To evaluate the prognostic value of extreme levels of the N-terminal pro-brain natriuretic peptide (NT-proBNP) measured at any time during hospitalization for heart failure (HF).

A retrospective cohort study including patients hospitalized for HF in a secondary-level hospital with at least one NT-proBNP measurement. Two groups were defined: patients with extreme NT-proBNP levels (>50,000pg/mL) and those with elevated NT-proBNP levels (>1800pg/mL and <20,000pg/mL). The primary outcome was a composite of (1) in-hospital mortality; (2) HF readmission, and (3) 6-month mortality. Cox survival models were used for analysis.

A total of 83 patients with extreme NT-proBNP levels and 100 with elevated NT-proBNP levels were included; 61% were women, with a median age of 87 years. Comorbidity burden was high and similar between groups (median Charlson index: 8). The primary outcome was more frequent in patients with extreme NT-proBNP levels: 25.02 vs. 10.53 events per 100 patient-months (HR 2.07; 95% CI: 1.37-3.14). Both in-hospital and 6-month mortality were significantly higher in the extreme NT-proBNP group, while HF readmissions were numerically higher but not statistically significant. These results remained consistent after multivariable adjustment.

Patients hospitalized for HF with NT-proBNP levels>50,000pg/mL have a worse prognosis than those with NT-proBNP<20,000pg/mL, representing a high-risk subgroup with short-term mortality.

Background: Preeclampsia, a pregnancy complication marked by hypertension after 20 weeks of gestation, arises from placental factors that impair maternal vascular function. C-type natriuretic peptide (CNP), known for its vasodilatory role, may help counter preeclampsia-related vascular dysfunction. This study aimed to explore the effect of CNP on preeclampsia risk using the Mendelian randomization (MR) framework. Methods: Genetic instrumental variables that mimic the effects of CNP signaling (through natriuretic peptide receptor 2 [NPR2] activation or reduced NPR3-mediated clearance) were identified in the genes encoding the two receptors. This discovery emerged from a multiancestry genome-wide association study (GWAS) involving over 5 million individuals. Female-specific genetic association estimates were obtained from individual-level data comprising 198,402 female participants in the UK Biobank. Two-sample MR analyses were conducted to investigate the effects of NPR2 activation and NPR3 function on preeclampsia, utilizing the largest publicly available GWAS on preeclampsia, which included 296,824 female participants. Results: Genetically proxied reduced NPR3 function was associated with a lower risk of preeclampsia (odds ratio (OR): 0.46, 95% confidence interval 0.30-0.69). In contrast, genetically proxied increased NPR2 activation lacked significant association, likely due to underpowered genetic instruments. Sensitivity analyses indicated robust findings with minimal pleiotropy, meaning the genetic variants used primarily influenced preeclampsia through the intended biological pathway rather than affecting multiple unrelated traits. Conclusion: This study employed the MR paradigm to provide genetic evidence supporting the protective effects of CNP (through reduced NPR3 function) on the risk of preeclampsia. However, it is important to gather additional evidence from other sources before moving forward with clinical development efforts to explore CNP as a potential treatment for preeclampsia.

Background: Atrial natriuretic peptide (ANP) has emerged as a potential therapeutic agent in critical care settings due to its physiological effects on diuresis, natriuresis, and vasodilation. Despite several promising preclinical data, their clinical utility remains controversial, necessitating a comprehensive evaluation of existing evidence. Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Searches were performed in PubMed, Google Scholar, and Cochrane databases. Fifteen studies (n = 7187) comparing ANP to placebo in critically ill patients were included. Primary outcomes included mortality, hospital length of stay, ICU length of stay, and serum creatinine level. Risk ratios and mean differences with 95% confidence intervals were calculated using random-effects models. Results: ANP therapy showed no significant impact on mortality (RR 1.03, 95% CI: 0.89-1.19, p = 0.72) but significantly reduced hospital length of stay (MD -1.81 days, 95% CI: -1.91 to -1.72, p < 0.00001). ICU length of stay showed no significant difference between groups in subgroup analysis (MD +0.10 days, 95% CI: -0.03 to 0.23, p = 0.15). Subgroup analysis revealed improved creatinine levels with ANP (MD -0.19, 95% CI: -0.20 to -0.19, p < 0.00001), though high heterogeneity was noted across outcomes. Conclusions: ANP therapy shows promise in shortening hospital stays and enhancing renal function in select patients, but its effectiveness varies widely across clinical settings. Large-scale, multicenter studies are necessary to determine the ideal patient groups for ANP therapy in critical care.

Serum pro-brain natriuretic peptide (BNP) is a 108-amino-acid prohormone that inhibits vascular endothelial growth factor (VEGF) secretion, protecting pericytes from cell death and decreasing retinal vascularization. The purpose of this study was to investigate the correlation of serum pro-BNP with optical coherence tomography (OCT) indices in diabetic retinopathy.

This cross-sectional study investigated 96 consecutive subjects aged between 40 and 65 years: controls n = 24, no diabetic retinopathy (NoDR) n = 24, non-proliferative diabetic retinopathy (NPDR) n = 24, and proliferative diabetic retinopathy (PDR) n = 24. Same-day analysis of blood samples for serum pro-BNP levels was performed and spectral-domain OCT (SD-OCT) was used to measure the following OCT indices: OCT angiography (OCTA) superficial vessel density (SVD), deep vessel density (DVD), and foveal avascular zone (FAZ); OCT retinal nerve fiber layer (RNFL); and OCT ganglion cell analysis (GCA).

The mean serum pro-BNP levels for the control, NoDR, NPDR, and PDR groups were 14.07 ± 11.51, 27.35 ± 11.81, 280.44 ± 106.13, and 122.33 ± 43.66 pg/ml, respectively. The mean values of the various OCT parameters correlated with serum pro-BNP were OCTA SVD (r = - 0.360), OCTA DVD (r = 0.408), OCTA FAZ (r = 0.475), OCT RNFL (r = - 0.215) and OCT GCA (r = - 0.285; p<0.001).

The serum pro-BNP levels were higher in the NPDR group than in the NoDR group and much lower in the PDR group than in the NPDR group, reflecting a lowering of the protective barrier. These results correlated with the changes in various OCT indices.

Natriuretic peptides are produced predominantly by atrial cardiomyocytes in response to cardiovascular stress and attenuate cardiac maladaptation by reducing blood pressure, blood volume, and cardiac workload primarily through activation of natriuretic peptide receptors in the kidney and vasculature. However, mechanisms underlying cardiomyocyte exocytosis and natriuretic peptide secretion remain poorly defined. Manipulation of Rab3a GTPase activity by Rab3gap1 was recently found to modulate atrial natriuretic peptide (ANP) release by cardiomyocytes. Here, we examined upstream signaling mechanisms and the role of the Rab3a GTPase cycle in exocytosis and ANP secretion by cardiomyocytes. Pharmacological inhibition of the heterotrimeric G protein subunit G⍺q suppressed ANP secretion at baseline and prevented GTP loading of Rab3a and ANP release in neonatal rat cardiomyocytes in response to phenylephrine (PE). Similar to agonist-induced activation of ANP secretion, genetic overexpression of a constitutively active, GTP-loaded Rab3a mutant (Q81L) in neonatal rat cardiomyocytes resulted in enhanced intracellular distribution of Rab3a at endomembranes peripheral to the Golgi and promotion of ANP release, indicating that enhancement of Rab3a activity is sufficient to elicit ANP secretion by cardiomyocytes. Collectively, these data indicate G⍺q signaling downstream of receptor activation and Rab3a-regulated secretory pathway activity and exocytosis facilitate ANP release by cardiomyocytes that could potentially be harnessed to antagonize hypertension and adverse cardiac remodeling in cardiovascular disease.

Natriuretic peptide concentrations are inversely associated with risk of diabetes mellitus and may be protective from metabolic dysfunction.

We studied associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with incident diabetes, metabolic syndrome (MetS), and MetS components.

A total of 2899 participants with baseline (2003-2007) and follow-up (2013-2016) examinations and baseline NT-proBNP measurement in the REasons for Geographic And Racial Differences in Stroke study. Logistic regression models were fitted to incident MetS, MetS components, and diabetes; covariates included demographics, risk and laboratory factors. Incident diabetes was defined as fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or use of insulin or hypoglycemic drugs at follow-up but not baseline. Incident MetS was defined as participants with ≥3 harmonized criteria at follow-up and <3 at baseline.

A total of 310 participants (2364 at risk) developed diabetes and 361 (2059 at risk) developed MetS over a mean 9.4 years of follow-up. NT-proBNP was inversely associated with odds of incident diabetes (fully adjusted OR per SD higher log NT-proBNP 0.80, 95% CI 0.69-0.93) and MetS in the highest vs lowest quartile only (fully adjusted OR 0.59, 95% CI 0.37-0.92); the linear association with incident MetS was not statistically significant. NT-proBNP was inversely associated with incident dysglycemia in all models (fully adjusted OR per SD log NT-proBNP 0.65, 95% CI 0.53-0.79), but not with other MetS components. Effect modification by sex, race, age, or body mass index was not observed.

NT-proBNP was inversely associated with odds of diabetes, MetS, and the MetS dysglycemia component. The metabolic implications of B-type natriuretic peptides appear important for glycemic homeostasis.

Cardiorenal syndrome (CRS) is a common and critical complication of sepsis, with high morbidity and mortality rates. Studies on biomarkers for the early prediction of septic CRS are sporadic. Classic and novel potential biomarkers were identified to explore their diagnostic performance of in patients with septic CRS.

A total of 138 patients with sepsis from Peking University People's Hospital were enrolled in this prospective observational study, which was conducted between May 2019 and June 2022. The patients were divided into non-CRS (n = 106) and CRS (n = 32) groups. Serum levels of cystatin C, KIM-1, neutrophil gelatinase-associated lipocalin (NGAL), and α-Klotho were detected at admission using enzyme-linked immunosorbent assay. The relationship between the biomarker levels and risk factors of CRS were analyzed, as well as discrimination accuracy comparisons were performed.

The incidence of CRS in patients with sepsis was 23.2% (32/138) during hospitalization, with an obvious mortality. Compared with the non-CRS group, serum cystatin C, brain natriuretic peptide (BNP), troponin-I (TNI), KIM-1, and NGAL levels were both significantly elevated at admission in patients with sepsis complicated with CRS. Logistic regression analysis revealed that BNP, TNI, cystatin C, albumin, Lac, D-dimer were risk factors for CRS in sepsis patients. Compared with other biomarkers, serum cystatin C had moderate discriminative power for predicting septic CRS (area under a receiver operating characteristic curve, 0.746; sensitivity, 0.719; specificity, 0.783). BNP combined with cystatin C and D-dimer demonstrated an excellent discrimination performance, for its AUROC was up to 0.878 (sensitivity, 0.844; specificity, 0.759).

Serum cystatin C, BNP, TNI, KIM-1, and NGAL levels are elevated in patients with septic CRS. Our study provides reliable evidence that cystatin C in combination with BNP and D-dimer might better predict septic CRS upon admission. Further research on sensitive biomarkers is needed.

Anlotinib is widely used in the treatment of lung cancer. However, there remains a lack of predictive biomarkers to effectively gauge the response to anlotinib therapy. We conducted a retrospective study to preliminarily explore potential risk factors that might predict outcomes in lung cancer patients undergoing anlotinib treatment.

We retrospectively analyzed lung cancer patients treated with anlotinib at our hospital between 1 June 2018 and 1 June 2021. Data were gathered from electronic medical records. Demographic and clinical characteristics of patients, progression-free survival (PFS), and overall survival (OS) were described. Predictive factors related to treatment efficacy were preliminarily analyzed using Cox regression and Kaplan-Meier survival analyses.

After adjusting for potential confounders, clinical stage IV (hazard ratio [HR] = 2.52, 95% confidence interval [CI], 1.09-5.82, p = 0.0311), N-terminal fragment brain natriuretic peptides (NT-pro-BNP) > 300 pg/mL (HR = 2.54, 95% CI, 1.17-5.52, p = 0.0183), and neuron-specific enolase (NSE) > 16.3 ng/mL (HR = 1.70, 95% CI, 1.03-2.81, p = 0.0389) were associated with shorter OS, whereas age (HR = 0.96, 95% CI, 0.94-0.99, p = 0.0055) was associated with a longer PFS in fully adjusted model. Kaplan-Meier analyses of cumulative risk factors (clinical stage IV, NT-pro-BNP > 300 pg/mL, and NSE > 16.3 ng/mL) indicated that patients with a greater number of coexisting risk factors had significantly shorter OS (p < 0.0001).

Clinical stage IV, NT-pro-BNP level, and NSE level were identified as independent prognostic factors for lung cancer patients undergoing anlotinib treatment. Patients with multiple high-risk factors may derive limited benefit from anlotinib.

Atrial cardiomyopathy (AC) has been defined by the European Heart Rhythm Association as "Any complex of structural, architectural, contractile, or electrophysiologic changes in the atria with the potential to produce clinically relevant manifestations".1 The left atrium (LA) plays a key role in maintaining normal cardiac function; in fact atrial dysfunction has emerged as an essential determinant of outcomes in different clinical scenarios, such as valvular diseases, heart failure (HF), coronary artery disease (CAD) and atrial fibrillation (AF). A comprehensive evaluation, both anatomical and functional, is routinely performed in cardiac imaging laboratories. Recent advances in imaging techniques offer opportunities for evaluation of LA function, fundamental in clinical practice for early cardiovascular (CV) risk estimation, choice of therapeutic intervention and follow up. In this review we explore the concept of AC, its diagnosis through a multimodal approach, ranging from the historical electrocardiogram to the latest CV imaging techniques and its clinical implications.

Congestion in patients with heart failure (HF) predicts adverse outcomes and is a leading cause of hospitalisation. Understanding congestion mechanisms helps in HF management and underscores the importance of tailored therapies to treat vascular and tissue congestion, improving patient outcomes. In this setting, several tools are available to detect congestion. Biomarker measurement is a simple, valid and affordable method to evaluate congestion in patients with HF. Natriuretic peptides are the most widely available tool in acute and chronic HF, helping diagnosis, risk stratification and management. Novel biomarkers can potentially become reliable allies in diagnosing and monitoring patients with HF. This review aims to assess the current scientific literature on biomarkers for managing HF, evaluate their clinical utility and explore future perspectives in this field.

The aim of the present study was to evaluate the impact of chronic treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) on short-term clinical outcomes after an episode of AHF.

A secondary analysis of patients included in the EAHFE (Epidemiology of Acute Heart Failure in Emergency Departments) cohort, which includes patients diagnosed with AHF in 45 Spanish Emergency Departments (EDs). The primary outcome was all-cause in-hospital mortality. The secondary outcomes were all-cause death within 7 days, need for hospital admission and prolonged hospitalisation defined as a stay longer than or equal to 7 days. Multiple regression and propensity-matching was used for multivariate adjustment.

Of the 17,920 patients, 10,041 (56 %) were receiving chronic treatment with ACEI/ARB. The mean age was 80.4 years and 55.7 % were women. Adjusted odds ratios (aOR) were 0.76 (95 % CI 0.71-0.82) for in-hospital mortality witch multiple regression and 0.74 (95 %CI 0.63-0.88) with propensity-matching. aOR were 0.72; (95 %CI 0.65-0.79) and 0.70 (95 %CI 0.57-0.87) for mortality at the 7-day follow-up, respectively. The sensitivity analysis ACEI/ARB were associated with few all-cause deaths in patients with elevated natriuretic peptides in the EDs (aOR 0.74; 95 % CI 0.68-0.80), patients requiring hospital admission (aOR 0.78; 95 % CI 0.73-0.84) and patients with a history of HF (aOR 0.72; 95 % CI 0.66-0.78).

Chronic use of ACEI/ARB was associated with better short-term outcomes in terms of all-cause in-hospital mortality in patients with AHF who attend an EDs.

Hypertension, a prevalent cardiovascular condition globally, remains a significant public health concern due to its association with increased cardiovascular morbidity and mortality. Despite the availability of various antihypertensive therapies, achieving optimal blood pressure control in patients remains a challenge. Valsartan/sacubitril (ARNi), marketed as Entresto by Novartis, combines valsartan, an angiotensin receptor blocker, with sacubitril, an inhibitor of neprilysin. Neprilysin is responsible for breaking down natriuretic peptides and other vasoactive substances. Inhibiting neprilysin prevents the degradation of natriuretic peptides, enhancing their beneficial effects on blood pressure regulation. Natriuretic Peptides, including atrial natriuretic peptide (ANP) and brain natriuretic peptides (BNP), play pivotal roles in regulating blood pressure and cardiovascular homeostasis by promoting vasodilation, natriuresis, and antagonizing the renin-angiotensin-aldosterone system. Therefore, this combo drug lessens sensitivity to natriuretic peptides and tackles the processes in hypertension that activate the renin-angiotensin-aldosterone system. This review provides an overview of how natriuretic peptides (NPs) contribute to blood pressure regulation for the treatment of hypertension through inhibiting neprilysin. It highlights the ARNi's dual action that works synergistically by blocking the harmful effects of angiotensin II on blood vessels while simultaneously increasing the levels of beneficial natriuretic peptides. Schematic representation of the mechanism of action of ARNi. Abbreviation: -Renin angiotensin aldosterone system (RAAS), Natriuretic peptides (NP), Atrial Natriuretic peptide (ANP), Brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), Angiotensin II (Ang II), Angiotensin receptor neprilysin inhibitor (ARNI).

Atrial fibrillation (AF) screening should be considered in elderly patients with high risk of stroke, which include individuals with hypertension. The biomarker N-terminal prohormone of brain natriuretic peptide (NT-proBNP) can predict incident AF and is increased in hypertensive individuals. The aim of this study is to investigate the incidence of screening-detected AF in elderly individuals in relation to NT-proBNP and hypertension.

STROKESTOP II is a randomized controlled trial in which 75/76-years-old individuals were invited to a screening study for AF using NT-proBNP as a discriminator of high risk. In this sub-study, a prior hypertension diagnosis was self-reported by participants and measured blood pressure was stratified into hypertension-grades. Individuals with both increased blood pressure (≥140 mmHg) and NT-proBNP ≥ 125 ng/L were defined as a high-risk group. The lowest risk-group was defined as normotensive participants with NT-proBNP < 125 ng/L.

NT-proBNP increased gradually for every hypertension-grade above hypertension-grade 1 compared to normotensive participants. Screening-detected AF was most common in normotensive participants with increased NT-proBNP (n = 90/1922, 4.7 %), followed by patients with both NT-proBNP > 125 ng/l and SBP ≥ 140 mmHg, (AF = 65/1741, 3.7 %) compared to the low-risk group (AF = 2/1444, 0.1 %), p < 0.001.

NT-proBNP is elevated in elderly patients with hypertension and increases with grades of hypertensive disease. NT-proBNP is a strong predictor of AF regardless of high blood pressure, and the risk for screening-detected AF is very low in participants with normal blood pressure and low NT-proBNP. A combination of blood pressure and NT-proBNP could identify suitable participants for AF screening.

Febrile neutropenia (FN) is a common consequence of intensive chemotherapy in hematological patients. More than 90% of the patients with acute myeloid leukemia (AML) develop FN, and 5%-10% of them die from subsequent sepsis. FN is very common also in autologous stem cell transplant recipients, but the risk of death is lower than in AML patients. In this review, we discuss biomarkers that have been evaluated for diagnostic and prognostic purposes in hematological patients with FN. In general, novel biomarkers have provided little benefit over traditional inflammatory biomarkers, such as C-reactive protein and procalcitonin. The utility of most biomarkers in hematological patients with FN has been evaluated in only a few small studies. Although some of them appear promising, much more data is needed before they can be implemented in the clinical evaluation of FN patients. Currently, close patient follow-up is key to detect complicated course of FN and the need for further interventions such as intensive care unit admission. Scoring systems such as q-SOFA (Quick Sequential Organ Failure Assessment) or NEWS (National Early Warning Sign) combined with traditional and/or novel biomarkers may provide added value in the clinical evaluation of FN patients.

Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase A/natriuretic peptide receptor A (GC-A/NPRA), stimulating natriuresis and diuresis and reducing blood pressure (BP), but the role of ANP/NPRA signaling in podocytes (highly specialized epithelial cells covering the outer surfaces of renal glomerular capillaries) remains unclear. This study aimed to determine the effect of conditional deletion of podocyte-specific Npr1 (encoding NPRA) gene knockout (KO) in male and female mice. Tamoxifen-treated wild-type control (PD Npr1 f/f; WT), heterozygous (PD-Cre-Npr1 f/+; HT), and KO (PD-Cre-Npr1 f/-) mice were fed a normal-, low-, or high-salt diet for 4 wk. Podocytes isolated from HT and KO male and female mice showed complete absence of Npr1 mRNA and NPRA protein compared with WT mice. BP, plasma creatinine, plasma sodium, urinary protein, and albumin/creatinine ratio were significantly increased, whereas plasma total protein, albumin, creatinine clearance, and urinary sodium levels were significantly reduced in the HT and KO male and female mice compared with WT mice. These changes were significantly greater in males than in females. On a normal-salt diet, glomerular filtration rate was significantly decreased in PD Npr1 HT and KO male and female mice compared with WT mice. Immunofluorescence of podocin and synaptopodin was also significantly reduced in HT and KO mice compared with WT mice. These observations suggest that in podocytes, ANP/NPRA signaling may be crucial in the maintenance and regulation of glomerular filtration and BP and serve as a biomarker of renal function in a sex-dependent manner.NEW & NOTEWORTHY Our results demonstrate that the podocyte-specific deletion of Npr1 showed increased blood pressure (BP) and altered biomarkers of renal functions, with greater magnitudes in animals fed a high-salt diet in a sex-dependent manner. The results suggest a direct and sex-dependent effect of Npr1 ablation in podocytes on the regulation of BP and renal function and reveal that podocytes may be considered an important target for the ANP-BNP/NPRA/cGMP signaling cascade.

Corin plays important roles in the regulation of blood volume and pressure and cardiac function by activating natriuretic peptide pathway, exerting multiple cardioprotective effects. But the impacts of soluble corin on clinical outcomes after ischemic stroke are unclear. We aimed to investigate the associations between serum soluble corin and long-term clinical outcomes after acute ischemic stroke.

We measured the concentrations of serum soluble corin in 3162 participants (2010 men and 1152 women) from the China Antihypertensive Trial in Acute Ischemic Stroke. The clinical outcomes were recurrent stroke, cardiovascular events, all-cause mortality, and unfavorable functional outcome within 24 months after stroke. Risk reclassification for study clinical outcomes of models with soluble corin were evaluated. Serum soluble corin was inversely associated with recurrent stroke, cardiovascular events, and unfavorable functional outcome after ischemic stroke. After adjusting for multiple covariates, each additional SD of log-corin was associated with a 21% (95% CI, 11-30), 16% (95% CI, 6-26), and 12% (95% CI, 3-21) decreased risk for recurrent stroke, cardiovascular events, and unfavorable functional outcome, respectively. Furthermore, the addition of soluble corin to the basic model with conventional risk factors significantly improved risk discrimination for recurrent stroke, cardiovascular events, and the composite outcome of all-cause mortality and cardiovascular events, as shown by C-statistics (all P<0.05).

Serum soluble corin was associated with decreased risks of long-term clinical outcomes, and may be a promising prognostic biomarker for risk stratification in patients with acute ischemic stroke.

Thrombotic microangiopathy (TMA) on kidney biopsy is a pattern of endothelial injury commonly seen in malignant hypertension (mHTN), but treatment strategies are not well established.

To evaluate the kidney outcomes of angiotensin receptor-neprilysin inhibitor (ARNI), specifically sacubitril/valsartan, vs angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy for patients with mHTN-associated TMA.

This single-center cohort study enrolled consecutive patients in China diagnosed with mHTN-associated TMA through kidney biopsy from January 2008 to June 2023. Follow-up was conducted until the conclusion of the study period. Data were analyzed in September 2023.

Treatment with sacubitril/valsartan or ACEI/ARBs during hospitalization and after discharge.

The primary outcome was a composite of kidney recovery: a 50% decrease in serum creatinine level, decrease in serum creatinine levels to the reference range, or kidney survival free from dialysis for more than 1 month. The secondary and tertiary outcomes were a 15% increase in the estimated glomerular filtration rate (eGFR) relative to baseline and kidney survival free from dialysis, respectively. Propensity score matching (PSM) and Cox proportional hazards regression analysis were used to evaluate the association between sacubitril/valsartan and ACEI/ARB therapy with kidney recovery outcomes.

Among the 217 patients (mean [SD] age, 35.9 [8.8] years; 188 men [86.6%]) included in the study, 66 (30.4%) received sacubitril/valsartan and 151 (69.6%) received ACEI/ARBs at baseline. Sacubitril/valsartan treatment was associated with shorter time to the primary outcome compared with ACEI/ARB treatment (20 of 63 [31.7%] vs 38 of 117 [32.5%]; adjusted hazard ratio [aHR], 1.85; 95% CI, 1.05-3.23). Sacubitril/valsartan treatment was independently associated with shorter time to a 15% increase in eGFR (15 of 46 [32.6%] vs 46 of 83 [55.4%]; aHR, 2.13; 95% CI, 1.09-4.17) and kidney survival free from dialysis (11 of 23 [47.8%] vs 16 of 57 [28.1%]; aHR, 2.63; 95% CI, 1.15-5.88) compared with ACEI/ARB treatment. These differences remained significant in the PSM comparison.

In this cohort study, sacubitril/valsartan treatment was associated with a potential kidney function benefit in patients with mHTN-associated TMA compared with ACEI/ARB treatment. The findings suggested that sacubitril/valsartan could be a superior therapeutic approach for managing this serious condition in terms of kidney recovery.

Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3-8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.

Preeclampsia is a serious condition of pregnancy, complicated by aberrant maternal vascular dysfunction. CNP (C-type natriuretic peptide) contributes to vascular homeostasis, acting through NPR-B (natriuretic peptide receptor-B) and NPR-C (natriuretic peptide receptor-C). CNP mitigates vascular dysfunction of arteries in nonpregnant cohorts; this study investigates whether CNP can dilate maternal arteries in ex vivo preeclampsia models.

Human omental arteries were dissected from fat biopsies collected during cesarean section. CNP, NPR-B, and NPR-C mRNA expression was assessed in arteries collected from pregnancies complicated by preeclampsia (n=6) and normotensive controls (n=11). Using wire myography, we investigated the effects of CNP on dilation of arteries from normotensive pregnancies. Arteries were preconstricted with either serum from patients with preeclampsia (n=6) or recombinant ET-1 (endothelin-1; vasoconstrictor elevated in preeclampsia; n=6) to model vasoconstriction associated with preeclampsia. Preconstricted arteries were treated with recombinant CNP (0.001-100 µmol/L) or vehicle and vascular relaxation assessed. In further studies, arteries were preincubated with NPR-B (5 µmol/L) and NPR-C (10 µmol/L) antagonists before serum-induced constriction (n=4-5) to explore mechanistic signaling.

CNP, NPR-B, and NPR-C mRNAs were not differentially expressed in omental arteries from preeclamptic pregnancies. CNP potently stimulated maternal artery vasorelaxation in our model of preeclampsia (using preeclamptic serum). Its vasodilatory actions were driven through the activation of NPR-B predominantly; antagonism of this receptor alone dampened CNP vasorelaxation. Interestingly, CNP did not reduce ET-1-driven omental artery constriction.

Collectively, these data suggest that enhancing CNP signaling through NPR-B offers a potential therapeutic strategy to reduce systemic vascular constriction in preeclampsia.

We determined the epigenetic mechanisms regulating mean arterial pressure (MAP) and renal dysfunction in guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene-targeted mice. The Npr1 (encoding NPRA) gene-targeted mice were treated with class 1 specific histone deacetylase inhibitor (HDACi) mocetinostat (MGCD) to determine the epigenetic changes in a sex-specific manner. Adult male and female Npr1 haplotype (1-copy; Npr1+/-), wild-type (2-copy; Npr1+/+), and gene-duplicated heterozygous (3-copy; Npr1++/+) mice were intraperitoneally injected with MGCD (2 mg/kg) for 14 days. BP, renal function, histopathology, and epigenetic changes were measured. One-copy male mice showed significantly increased MAP, renal dysfunction, and fibrosis than 2-copy and 3-copy mice. Furthermore, HDAC1/2, collagen1alpha-2 (Col1α-2), and alpha smooth muscle actin (α-SMA) were significantly increased in 1-copy mice compared with 2-copy controls. The expression of antifibrotic microRNA-133a was attenuated in 1-copy mice but to a greater extent in males than females. NF-κB was localized at significantly lower levels in cytoplasm than in the nucleus with stronger DNA binding activity in 1-copy mice. MGCD significantly lowered BP, improved creatinine clearance, and repaired renal histopathology. The inhibition of class I HDACs led to a sex-dependent distinctive stimulation of acetylated positive histone marks and inhibition of methylated repressive histone marks in Npr1 1-copy mice; however, it epigenetically lowered MAP, repaired renal fibrosis, and proteinuria and suppressed NF-kB differentially in males versus females. Our results suggest a role for epigenetic targets affecting hypertension and renal dysfunction in a sex-specific manner.

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.

Heart failure (HF) and atrial fibrillation (AF) are prevalent cardiovascular diseases that contribute significantly to morbidity, mortality, hospitalisation, and healthcare costs. It is not uncommon for these conditions to coexist and have mutually reinforcing effects. A critical factor in the aetiology of these conditions is oxidative stress, driven by reactive oxygen species (ROS), which contributes to atrial remodelling and fibrosis. The recent introduction of new drugs for the treatment of heart failure has also had an impact on the management of atrial fibrillation due to their influence on oxidative stress. The objective of this review is to analyse the effects of these therapies, including their role in mitigating ROS, on the prevention and treatment of AF in HF patients.

The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans-membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman et al. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss-of-function variant of the gene encoding corin (Cor-/-). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac-derived ANP in these patients, as implied by Feldman et al. Yet, in this mini-review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na+ and water exertion. Collectively, it seems that beside the classic well-established cardio-renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion.

The pioneering work of Dr Lewis K. Dahl established a relationship between kidney, salt, and high blood pressure (BP), which led to the major genetic-based experimental model of hypertension. BP, a heritable quantitative trait affected by numerous biological and environmental stimuli, is a major cause of morbidity and mortality worldwide and is considered to be a primary modifiable factor in renal, cardiovascular, and cerebrovascular diseases. Genome-wide association studies have identified monogenic and polygenic variants affecting BP in humans. Single nucleotide polymorphisms identified in genome-wide association studies have quantified the heritability of BP and the effect of genetics on hypertensive phenotype. Changes in the transcriptional program of genes may represent consequential determinants of BP, so understanding the mechanisms of the disease process has become a priority in the field. At the molecular level, the onset of hypertension is associated with reprogramming of gene expression influenced by epigenomics. This review highlights the specific genetic variants, mutations, and epigenetic factors associated with high BP and how these mechanisms affect the regulation of hypertension and kidney dysfunction.

The prognostic significance of pretransplant N-terminal pro-brain (B)-type natriuretic peptide (NT-proBNP) level has not been investigated in lung transplant recipients. The electronic files of 173 patients with chronic lung disease who underwent lung transplantation in 2018-2022 at a tertiary medical center were retrospectively reviewed. Right heart catheterization (RHC) and NT-proBNP determination were performed preoperatively in all cases. Pretransplant demographic, clinical, and laboratory data were compared between posttransplant survivors and nonsurvivors. Correlations of NT-proBNP values with lung function and RHC parameters and all-cause mortality were analyzed. NT-proBNP level correlated positively with mean pulmonary artery pressure (R = 0.51, p < 0.001) and pulmonary vascular resistance (PVR) (R = 0.45, p = 0.0013), and negatively with diffusing lung capacity for carbon monoxide (R = -0.25, p = 0.0017), cardiac index (R = -0.26, p = 0.001), and cardiac output (R = -0.23, p = 0.004). Over a median follow-up time of 23.22 months, 74 patients died. On univariate analysis, mortality was significantly associated with higher log-NT-proBNP (hazard ratio [HR] = 0.54, 95% confidence interval [CI] 1.15-2.05, p = 0.016), older age at transplant registration (HR = 1.033, 95% CI 1.009-1.058, p = 0.0068), higher PVR (HR 1.15, 95% CI 1.07-1.23, p = 0.015), and lower cardiac output (HR = 0.62, 95% CI 0.42-0.92, p = 0.045). On multivariate analysis adjusted for age, sex, and body mass index, mortality significance was maintained only for higher log-NT-proBNP (HR = 1.54, 95% CI 1.12-2.11, p = 0.007). Among lung transplant recipients, pretransplant NT-proBNP levels correlated well with RHC parameters and were strongly associated with posttransplantation mortality. Assessment of NT-proBNP may improve risk stratification of lung transplant candidates.

Sodium and water retention is a mainstay of the pathophysiology leading to ascites formation in patients with advanced cirrhosis. Refractory ascites denotes the most severe ascites status with limited treatment options and a poor prognosis. We investigated the efficacy and safety of the natriuretic peptide ularitide in patients with refractory cirrhotic ascites.

We conducted a randomized placebo-controlled trial investigating ularitide to manage refractory ascites. Until trial termination after interim analyses, we randomized 17 participants in a 2:1 ratio between ularitide (n=11) and placebo (n=6). While hospitalized, the participants received treatment for up to 48 hours. The primary efficacy endpoint was a change in renal water excretion, and secondary end points included changes in renal sodium excretion rate and body weight. The starting dose was 30 ng/kg/min, though later reduced to 20 for safety reasons.

In contrast to the study hypothesis, the mean urine production decreased after 24 hours of ularitide treatment compared with the baseline level (22.8 vs. 47.5 mL/h, p=0.04) and decreased more in participants randomized to ularitide than placebo (24.7 vs. -6.2 mL/h, p=0.05). Ularitide did not increase the renal sodium excretion rate or reduce the weight gain. The incidence rate ratio of adverse reactions in ularitide versus placebo was 8.5 (95% CI: 2-35, p=0.003). Participants treated with ularitide developed serious blood pressure reductions, impacting their renal responsiveness.

Ularitide in doses of 20-30 ng/kg/min did not benefit urine production and renal sodium excretion rate in patients with refractory ascites. The participants randomized to ularitide overall developed more adverse reactions than placebo. EudraCT no. 2019-002268-28.

Left ventricular remodeling is an adaptive process initially developed in response to acute myocardial infarction (AMI), but it ends up with negative adverse outcomes such as infarcted wall thinning, ventricular dilation, and cardiac dysfunction. A prolonged excessive inflammatory reaction to cardiomyocytes death and necrosis plays the crucial role in the pathophysiological mechanisms. The pharmacological treatment includes nitroglycerine, β-blockers, ACEi/ARBs, SGLT2i, mineralocorticoid receptor antagonists, and some miscellaneous aspects. Stem cells therapy, CD34+ cells transplantation and gene therapy constitute the promissing therapeutic approaches for post AMI cardiac remodeling, thereby enhancing angiogenesis, cardiomyocytes differenciation and left ventricular function on top of inhibiting apoptosis, inflammation, and collagen deposition. All these lead to reduce infarct size, scar formation and myocardial fibrosis.

Whether serum concentration of procalcitonin (PCT), brain natriuretic peptide (BNP) and albumin (Alb) have an association with the outcome of hospitalized older patients is unclear. We investigated clinical outcomes and any predictive factors in hospitalized Japanese older patients with a risk of infection.

In the retrospective study, 820 Japanese patients were followed up for 30 days or until death. During the observation period, 656 patients survived and 164 patients died. The predictive factors of death were analyzed according to demographic and clinical variables.

The survival rate was decreased as the serum PCT increased from <0.5 to ≥10 ng/mL, as was also the case with BNP from <300 to ≥300 pg./mL, whereas low Alb (<2.5 g/dL) showed a lower survival rate than high Alb (≥2.5 g/dL; P < 0.01). Using the Cox regression model, the multivariable-adjusted hazard ratios (95% confidence interval) were as follows: PCT 0.5-2 versus <0.5 ng/mL: 1.61(1.04-2.49), PCT 2-10 versus <0.5 ng/mL: 1.91(1.15-3.16), PCT ≥10 versus <0.5 ng/mL: 2.90(1.84-4.59), high BNP 1.26 (0.89-1.76) and low Alb 0.68 (0.52-0.87). The mortality rate increased as the number of scores (PCT + BNP + Alb) increased.

Concentration-dependent high PCT, high BNP and low Alb were positive risk factors associated with poor prognosis in hospitalized older patients with a risk of infection. Geriatr Gerontol Int 2024; 24: 571-576.

While progress has been made in the management of most aspects of cardiovascular disease, the incidence and prevalence of heart failure (HF) remains high. HF affects around a million people in the UK and has a worse prognosis than most cancers. Patients with HF are often elderly with complex comorbidities, making accurate assessment of HF challenging. A timely diagnosis and initiation of evidence-based treatments are key to prevent hospitalisation and improve outcomes in this population. Biomarkers have dramatically impacted the way patients with HF are evaluated and managed. The most studied biomarkers in HF are natriuretic peptides (NPs). Since their discovery in the 1980s, there has been an explosion of work in the field of NPs and they have become an important clinical tool used in everyday practice to guide diagnosis and prognostic assessment of patients with HF. In this article, we will review the physiology of NPs and study their biological effects. Then, we will discuss the role of NPs in the diagnosis, management and prognostication of patients with HF. We will also explore the role of NPs as a potential therapeutic agent.

The cardiovascular system is mainly responsible for the transport of substances necessary to cellular metabolism. However, for the good performance of this function, there is need for adequate control of blood pressure levels of tissue perfusion and systemic arterial. Acute myocardial infarction is one of the complications of the cardiovascular system, that most affects the population around the world. This condition can be defined as a disease generated by an imbalance of oxygen concentrations used in cardiovascular metabolism, this change usually occurs because coronary occlusion, which prevents myocardial blood flow. The diagnosis is based on the set of clinical and laboratory investigations, which are in the release of cardiac enzyme biomarkers, cardiovascular and hemodynamic changes and cardiac accommodations. The treatment consists in the use of concomitant cardiovascular drugs, such as: antihypertensive, antiplatelet and hypolipidemic. Despite improvements in clinical and pharmacological management, acute myocardial infarction remains the leading cause of death worldwide. This finding encourages the scientific research of new drugs for the treatment of myocardial infarction or supporting therapies aimed at reducing the levels of deaths and comorbities generated by cardiovascular diseases.

LncRNA-based control affects cardiac pathophysiologies like myocardial infarction, coronary artery disease, hypertrophy, and myotonic muscular dystrophy. This study used a gene-break transposon (GBT) to screen zebrafish (Danio rerio) for insertional mutagenesis. We identified three insertional mutants where the GBT captured a cardiac gene. One of the adult viable GBT mutants had bradycardia (heart arrhythmia) and enlarged cardiac chambers or hypertrophy; we named it "bigheart." Bigheart mutant insertion maps to grin2bb or N-methyl D-aspartate receptor (NMDAR2B) gene intron 2 in reverse orientation. Rapid amplification of adjacent cDNA ends analysis suggested a new insertion site transcript in the intron 2 of grin2bb. Analysis of the RNA sequencing of wild-type zebrafish heart chambers revealed a possible new transcript at the insertion site. As this putative lncRNA transcript satisfies the canonical signatures, we called this transcript grin2bb associated RNA transcript (grin2bbART). Using in situ hybridization, we confirmed localized grin2bbART expression in the heart, central nervous system, and muscles in the developing embryos and wild-type adult zebrafish atrium and bulbus arteriosus. The bigheart mutant had reduced Grin2bbART expression. We showed that bigheart gene trap insertion excision reversed cardiac-specific arrhythmia and atrial hypertrophy and restored grin2bbART expression. Morpholino-mediated antisense downregulation of grin2bbART in wild-type zebrafish embryos mimicked bigheart mutants; this suggests grin2bbART is linked to bigheart. Cardiovascular tissues use Grin2bb as a calcium-permeable ion channel. Calcium imaging experiments performed on bigheart mutants indicated calcium mishandling in the heart. The bigheart cardiac transcriptome showed differential expression of calcium homeostasis, cardiac remodeling, and contraction genes. Western blot analysis highlighted Camk2d1 and Hdac1 overexpression. We propose that altered calcium activity due to disruption of grin2bbART, a putative lncRNA in bigheart, altered the Camk2d-Hdac pathway, causing heart arrhythmia and hypertrophy in zebrafish.

The need for biomarkers for acute ischemic stroke (AIS) to understand the mechanisms implicated in pathological clot formation is critical. The levels of the brain natriuretic peptides known as brain natriuretic peptide (BNP) and NT-proBNP have been shown to be increased in patients suffering from heart failure and other heart conditions. We measured their expression in AIS clots of cardioembolic (CE) and large artery atherosclerosis (LAA) etiology, evaluating their location inside the clots, aiming to uncover their possible role in thrombosis. We analyzed 80 thrombi from 80 AIS patients in the RESTORE registry of AIS clots, 40 of which were of CE and 40 of LAA etiology. The localization of BNP and NT-BNP, quantified using immunohistochemistry and immunofluorescence, in AIS-associated white blood cell subtypes was also investigated. We found a statistically significant positive correlation between BNP and NT-proBNP expression levels (Spearman's rho = 0.668 p < 0.0001 *). We did not observe any statistically significant difference between LAA and CE clots in BNP expression (0.66 [0.13-3.54]% vs. 0.53 [0.14-3.07]%, p = 0.923) or in NT-proBNP expression (0.29 [0.11-0.58]% vs. 0.18 [0.05-0.51]%, p = 0.119), although there was a trend of higher NT-proBNP expression in the LAA clots. It was noticeable that BNP was distributed throughout the thrombus and especially within platelet-rich regions. However, NT-proBNP colocalized with neutrophils, macrophages, and T-lymphocytes, suggesting its association with the thrombo-inflammatory process.

This study investigated prognostic factors in elderly patients (80 years and older) undergoing mechanical thrombectomy (MT) for anterior circulation large vessel occlusion (LVO) in acute stroke treatment. Of 59 cases, 47.5% achieved a favorable outcome (mRS ≤ 3) at three months, with a mortality rate of 20.3%. Factors associated with better outcomes included younger age, lower admission National Institute of Health Stroke Scale (NIHSS) scores, lower N-terminal pro-brain natriuretic peptide (NT-proBNP) and D-dimer levels, the presence of the first pass effect (FPE), and successful recanalization. However, logistic regression showed that only lower admission NIHSS scores were significantly correlated with favorable outcomes. In addition, this study suggests that lower admission NT-proBNP and D-dimer levels could potentially serve as prognostic indicators for elderly LVO patients undergoing MT.

Heart failure (HF) readmission post-transcatheter aortic valve implantation (TAVI) is common; however, its anatomical predictors remain unclear. This study identified a small systolic left ventricular inflow-outflow (LVIO) angle, evaluated using computed tomography, as a potential anatomical predictor associated with HF readmission post-TAVI. Patients with a small systolic LVIO angle may require close follow-up post-TAVI.