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AIMS To evaluate the performance of the WATCH-DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). METHODS AND RESULTS Adults with diabetes/pre-diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning- [WATCH-DM(ml)] and integer-based [WATCH-DM(i)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C-index) and calibration by the Greenwood-Nam-D'Agostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C-index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH-DM(ml) and WATCH-DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C-indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P ≥0.10). The C-index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (

Aims N‐terminal pro‐b‐type natriuretic peptide (NT‐proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT‐proBNP targets and clinical outcomes. Methods A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence‐Based Therapy Using Biomarker Intensified Treatment trial. NT‐proBNP was analysed every 3 months. Results Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43–76], and median BMI was 29 kg/m2 (IQR 25–34). Patients with AF, eGFR 60 mL/min/1.73 m2, P

Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans., Graphical Abstract An in-depth review of existing pre-clinical HFpEF mouse models with validation of their translational value using the HFA-PEFF and H2FPEF scores.

NPCdc is a natriuretic peptide synthesized from the amino acid sequence of the Crotalus durissus cascavella snake venom peptide, NP2Casca. NPCdc presents hypotensive and antioxidants effects. This study aimed to investigate in vivo whether angiotensin I-converting enzyme (ACE) inhibition would influence the impact of NPCdc in arterial pressure of rats submitted to 5/6 nephrectomy (Nx). Adult male Wistar rats following a 5/6 Nx were treated with enalapril (NxE group, 10 mg/kg/day, n = 9) or vehicle (Nx group, n = 8) for two weeks. On the 15th day after Nx, rats were anaesthetized and submitted to mean arterial pressure (MAP) determination before and after receiving two intravenous injections of saline (vehicle, n = 9) or NPCdc (0.3 μg/kg dissolved in saline, n = 18) separated by a 20-min interval. The kidneys were submitted to oxidative stress analysis. The basal MAP of the NxE group was nearly 20% lower (P 0.05) than non-treated rats. NPCdc administration decreased the MAP in both groups; however, in the NxE group, the effects were observed only in the second injection. The peptide also decreased the NADPH oxidase activity in the renal cortex. Additionally, the hydrolysis of NPCdc by recombinant neprilysin (NEP) was monitored by mass spectrometry. NPCdc was cleaved by NEP at different peptides with an inhibition constant (Ki) of 1.5 μM, determined by a competitive assay using the NEP fluorescence resonance energy transfer (FRET) peptide substrate Abz-(d)Arg-Gly-Leu-EDDnp. Docking experiments confirmed the high affinity of NPCdc toward NEP. These findings provide new insights into the antihypertensive and antioxidant mechanism of action of NPCdc. Altogether, the results presented here suggest that NPCdc must be further studied as a potential therapy for cardiorenal syndromes.

Deficits in upper and lower urinary tract function, which include detrusor overactivity, urinary incontinence, detrusor-sphincter dyssynergia, and polyuria, are among the leading issues that arise after spinal cord injury (SCI) affecting quality of life. Given that overproduction of urine (polyuria) has been shown to be associated with an imbalance in key regulators of body fluid homeostasis, the current study examined the timing of changes in levels of various relevant hormones, peptides, receptors, and channels post-contusion injury in adult male Wistar rats. The results show significant up- or downregulation at various time points, beginning at 7 days post-injury, in levels of urinary atrial natriuretic peptide, serum arginine vasopressin (AVP), kidney natriuretic peptide receptor-A, kidney vasopressin-2 receptor, kidney aquaporin-2 channels, and kidney epithelial sodium channels (β- and γ-, but not α-, subunits). The number of AVP-labeled neurons in the hypothalamus (supraoptic and -chiasmatic, but not paraventricular, nuclei) was also significantly altered at one or more time points. These data show significant fluctuations in key biomarkers involved in body fluid homeostasis during the post-SCI secondary injury phase, suggesting that therapeutic interventions (e.g., desmopressin, a synthetic analogue of AVP) should be considered early post-SCI.

B-type (or brain) natriuretic peptide (BNP) is synthesized in cardiac myocytes and released constitutively into the circulation. Pressure/volume overload, neurohumoral factors, cytokines, and ischemia enhance BNP gene expression, and then precursor proBNP is produced. It has been thought that proBNP is cleaved into active BNP molecule and inactive marker molecule NT-proBNP intracellularly by processing enzyme furin, and they are released into the circulation. However, recent studies have shown that considerable amount of uncleaved proBNP circulates in the blood. The commercially available BNP assay kits consist of two antibodies that sandwich the BNP molecule. Therefore, if proBNP is present, BNP assay kit cross-reacts to proBNP and measures it as BNP. Therefore, it should be noted that the current BNP value is proBNP plus BNP. BNP and NT-proBNP have been established as a biomarker for heart failure patients presenting dyspnea. But many pitfalls are present for interpreting the BNP value. For example, the presence of renal dysfunction, age, female sex, atrial fibrillation, inflammation, hyperthyroidism, use of sacubitril/valsartan, and macro-proBNPemia overestimate BNP value, whereas the presence of obesity, immediately after acute coronary syndrome onset, and pericardial effusion underestimate BNP value. In the management for heart failure patients, BNP plays an important role. Therefore, clinicians should note the pitfall of interpretation of BNP and we describe the mechanism involved.

Objective: To evaluate the possible associations between serum Neprilysin (NEP) levels and preeclampsia and mild and severe preeclampsia subgroups. Materials and methods: Fifty -five consecutive women with mild preeclampsia and fifty -five consecutive women with severe preeclampsia were compared with 110 approximately gestational age-matched (+/- 1 week) women with an uncomplicated pregnancy. Results: Mean serum NEP was significantly higher in women with preeclampsia compared to that of the gestational age-matched-controls (231.62 +/- 65.30 pg/mL vs. 187.75 +/- 84.38 pg/mL, p < 0.001). Mean serum NEP was significantly higher in the mild preeclampsia group compared to its gestational age -matched control group (228.84 +/- 67.26 pg/mL vs. 186.14 +/- 85.09 pg/mL, p = 0.008); and in the severe preeclampsia group compared to its gestational age-matched control group (234.45 +/- 63.85 pg/mL vs. 189.29 +/- 84.59 pg/mL, p = 0.004). Serum NEP was positively correlated with systolic and diastolic blood pressure, BUN, uric acid, and creatinine. Conclusion: Mean serum NEP was significantly higher in women with preeclampsia than women with an uncomplicated pregnancy. Further studies are needed to elucidate the possible therapeutic role of NEP inhibitors to treat preeclampsia. (c) 2021 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Istanbul Cerrahpasa University, Istanbul, Turkey; Carl von Ossietzky University Oldenburg, University Hospital for Obstetrics and Gynecology in Klinikum Oldenburg AoEuroR, Oldenburg, Germany This study was financed by Istanbul Cerrahpasa University, Istanbul, Turkey, and Carl von Ossietzky University Oldenburg, University Hospital for Obstetrics and Gynecology in Klinikum Oldenburg AoEuroR, Oldenburg, Germany.

Aims The cardiac natriuretic peptides (atrial natriuretic peptide [ANP] and B-type natriuretic peptide [BNP]) are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities. Methods and results We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP deficient (Nppa-/-) or BNP deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human derived induced pluripotent stem cell cardiomyocytes (iPS-CM). In the unstressed state, both ANP and BNP deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodeling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild type hearts to stress induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen activated protein kinase (p38 MAPK) signaling cascade. Conclusions Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signaling which sensitizes the heart to stress induced ventricular arrhythmias. Translational perspective Our study found that ANP or BNP deficiency leads to increased sudden death and ventricular arrhythmias after acute myocardial stress in murine models. We discovered that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels and uncovered a unique role for these peptides in regulating cardiomyocyte p38 MAPK and CREB signaling through a cGMP-PKG1 pathway. Importantly, this signaling pathway was conserved in human cardiomyocytes. This study provides mechanistic insight into how modulating natriuretic peptide levels in human heart failure patients reduces sudden death and mortality.

Aims Heart rate (HR) is a critical indicator of cardiac performance that is determined by sinoatrial node (SAN) function and regulation. Natriuretic peptides, including C-type NP (CNP), have been shown to modulate ion channel function in the SAN when applied exogenously. CNP is the only NP that acts as a ligand for natriuretic peptide receptor-B (NPR-B). Despite these properties, the ability of CNP and NPR-B to regulate HR and intrinsic SAN automaticity in vivo, and the mechanisms by which it does so, are incompletely understood. Thus, the objective of this study was to determine the role of NPR-B signalling in regulating HR and SAN function. Methods and results We have used NPR-B deficient mice (NPR-B+/−) to study HR regulation and SAN function using telemetry in conscious mice, intracardiac electrophysiology in anaesthetized mice, high-resolution optical mapping in isolated SAN preparations, patch-clamping in isolated SAN myocytes, and molecular biology in isolated SAN tissue. These studies demonstrate that NPR-B+/− mice exhibit slow HR, increased corrected SAN recovery time, and slowed SAN conduction. Spontaneous AP firing frequency in isolated SAN myocytes was impaired in NPR-B+/− mice due to reductions in the hyperpolarization activated current (If) and L-type Ca2+ current (ICa,L). If and ICa,L were reduced due to lower cGMP levels and increased hydrolysis of cAMP by phosphodiesterase 3 (PDE3) in the SAN. Inhibiting PDE3 or restoring cGMP signalling via application of 8-Br-cGMP abolished the reductions in cAMP, AP firing, If, and ICa,L, and normalized SAN conduction, in the SAN in NPR-B+/− mice. NPR-B+/− mice did not exhibit changes in SAN fibrosis and showed no evidence of cardiac hypertrophy or changes in ventricular function. Conclusions NPR-B plays an essential physiological role in maintaining normal HR and SAN function by modulating ion channel function in SAN myocytes via a cGMP/PDE3/cAMP signalling mechanism.

Background : N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. Objective : To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. Methods : In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels ( 3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. Results : A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. Conclusions : The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

We would thank Dr Gaetano Ruocco for his technical support and gure drafting.

Natriuretic peptides have long been known for their cardiovascular function. However, a growing body of evidence emphasizes the role of natriuretic peptides in the energy metabolism of several substrates in humans and animals, thus interrelating the heart, as an endocrine organ, with various insulin-sensitive tissues and organs such as adipose tissue, muscle skeletal, and liver. Adipose tissue dysfunction is associated with altered regulation of the natriuretic peptide system, also indicated as a natriuretic disability. Evidence points to a contribution of this natriuretic disability to the development of obesity, type 2 diabetes mellitus, and cardiometabolic complications; although the causal relationship is not fully understood at present. However, targeting the natriuretic peptide pathway may improve metabolic health in obesity and type 2 diabetes mellitus. This review will focus on the current literature on the metabolic functions of natriuretic peptides with emphasis on lipid metabolism and insulin sensitivity. Natriuretic peptide system alterations could be proposed as one of the linking mechanisms between adipose tissue dysfunction and cardiovascular disease.

Background Physiological adaptation in pregnancy is characterized by remodeling of endocrine, cardiovascular and renal functions leading to fluid retention, volume expansion, altered cardiac loading conditions and hyperdynamic circulation. Natriuretic peptides have been used as biomarkers of cardiovascular function, but their associations with gestational age-related changes in maternal cardiac, endothelial and renal function have not been elucidated. The aim of this study was to establish longitudinal reference values for maternal plasma atrial natriuretic peptide (proANP) and C-type natriuretic peptide (CNP) and investigate their temporal association with cardiovascular and renal function in the second half of pregnancy. Methods This study was a prospective longitudinal study of 53 low-risk pregnancies. Women were examined every 3–5 weeks during 22–40 weeks of gestation (252 observations). Fasting maternal blood samples were obtained to measure proANP, CNP, creatinine, cystatin C, uric acid, and fibrinogen levels. Cardiac function and systemic hemodynamics were assessed noninvasively by impedance cardiography (ICG) and vascular endothelial function by flow-mediated vasodilation of brachial artery (FMD). Results The plasma proANP (R2adj = 0.79; P = 0.007), CNP (R2adj = 0.54; P = 0.005) decreased between 22 and 40 weeks. The creatinine (R2adj = 0.90; P 2adj = 0.93; P = 2adj = 0.83; P 2adj = 0.93; P 2adj = 0.79; P 2adj = 0.50; P 2adj = 0.62; P 2adj = 0.62; P = 0.438) and thoracic fluid content (R2adj = 0.72; P = 0.132) did not change significantly with gestation. The proANP was associated with thoracic fluid content (R2adj = 0.74; P 2adj = 0.78; P = 0.034) but not with other variables of systemic hemodynamics, endothelial function, or renal function. The CNP was not associated significantly with parameters of cardiovascular or renal function. Conclusion Longitudinal reference values for maternal plasma proANP and CNP were established. These natriuretic peptides decreased slightly with advancing gestation, but they did not reflect the temporal physiological changes in maternal systemic hemodynamics, vascular endothelial function and renal function during the second half of pregnancy. The proANP correlated with the thoracic fluid content reflecting volume load in pregnancy.

Objectives: The authors aimed to evaluate the role of N-terminal proANP (NT-proANP) and of NT-proBNP circulating levels as predictive markers of death due to systemic sclerosis (SSc).Methods: The a...

Background and Purpose: Outcome prognostication in ischemic stroke patients remains challenging due to limited predictive properties of existing models. Blood-based biomarkers might provide additional information to established prognostic factors. We intended to identify the most promising prognostic biomarkers in ischemic stroke, their incremental prognostic value, and whether their predictive value differs among etiologies. Methods: We searched MEDLINE (Ovid) and Institute for Scientific Information Web of Knowledge for articles reporting the predictive performance of blood-based biomarkers measured up to 7 days after ischemic stroke and reporting functional outcome or death at least 7 days after stroke. This work updates a previous systematic review (up to January 2007), follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and was registered (International Prospective Register of Systematic Reviews PROSPERO 2018; https://www.crd.york.ac.uk/PROSPERO /; Unique identifier: CRD42018094671). Results: Two hundred ninety-one articles published between January 2007 and August 2018 comprising 257 different biomarkers met inclusion criteria. Median sample size was 232 (interquartile range, 110–455); 260 (89%) articles reported regression analyses with 78% adjusting for stroke severity, 82% for age, 67% for both, and 9% for none of them; 37% investigated discrimination, 5% calibration, and 11% reclassification. Including publications from a previous systematic review (1960–January 2007), natriuretic peptides, copeptin, procalcitonin, mannose-binding lectin, adipocyte fatty acid–binding protein, and cortisol were the biomarkers most consistently associated with poor outcome in higher-quality studies showing an incremental value over established prognostic factors. Other biomarkers were less consistently associated with poor outcome or were reported in lower quality studies. High heterogeneity among studies precluded the performance of a meta-analysis. Conclusions: The number of reports on prognostic blood-based biomarkers in ischemic stroke increased 3.5-fold in the period January 2007 to August 2018. Although sample size increased, methodological flaws are still common. Natriuretic peptides and markers of inflammation, atherogenesis, and stress response are the most promising prognostic biomarkers among identified studies.

Purpose of review Chronic kidney disease (CKD) is associated with increased risk of progression to end-stage kidney disease and cardiovascular events. There is limited evidence that available treatments have beneficial effects on cardiorenal outcomes in all people with nondiabetic CKD. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. Recent findings NEPi enhances the activity of the natriuretic peptide system producing natriuresis, diuresis and inhibition of the renin–angiotensin system and sympathetic nervous system. Sacubitril/valsartan is the first Angiotensin receptor-neprilysin inhibitor (ARNI) to be produced and has been shown to substantially improve cardiovascular outcomes in heart failure and delay progression of kidney disease in this population. Although ARNIs have not shown similar effects on kidney function in the short-to-medium term in people with CKD, they are associated with substantial reductions in cardiac biomarkers and blood pressure in CKD. Summary These data suggest that NEPi with an ARNI could benefit patients with CKD by reducing the risk of cardiovascular disease and have the possibility of retarding the progression of CKD (hence delaying the need for renal replacement therapy).

Treatment of patients with heart failure with reduced ejection fraction (HFrEF) with currently available therapies reduces morbidity and mortality. However, implementation of these therapies is a problem with only few patients achieving guideline-recommended maximal doses of therapy. In an effort to improve guideline adherence and uptitration, several trials have investigated a biomarker-guided strategy (using natriuretic peptide targets in specific), but although conceptually promising, these trials failed to show a consistent beneficial effect on outcomes. In this review, we discuss different methodological issues that may explain the failure of these trials and offer potential solutions. Moreover, alternative approaches to increase heart failure guideline adherence are evaluated.

Background/Aim. The evaluation of blood levels of cardiac troponin I (cTnI), D-dimer, B-type natriuretic peptide (BNP), and C-reactive protein (CRP) on admission and during the treatment of pulmonary embolism (PE) are the part of routine diagnostic process and estimation of mortality risk. The aim of this study was to evaluate the predictive value of these biomarkers on admission for all-cause 30-day mortality in consecutive PE patients regarding whether they classified as spontaneous, transiently provoked, or permanently provoked PE. Methods. This retrospective analysis was gained from the data of 590 PE patients from the Serbian University Multicenter Pulmonary Embolism Registry (SUPER). Patients had at least one of these biomarkers (BNP, CRP, cTnI, and D-dimer) measured during the first 24 hours upon admission. Results. Receiver operating characteristic (ROC) curve analyses demonstrated that BNP had the highest prognostic accuracy for 30-day mortality in patients (n = 219) who had data for all examined biomarkers. BNP provided an AUC of 0.785 (p < 0.001). Separately, BNP had the highest c-statistic for all three groups of patients. CRP had a modest predictive value for the 30-day all-cause mortality in the group with transient provoked PE. Troponin I had a very modest predictive value for the 30-day all-cause mortality only in patients with spontaneous PE, and D-dimer was a very weak predictor of this end-point only in patients with persistent provoked PE. Conclusion. Patients with spontaneous, transient provoked, and persistent provoked PE have a significantly different pro-file of blood biomarkers level with different prognostic significance for early all-cause mortality.

Background Obese patients have lower plasma concentrations of the cardiac natriuretic peptides (NPs) than their age- and sex-matched counterparts. This may reflect lower production and/or increased peptide clearance. It is unclear whether NP bioactivity is affected by obesity. Methods We studied the effects of obesity on B-type natriuretic peptide (BNP) clearance and bioactivity by comparing results from standardized intravenous infusions of BNP administered 2 weeks before and 6 months after bariatric surgery in 12 consecutive patients with morbid obesity (body mass index, BMI > 35 kg/m2). Anthropometric, clinical, neurohormonal, renal, and echocardiographic variables were obtained pre- and postsurgery. Pre- vs postsurgery calculated intrainfusion peptide clearances were compared. Results BMI (44.3 ± 5.0 vs 33.9 ± 5.2 kg/m2, P Conclusion Obesity is associated with increased clearance, but preserved bioactivity, of BNP.

OBJECTIVE Few studies have compared midregional proatrial natriuretic peptide (MR-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP). We compared their value as risk markers for all-cause mortality and cardiovascular (CV) and renal complications in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS MR-proANP and NT-proBNP were measured in 664 individuals. Hazard ratios (HRs) were assessed per doubling of NT-proBNP or MR-proANP for risk of a composite of ischemic events, heart failure (HF), a combined renal end point of end-stage kidney disease (ESKD), decline in estimated glomerular filtration rate (eGFR) ≥30%, and all-cause mortality or individual end points. Adjustments included CV risk factors and addition of MR-proANP or NT-proBNP. RESULTS Median follow-up was 5.1–6.2 years. MR-proANP was associated with higher risk of all-cause mortality (n = 57; HR 1.7, 95% CI 1.1–2.7), combined CV end point (n = 94; 1.6, 1.1–2.2), HF (n = 27; 2.8, 1.5–5.2), combined renal end point (n = 123; 1.6, 1.2–2.1), and ESKD (n = 21; 3.1, 1.2–7.8) independent of CV risk factors (P ≤ 0.02). After addition of NT-proBNP, significance for all end points was lost. A doubling of NT-proBNP was associated with higher risk of all-cause mortality (HR 1.5, 95% CI 1.2–1.8), the combined CV end point (1.3, 1.1–1.5), HF (1.7, 1.3–2.1), and the combined renal end point (1.3, 1.1–1.4) independent of CV risk factors (model 2 [P < 0.001]) and MR-proANP (model 3 [P ≤ 0.03]). There was no association with decline in eGFR ≥30% (n = 93). CONCLUSIONS Higher NT-proBNP was independently associated with all-cause mortality, CV disease, HF, and the combined renal end point. MR-proANP was associated with all end points but decline in eGFR, although not independent of NT-proBNP. MR-proANP may contribute to the predictive value of NT-proBNP for risk stratification in type 1 diabetes.

Aims Morbid obesity is a risk factor for cardiovascular disease. The relative effects of Roux-en-Y gastric bypass surgery (GBS) and intensive lifestyle intervention (ILI) on subclinical myocardial injury, the activity of the cardiac natriuretic system, and systemic inflammation remain unclear. Methods In a 59-week non-randomized clinical trial that included 131 patients with morbid obesity, we compared the effects of GBS and ILI on concentrations of cardiac troponin T (cTnT) and I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP). Results In the GBS and ILI group, median body mass index (BMI) was reduced by 14.4 kg/m2 versus 3.9 kg/m2, respectively (p value < 0.001). Cardiac troponins decreased after GBS, p = 0.014 (cTnT) and p = 0.065 (cTnI) and increased significantly in those treated with ILI (p values ≤ 0.021) (between-group differences for deltas: p ≤ 0.003). NT-proBNP increased in both groups, but significantly more in the GBS than in the ILI group (between-group differences for deltas: p = 0.008). CRP decreased significantly within the GBS and the ILI group, with this change significantly greater in the GBS group (between-group differences for deltas p < 0.001). The dominating mediator of the biomarker changes was weight loss. Prior coronary artery disease and diabetes were predictive of the magnitude of the changes in cTnI and NT-proBNP, respectively. Conclusion Compared to ILI, GBS was associated with reduced subclinical myocardial injury and systemic inflammation, and enhancement of the cardiac natriuretic peptide system. The biomarker changes were predominantly mediated by weight loss.

Heart failure is one of the leading healthcare problems in the world. Clinical data lacks sensitivity and specificity in the diagnosis of heart failure. Laboratory biomarkers are a non-invasive method of assessing suspected decompensated heart failure. Biomarkers such as natriuretic peptides have shown promising results in the management of heart failure. The literature does not provide comprehensive guidance in the utilization of biomarkers in the setting of acute heart failure syndrome. Many conditions that manifest with similar pathophysiology as acute heart failure syndrome may demonstrate positive biomarkers. The following is a review of biomarkers in heart failure, enlightening their role in diagnosis, prognosis and management of heart failure.

Studies on the association of elevated B-type natriuretic peptide (BNP)/N-terminal pro-B-type natriuretic peptide (NT-proBNP) level with adverse clinical outcomes have yielded conflicting results in patients with atrial fibrillation (AF). This meta-analysis aimed to assess the prognostic value of BNP/NT-proBNP level in AF patients. A comprehensive literature search was conducted using PubMed and Embase databases up to July 1, 2020. Studies investigating the association between BNP/NT-proBNP level and adverse clinical outcomes in patients with AF were eligible. Outcome measures were all-cause mortality, stroke/systemic embolism, major bleed, and major adverse cardiovascular events (MACEs). Ten studies recruiting 29 543 patients with AF were included. Elevated BNP/NT-proBNP level was independently associated with higher risk of all-cause mortality (risk ratios [RR] 1.92; 95% confidence intervals [CI] 1.50-2.45), stroke/systemic embolism (risk ratio [RR] 2.53; 95% CI 2.00-3.19), and MACEs (RR 2.17; 95% CI 1.89-2.49). However, the association between elevated BNP/NT-proBNP level and major bleed was not statistically significant (RR 1.14; 95% CI 0.92-1.40). Elevated BNP/NT-proBNP level is significantly associated with higher risk of all-cause mortality, stroke/systemic embolism, and MACEs. Determination of BNP/NT-proBNP level may play an important role in risk stratification of AF patients.

ObjectivesNatriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice.MethodsThe Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fractionResultsOf 1159 patients (mean age: 72.1±10.2 years, median CHA2DS2-VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169–1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA2DS2-VASc scores and had more OAC prescription (all pConclusionNT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value.Trial registration numberUMIN000005834.

Introduction In patients with heart failure with reduced ejection fraction (HFrEF), volume overload is associated with mortality. Few studies that have examined the relation between volume and long-term kidney function outcomes in HFrEF. Methods Using data from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression models to evaluate the association between volume overload as evaluated by B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), and a clinical congestion score (scale of 0–12) composed of pedal edema, jugular venous distension, rales, and orthopnea with the occurrence of estimated glomerular filtration rate (eGFR) decline by >40%, and incident chronic kidney disease (CKD) stage ≥4 defined by eGFR of 40% and 337 (10%) developed incident CKD stage ≥4. In multivariable models, compared with those in the quartile of lowest NT-proBNP, those within the highest quartile had a significantly higher risk of eGFR decline by >40% (hazard ratio [HR] = 2.62 [95% confidence interval {CI} = 1.62, 4.23]) and incident CKD stage ≥4 (HR = 2.66 [95% CI = 1.49, 4.77]), with similar trends for BNP. Similarly in multivariable models, patients in the quartile of highest congestion score had a 48% increased risk for eGFR decline by >40% (HR = 1.48 [95% CI = 1.07, 2.06]) and a 42% increased risk for CKD stage ≥4 (HR = 1.42 [95% CI = 1.01, 1.99]), compared with the lowest quartile. Conclusion Volume overload, as indicated both by elevated natriuretic peptides and clinical signs and symptoms, is associated with increased risk for clinically important kidney function outcomes in HFrEF., Graphical abstract

Cell‐cycle regulatory proteins (p21Cip1/p27Kip1) inhibit cyclin and cyclin‐dependent kinase (CDK) complex that promotes fibrosis and hypertrophy. The present study examined the role of CDK blockers, p21Cip1/p27Kip1 in the progression of renal fibrosis and dysfunction using Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor‐A, GC‐A/NPRA) gene‐knockout (0‐copy; Npr1−/−), 2‐copy (Npr1+/+), and 4‐copy (Npr1++/++) mice treated with GC inhibitor, A71915 and cGMP‐dependent protein kinase (cGK) inhibitor, (Rp‐8‐Br‐cGMPS). A significant decrease in renal cGMP levels and cGK activity was observed in 0‐copy mice and A71915‐ and Rp‐treated 2‐copy and 4‐copy mice compared with controls. An increased phosphorylation of Erk1/2, p38, p21Cip1, and p27Kip1 occurred in 0‐copy and A71915‐treated 2‐copy and 4‐copy mice, while Rp treatment caused minimal changes than controls. Pro‐inflammatory (TNF‐α, IL‐6) and pro‐fibrotic (TGF‐β1) cytokines were significantly increased in plasma and kidneys of 0‐copy and A71915‐treated 2‐copy mice, but to lesser extent in 4‐copy mice. Progressive renal pathologies, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were observed in 0‐copy and A71915‐treated 2‐copy and 4‐copy mice, but minimally occurred in Rp‐treated mice compared with controls. These results indicate that Npr1 has pivotal roles in inhibiting renal fibrosis and hypertrophy and exerts protective effects involving cGMP/cGK axis by repressing CDK blockers p21Cip1 and p27Kip1.

An enormous amount of experimental and clinical evidence has clearly shown that the measurement of cardio-specific biomarkers is able to significantly and independently improve the diagnostic accuracy and risk stratification in cardiovascular diseases. Furthermore, many recent studies have reported that the measurement of cardio-specific biomarkers has a positive impact also on the management and outcome of patients with cardiovascular diseases. Considering the significant and independent information associated with cardio-specific biomarkers, several studies have recently reported that the combined dosage of natriuretic peptides and cardiac troponins may be convenient not only for the diagnosis, prognosis, and treatment of heart disease, but also for general screening of the population for individuals with high cardiovascular risk. Due to the higher cost of cardio-specific biomarkers compared with other laboratory tests, the clinical adequacy of the combined measurement of natriuretic peptides and cardiac troponins must be carefully evaluated. Consequently, an increase in the clinical use of a laboratory test should be based not only on the favorable pathophysiological characteristics of a biomarker, but also on the high performance of the methods used for biomarker dosing. The purpose of this review is to discuss the clinical relevance and the possible cost efficiency of the combined dosage of natriuretic peptides and cardiac troponins in some clinical conditions, in particular those most frequently observed in patients with critical illnesses admitted to the emergency room.

Background: It is a matter of debate whether sodium and potassium intake are associated with heart disease. Further, the mechanisms underlying associations of sodium and potassium intake with cardiac events, if any, are not fully understood.Objectives: We examined cross-sectional associations of 24-h urinary sodium excretion (UNaE) and potassium excretion (UKE), as estimates of their intakes, with high-sensitivity cardiac troponins T (hs-cTnT) and I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), which are markers of cardiomyocyte injury and cardiac dysfunction.Methods: We included 2961 participants from the population-based Maastricht Study (mean +/- SD age 59.8 +/- 8.2 y, 51.9% men), who completed the baseline survey between November 2010 and September 2013. Associations were examined with restricted cubic spline linear regression analyses and ordinary linear regression analyses, adjusted for demographics, lifestyle, and cardiovascular disease (CVD) risk factors.Results: Median [QR] 24-h UNaE and UKE were 3.7 (2.8-4.71 g/24 h and 3.0 12.4-3.61 g/24 h, respectively. After adjustment for potential confounders, 24-h UNaE was not associated with hs-cTnT, hs-cTnI, and NT-proBNP concentrations. In contrast, after adjustment for potential confounders, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. For example, as compared with the third/median quintile of 24-h UKE (range: 2.8-3.2 g/24 h), participants in the first quintile (range: 0.5-2.3 g/24 h) had 1.05 (95% CI: 0.99, 1.11) times higher hs-cTnT and 1.14 (95% CI: 1.03, 1.26) times higher NT-proBNP. Associations were similar after further adjustment for estimated glomerular filtration rate, albuminuria, blood pressure, and serum potassium.Conclusions: Twenty-four-hour UNaE was not associated with the studied cardiac biomarkers. In contrast, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. This finding supports recommendations to increase potassium intake in the general population. In addition, it suggests that cardiac dysfunction and/or cardiomyocyte injury may underlie previously reported associations of lower potassium intake with CVD mortality.

The objective: to present current information about definitions, etiopathogenesis, clinical, laboratory and hemodynamic manifestations of septic cardiopathy, based on published data and the results of our own research.Results: septic cardiopathy is the most important pathogenetic component of sepsis, and cardiac dysfunction makes a significant contribution to its outcomes. It is found out that after staying in the intensive care unit for 3-4 days, the level of the inactive part of the precursor of the B-type natriuretic peptide (NT-proBNP) > 3,450 pg/ml indicates of the risk of death: area under ROC curve (AUC) 0.708 (p = 0.0041), sensitivity 63.6%, and specificity 66.7%. At the same time, NT-proBNP > 5,250 pg/ml is associated with the use of inotropic drugs: AUC 0.769 (p = 0.0007), sensitivity 76.9%, specificity 79.0%. The article describes the detection of septic cardiopathy using transpulmonary thermodilution and calculation of such indices as afterload-related cardiac performance and cardiac function index. Data on the age-related parameters of central hemodynamics and risk of pathological decrease in certain blood circulation indices characteristic of older patients are presented. The article discusses the feasibility of treating septic cardiopathy as a variant of acute heart failure, which can be manifested not only by a decreased systolic function (low left ventricular ejection fraction) but also by increased end-diastolic pressure in the ventricles (diastolic dysfunction) with a normal left ventricular ejection fraction.

The objective: based on the published data to describe the conceptual issues of the problem of perioperative cardiac complications in non-cardiac surgery.Results: changes made to international guidelines over the past 3–4 years based on evidence-based studies and meta-analyzes have been analyzed. The article presents data on the etiopathogenesis of various postoperative cardiac complications, assessment of their risk based on the evaluation of functional activities of patients, cardiac risk indices, and modern biomarkers (B-type natriuretic peptides, cardiospecific troponins). The contemporary recommendations on adjuvant pharmacological cardioprotection and rational pharmacotherapy in the perioperative period are analyzed. The article describes specific parameters of diagnostic, treatment and prevention tactics in patients with coronary heart disease, hypertension, chronic heart failure, heart defects, and implanted electronic devices. It concludes that the implementation of the comprehensive strategy aimed at the reduction of risk of pulmonary complications should ensure the decrease in their frequency and mortality due to them.

Biomarkers are well established for the diagnosis of myocardial infarction, heart failure and cardiac fibrosis. Different papers on cardiac biomarker evolution during exercise have been published in the literature and generally show mild to moderate elevations. However, the mechanism responsible for these elevations, reflecting physiological or even pathophysiological changes, still has to be clearly elucidated. There are also indications of higher cardiac risk in poorly trained athletes than in well-trained athletes. Whether regular repetition of intensive exercise might lead, in the longer term, to fibrosis and heart failure remains to be determined. In this review, we summarized the main research about the effects of intense exercise (in particular, running) on cardiac biomarkers (including troponins, natriuretic peptides, etc.). We found that cardiac fibrosis biomarkers seemed to be the most informative regarding the biological impact of intense physical activity.

Natriuretic peptides (NPs) have been reported to have critical roles in follicular development and oocyte maturation in rodents. This study aimed to extend our current understanding of NP-mediated signalling pathways and mechanisms of action in the follicles of a monovulatory species. Ovine granulosa cells (GCs) and theca cells (TCs) were cultured under conditions designed to allow gonadotrophin-stimulated cell differentiation. Gene expression analysis was performed by qualitative (q)PCR for NPs and NPRs (between 16 and 96 h of culture) and VEGF120 and VEGF164 (between 16 and 144 h of culture). A qualitative analysis of the production of NP/NPR family members and NP ligand/receptor associations was carried out utilising a highly sensitive immunological approach known as ‘proximity ligation assay’ (PLA). All NPRs were observed in GCs, while NPRA was absent in TCs. In GCs, gene expression of NPRA, NPRB and NPRC was apparent but only active BNP and CNP and not ANP, were detected. Also in GCs, ANP but not CNP was able to significantly (P P 164 by ANP and CNP (P 120 by ANP (P

OBJECTIVES: The authors sought to evaluate the prognostic significance of baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. BACKGROUND: Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). METHODS: In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. RESULTS: Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. CONCLUSIONS: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). ispartof: JACC-HEART FAILURE vol:8 issue:5 pages:372-381 ispartof: location:United States status: published

Cardiac Resynchronization Therapy (CRT) is an effective treatment strategy for heart failure. It significantly improves clinical symptoms and decreases mortality and long-term morbidity. However, some patients do not respond properly to this treatment. In this review, the role of different biomarkers in predicting response to CRT is discussed. Some biomarkers, including natriuretic peptides and inflammatory markers have promising results but further trials are needed for more evaluation. Methods: All the studies reporting the extent of biomarkers for predicting the response to cardiac resynchronization therapy were included in this study. For studies using the same database, the ones with a higher number of cases and more complete data were included. Conclusions were drawn from relevant randomized controlled clinical trials and meta-analyses about CRT implantation and its associated alterations in biomarker levels. Cardiac Resynchronization in Heart Failure (CARE-HF) study was the first and the largest study on patients with CRT with the longest followup, which showed a significant correlation between BNP levels and long-term CRT outcome. CRP has been demonstrated to be a mediator of inflammation and a marker indicating the presence of an inflammatory process. Conclusion: Natriuretic peptides, including BNP, markers of collagen synthesis like PINP, inflammatory markers, especially CRP, gal-3, and CT-apelin yield promising results in left ventricular remodeling and their relationship with response to CRT implantation is seen. Although more research is needed in this area as little information is available for baseline and preprocedural measurements, so that it would be easy to choose appropriate candidates for CRT implantation.

Introduction: As an analogue of uroguanylin plecanatide binds to the Guanylate Cyclase-C receptor activating fluid and ion secretion in the small intestine with the same pH-dependent binding kinetics as the natural ligand. Plecanatide has been FDA approved as safe and effective for the indications of Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C).Areas covered: All clinical trial results supporting approval of plecanatide in IBS-C are reported, evaluated and interpreted in the context of the complex pathophysiology of functional diseases and the barriers that must be overcome for appropriate protocol design and conduct.Expert opinion: The Expert Opinion section discusses safety and efficacy of plecanatide for IBS-C. Broader consideration of some of the inherent challenges in understanding and treating functional gastrointestinal disorders includes: 1. the difficulty of understanding diseases with complex pathophysiology that clinically present with a few simple symptoms, 2. exploring the pathophysiology of functional diseases using pharmacophysiology, 3. value of 'Set Theory' in the evaluation of complex clinical data and 4. physiologic and pathophysiologic insight gained by evaluation 'physiologic redundancy' and 'conservation of function'.

In clinical practice, atrial fibrillation (AF) is known as the most common sustained arrhythmia. Therefore, identification of individuals at risk of AF development/recurrence or its associated complications has emerged as a hot topic in the field of cardiology. Recently, several biomarkers have been introduced to predict AF and its consequences; however, use of biomarkers in AF management has not been highly recommended by guidelines yet. While utilization of natriuretic peptides (NPs) including brain (B-type) NPs (BNPs) in heart failure management has been well established, their use in relation to AF has not been fully understood. Accordingly, this review article aimed at presenting an overview of the role of NPs in predicting AF development/recurrence as well as its complications and making suggestions for their use in management of patients with AF in clinical settings.

Symptoms of heart failure (HF) are due in large part to elevation of left and/or right ventricular filling pressures. Although abnormal diastolic function is difficult to define, it contributes to the elevation of filling pressures. Tests that characterize aspects of diastolic function or structural changes associated with diastolic dysfunction, may help in establishing a diagnosis of HF, assessing prognosis, and guiding treatments. Individual echocardiographic parameters correlate weakly with LV (LV) filling pressures measured directly. However, a combination of multiple parameters improves accuracy for detection of elevated filling pressures. Serum natriuretic peptide levels are related to ventricular filling pressures and, when elevated, are a key diagnostic criterion for HF. Currently available evidence is not adequate to recommend serial echocardiographic studies or natriuretic peptide level measurements to assess changes in filling pressures or to guide HF therapy. Measurements of inferior vena cava size and dynamics have potential for identifying inadequate decongestion during episodes of acute decompensated HF but have not yet demonstrated utility in improving HF outcomes. Direct measurement of LV filling pressures using implanted pressure sensors is the only "diastolic assessment" thus far that has proven efficacy in reducing HF hospitalization rates.

AIMS: Heart failure (HF) patients are at high-risk of cardiovascular (CV) events, including CV death. Nonetheless, a substantial proportion of these patients die from non-CV causes. Identifying patients at higher risk for each individual event may help selecting patients for clinical trials and tailoring cardiovascular therapies. The aims of the present study are to: (i) characterize patients according to CV vs. non-CV death; (ii) develop models for the prediction of the respective events; (iii) assess the models' performance to differentiate CV from non-CV death. METHODS AND RESULTS: This study included 2309 patients with HF from the BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Competing-risk models were used to assess the best combination of variables associated with each cause-specific death. Results were validated in an independent cohort of 1738 HF patients. The best model to predict CV death included low blood pressure, estimated glomerular filtration rate ≤ 60 mL/min, peripheral oedema, previous HF hospitalization, ischaemic HF, chronic obstructive pulmonary disease, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin (c-index = 0.73). The non-CV death model incorporated age > 75 years, anaemia and elevated NT-proBNP (c-index = 0.71). Both CV and non-CV death rose by quintiles of the risk scores; yet these models allowed the identification of patients in whom absolute CV death rates clearly outweigh non-CV death ones. These findings were externally replicated, but performed worse in a less severely diseased population. CONCLUSIONS: Risk models for predicting CV and non-CV death allowed the identification of patients at higher absolute risk of dying from CV causes (vs. non-CV ones). Troponin helped in predicting CV death only, whereas NT-proBNP helped in the prediction of both CV and non-CV death. These findings can be useful both for tailoring therapies and for patient selection in HF trials in order to attain CV event enrichment.

Objective The focus of this review was to elicit the mechanistic logic of the experimental and clinical study designs of natriuretic peptides (NP) in acute kidney injury (AKI) and to understand their respective outcomes. Methods Online search of PubMed and manual review of articles. Randomized trials, observational and physiologic studies of NPs and AKI were extracted. Rationale, design and study outcomes were analyzed. Results In experimental models of AKI, infusion of NP prevented post-ischemic fall in renal blood flow (RBF) or improvement in RBF, GFR, diuresis and natriuresis and demonstrated anti-inflammatory properties. NPs were most effective in the early stages of AKI, also in established phase of AKI but their effectiveness were limited to the time of infusion. Hypotension was a major side-effect. Based on these observations, preliminary clinical studies were performed which demonstrated improved urine output, RBF and GFR and reduced need for dialysis. However, randomized, controlled trials failed to demonstrate improvement in dialysis-free survival in different cohorts and study designs. Although NPs reduced the incidence of AKI in the postoperative period in cardiac surgery, it was not associated with improved long-term survival. In contrast to randomized trials, meta-analysis reported favorable results. Conclusions Reasons for the divergence of experimental and clinical outcomes of NPs in AKI are discussed in this review article.

There is robust clinical trial evidence supporting the role of natriuretic peptides [NPs] in the assessment of patients presenting with suspected acute heart failure [AHF]. Despite the fact that clinical guidelines have for some time advocated NP measurement, the availability and uptake of NP testing in acute care services remains patchy and incomplete. The reasons for this are multifactorial but are underpinned by compartmentalised management and budget structures within complex healthcare delivery organisations. This paper outlines a value proposition for NP testing in the acute care setting which crosses the continuum of services and budgets. It articulates the expected benefits to each stakeholder in terms of efficiency of processes, clinical outcomes and cost effectiveness. It describes a pathway to implementation and suggests metrics that may be used to measure the effectiveness of introduction of NP testing. It is hoped that the value proposition will facilitate the uptake of NT testing fostering collaboration between laboratory, clinical, management and finance teams and by informing the development of business cases.

Left atrial appendage (LAA) exclusion is the cornerstone of stroke prevention in surgical treatment of atrial fibrillation (AF). Still, little is known about the direct hemodynamic consequences of LAA closure. In the current pilot study, where we aimed to evaluate these consequences in patients undergoing hybrid AF ablation with LAA exclusion by an atrial clip, seven patients were included. Hemodynamic and intracardiac pressure measurements such as systemic, pulmonary artery (PA), central venous and LA pressure, cardiac output and indexed left ventricular stroke volume (LVSVi) were measured directly before (T0) and after (T1), and 10 minutes after (T2) LAA closure. We found no differences between all timepoints for LA pressure, PA pressure and LVSVi. As such, this is the first study describing the direct hemodynamic consequences of LAA exclusion. LAA exclusion by use of an atrial clip is safe and does not directly affect hemodynamic and intracardiac pressures.

Cardiac tumours are exceedingly rare. The incidence rate of these tumours is around 0.02%. Primary tumours are far less common than metastases to heart. Myxomas are the most common primary cardiac ...

Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is natriuretic peptides. The natriuretic peptide clearance receptor (NPRC) binds and degrades natriuretic peptides. As a result, NPRC inhibits natriuretic peptide‐induced cGMP generation. To enhance cGMP generation in podocytes, we blocked natriuretic peptide clearance using the specific NPRC ligand ANP(4‐23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non‐TG animals. We found that natriuretic peptides protected cultured podocytes from PAN‐induced apoptosis, and that ANP(4‐23) enhanced natriuretic peptide‐induced cGMP generation in vivo. PAN‐induced heavy proteinuria in vehicle‐treated TG mice, and this increase in albuminuria was reduced by treatment with ANP(4‐23). Treatment with ANP(4‐23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4‐23)‐treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit natriuretic peptide clearance more effectively., The effects of blocking natriuretic peptide clearance from the circulation was examined in a mouse model of focal segmental glomerulosclerosis (FSGS). We found that blockade of the natriuretic clearance receptor protected glomerular podocytes from apoptosis and inhibited albuminuria in FSGS.

Background Sacubitril/valsartan has been shown to significantly reduce cardiovascular mortality and hospitalizations due to heart failure in patients with reduced ejection fraction (HFrEF) when compared to enalapril. Data about sacubitril/valsartan in patients with a history of cancer are scarce, as these patients were excluded from the pivotal trial, PARADIGM-HF. The aim of the current study was to assess tolerability of sacubitril/valsartan in patients with a history of cancer. Methods We identified 225 patients at our heart failure out-patient unit who fulfilled the indication criteria to receive sacubitril/valsartan. Out of these, 9.3% (n = 21) had a history of histologically confirmed cancer. Oncologic surgery was performed in 16 (76.2%) patients, 11 (52.4%) patients received previous antineoplastic therapy and 9 patients (42.9%) radiation. Results Sacubitril/valsartan was withdrawn in 3 of 21 patients (14.3%) because of dizziness (n = 2) or pruritus (n = 1). After a median follow-up of 12 months (range 1–34 months), NYHA functional class improved significantly from NYHA 3 to NYHA 2 (mean -0.6, p = 0.006) and left ventricular ejection fraction as assessed by echocardiography increased significantly from 26.8 ± 5.4% to 39.2 ± 10% (mean + 12%, CI 95% [8.4–16.4], p = 0.0004). NT-proBNP was significantly reduced (baseline median 2774 pg/ml, range 1441 – 12,982 vs follow-up 1266 pg/ml, range 199–6324, p = 0.009). There was no significant change in creatinine levels (1.18 ± 0.4 vs 1.22 ± 0.4 mg/dl; mean + 0.005 mg/dl, CI 95% [-0.21- 0.12], p = 0.566). Conclusions In our pilot study we show that sacubitril/valsartan is generally well tolerated in patients with HFrEF and history of cancer. Importantly, even patients with long-standing cardiotoxicity induced heart failure can be treated and up-titrated with sacubitril/valsartan to usual target dosages, leading to improvement in LV function and biomarkers. Larger studies are needed to confirm these findings in cancer patients with cardiotoxicity.

Background: Acute heart failure (HF) represents an increasingly common and challenging presentation in the emergency room, also inducing a great socio-economic burden. Extensive research was conducted toward finding an ideal biomarker of acute HF, both in terms of sensitivity and specificity, but today practicians’ interest has shifted towards a more realistic multimarker approach. Natriuretic peptides (NPs) currently represent the gold standard for diagnosing HF in routine clinical practice, but novel molecules, such as sST2, emerge as potentially useful biomarkers, providing additional diagnostic and prognostic value. Methods: We conducted a prospective, single-center study that included 120 patients with acute HF and 53 controls with chronic HF. Of these, 13 patients (eight with acute HF, five from the control group) associated the coronavirus-19 disease (COVID-19). The diagnosis of HF was confirmed by a complete clinical, biological and echocardiographic approach. Results: The serum levels of all studied biomarkers (sST2, NT-proBNP, cardiac troponin) were significantly higher in the group with acute HF. By area under the curve (AUC) analysis, we noticed that NT-proBNP (AUC: 0.976) still had the best diagnostic performance, closely followed by sST2 (AUC: 0.889). However, sST2 was a significantly better predictor of fatal events, showing positive correlations for both in-hospital and at 1-month mortality rates. Moreover, sST2 was also associated with other markers of poor prognosis, such as the use of inotropes or high lactate levels, but not with left ventricle ejection fraction, age, body mass index or mean arterial pressure. sST2 levels were higher in patients with a positive history of COVID-19 as compared with non-COVID-19 patients, but the differences were statistically significant only within the control group. Bivariate regression showed a positive and linear relationship between NT-proBNP and sST2 (r(120) = 0.20, p &lt, 0.002). Conclusions: we consider that sST2 has certain qualities worth integrating in a future multimarker test kit alongside traditional biomarkers, as it provides similar diagnostic value as NT-proBNP, but is emerging as a more valuable prognostic factor, with a better predictive value of fatal events in patients with acute HF.

Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention. However, its pathogenesis remains largely unclarified. Corin, a cardiac serine protease, is responsible for converting proANP and proBNP to biologically active peptides. Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and proprotein convertase subtilisin/kexin-6 (PCSK6), a key enzyme in the conversion of procorin to corin, has not been studied simultaneously in the cardiac and renal tissues in cardiorenal syndrome. Thus, this study aims to examine the status of PCSK6/corin in the cardiac and renal tissues of rats with CHF induced by the creation of aorto-caval fistula (ACF). We divided rats with ACF into two subgroups based on the pattern of their urinary sodium excretion, namely, compensated and decompensated. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more profound in the decompensated subgroup. Corin immunoreactive peptides were detected in all heart chambers at the myocyte membranal and cytosolic localization and in the renal tissue, especially in the apical membrane of the proximal tubule, mTAL, and the collecting duct. Interestingly, the expression and abundance of corin in both the cardiac ventricles and renal tissues were significantly increased in compensated animals as compared with the decompensated state. Noteworthy, the abundance of PCSK6 in these tissues followed a similar pattern as corin. In contrast, furin expression was upregulated in the cardiac and renal tissues in correlation with CHF severity. We hypothesize that the obtained upregulation of cardiac and renal PCSK6/corin in rats with compensated CHF may represent a compensatory response aiming at maintaining normal Na+ balance, whereas the decline in these two enzymes may contribute to the pathogenesis of avid sodium retention, cardiac hypertrophy, and blunted atrial natriuretic peptide/brain natriuretic peptide actions in decompensated CHF.

AIMS: Guidelines support the role of B-type natriuretic peptide (BNP) and amino-terminal pro-BNP (NT-proBNP) for risk stratification of patients in programmes to prevent heart failure (HF). Although biologically formed in a 1:1 ratio, the ratio of NT-proBNP to BNP exhibits wide inter-individual variability. A report on an Asian population suggests that molar NT-proBNP/BNP ratio is associated with incident HF. This study aims to determine whether routine, simultaneous evaluation of both BNP and NT-proBNP is warranted in a European, Caucasian population.METHODS AND RESULTS: We determined BNP and NT-proBNP levels for 782 Stage A/B HF patients in the STOP-HF programme. The clinical, echocardiographic, and biochemical associates of molar NT-proBNP/BNP ratio were analysed. The primary endpoint was the adjusted association of baseline molar NT-proBNP/BNP ratio with new-onset HF and/or progression of left ventricular dysfunction (LVD). We estimated the C-statistic, integrated discrimination improvement, and the category-free net reclassification improvement metric for the addition of molar NT-proBNP/BNP ratio to adjusted models. The median age was 66.6 years [interquartile range (IQR) 59.5-73.1], 371 (47.4%) were female, and median molar NT-proBNP/BNP ratio was 1.91 (IQR 1.37-2.93). Estimated glomerular filtration rate, systolic blood pressure, left ventricular mass index, and heart rate were associated with NT-proBNP/BNP ratio in a linear regression model (all P < 0.05). Over a median follow-up period of 5 years (IQR 3.4-6.8), 247 (31.5%) patients developed HF or progression of LVD. Log-transformed NT-proBNP/BNP ratio is inversely associated with HF and LVD risk when adjusted for age, gender, diabetes, hypertension, vascular disease, obesity, heart rate, number of years of follow-up, estimated glomerular filtration rate, and baseline NT-proBNP (odds ratio 0.71, 95% confidence interval 0.55-0.91; P = 0.008). However, molar NT-proBNP/BNP ratio did not increase the C-statistic (Δ -0.01) and net reclassification improvement (0.0035) for prediction of HF and LVD compared with NT-proBNP or BNP alone. Substitution of NT-proBNP for BNP in the multivariable model eliminated the association with HF and LVD risk.CONCLUSIONS: This study characterized, for the first time in a Caucasian Stage A/B HF population, the relationship between NT-proBNP/BNP ratio and biological factors and demonstrated an inverse relationship with the future development of HF and LVD. However, this study does not support routine simultaneous BNP and NT-proBNP measurement in HF prevention programmes amongst European, Caucasian patients.

Background: Given rising morbidity, mortality, and costs due to heart failure (HF), new approaches for prevention are needed. A quantitative risk-based strategy, in line with established guidelines for atherosclerotic cardiovascular disease prevention, may efficiently select patients most likely to benefit from intensification of preventive care, but a risk-based strategy has not yet been applied to HF prevention.Methods and Results: The Feasibility of the Implementation of Tools for Heart Failure Risk Prediction (FIT-HF) pilot study will enroll 100 participants free of cardiovascular disease who receive primary care at a single integrated health system and have a 10-year predicted risk of HF of ≥5% based on the previously validated Pooled Cohort equations to Prevent Heart Failure. All participants will complete a health and lifestyle questionnaire and undergo cardiac biomarker (B-type natriuretic peptide [BNP] and high-sensitivity cardiac troponin I [hs-cTn]) and echocardiography screening at baseline and 1-year follow-up. Participants will be randomized 1:1 to either a pharmacist-led intervention or usual care for 1 year. Participants in the intervention arm will undergo consultation with a pharmacist operating under a collaborative practice agreement with a supervising cardiologist. The pharmacist will perform lifestyle counseling and recommend initiation or intensification of therapies to optimize risk factor (hypertension, diabetes, and cholesterol) management according to the most recent clinical practice guidelines. The primary outcome is change in BNP at 1-year, and secondary and exploratory outcomes include changes in hs-cTn, risk factor levels, and cardiac mechanics at follow-up. Feasibility will be examined by monitoring retention rates.Conclusions: The FIT-HF pilot study will offer insight into the feasibility of a strategy of quantitative risk-based enrollment into a pharmacist-led prevention program to reduce heart failure risk.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT04684264