Renin-angiotensin Research Articles

(Pro)renin receptor aggravates myocardial pyroptosis in diabetic cardiomyopathy through AMPK-NLRP3 pathway

IntroductionAs one of the most common complications of diabetes, diabetic cardiomyopathy (DCM) is the main cause of heart failure in patients with diabetes. However, the lack of effective treatments for DCM remains a clinical challenge. (Pro) renin receptor (PRR) is a member of renin angiotensin aldosterone system (RAAS). Here, we aim to determine whether PRR is involved in myocardial pyroptosis in diabetic cardiomyopathy.MethodsWe established diabetic rats model by intraperitoneal injection of streptozotocin (STZ). PRR overexpression adenovirus or PRR knockdown adenovirus was injected into the tail vein. Western blot, histopathology and immunohistochemistry staining, ELISA and Echocardiography were used to detect cardiac function changes and myocardial injury levels of DCM rats. Primary cardiomyocytes were stimulated with high glucose and PRR overexpression or PRR knockdown was achieved by adenovirus transfection, we also used the inhibitor of AMPK to decrease the activity of AMPK. Western blot, Real-time PCR, Immunofluorescence and ELISA were used to detect the level of PRR and pyroptosis in cardiomyocyte.ResultsWe found that high glucose increased the expression of PRR in heart. After overexpression of PRR, the expression of the pyroptosis related proteins such as Caspase-1, IL-1β, IL-18, and NLRP3 was significantly increased, the phosphorylation level of AMPK was significantly decreased, and the fibrosis level was significantly increased, thus aggravating the cardiac function injury of DCM. On the contrary, PRR knockdown can alleviate the level of myocardial pyroptosis in DCM and improve cardiac function. The related mechanism was that PRR could inhibit AMPK phosphorylation and promote the activation of NLRP3 inflammasome.DiscussionPRR aggravated pyroptosis of cardiomyocyte, increased the dysfunction of cardiomyocyte, and may be related to the decrease of AMPK phosphorylation and the overactivation of NLRP3. This may provide new ideas and targets for the treatment of DCM.

LNX1-AS2 as a Key Prognostic and Immunotherapy Response Biomarker for Lung Adenocarcinoma.

The role of LNX1 antisense RNA 2 (LNX1-AS2) in lung adenocarcinoma (LUAD) remains unclear. This study aimed to investigate the association between LNX1-AS2 and LUAD by employing bioinformatics analysis and experimental validation. Statistical analysis and database interrogation were utilized to assess correlations among LNX1-AS2 expression, clinical characteristics of LUAD patients, prognostic factors, regulatory networks, and immune infiltration. LNX1-AS2 expression in LUAD cell lines was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). The study found significantly elevated levels of LNX1-AS2 expression in patients with LUAD. Furthermore, elevated LNX1-AS2 expression in LUAD patients did not significantly correlate with gender (p = 0.041) or race (p = 0.049). Importantly, high LNX1-AS2 expression levels were associated with poorer overall survival (OS, p = 0.042) and disease-specific survival (DSS, p = 0.040) in LUAD patients. Additionally, high LNX1-AS2 expression (p = 0.015) was independently correlated with OS in LUAD patients. The phenotype characterized by high LNX1-AS2 expression was also found to be enriched for asthma, allograft rejection, drug metabolism cytochrome P450, metabolism of xenobiotics by cytochrome P450, olfactory transduction, renin-angiotensin system, retinol metabolism, pentose and glucuronate interconversions, and porphyrin and chlorophyll metabolism. A significant correlation was identified between the expression levels of LNX1-AS2 and immune infiltration in the context of LUAD. Elevated expression of LNX1-AS2 was notably detected in LUAD cell lines as opposed to Beas-2B. A noteworthy relationship was established among increased LNX1-AS2 expression in LUAD patients, unfavorable prognosis, and heightened immune infiltration. These findings suggest that the LNX1-AS2 gene could serve as a valuable prognostic indicator for LUAD and a potential predictor of response to immunotherapy.

Risk of developing hyperkalemia in patients with hypertension treated with combination antihypertensive therapy - a retrospective register-based study.

The risk of hyperkalemia in relation to different combinations of antihypertensive therapy remains to be elucidated. In this Danish register-based study, we aimed to investigate the risk of developing hyperkalemia in relation to different combinations of antihypertensive therapy. Using incidence density matching, we matched a hyperkalemic patient to five normokalemic patients on eGFR groups, age, sex, and time between study entry and date of potassium measurement. Combination therapies were subdivided into eight groups: beta blockers (BB) + calcium channel blockers (CCB), BB + renin angiotensin system inhibitors (RASi), BB + RASi + mineralocorticoid receptor antagonists (MRA), CCB + RASi, CCB + RASi + thiazides, CCB + thiazides, RASi + thiazides, and other combinations. Multivariable conditional logistic regression was used to estimate the odds of hyperkalemia within 90 days for each of the eight antihypertensive combination therapies. A total of 793 patients with hyperkalemia were matched to 3598 normokalemic patients. In multivariable analysis, odds of developing hyperkalemia when being treated with BB + RASi + MRA was 1.95 (95% CI, 1.39-2.72) compared to RASi + thiazides (reference). CCB + thiazides (OR, 0.76 [95% CI, 0.45-1.28]) and CCB + RASi + Thiazid (OR 0.81 [95% CI, 0.51-1.28]) were among the others not significantly associated with hyperkalemia. Combinations of BB + RASi + MRA were significantly associated with an increased risk of developing hyperkalemia within 90 days of initiating treatment. Patients treated with BB + RASi + MRA within 90 days of treatment initiation, were associated with an increased hyperkalemia risk. When treating hypertensive patients with combination antihypertensive therapy, identifying and monitoring patients with a high risk of dyskalemias is a crucial goal to avoid serious adverse effects and detrimental outcomes related to dyskalemia.

Association of ACE2 Gene Variants with Adverse Perinatal Outcomes in COVID-19 Infected Pregnant Women in Kazakhstan

SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors located on membranes to enter host cells. Nevertheless, the ACE2 gene primarily encodes for a zinc metalloproteinase, which is a part of the renin–angiotensin system (RAS). ACE2 downregulation results in the deregulation of RAS in favor of pro-fibrosis, pro-apoptosis, oxidative stress, pro-inflammation, aldosterone production and release, and blood vessel contraction axis. ACE2 is highly expressed in the placenta. There are both axes of the RAS system in the placenta. This study aims to assess the perinatal outcomes with ACE2 receptor polymorphisms in pregnant women infected with SARS-CoV-2 during pregnancy. The case-control study was conducted to determine the association of ACE2 single-nucleotide polymorphisms in 171 COVID-19-positive pregnant subjects and 112 control subjects. The recessive mutations of rs2158082 and rs4830974 were associated with an increased risk of low birthweight and preterm birth, whereas the dominant mutation of rs2285666 (CT + TT) was associated with decreased odds of low birthweight. COVID-19 was not a significant factor contributing to the adverse perinatal outcomes in our sampling. These findings may help to clarify the controversy regarding the increased risk of adverse perinatal outcomes observed during COVID-19 as well as provide new perspectives for research on the genetic factors associated with a higher risk of adverse perinatal outcomes.

Clash of the Titans: the first multi-center retrospective comparative study between da Vinci and Hugo™ RAS surgical systems for the treatment of deep endometriosis

Background The proliferation of several robotic platforms presents an opportunity to pinpoint the most suitable system for specific procedures and patient profiles. This study aims to explore differences in complications and functional outcomes among patients undergoing deep endometriosis excision with the da Vinci surgical system compared to the Hugo™ RAS system. Method This is a retrospective, multicenter cohort study. Patients were categorized based on the surgical system used: the Da Vinci system and the Hugo™ RAS system. Perioperative complications, functional outcomes (via validated questionnaire: BFLUTS, KESS, GIQLI), and pain symptoms both before and after surgery were compared between the two groups. Results A total of six postoperative complications were reported: four in the Da Vinci system group (20%) and two in the Hugo™ RAS system group (12.5%). No difference in the mean operative time (p = 0.647), median estimated blood loss (p = 0.179), and hospital stay (p < 0.0001) was found between the two groups. A significant difference was reported in questionnaire score changes and dyspareunia severity in the da Vinci system arm. Conclusions Both robotic systems offer comparable performances in terms of intraoperative complications, although there was a higher incidence of postoperative complications in patients who underwent surgery with the Da Vinci system. Moreover, there was an improvement in dyspareunia, urinary, and gastrointestinal function in the same group.

Relationship between clinical congestion and worsening renal function after intravenous initiation of furosemide in patients with acute heart failure.

To investigate if worsening renal function (WRF) appearing in some patients with acute heart failure (AHF) after intravenous furosemide initiation is influenced by severity of congestion. We conducted a retrospective secondary analysis of consecutive patients diagnosed with AHF and prospectively included in 10 Spanish emergency departments (EDs) for whom serum creatinine at ED arrival and after 2-7days of intravenous furosemide initiation were available. Congestion was clinically evaluated by identification of 7 signs/symptoms and by chest X-ray. The outcome was WRF, defined as a delta-creatinine ≥ 0.3mg/dL. Risk of WRF according to congestion was estimated in models adjusted by patient baseline characteristics and vitals at ED arrival, and interaction was also investigated. We included 3027 patients (median age 82years, 56% women), and 657 (21.7%) presented WRF after intravenous furosemide initiation. When signs/symptoms were individually considered, only lower limbs edema was associated with decreased risk of WRF (20.1% vs. 24.8%; OR = 0.76, 95%CI = 0.64-0.91). After adjustment, lower limbs edema persisted inversely associated with WRF (aOR = 0.78, 95%CI = 0.65-0.94), with significant lower risk for patients ≤ 80years and without chronic kidney disease, functional limitation, and hypoxemia (p for interaction 0.01, 0.04, 0.02 and 0.03, respectively). Neither degree of clinical congestion (number of signs/symptoms of congestion) nor radiological congestion in chest X-ray were related to WRF. Worsening renal function was associated with a higher 1-year all-cause mortality (40.1% vs 34.6%; HR = 1.27, 1.10-1.46; aHR = 1.331, 1.151-1.540). In patients with WRF, liver cirrhosis, chronic treatment with loop diuretics and renin-angiotensin system inhibitors, age (> 80years), dementia, heart valve disease and NYHA class III-IV were associated with higher mortality. Intravenous furosemide initiation in patients with AHF without lower limbs edema must be cautious, as they are at increasing risk of developing WRF during the next following days, which in turn is associated with a higher 1-year mortality.

Understanding the benefits of renin-angiotensin-aldosterone system inhibitors and influence of hyperkalaemia on their prescription: a UK survey of healthcare professionals' views and practice

Abstract Background Renin–angiotensin–aldosterone system inhibitors (RAASi) improve outcomes in heart failure with reduced ejection fraction (HFrEF) and they should be increased to the maximally tolerated dose. However, their use is often hindered by hyperkalaemia leading to discontinuation or down titration. Purpose Assess perceptions of primary and secondary healthcare professionals regarding benefits of RAASi according to indication and, in the context of developing hyperkalaemia, to identify barriers to optimal utilisation, and to explore options for improving management protocols, specifically in HFrEF. Methods An electronic survey was distributed in primary and secondary care setting in Hampshire, UK, to evaluate knowledge about benefits of RAASi, clinical response to varying level of potassium (K+), and decision-making using several clinical scenarios. Hyperkalaemia was graded into mild (serum K+ 5.5 – 5.9 mmol/L), moderate (serum K+ 6.0 – 6.4 mmol/L) or severe (serum K+ ≥ 6.5 mmol/L). Results Between November 2021 and January 2023, 300 questionnaires were completed by 274 (91%) physicians (varying grades of seniority), 22 (7%) non-medical prescribers, and 4 (1%) pharmacists. 80% were working in secondary care across different specialities (31 working in cardiology and 15 in nephrology). The majority were aware of prognostic benefit of angiotensin converting enzyme inhibitors (ACEi) in patients with HFrEF although this was lower for mineralocorticoid receptor antagonists (MRA) (Fig 1). Fewer than 2/3 of respondents were aware of impact of ACEi on symptoms. In the presence of mild hyperkalaemia, 75% and 88% of healthcare professionals would stop or reduce ACEi and MRA, respectively. In moderate or severe hyperkalaemia, this increased to 96% and 97%, respectively (Fig 2A-B). When considering the scenario of a patient with HFrEF who had ACEi stopped due to K+ 5.9 mmol/L, the potassium at which the responder would consider re-starting the ACEi ranged from 77% when potassium level &amp;lt; 5.5 mmol/L to 1% in moderate or severe hyperkalaemia (Fig 2C). 74% of healthcare professionals were familiar with local hyperkalaemia management protocol and 93% supported dedicated training on RAASi dose adjustment and hyperkalaemia management. Conclusion This survey, across a broad range of healthcare professionals, shows uncertainties around knowledge of benefits of RAASi in patients with HFrEF and there is sizeable variation in the prescribing response to degrees of hyperkalaemia. Given the voluntary nature of the survey, it is plausible that these data are biased towards individuals with greater understanding. Regardless, there is a need for continued education with a goal of improving patient-centred care.

Effect of spironolactone wash-out on albuminuria after long-term treatment in individuals with type 2 diabetes and high risk of kidney disease-An observational follow-up of the PRIORITY study.

This study aimed to explore the effect of discontinuation of long-term spironolactone treatment on markers of kidney function in individuals with type 2 diabetes (T2D) at high risk of kidney disease enrolled in the Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria (PRIORITY) study. An observational study following the nested randomised part of the PRIORITY study was conducted. A total of 115 individuals with T2D and normoalbuminuria but high risk for progression based on urinary proteomics, randomised to daily spironolactone (n = 50) or placebo (n = 65) for a median of 2.5 years, were re-examined approximately 6 weeks after the final visit in the PRIORITY study. Primary endpoint was relative change in geometric mean of urinary albumin-creatinine ratio (UACR) between the final visit in PRIORITY (baseline) and follow-up. Secondary endpoints were change in estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP) and serum potassium. No change in UACR was observed in neither the spironolactone (geometric mean change: 17%; 95% CI -12, 55; p = 0.28) nor the placebo (5%; 95% CI -13, 26; p = 0.63) group at follow-up. No difference in UACR between the groups was observed at follow-up (relative difference in geometric mean: 11%, 95% CI -26, 67; p = 0.60). For eGFR and SBP, an increase after discontinuation of spironolactone was observed, as well as for SBP after placebo discontinuation. Potassium levels were lower after discontinuation of spironolactone, but higher after placebo discontinuation (all p < 0.05). UACR did not change after discontinuation of long-term treatment with spironolactone. However, an increase in eGFR was observed supporting a haemodynamic effect of spironolactone in the kidneys.

Prognostic impact of secondary prevention medical therapy in patients with Takotsubo cardiomyopathy: a Bayesian network meta-analysis

Abstract Background Takotsubo cardiomyopathy (TTC) is a form of transient left ventricular systolic dysfunction without evidence of complicated coronary artery disease. Although initially considered a benign condition, recent studies have demonstrated a significant risk of acute phase complications and a mortality rate between 1-8%. Efficacy of medical therapy in secondary prevention of all-cause mortality and TTC recurrence is not well established. We performed a systematic review and network meta-analysis to evaluate prognostic impact of secondary prevention medical therapy in patients with TTC. Methods PubMed, MEDLINE, EMBASE, CENTRAL, and Web of Science were searched up to January 6, 2024. Eligible studies included multivariable-adjusted or propensity matched studies of patients receiving medical therapy with B-blockers (BB), renin–angiotensin–aldosterone system (RAAS) inhibitors, aspirin and statins after an index presentation with TTC. The primary outcome was all-cause mortality at any time point. Secondary outcome was TTC recurrence. Random-effect hierarchical Bayesian meta-analyses was performed. Results We identified 15 observational studies. TTC mortality was reported in 435 (4.4%) out of 9735 patients. Mean age was 70.2 ± 4 years and 8858 patients (91.5%) were females. There were no differences in all-cause mortality when comparing BB versus control (OR 0.83; 95% CI 0.47 to 1.47, p=0.52); BB versus RAAS inhibitors (OR 1.03; 95% CI 0.61-1.63), BB versus aspirin (OR 1.02; 95% CI 0.471-2.25) and BB versus statins (OR 0.871; 95% 0.432-1.75). No significant differences were also observed for TTC recurrence. Conclusion This network meta-analysis found no significant difference in all-cause mortality or recurrence rates in Takotsubo cardiomyopathy with the use of secondary prevention medical therapies, including beta-blockers, RAAS inhibitors, aspirin, and statins

Association of osteopontin and shrunken pore syndrome with hospitalization for renal failure in acute heart failure patients

Abstract Background Shrunken pore syndrome (SPS) emerges as a distinctive manifestation of glomerular filtration dysfunction mainly manifested by the impairment of moderate-sized molecular filtration, distinguished by a variance in renal filtration between cystatin C and creatinine. SPS exhibits correlations with adverse prognosis of various cardiovascular diseases. A decline in renal function correlates with a poor prognosis among individuals with heart failure (HF). Osteopontin (OPN), a protein involved to bone mineralization, has been linked to deteriorating renal function and heightened risk for adverse outcomes in patients with chronic kidney disease. Purpose To explore if OPN and SPS are associated with hospitalization for renal failure in patients with acute HF. Methods Cystatin C and creatinine were analyzed in 395 hospitalized HF patients, of which 324 also had osteopontin (OPN) analyzed using a proximity extension assay. SPS was calculated using the CKD-EPI Equations for Glomerular Filtration Rate and defined as a cystatin C-based estimated glomerular filtration rate (eGFR) &amp;lt;60% of the creatinine based eGFR. Hospitalization for renal failure was extracted from regional registries using ICD10 codes N17-N19. Logistic and Cox regression models were deployed to explore a) OPN’s association with SPS; b) OPN’s association with hospitalization for renal failure; and c) SPS’s association with hospitalization for renal failure, adjusting for age, sex, systolic blood pressure and use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Results The study population had a mean age of 74.8 (±12.0) years, 32.4% were women and 104 (26.5%) patients presented with SPS (Table 1). During the median follow-up period of 71 (interquartile range 56-88) months, 35 (8.9%) patients were hospitalized for renal failure. OPN was associated with the prevalence of SPS (OR 1.66; 95%CI 1.08-2.27; p=0.002), as well as with higher risk of hospitalization due to renal failure (HR 2.71; 95%CI 1.61-4.56; p&amp;lt;0.001). Further, also prevalent SPS was associated with higher risk of hospitalization due to renal failure (HR 2.44; 95%CI 1.14-5.24; p=0.022). Conclusions Here, we demonstrate that higher OPN levels are associated with a higher prevalence of SPS and an elevated risk of hospitalization due to renal failure among patients with HF. Additionally, the presence of SPS was associated with a higher risk of renal failure-related hospitalizations. These findings highlight the potential utility of OPN and SPS as biomarkers for identifying heart failure patients at risk of renal function decline, underscoring the importance of early risk stratification and targeted interventions in this population.

Conditional over-expression of heme-oxygenase 1 in myelomonocytic cells reduces AngII-induced hypertension and vascular inflammation in mice

Abstract Background Systemic arterial Hypertension is one of the most important risk factor responsible for morbidity and mortality world-wide. Angiotensin II (Ang II), a potent vasoconstrictor and key player in the renin-angiotensin-aldosterone system (RAAS) is responsible for vascular dysfunction, inflammation, and tissue damage. Heme oxygenase-1 (HO-1) overexpression may confer antioxidant and anti-inflammatory properties in Ang II-induced hypertension through its action on heme catabolism, generating carbon monoxide (CO), ferritin and biliverdin/bilirubin by the action of biliverdin reductase A (BLVRA). Methods and results Male 9–12-weeks-old HO-1indxLySMCre/wt and LySMCre/wt mice were infused with AngII (1mgAngII/Day/Kg) for 7 days to induce hypertension and compared to sham treatment. Blood pressure monitoring by tail-cuff method, and endothelium-dependent vasodilator studies via organ chamber system using acetylcholine (ACh) in isolated aortic segments (~4 mm), revealed that overexpression of HO-1 in myeloid cells resulted in decreased systolic blood pressure and improved endothelial function in AngII-infused HO-1indxLySMCre/wt mice compared to controls. Concurrently, increased BLVRA expression in liver tissue and elevated plasma bilirubin levels were detected by transcriptome analysis and high-performance liquid chromatography, respectively. These results were supported by a reduction in the expression of inducible cytokines and cell adhesion molecules (CAMs) in the aorta, assessed using qPCR. Bone marrow transplant experiments demonstrated that bone marrow from LysMcre mice in HO-1indxLySMCre/wt mice abrogated the protective effect of HO-1, resulting in endothelial damage and increased blood pressure, potentially due to decreased liver BLVRA expression and the accumulation of bone marrow-derived cells in the vessel wall in response to AngII. Additionally, adeno-associated viral vector (AAV) transfection targeting specifically BLVRA activity in liver lead to an increase in blood pressure values and worse endothelium relaxation, in parallel with higher oxidative stress and the blood neutrophils concentration, as assessed in whole blood by using oxidative burst method and blood count system respectively. Conclusion The overexpression of HO-1 in myeloid cells confers anti-inflammatory protection in AngII-induced arterial hypertension in mice. Myeloid cells bone marrow-derived overexpressing HO-1 regulate the differentiation and infiltration of pro-inflammatory immune cells in the vasculature. BLVRA expression and bilirubin levels downstream of HO-1 play a critical role in protecting against vascular damage by reducing leukocyte infiltration.

Integrated multi-omics predictive analysis of atherosclerosis: a sub-study from the Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) trial

Abstract Background/Introduction Mineralocorticoid receptor (MR) antagonists (MRA) are beneficial in cardiorenal outcomes in randomized controlled trials but the mechanisms are unclear. MAGMA was an NHLBI sponsored randomized, double-blind, placebo controlled, 12-month trial comparing Spironolactone (n = 37) vs. placebo (n = 42) in Type 2 diabetics with CKD stages 3-4 on maximal renin-angiotensin system (RAS) blockade and a prior atherosclerotic event and/or left ventricular (LV) hypertrophy. The primary outcome of percent (%) change in total aortic wall volume (TWV) at 12 months, measured by magnetic resonance imaging (MRI), was significantly reduced by Spironolactone. Purpose/Originality The purpose of this analysis was to understand mechanistic pathways of MRAs using a multi-omics approach that could help tease out molecular mechanisms of benefit. Revealing for the first time which of these integrated pathways are predictive of the primary outcome will help design treatments for targeted interventions. Methods Plasma and peripheral blood mononuclear cells from patients randomized to Spironolactone or placebo at baseline and 3-months were measured for aptamer-based proteomic biomarkers (7,596 proteins) and 10-X platform-based single-cell RNA-sequencing (scRNAseq), respectively. Pre-selected candidate predictors were used as inputs of a predictive model of changes of TWV. We fit a Mixed-Multivariate Random Forest (RF) model, a variation of the RF supervised tree-based machine learning method to take the experimental design into account in the regression formulation. The two sources of "omics predictors" were integrated into a supervised multi-omics model to jointly explain the outcome using an extension of Sparse Generalized Canonical Correlation Analysis (SGCCA). Integrated multiome functional analyses with graphical visualizations were carried out by statistical enrichment analysis using Over Representation Analysis (ORA) and Gene Set Enrichment Analysis (GSEA) against databases of gene ontologies, biological pathways, putative regulatory motifs, proteins, or disease annotations. Results The plasma proteome in response to Spironolactone revealed downregulation of MR targets including fibrosis, immune activation/inflammation, leukocyte activation, proliferation and pathways involved in cytokine stimulation. scRNAseq pathways revealed negative regulation of cytokines production such as IL-2 and redistribution of multiple cell types. Predictors of plaque progression involved cytokine-receptor, complement-coagulation, cell adhesion and axonal guidance targets. Multiome integrated functional analyses results of predictive pathways will be presented. Conclusions The changes in plasma proteomic profile with Spironolactone were consistent with the phenotype of reduced atherosclerosis and downregulation of multiple inflammatory, immune response and profibrotic pathways.

Pregnancy protection in women of child-bearing age prescribed ACE inhibitors, ARBs or statins - A nationwide cohort study

Abstract Background Cardiometabolic disorders, including hypertension, type-2 diabetes, and hyperlipidemia are increasingly prevalent among younger people. Consequently, women of child-bearing age may be prescribed renin-angiotensin system (RAS) inhibitors and statins. Both angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are known teratogens. Statins are considered possibly teratogenic. In Denmark, ACEIs and ARBs have a ‘Do not use’ recommendation in pregnancy while statins ‘Should not be used’ in pregnancy. Previous studies have reported widespread use of RAS inhibitors without concomitant contraception among women of child-bearing age. This study investigated the situation in Denmark. Purpose To examine prescribing patterns of RAS inhibitors and statins alongside use of concomitant contraception among women of child-bearing age in Denmark. Methods Using nationwide Danish registers, women aged 15–50 years initiating ACEIs, ARBs and statins during 1995–2021 were identified and use of concomitant contraception was evaluated. Contraception was categorized as oral pill, implant, intrauterine device (IUD), or non-use. The duration of protection was assumed to be 1 year for oral contraceptives, 2 years for implants and 4 years for IUDs. Where multiple types of contraceptives were retrieved by individual patients, they were categorized as taking the contraceptive retrieved most recently. Data on non-prescription contraceptives were unavailable, e.g., condoms. Women unable to conceive due to infertility were excluded. Results 79 547 women (median age: 44 years; [interquartile range (IQR): 39–47]) on ACEIs, 64 326 women (median age: 44 years [IQR: 38–48]) on ARBs, and 71 499 women (median age: 45 years [IQR: 40–48]) on statins were included (Figure 1). Correspondingly, 69.1%, 62.8%, and 73.5% were not on contraceptives when starting treatment. Among women prescribed contraception: 70.2%/56.2%/63.1% were on oral contraceptives, 25.3%/30.9%/26.6% had IUDs and 4.5%/12.9%/10.3% had implants, respectively (Figure 1). Younger patients aged 15–29 years were least likely to be unprotected with 41.8%/29.7%/33.4% being unprotected. Among women aged 25 to 35 years the percentage of unprotected women was 51.3%/41.1%/47.7%. Older patients were more likely to have IUDs. Conclusion Substantial numbers of women of child-bearing age were prescribed ACEIs, ARBs and statins from 1995–2021. Most were not prescribed contraceptives. The lack of prescribed pregnancy protection was prevalent even among the youngest women aged 15–29 years and women aged 25 to 35 years, who are the most likely to become pregnant—inferring a potential risk of teratogenic exposure during pregnancy (Figure 2). Subsequent studies should investigate the extent of exposure to ACEIs, ARBs, and statins during pregnancy and the impact of the exposure on pregnancy outcomes.Figure 1 Contraceptive useFigure 2 Study rationale

Disparities in SGLT2i utilization among heart failure patients with different ejection fraction in China: findings from chinese cardiovascular association database-heart failure center registry

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended for heart failure (HF) patients regardless of left ventricular ejection fraction (LVEF). Although Chinese HF guidelines still recommend traditional renin–angiotensin–aldosterone system inhibitors, beta blockers, mineralocorticoid receptor antagonists, the Chinese Cardiovascular Association (CCA) HF Center Registry has launched a project to promote the guideline-directed medical therapy (GDMT) for HF patients in China. However, data on the utilization of GDMT in Chinese HF patients is scarce, especially SGLT2i. Purpose We aimed to investigate the usage status of SGLT2i in HF patients with different LVEFs and explore associated factors with SGLT2i adoption in hospitalized HF Chinese patients. Methods This is a retrospective real world study using data from the CCA Database-HF Center Registry. The study included HF patients hospitalized in 52 secondary or tertiary hospitals, including 26 accredited heart failure centers (HFC) and 26 non-accredited heart failure centers (NHFC). Centers that meet the 25 quality control standards established by CCA can be accredited as HFC. We evaluated the use rate of SGLT2i overall and by HF type, as well as the change of SGLT2i usage rate at discharge during the study period from 1st July 2022 to 31st March 2023. LASSO and multivariable logistic regression were also used to explore associated factors of SGLT2i adoption at discharge. Result We included 8,843 hospitalized HF patients: 5,326 (60.2%) were male, 2,980 (33.7%) HFrEF, 1,624 (18.4%) HFmrEF, 3,653 (41.3%) HFpEF and 586 (6.6%) lacked EF data. Overall, SGLT2i were adopted in 3,666 (41.5%) HF patients at discharge (58.1% in HFrEF, 45.3% in HFmrEF, 28.8% in HFpEF). Overall, the usage rate of SGLT2i at discharge rose from 35.2% to 50.2%. Specifically, for HFrEF patients, there was a rise from 56.2% to 64.4%. For HFmrEF and HFpEF patients, the usage rate increased from 37.5% to 54.4% and from 22.2% to 35.7%, respectively (Figure 1). The usage rate of SGLT2i was higher in HFC compared with NHFC (47.1% vs. 35.8%, p&amp;lt;0.001). In multivariable logistic regression, older age, new-onset heart failure, hospital location, etc. were associated with a lower usage rate of SGLT2i at discharge. In contrast, HFC, dilated cardiomyopathy, obesity, etc. were associated with a higher utilization rate of SGLT2i (Figure 2). HF classification by LVEF was also an independent influencing factor even after adjusting other factors; when HFrEF was used as a reference, the use rate of SGLT2i was lower in HFmrEF (OR 0.79, 95% CI 0.69 - 0.91) and HFpEF (OR 0.44, 95% CI 0.39 - 0.49). Conclusion In clinical practice in China, the usage rate of SGLT2i for HF treatment is increasing but needs to be further improved. Disparities exist in usage rates among HF patients with different LVEFs. Addressing this disparity necessitates a targeted approach, emphasizing increased utilization in HF patients regardless of LVEF.SGLT2i usage rate in HFFactors affecting SGLT2i adoption in HF

Comparative analysis of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor and mineralocorticoid receptor antagonists in heart failure with mildly reduced ejection fraction

Abstract Background Apart from sodium-glucose co-transporter 2 inhibitors, the efficacy of renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI)j8788 as well as mineralocorticoid receptor antagonist (MRA) in patients with heart failure with mildly reduced ejection fraction remains uncertain. We assessed the association between these medications and outcomes in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods Patients with HFmrEF from our university hospital-integrated Medical Database were included. Associations between the medications and cardiovascular mortality/heart failure hospitalization were evaluated using Cox regressions in a 1:1 propensity score-matched cohort. Inverse probability of treatment weighting was employed to balance baseline patient characteristics. Results Of 2584 patients with HFmrEF, 17% received MRA and 43% received RASI/ARNI. Predictors of MRA use included older age, slightly higher ejection fraction, lower NT-proBNP level, and eGFR &amp;gt;60 mL/min/1.73 m^2. Predictors of RASI/ARNI use included higher body mass index, lower NT-proBNP level, normal uric acid level, normal potassium level, and eGFR &amp;gt;60 mL/min/1.73 m^2. MRA use was not associated with a lower risk of cardiovascular death and hospitalization for heart failure (hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.78–1.02 and HR = 1.01, 95% CI: 0.94–1.09, respectively). Conversely, RASI/ARNI use was associated with a lower risk of cardiovascular death but not hospitalization for heart failure (HR = 0.82, 95% CI: 0.71–0.94 and HR = 0.995, 95% CI: 0.924–1.07, respectively). Notably, landmark analysis revealed no significant difference in the risk of outcomes when the follow-up duration exceeded two years. Conclusions The effect of MRA on cardiovascular death and hospitalization for heart failure was neutral, whereas RASI/ARNI was associated with a lower risk of cardiovascular death. Our findings suggest that RASi use may be more beneficial than MRA use in patients with HFmrEF.

Prognostic implications of guideline-directed medical therapy in functional mitral regurgitation: a meta-analysis

Abstract Background Randomized evidence of the role of heart failure medical therapy for patients with functional mitral regurgitation (FMR) is lacking. Purpose The present meta-analysis sought to investigate the independent long-term prognostic impact of the different medical categories recommended in heart failure, for subjects with FMR. Methods A systematic literature review was conducted in electronic databases to identify studies reporting the association of renin angiotensin system inhibitors (RASi), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) with outcomes in FMR. A random-effects meta-analysis was conducted to quantify the unadjusted and adjusted hazard ratios [(a)HRs] for all-cause death and the composite outcome in each medical category. Results The final sample comprised 12 studies with 6,715 FMR patients (Picture 1). The use of RASi and BBs was associated with a significantly lower risk for all-cause mortality (HR 0.52 [0.39-0.68]; p &amp;lt;0.00001, I2 =62 % and HR 0.62 [0.49-0.77]; p &amp;lt;0.0001, I2 =44 % respectively) and for the composite outcome (HR 0.54 [0.44-0.67]; p &amp;lt;0.00001, I2 =33 % and HR 0.62 [0.52-0.75], p &amp;lt;0.00001, I2 =35% respectively) in unadjusted models (Picture 2). Both RASi (aHR 0.73 [0.56-0.95], p =0.02, I2 =52%) and BBs (aHR 0.60 [0.41-0.88], p = 0.009, I2 =55%) retained their association with the composite outcome in pooled adjusted models (Picture 2). The prognostic benefit of using RASi or BBs was retained in subgroup analysis including only patients with moderate of severe FMR. MRAs did not demonstrate a significant association with improved outcomes in FMR. Conclusions RASi and BBs appear to have a favorable prognostic impact in patients with FMR, regardless of regurgitation severity.Study flow chart for study selectionPharmacotherapy and prognosis in FMR

Prevalent and incident anemia in PARAGON-HF

Abstract Background Anemia is a common comorbidity in patients with heart failure (HF) and is associated with adverse prognosis. Renin-angiotensin system inhibitors (RASi) have been shown to lower hemoglobin levels, potentially related to direct reductions in erythropoetin levels and hematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anemia in patients with HF with mildly reduced or preserved ejection fraction. Methods PARAGON-HF was a global, multicenter randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction≥45%. Anemia was defined as hemoglobin &amp;lt;120 g/L in women and &amp;lt;130 g/L in men. We evaluated changes in hemoglobin, risks of incident anemia and new oral iron initiation during follow-up. We also assessed treatment effects on the primary composite endpoint of total HF hospitalizations (HFH) and cardiovascular (CV) death according to anemia status. Results Among 4,795 participants with a hemoglobin measurement available, 1,111 (23.2%) had anemia at randomization of which 3.5%, 77.7%, and 18.8% were characterized as micro-, normo-, and macrocytic anemia. 5.6% were treated with oral iron at baseline. Over a 2.7-year median follow-up period, patients with anemia were at nearly twice the risk of the primary outcome (21.6 vs. 11.5 per 100py; rate ratio 1.90; 95% CI: 1.62-2.21; P&amp;lt;0.001). Compared with valsartan, sacubitril/valsartan significantly slowed the decline in hemoglobin levels by 1.4 g/L (95% CI: 0.4-2.4 g/L; P = 0.005; Figure 1 Panel A). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anemia (30.3% vs. 37.6%; HR 0.76; 95% CI: 0.68-0.85; P&amp;lt;0.001; Figure 1 Panel B) and starting oral iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI: 0.67-0.97; P = 0.026; Figure 2). Treatment effects of sacubitril/valsartan vs. valsartan on the primary endpoint were consistent among patients with and without anemia (Pinteraction=1.00). Conclusions Among patients with HF with mildly reduced or preserved ejection fraction, treatment with sacubitril/valsartan resulted in slower declines in hemoglobin, lower rates of incident anemia, and fewer new initiations of iron therapy compared with RASi.

Clinical phenotyping and treatment response in patients with chronic heart failure: a latent class analysis from a Japanese multicentre registry

Abstract Background There are diversities of pathophysiology and co-morbidities in patients with chronic heart failure (HF), irrespective of left ventricular ejection fraction (LVEF). Therefore, the identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual HF patient. Purpose We sought to identify phenogroups of patients with different prognosis and response to medical therapies in patients with chronic HF. Methods A total of 1565 patients with a broad spectrum of LVEF in a prospective multicentre registry of patients with chronic HF were enrolled between January 2020 and December 2023. Latent class analysis was performed in each subgroup using 80 features including patients’ demographics, laboratory, and echocardiographic data. The optimal number of phenogroups was determined using the first minimum of the Bayesian information criterion. The primary outcome was a composite of all-cause death and hospitalisation due to worsening HF. Results The analysis subclassified patients into six phenogroups. Patients in phenogroup A (young non-ischaemic cardiomyopathy, n = 242, 15.5%) were the youngest and had lower LVEF and lowest prevalence of coronary artery disease (CAD) and other comorbidities. Phenogroup B (atrial fibrillation [AF] and small left atrium, n = 282, 18.0%) had higher proportion of AF but smaller left atrium volume. Phenogroup C (ischaemic cardiomyopathy, n = 204, 13.0%) had the highest proportion of CAD and lower LVEF. Phenogroup D (classical HF with preserved ejection fraction [HFpEF], n =308, 19.7%) had the highest age, proportion of female, LVEF and thickness of LV wall. Phenogroup E (elderly and AF , n = 235, 15.0%) had higher age, the highest proportion of AF and largest left atrium volume. Phenogroup F (biventricular failure and multiple comorbidities, n = 294, 18.8%) had the highest proportion of co-morbidities and the lowest LVEF, right ventricular systolic function and renal function. During a median follow-up period of 538 (interquartile range 286-701) days, the incidence of the primary outcome significantly differed among the phenogroups (P &amp;lt; 0.001, Figure 1). Regarding treatment response for renin-angiotensin system blockers and beta blockers, there were no significant associations between the use of renin-angiotensin system blockers and the risk of the primary outcome among the phenogroups whereas the use of beta-blockers was significantly associated with increased risk of the primary outcome in patients classified to phenogroup D (classical HFpEF) (hazard ratio 1.83 95% confidence interval 1.05-3.19) among the phenogroups (Figure 2). Conclusion We identified six phenogroups with distinct clinical outcomes in patients with chronic HF, and the use of beta-blockers might have unfavorable effect in the classical HFpEF phenogroup. This phenotyping provides novel risk stratification and may aid in clinical decision making.Clinical outcomes among the phenogroupsTreatment effect among the phenogroups

Effects of Sacubitril/Valsartan on all-cause hospitalizations in heart failure: participant-level pooled analysis of PARADIGM-HF and PARAGON-HF

Abstract Background Sacubitril/valsartan is indicated to reduce the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with chronic HF. However, many of these patients are older and have multiple comorbidities that increase the risk of hospitalizations other than HF, yet the effects of sacubitril/valsartan on hospitalizations of any cause have not been well described. Methods PARADIGM-HF and PARAGON-HF were phase-3, global multicenter randomized clinical trials that evaluated sacubitril/valsartan versus enalapril (in PARADIGM-HF) or valsartan (in PARAGON-HF) across the spectrum of left ventricular ejection fraction (LVEF; ≤40% in PARADIGM-HF and ≥45% in PARAGON-HF). We pooled individual participant-level data from these 2 trials to examine the effects of sacubitril/valsartan on time-to-first investigator-reported all-cause and cause-specific hospitalization using Cox proportional hazards models, stratified by geographic region and trial. We additionally examined heterogeneity in treatment response by LVEF. Results Over 2.8 years median follow-up, among 13,194 participants in the pooled PARADIGM-HF/PARAGON-HF, sacubitril/valsartan significantly reduced the risk of all-cause hospitalizations compared with renin-angiotensin system inhibitor (HR 0.92; 95% CI 0.88-0.97; P=0.002); Figure 1 Panel A. The absolute risk reduction (ARR) was 2.1 per 100 patient-years corresponding to a number-needed-to-treat (NNT) of 48 patient-years of treatment exposure to prevent 1 all-cause hospitalization. Reductions in overall hospitalizations among patients with identifiable causes (N=5,783) seemed to be primarily driven by lower rates of cardiac and pulmonary hospitalizations associated with sacubitril/valsartan. Patients treated with sacubitril/valsartan did not have a higher rate of composite non-cardiac hospitalizations (Figure 1 Panel B). Similarly, sacubitril/valsartan reduced the risk of the composite of all-cause hospitalization or all-cause mortality (HR 0.92; 95% CI 0.87-0.96; P&amp;lt;0.001), with an ARR of 2.5 per 100 patients-years and an NNT of 40 patient-years. For all-cause hospitalization, we observed significant heterogeneity by LVEF as a continuous measure (Pinteraction=0.027); treatment effects were most apparent in those with an LVEF below 60% (HR 0.91 95% CI 0.86-0.96; Figure 2). Conclusions In a pooled analysis of &amp;gt;13,000 patients with chronic HF, sacubitril/valsartan reduced hospitalization for any reason with benefits most apparent among those with an LVEF below normal.

Systolic plood pressure response to ASi BI 690517 with and without empagliflozin in CKD

Abstract Background and Aims: BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may provide additive efficacy and also mitigate risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given alone or in combination with empagliflozin (EMPA), for albuminuria reduction in people with CKD and with or without type 2 diabetes.1 Here, we present a secondary analysis for effects on systolic blood pressure (SBP). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomised (R1) 1:1 to receive background EMPA 10 mg or placebo (PBO-EMPA) during an 8-week run-in. They were then re-randomised (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBO-ASI for 14 weeks, in addition to their assigned EMPA or PBO-EMPA therapy. Participants had mean baseline SBP ≥110 and ≤160 mmHg. Elevated blood pressure (BP) was defined as SBP ≥140 mmHg or DBP ≥90 mmHg and receiving ≥2 classes of anti-HTN medication. Changes in SBP from R2 baseline to Week 14 were analysed to assess BI 690517 effects with and without EMPA use. Results Of 714 people randomised at R1, 586 were randomised at R2, and the treated set consisted of 583 people. Demographics and clinical characteristics were similar between dose groups.1 At R2 baseline, 169 (29.0%) people had elevated BP. Mean SBP was 142.7 mmHg in the elevated BP group versus 129.2 mmHg in the non-elevated BP group. Treatment with BI 690517 consistently reduced SBP with reductions that were comparable in people with and without elevated BP (p-value for interaction not significant) (Table). Conclusions In people with CKD, BI 690517 reduced SBP in people with and without elevated BP.(Table)