCBs). Additionally, 264 (68.8%) had a history of hypertension, and 20 (5.2%) demonstrated good drug adherence. Patients with good drug adherence had lower odds of EAs (Adjusted Prevalence Odds Ratio [Adjusted POR] = 0.2, 95% CI: 0.1-0.7, p = 0.009). Those on diuretics had higher odds of EAs compared to those on ACEIs/ARBs and CCBs, with an Adjusted POR of 5.7 (95% CI: 1.3-15.0, p = 0.019). A history of hypertension also increased the odds of EAs (Adjusted POR = 4.0, 95% CI: 1.9-8.4, p < 0.001). The prevalence of EAs in patients with HF at HRRH was high, with hypocalcemia being the most common. Patients with good drug adherence had lower odds of EAs. On the other hand, diuretic use and a history of hypertension were associated with increased odds of EAs.

Bladder Symptoms Prvoked by Short, Rapid Acting Loop Diuretics: A Frequent But Often Overlooked Problem.

Bladder dysfunction entails overactive bladder (OAB) defined as symptoms of urinary urgency, frequency, and/or nocturia with or without incontinence if there is no obvious pathology or infection or lower urinary tract symptoms (LUTS) that includes recognized causes of bladder dysfunction. Literature search. Symptoms of OAB are reported in about 15% of the adult US population. This is increased 2- to 3- fold in patients with congestive heart failure (CHF), hypertension, cardiovascular disease (CVD), chronic kidney disease (CKD) or the elderly where it often accompanies prescription for short, rapid acting loop diuretics. However, less than 2% of patients seeking care for OAB receive treatment. The fear of urinary incontinence from short, rapid acting loop diuretics may contribute to medication nonadherence and less well controlled, apparently resistant hypertension. The bladder contracts to rapid stretch. Thus, less rapid acting diuretics such as thiazides or extended-release formulations of loop diuretics may be preferable for those with bladder dysfunction. Alternatively, the use of a mineralocorticosteroid receptor antagonist, angiotensin receptor antagonist/neprilysin inhibitor or sodium glucose linked transport type 2 inhibitor may allow a reduction in dose of a short, rapid acting loop diuretic for those with bladder dysfunction. A worsening of symptoms from bladder dysfunction by short, rapid acting loop diuretics occurs frequently in patients with CVD, CHF, hypertension and CKD where it can contribute to impaired quality of life and poor adherence and thereby to worsening outcomes.

Unveiling Wide Spectrum Therapeutic Implications and Signaling Mechanisms of Valsartan in Diverse Disorders: A Comprehensive Review.

Valsartan is an orally active non-peptide angiotensin receptor antagonist, an effective and well-tolerated anti-hypertensive drug. Besides its antihypertensive action, it has clinical implications in many other disorders, like heart failure (HF), arrhythmia, chronic kidney disease (CKD), diabetic complications (DM), atherosclerosis, etc. Besides angiotensin receptor blocking activity, valsartan reduces circulating levels of biochemical markers, such as hs-CRP, which is responsible for its anti-inflammatory and anti-oxidant activity. Moreover, valsartan also acts by inhibiting or inducing various signalling pathways, such as inducing autophagy via the AKT/mTOR/S6K pathway or inhibiting the TLR/NF-kB pathway. The current review exhaustively discusses the therapeutic implications of valsartan with specific emphasis on the mechanism of action in various disorders. The article provides a detailed spectrum of the therapeutic profile of valsartan and will likely be very useful to researchers working in the relevant research areas.

Finerenone: A Novel Drug Discovery for the Treatment of Chronic Kidney Disease.

The most common cause of chronic kidney disease (CKD) is diabetic nephropathy (DN). Primarilymineralocorticoid receptor antagonists (MRAs) (spironolactone and eplerenone), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for the treatment of CKD, but due to the high risk of hyperkalaemia, the combination was infrequently used. Currently after approval by FDA in 2021, finerenone was found to be effective in the treatment of CKD. Finerenone slowdowns the progression of diabetic nephropathy and lessens the cardiovascular morbidity in DN patients. The main objective of this review article is to provide a comprehensive and insightful overview of the role of finerenone by mainly focusing on its pharmacological properties, toxicity, uses, bioanalytical technique used for determination, and treatment options. Finerenone works by inhibiting the action of the mineralocorticoid receptor. Finerenone is quickly absorbed from the digestive tract after oral treatment and achieves peak plasma concentrations in 1-2 hours. Finerenone is actively metabolized through oxidation, epoxidation substitution, and direct hydroxylation. Elimination of finerenone is done through urine and feces. Determination of finerenone can be done through HPLC-MS and LSC. The present review covers the complete picture of ADME properties, bioanalytical techniques, clinical trials, toxicity, and possible avenues in this arena. Finerenone is effective compared to other mineralocorticoid receptor-like spironolactone and eplerenone, for the treatment of chronic kidney disease.

Mitochondrial Reactive Oxygen Species Dysregulation in Heart Failure with Preserved Ejection Fraction: A Fraction of the Whole

Heart failure with preserved ejection fraction (HFpEF) is a multifarious syndrome, accounting for over half of heart failure (HF) patients receiving clinical treatment. The prevalence of HFpEF is rapidly increasing in the coming decades as the global population ages. It is becoming clearer that HFpEF has a lot of different causes, which makes it challenging to find effective treatments. Currently, there are no proven treatments for people with deteriorating HF or HFpEF. Although the pathophysiologic foundations of HFpEF are complex, excessive reactive oxygen species (ROS) generation and increased oxidative stress caused by mitochondrial dysfunction seem to play a critical role in the pathogenesis of HFpEF. Emerging evidence from animal models and human myocardial tissues from failed hearts shows that mitochondrial aberrations cause a marked increase in mitochondrial ROS (mtROS) production and oxidative stress. Furthermore, studies have reported that common HF medications like beta blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists indirectly reduce the production of mtROS. Despite the harmful effects of ROS on cardiac remodeling, maintaining mitochondrial homeostasis and cardiac functions requires small amounts of ROS. In this review, we will provide an overview and discussion of the recent findings on mtROS production, its threshold for imbalance, and the subsequent dysfunction that leads to related cardiac and systemic phenotypes in the context of HFpEF. We will also focus on newly discovered cellular and molecular mechanisms underlying ROS dysregulation, current therapeutic options, and future perspectives for treating HFpEF by targeting mtROS and the associated signal molecules.

Telmisartan potentiates the ITE-induced aryl hydrocarbon receptor activity in human liver cell line.

Telmisartan is an angiotensin receptor blocker (ARB) approved by the Food and Drug Administration of the US for the treatment of hypertension. It possesses unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a 24-h sustained reduction of blood pressure. Besides well-known antihypertensive and cardioprotective effects, there is also strong clinical evidence that telmisartan confers renoprotection. Aryl hydrocarbon receptor (AhR) belongs to the steroid receptor family. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous ligand of AhR. Cytochrome P450 (CYP) 1A1 is an AhR-target gene. In this article, we demonstrated that telmisartan (2.5-60μM) enhanced CYP1A1 promoter activity and expressions of mRNA and protein. Telmisartan-induced CYP1A1 expression was blocked by the AhR antagonist CH-223191 in liver cell lines and was negligible in the AhR signaling-deficient mutant cells. In addition, telmisartan induced transcriptional activity mediated by aryl hydrocarbon response element in both human and mouse cells, and was able to induce AhR translocation into the nucleus. Accordingly, telmisartan is an AhR agonist. It also acted synergistically with ITE to further enhance the expression of CYP1A1 mRNA and protein. This synergistic effect was more pronounced in cells with AhR overexpression compared to those without. AhR activity has strong association with the progression of chronic renal disease. Our study demonstrated that telmisartan is an AhR agonist and has synergistic effect with ITE, an indole derivative, to potentiate the effect on AhR. This finding may provide additional clues about the mechanism of the protective effect of telmisartan on the kidney.

Facilitating and restraining virus infection using cell-attachable soluble viral receptors

SARS-CoV-2 uses the receptor binding domain (RBD) of its spike protein to recognize and infect host cells by binding to the cell surface receptor angiotensin converting enzyme 2 (ACE2). The ACE2 receptor is composed of peptidase domain (PD), collectrin-like domain, transmembrane domain, and short cytoplasmic domain, and may exist as a dimer on cell surface. The RBD binding site is located atop of the ACE2 PD, but the involvement of other domains in virus infection is uncertain. We found that the ACE2 PD alone, whether anchored to cell membrane via a glycosylphosphatidylinositol anchor or attached to another surface protein, is fully functional as a receptor for spike-mediated cell fusion and virus infection. However, for ACE2 to function as the viral receptor, the RBD binding site must be positioned in close proximity to the cell membrane. Elevating the surface height of ACE2 using long and rigid protein spacers reduces or eliminates cell fusion and virus infection. Moreover, we found that the RBD-targeting neutralizing antibodies, nanobodies, and de novo designed miniprotein binders, when present on cell surface, also act as viral receptors, facilitating cell fusion and virus infection. Our data demonstrate that RBD binding and close membrane proximity are essential properties for a receptor to effectively mediate SARS-CoV-2 infection. Importantly, we show that soluble RBD-binders can be engineered to make cells either susceptible or resistant to virus infection, which has significant implications for antiviral therapy and various virus-mediated applications.

Healthcare performance for patients with heart failure in Iran: addressing the tip of the iceberg.

Chronic diseases, such as heart failure with reduced ejection fraction (HFrEF), remain significant factors in the healthcare burden in Iran. Healthcare systems must have comprehensive data on the current usage, costs, and quality of care to tackle these challenges and formulate strategic plans effectively. The study included 209 patients with a mean age of 58 years (SD = 16.5) who met the inclusion criteria of having an ejection fraction of less than 40% and a confirmed diagnosis of HFrEF. This study used nationally representative data to assess the healthcare usage, costs, and quality of HFrEF management in Iran. The most used services were medication dispensing (76%) and outpatient visits (53%), while rehabilitation (3%) and homecare (2%) were used less frequently. The annual per-patient direct medical cost was $1,464, with $308 (21%) paid out-of-pocket (OOP). Hospitalization accounted for most of the total cost (68%), and pharmacy expenses comprised the largest portion of OOP payments (46%). Echocardiography was performed for 91.1% of patients upon admission. Only 71.6% of patients had arrangements for a cardiology visit within seven days following hospital discharge. Additionally, only 67.5% of patients received prescriptions for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and 85% were prescribed beta-blockers. Patients with heart failure in Iran face challenges in accessing adequate cardiac care, including a lack of care continuity and advanced cardiac services. The study provided an essential benchmark for future healthcare reform.

Clinicopathological Features of Membranous Nephropathy Complicated by IgA Nephropathy: A Retrospective Analysis of Seven Cases.

Aims/Background Both membranous nephropathy (MN) and immunoglobulin A nephropathy (IgAN) are immune complex-mediated glomerular diseases, but the concurrent occurrence of these two conditions in the same patient is not common, a phenomenon that is currently not supported by clinical data in terms of treatment and prognosis. This study explores the clinical and pathological characteristics, as well as the treatment outcomes, of patients affected by MN and IgAN simultaneously. Methods The clinical data, pathological features, and diagnostic and therapeutic information of seven cases of MN complicated by IgAN, treated between December 2015 and December 2022, were retrospectively analyzed. Results Among the seven cases, there were two male and five female patients, with an average age of 57.3 ± 9.2 years. All patients presented with clinical manifestations of proteinuria and edema upon admission, with an average 24-hour urine protein of 3716.6 ± 1519.4 mg/24 h. Phospholipase A2 receptor (PLA2R) expression was detected in all seven cases, and nephrotic syndrome was clinically diagnosed in five cases. Additionally, all seven cases showed microscopic hematuria, with intermittent gross hematuria in two cases. All seven patients included in this study underwent renal biopsy. After disease staging, the patients had MN stages I-III and IgAN stages II-III. Pathological findings revealed abnormal glomerular basement membrane (GBM) and diffuse immunoglobulin G (IgG) deposition in the subepithelial space, predominantly of the IgG4 subtype. Simultaneously, there was diffuse mesangial zone deposition of immunoglobulin A (IgA) to varying degrees, co-localization of complement component C3 and IgA, and mesangial cell proliferation. Treatment strategies included angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in combination with steroids or immunosuppressive therapies such as tacrolimus, cyclophosphamide, and rituximab. After 2-6 months of treatment, all patients achieved complete remission with a favourable prognosis. Conclusion MN accompanied by IgAN tends to occur more frequently in middle-aged and elderly individuals, with a relatively low incidence. The latent feature of the comorbidities manifests as a form of IgAN superimposed on the background of MN. Utilizing ACEI or ARB in combination with steroids or various immunosuppressive therapies represents a potentially effective treatment strategy.

Retrospective Analysis of Factors Influencing the Hemoglobin Level-increasing Effect of Sodium-glucose Co-transporter-2 Inhibitors.

In several studies, Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been reported to increase hemoglobin (Hb) levels. In a study in which Hb levels were compared between patients who received SGLT2i and dipeptidyl peptidase-4 inhibitors, some patients exhibited increased Hb levels (>1.0 g/dl), whereas some exhibited unchanged Hb levels. Notably, several factors may influence the Hb-increasing effect of SGLT2i. This study aimed to analyze the factors influencing the Hb-increasing effect of SGLT2i. Type 2 diabetes patients were divided into three groups: SGLT2i (SGLT2i only group, n=36), those receiving a combination of SGLT2i and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) (SGLT2i+ACEi/ARBs group, n=32), and those not receiving these drugs (control group, n=49). We retrospectively analyzed Hb changes in these groups. Kaplan-Meier curves compared Hb changes from SGLT2i initiation to day 63, with an Hb increase defined as ≥0.5 g/dl. In addition, sex, age, ACEi/ARBs, estimated glomerular filtration rate, and hematocrit levels were analyzed using Cox proportional hazards as factors influencing Hb-increasing events. Hb-increasing event rates were 61%, 41%, and 20% in the SGLT2i only, SGLT2i+ACEi/ARBs, and control groups, respectively. The Kaplan-Meier curves showed significantly higher Hb-increasing event rates in the SGLT2i only group than in the control and SGLT2i+ACEi/ARBs groups. In the Cox proportional hazards model, ACEi/ARBs use was associated with a 39% reduction in the incidence of Hb-increasing events. SGLT2i exhibit a Hb-increasing effect, which may be reduced by ACEi/ARBs.

The role of beta blockers in the treatment of cardiovascular diseases

Beta-blockers are used to treat various cardiovascular diseases, including hypertension and chronic heart failure. They act by suppressing the effects of catecholamines through various pathways and affect heart rate, strength, and renin release, providing antihypertensive and anti-ischemic effects. The individual effects of various drugs on clinical outcomes in this group were determined according to characteristics of the patient, underlying disease, and type of beta-blocker used. In recent years, beta-blockers have faced a serious obstacle when new guidelines on hypertension suggest their use as second-line therapy after angiotensin converting enzyme inhibitors, angiotensin receptor blockers and slow calcium channel blockers in the absence of clear indications. In fact, these recommendations were based on meta-analyses that showed that beta-blockers have fewer beneficial effects on overall mortality, cardiovascular events, and brain stroke. In addition, according to currently available data, the appointment of beta-blockers for diseases such as heart failure with preserved ejection fraction and stable coronary heart disease can cause more harm than good outcomes. Bisoprolol is a beta-blocker with the highest selectivity for beta1-adrenergic receptors, which determines the rare frequency of side effects that develop because of its use. This review presents current data on the use of beta-blockers for treating cardiovascular diseases, with an emphasis on the use of bisoprolol.

The influence of the daily salt-intake on the antihypertensive action and atrial natriuretic peptide level in patietns with angiotensin receptor neprilysin inhibition

Abstract Background The angiotensin receptor–neprilysin inhibitor (ARNI) is a drug which acts through angiotensin receptor blocking effect and the increase in atrail natriuretic peptide (ANP) through neprilysin inhibitor in hypertension (HT). These combined effects result in a reduced risk of hospitalization for heart failure or death from cardiovascular causes. ANP is also known for its various cardioprotective effects including vasodilator and natriuretic action. Acording to Guyton's pressure-natriuresis curve, the efficacy of angiotensin receptor blocker drugs is diminished in HT cases with high daily salt inatke. However, whether the effect of ARNI on HT is attenuated in patients with high daily salt intake remains unclear. Purpose The present study investigated the influence of a daily salt intake on the antihypertensive action and ANP level in patients with ARNI. Methods Fourty-four consecutive essential HT patients on ARNI were enrolled. Blood pressure and ANP level were measured at baseline (before taking ARNI) and 3 weeks later. ARNI (200mg) was prescribed and maintained during the study. In addtion, the daily salt intake was calculated using creatinine and natrium levels in urine, age, and body weight according to Japanese hypertensive guideline at baseline and 3 weeks later. Results The average age was 70±8 years old. About 50% (N=23) was male. The mean sytolic and diastolic blood pressure was 148±14mmHg and 89±10mmHg, respectively. The mean daily salt intake was 9.5±2.2 g/day at baseline. The mean ANP level was 529±300pg/ml. At follow up (3 weeks later), the mean systolic and diastolic blood pressure significanly went down to 132± 18 mmHg and 70± 9 mmHg, respectively (p=0.03). ANP level also increased from 529±300pg/ml to 793±580pg/ml. However, the mean daily salt intake was almost same as the baseline at 9.4±3.2 g/day. The patients were divided into 2 groups; high daily salt intake (N=20 with mean daily salt intake 10.5±1.7g/day)) and low daily salt intake (N=24 with 8.4±3.1g/day) groups compared to the baseline. The absolute and percentage changes in systolic blood pressure were almost same in the high and low daily salt intake groups (-12.7±15.8mmHg vs -13.7±14.2mmHg, p=0.75; -5.8±6.5% vs.-7.0±9.6%, p=0.58, respectively). However, the change rate in ANP level was significantly higer in the high daily salt intake group than in the low daily salt intake group (155±63 vs. 12±16%, p=0.01). Conclusion ARNI demonstrates effectiveness in lowering the blood pressure even in patients with higher salt intake, unlike angiotensin receptor blocker. In cases with high salt intake, the notable increase in ANP levels may contribute to decreasing blood pressure through vasodilator and natriuretic action.

Elegibility for Sacubitril/Valsartan in italian clinical practice: insights from the OPTIMA-HF registry

Abstract Background/Introduction Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. Among them, angiotensin receptor blocker/neprylisin inhibitor (ARNi) are the foundation of neuro-hormonal blockade in patients with HFrEF, however the degree to which gaps in this medication use and dosing persist in outpatient practice is unclear. Purpose To assess the proportion of patients with HFrEF who are eligible for ARNi based on the PARADIGM-HF trial criteria and the association between eligibility and baseline characteristics. Methods The OPTIMA-HF (Optimization of Therapy in the Italian Management of Heart Failure) registry included outpatients in Italy with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/ARNI, beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Outpatients with HFrEF from 29 ambulatory cardiology practices and university hospitals in the OPTIMA-HF registry recruited between January 2022 and September 2023 were included. Of 1291 patients, 1018 (79%) met the PARADIGM-HF criteria and 949 of them (93%) were on ARNi. Of the enrolled patients, 342 (27%) were not on ARNi, however only 129 (38%) did not met the PARADIGM-HF inclusion criteria for ARNi prescription. Reasons for not meeting PARADIGM-HF criteria were no beta-blocker background therapy (22%), hyperkalemia (4%), hypotension (15%), chronic kidney disease (65%) and hyperkalemia (79%). In a logistic regression model not being on ARNi was associated with older age, chronic kidney disease, not being on cardiac resynchronization therapy, lower systolic blood pressure, lower BMI, and higher PAPs (Figure), representing the picture of a more fragile patient net of compliance with the PARADIGM-HF criteria. Conclusions Among outpatients with HFrEF in the OPTIMA-HF Registry, 79% met the PARADIGM-HF criteria. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Angiotensin-II receptor type 1 and endothelin-1 receptor type A agonistic autoantibodies in patients with STEMI: new kids on the block

Abstract Background The Prognosis after ST-elevation myocardial infarction (STEMI) remains poor. Angiotensin-II and endothelin-1 contribute to adverse prognosis after STEMI through molecular mechanisms that lead to myocardial inflammation, fibrosis and, ultimately, adverse myocardial remodeling. Functional autoantibodies against angiotensin II type 1 (AT1R-AAs) and endothelin-1 type A (ETAR-AAs) receptors bind to the same receptors as natural ligands, eliciting similar (and amplified) responses. In patients with STEMI, AT1R-AAs and ETAR-AAs have been associated with a higher risk of developing microvascular obstruction and left ventricular remodeling. Both microvascular obstruction and left ventricular remodeling are associated with a poor prognosis. Purpose To assess the prognostic role of AT1R-AAs and ETAR-AAs after STEMI. Methods Consecutive STEMI patients who underwent primary percutaneous coronary intervention within 12 h after pain onset were enrolled in this prospective study. The levels of AT1R-AAs and ETAR ETAR-AAs at the time of hospital admission were measured using an enzyme-linked immunosorbent assay (ELISA) in all patients. The incidence of major adverse cardiovascular events (MACE, defined as a composite of cardiovascular mortality, myocardial re-infarction, and hospitalizations for heart failure) during follow-up was the primary outcome. Autoantibody seropositivity was defined according to ELISA’s kit manufacturer’s instructions (levels &amp;gt; 10 U/mL). Results Two hundred patients with STEMI were enrolled. The baseline characteristics of the patients are shown in Table 1. Of these, 110 (55%) were seronegative for both autoantibodies, 44 (22%) were seropositive for one autoantibody (but not both), and 46 (23%) were seropositive for both autoantibodies. The incidence of MACE over a 14-month median follow-up was higher in patients with double (31%) and single (25%) seropositivity than in seronegative patients (13%, p=0.009 and p=0.06, respectively). Survival free from MACE was significantly different across the different degrees of autoantibody seropositivity (Figure 1). In the multivariable Cox regression analysis, adjusted for the variables that were significant in the univariate analysis (highlighted in bold in Table 1), double seropositivity was independently associated with an increased risk of MACE (hazard ratio 2.386, 95 % CI 1.471-3.864, p&amp;lt;0.001). Conclusions The degree of seropositivity for AT1R-AAs and ETAR-AAs is associated with an increased risk of MACE after STEMI. Our findings provide valuable mechanistic insights into the pathophysiology of STEMI and pave the way for future therapies focused on the improvement of long-term prognosis after acute coronary syndromes.

Prognostic determinants in patients with heart failure with reduced ejection fraction after a first hospitalisation for acute heart failure. COMFE registry

Abstract Introduction The clinical characteristics and determinants for prognosis of patients with a first hospitalisation for heart failure (HF) with reduced left ventricular ejection fraction (LVEF &amp;lt;40%) are poor described and show heterogeneous results that need major investigation. Purpose The aim of our study was to identify the clinical characteristics, prognosis and their main determinants in a prospective registry of patients with HF and reduced LVEF with a first hospital admission for acute heart failure, prognosis and their main determinants in a prospective registry in these patients. Methods We carried out a prospective registry in 2 University Hospitals of patients admitted to cardiology department due to first-time HF hospitalisation with reduced LVEF. 231 admitted consecutively between March 2021 and September 2022 were included, with a mean follow-up of 381 days. Continuous variables were represented as median (interquartile range) and categorical variables as percentage %. A multivariate logistic regression was performed in which age, sex, comorbidities, treatment, rhythm at discharge and improvement in LVEF were included; and using the Wald method, the predictors of rehospitalization and/or death were identified. Data were analysed using SPSS v. 25.0. Results The main baseline characteristics are shown in Table 1. The population had a median age of 71 years, 75% were men, with a high prevalence of arterial hypertension (HBP) (69%) and hyperlipidemia (57%). Quadruple therapy (Na-Glucose cotransporter 2 inhibitor [SGLT2i], Beta-Blocker, mineralocorticoid receptor antagonist [MRA] and angiotensin receptor-neprilysin inhibitor [ARNI], angiotensin converting enzyme inhibitor [ACEi] or Angiotensin-II receptor blocker [ARB]) was achieved in 57% at discharge. The dynamics of NTproBNP was studied from admission to completed up-titration, observing an average reduction of 37% and 32% met the criteria for improved LVEF after. The etiology is described in Figure 1a, with ischemic heart disease being the most represented (31%). Multivariate Cox regression for the combined event of readmission/death from any cause showed that treatment with SGLT2i (OR 0,48 [CI 95%: 0,23-0,98 p:0,04]) and Beta-Blocker (OR 0,35 [CI 95%: 0,14-0,87 p:0,02]) at discharge and improved LVEF (OR 0,33 [CI 95%: 0,15-0,72 p:0,006]) were protective predictors against the event; but diabetes mellitus (DM) was a predictor of a worse prognosis (OR 2,9 [CI 95%: 1,52-5,5 p:0,001]) Fig. 1b. Conclusions Patients with a first admission for HF with reduced LVEF constitute a heterogeneous clinical group. Improvement in LVEF after drug up-titration and treatment with SGLT2i and Beta-blocker are independently associated with a better prognosis. Our findings may have implications for their clinical management.Table 1Figure 1

5-year valve academic research consortium-3 outcomes and predictors of mortality in a 10-year Asian transcatheter aortic valve implantation registry

Abstract Background Transaortic valvular implantation (TAVI) has revolutionised the management of aortic stenosis (AS). Uptake in Asia has caught up in recent years, after an initial lag due to expensive cost, limited subsidies, and scarce accessibility. Hence, longitudinal outcomes of TAVI remain largely unknown in Asian patients. Purpose This study aims to present the 5-year mortality endpoints in an Asian cohort followed up over a decade. Methods 253 patients with symptomatic severe aortic stenosis status post TAVI were retrospectively enrolled at a tertiary academic hospital from 2010-2021. The main outcomes were defined as short-term (30-day), mid-term (1-year) and long-term (5-year) all-cause mortality. Baseline demographics, procedural findings and clinical outcomes were analysed. Kaplan-Meier curves and multiple Cox regression analyses were constructed. Results The mean age was 75.2 + 10.2 years. 120 (47.4%) patients were female and 167 (66%) were Chinese. 168 patients (66.7%) received balloon-expandable valves, 80 patients (31.7%) underwent self-expandable valves, and 4 patients (1.6%) had mechanical-expandable valves. Malignancy was associated with worse short-term mortality at 30-days (HR 3.65, p = 0.054), while pulmonary disease and previous stroke were associated with worse long-term mortality at 5-years (HR 2.27, p = 0.012 and HR 2.02, p = 0.064). Worse all-cause mortality at 30-days, 1-year and 5-years were associated with high NT-Pro BNP levels (HR 1.04, p = 0.046; HR 1.05, p = 0.002 and HR 1.04, p &amp;lt; 0.001), the presence of peripheral arterial disease (PAD) (HR 4.32, p = 0.056; HR 4.48, p = 0.006 and HR 2.43, p = 0.023) and chronic kidney disease (CKD) (HR 6.19, p = 0.006; HR 6.77, p &amp;lt; 0.001 and HR 2.09, p = 0.008). Society of Thoracic Surgery (STS) score (HR 1.11, p = 0.001; HR 1.13, p &amp;lt; 0.001 and HR 1.12, p &amp;lt; 0.001) and Valve Academic Research Consortium (VARC) III endpoints of acute kidney injury (AKI) (HR 6.68, p = 0.047, HR 10.8, p &amp;lt; 0.001 and HR 6.99, p &amp;lt; 0.001), cardiogenic shock (HR 26.3, p &amp;lt; 0.001, HR 12.0, p &amp;lt; 0.001 and HR 4.29, p = 0.011) and structural complications (HR 40.3, p &amp;lt; 0.001, HR 18.1, p &amp;lt; 0.001 and HR 5.18, p = 0.008) were associated with worse all –cause mortality at time-points of 30-days, 1-year and 5-years respectively. On multivariate analyses adjusted for comorbidities and outcomes, STS score and structural complications were independent predictors of 30-day, 1-year, and 5-year all-cause mortality (HR 1.16; p = 0.003, HR 1.09, p = 0.003 and HR 1.10, p &amp;lt; 0.001) and (HR 62.7, p &amp;lt; 0.007; HR 18.9, p &amp;lt; 0.001 and HR 10.6, p = 0.001) respectively. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use was protective of survival within 1-year (HR 0.37, p = 0.022). Conclusions STS score and VARC III endpoints of structural complications were reliable predictors of all-cause mortality in Asian patients with TAVI. ACE inhibitor and ARB use was protective against mortality at 1-year.Cox regression analysesKaplan-Meier curves

Long-term continuation to pharmacological treatment for secondary prevention after a myocardial infarction: a register study

Abstract Background Pharmacological treatment for secondary prevention after acute myocardial infarction (MI) is crucial to prevent new events. Several studies report inconsistence and need for improvement of pharmacological treatment. Study follow-up is often less than 10 years and showing that continuation to drug treatment decreases with time. Objective To study long-term follow-up of nationally guideline recommended medical therapy (GDMT) for secondary prevention after a myocardial infarction. Method The study population consisted of individuals aged 18-84 years, who were hospitalized for a MI between January 2006 and December 2022 and were followed up to 16 years. The study subjects were identified through the National Inpatient Register and linked to the Prescribed Drug Register. Four classes of drugs were analyzed: antiplatelet/anticoagulant therapy, lowering therapy, betablockers and angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB). Time-updated survival analyses were used to investigate the relationship between continuation of preventive pharmacological treatment and mortality and recurrent MI after an acute MI. Results A total number of 139 413 individuals (mean age 69.1±10.6) were included and 33.3% were female. At baseline 51.2% had hypertension, 21.5% diabetes mellitus and 15.2% heart failure. All prescriptions of GDMT were decreased significantly after hospitalization after MI and during first years and remained plateau (figure 1). During follow-up 55487 persons died (39.8%, event rate 5.81 per 100 person years [95% CI 5.76-5.86]). Medication with antiplatelets/anticoagulantia, ACEi/ARB and statins decreased risk of all cause-mortality and myocardial infarction [HR 0.83 [95% CI 0.79-0.86], p-value &amp;lt;0.001, HR 0,79 [95% CI 0.77-0.83], p-value &amp;lt;0.001, HR 0.70 [95% CI 0.67-0.73], p-value &amp;lt;0.001) respectively. Conclusion Pharmacological treatment as a part of secondary prevention remained greatly underutilized both shortly and during long-term after MI. Usage of antiplatelets or antigulantia, ACEi or ARB and statins decreased the risk of all-cause mortality and recurrent myocardial infarction.

Cardiovascular mortality with oral potassium-binders in patients with CKD and heart failure

Abstract Introduction Hyperkalemia is an inherent consequence of advancing chronic kidney disease (CKD) as a result of the kidney’s decreased ability to excrete potassium. Heart failure patients with concomitant CKD may not tolerate maximum doses of guideline-directed medical therapies (GDMT) like ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), angiotensin receptor/neprilysin inhibitors (ARNI) and mineralocorticoid receptor antagonists (MRA) due to dose-limiting hyperkalemia. Many randomized controlled trials in heart failure exclude patients with advanced CKD. Two oral therapies exist to manage hyperkalemia - patiromer sorbitex calcium and sodium zirconium cyclosilicate. This study aims to identify the potassium-binder with better outcomes as defined by less readmissions, hyperkalemia episodes, and death. Purpose This project was undertaken to better understand the impact of using potassium-binders in CKD patients with heart failure. Improved management of hyperkalemia will be an avenue for optimization of GDMT in this population. Methods and materials The TriNetX research network was used for this study. Two cohorts of patients were created by using International Classification of Disease 10 (ICD-10) codes and CPT codes. Both cohorts consisted of patients with no prior history of hyperkalemia within 30 days of hospital discharge at which time one cohort was prescribed patiromer and the other received sodium zirconium cyclosilicate. Each cohort was prohibited from exposure to the other medication. The cohorts were balanced by propensity score matching and the greedy nearest neighbor algorithm for age, race, gender, ethnicity. They were also balanced for systolic and diastolic heart failure diagnoses, and for each individual stage of CKD (1 through 5 and end stage). They were also balanced for use of ACEi, ARBs, and MRAs. This resulted in 8,921 patients in each arm. They were then evaluated for the outcomes of hospital readmission, hyperkalemia episodes (&amp;gt;6.1 mmol/L), and death within 12 months. Results Patients treated with patiromer were more likely to be hospitalized over the following twelve months (44% vs 40%, RR 1.11, 95% CI (1.07,1.15), p value &amp;lt;0.0001). They were also more likely to experience hyperkalemia (11.7% vs 9.2%, RR 1.27, 95% CI (1.16,1.38), p value &amp;lt;0.0001). Patiromer was also associated with slightly greater all cause mortality (27% vs 25%, RR 1.08, 95% CI (1.03,1.13), p value 0.0021). Discussion This study demonstrates patiromer has more readmissions and hyperkalemia episodes along with greater mortality. In conclusion, sodium zirconium cyclosilicate was found to have better outcomes compared to that of patiromer. Further studies are necessary to better understand the utility of using sodium zirconium cyclosilicate as maintenance therapy for hyperkalemia in order to maximize GDMT in CKD patients with heart failure.

Risk stratification for a primary prevention ICD: Performance of the MADIT-ICD Benefit Score in contemporary real world patients

Abstract Background We have recently developed the MADIT-ICD Benefit Score to improve risk stratification for primary implantable cardioverter defibrillator (ICD) implantation by assessing the competing risk of life-threatening ventricular tachyarrhythmia (VTA) vs. non-arrhythmic mortality based using simple clinical variables. Patients with a MADIT-ICD Benefit Score of &amp;lt; 50 are more likely to experience non-arrhythmic mortality than life-threatening VTA, and therefore derive limited benefit from a prophylactic ICD. Purpose We aimed to provide data on the performance of the MADIT-ICD Benefit Score in a real world population, comprising patients with HFrEF and either ischemic or nonischemic cardiomyopathy (ICM/NICM) who are treated with contemporary guideline-directed medical therapy (GDMT). Methods The study population comprised 2875 patients who were implanted with a primary prevention ICD and prospectively followed in a large tertiary healthcare system (the University of Rochester Medical Center, including 3 affiliated hospitals in Upstate New York) between 2017 through 2023. Arrhythmic events were captured from device interrogation data, which were blindly adjudicated by 2 electrophysiologists. Results Among the 2875 study patients, mean age was 62 ± 15 years, 1265 (44%) were women, and 1667 (58%) had ICM. Guideline-directed medical therapies, including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, angiotensin receptor/neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose transport protein 2 (SGLT2) inhibitors, were prescribed to 43%, 36%, 96%, 67% and 32% of study patients, respectively. The 2-year cumulative incidence of VTA, after accounting for the competing risk of death, was 19% vs. 11% in patients with a Score of ≥50 vs. &amp;lt;50, respectively (p&amp;lt;0.001; Figure 1A). Findings regarding ICD shocks were consistent (8% vs. 4%, respectively, p&amp;lt;0.001; Figure 1B) The rate of VTA events at 4 years was directly correlated with increasing quartiles of the MADIT-ICD Benefit Score, while the corresponding rates of non-arrhythmic mortality were inversely correlated with score quartiles (Figure 1C). A similar direct correlation with increasing Benefit Score quartiles was observed when the endpoint of ICD shocks was assessed (Figure 1D). Accordingly, the benefit of the ICD (calculated as the difference between predicted rates of VTA/shock events and corresponding rates of non-arrhythmic mortality) was attenuated with decreasing quartiles of the MADIT-ICD Benefit Score (Figures 1C and 1D; right column). Conclusions We show good performance of the MADIT-ICD Benefit Score in a large cohort of real world ICD recipients who are treated with contemporary GDMT. These data support the use of the MADIT-ICD Benefit Score for improved risk stratification and for shared decision-making in contemporary candidates for a primary prevention ICD.