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The discovery of the heart as an endocrine organ resulted in a remarkable recognition of the natriuretic peptide system (NPS). Specifically, research has established the production of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart, which exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor (GC-A) and the second messenger, cGMP. C-type natriuretic peptide (CNP) is produced in the endothelium and kidney and mediates important protective auto/paracrine actions via GC-B and cGMP. These actions, in part, participate in the efficacy of sacubitril/valsartan in heart failure (HF) due to the augmentation of the NPS. Here, we will review important insights into the biology of the NPS, the role of precision medicine, and focus on the phenotypes of human genetic variants of ANP and BNP in the general population and the relevance to HF. We will also provide an update of the existence of NP deficiency states, including in HF, which provide the rationale for further therapeutics for the NPS. Finally, we will review the field of peptide engineering and the development of novel designer NPs for the treatment of HF. Notably, the recent discovery of a first-in-class small molecule GC-A enhancer, which is orally deliverable, will be highlighted. These innovative designer NPs and small molecule possess enhanced and novel properties for the treatment of HF and cardiovascular diseases.

The natriuretic peptide system (NPS) and renin-angiotensin-aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date supports this notion. This study was designed to systematically investigate ANGII–NPS interaction in humans, in vivo, and in vitro. Circulating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in vivo to determine the influence of ANGII on ANP actions. The underlying mechanisms were further explored via in vitro approaches. In humans, ANGII demonstrated an inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and the interaction term between ANGII and natriuretic peptides increased the predictive accuracy of the base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed a positive association between cGMP and ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at a physiological dose attenuated cGMP generation mediated by ANP infusion. In vitro, we found the suppressive effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT1) receptor and mechanistically involves protein kinase C (PKC), as this suppression can be substantially rescued by either valsartan (AT1 blocker) or Go6983 (PKC inhibitor). Using surface plasmon resonance (SPR), we showed ANGII has low binding affinity to the guanylyl cyclase A (GC-A) receptor compared to ANP or BNP. Our study reveals ANGII is a natural suppressor for the cGMP-generating action of GC-A via AT1/PKC dependent manner and highlights the importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular protection.

M-atrial natriuretic peptide (MANP) is a novel ANP (atrial natriuretic peptide) analog engineered to be an innovative particulate GC-A (guanylyl cyclase A) receptor activator. The rationale for its design was to develop a best-in-class GC-A activator with enhanced cGMP activating, natriuretic, aldosterone-suppressing, and blood pressure–lowering actions, compared with endogenous ANP, for the treatment of hypertension. Here, we report the first-in-human study on the safety, tolerability, neurohumoral, renal, and blood pressure–lowering properties of MANP in hypertension subjects. This was an open-label sequential single ascending dose design in which all subjects stopped all antihypertensive agents for 14 days before receiving a single subcutaneous injection of MANP. MANP was safe, well tolerated, activated cGMP, induced natriuresis, reduced aldosterone, and decreased blood pressure at or below the maximal tolerated dose. Thus, MANP has a favorable safety profile and produced expected pharmacological effects in human hypertension. Our results support further investigations of MANP as a potential future blood pressure–lowering, natriuretic and aldosterone-suppressing drug for hypertension especially resistant hypertension.

BackgroundNatriuretic peptide system (NPS) and renin angiotensin aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date support this notion.ObjectivesThis study was designed to systematically investigate ANGII-NPS interaction in humans, in vivo, and in vitro for translational insights.MethodsCirculating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in rat model to determine influence of ANGII on ANP actions. Multiple engineered HEK293 cells and surface plasmon resonance (SPR) technology were leveraged for mechanistic exploration.ResultsIn humans, ANGII showed inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and interaction term between ANGII and natriuretic peptide increased predicting accuracy of base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed positive association between cGMP with ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at physiological dose attenuated blood pressure reduction and cGMP generation triggered by ANP infusion. In vitro, we showed that the suppression effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT1) receptor and mechanistically involves protein kinase C (PKC), which can be substantially rescued by either valsartan (AT1blocker) or Go6983 (PKC inhibitor). Using SPR, we showed ANGII has low affinity for particulate guanylyl cyclase A (GC-A) receptor binding compared to ANP or BNP.ConclusionsOur study reveals ANGII as a natural suppressor for cGMP-generating action of GC-A via AT1/PKC dependent manner and highlights importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular disease.STRUCTURED GRAPHICAL ABSTRACTCLINICAL PERSPECTIVESAccumulating evidence continues to support the NPS as a promising therapeutic target via the function of the GC-A receptor and production of the second messenger cGMP for heart failure, hypertension, and other cardiovascular diseases. Improving our mechanistic understanding on GC-A/cGMP pathway regulation may further advance the development of novel NPS enhancing therapies. Here we report evidence from multiple avenues supporting a fundamental, yet previously underappreciated mechanism involving a negative action of ANGII in suppressing GC-A receptor-mediated cGMP production via an AT1receptor-dependent manner. This study also provides a solid rationale for the superiority of combinatory neurohormonal therapies such as sacubitril/valsartan in treating cardiovascular disease, and further highlights a promising therapeutic avenue of dual targeting both the NPS and RAAS to maximize protection.

Aim: Intrinsic renal sodium avidity (IRSA) is a hallmark feature of acute heart failure (AHF) and can be measured by evaluating the urinary sodium (UNa) concentration. The aim of this study is to assess the role of measuring IRSA through a random Una-sample and its association with decongestive response. Methods and results: A post-hoc analysis of the ROSE-AHF trial was performed in all patients with a random UNa spot sample before randomization (n = 339/360). Patients were categorized according to tertiles of UNa as high (range 19–40 mmol/L), intermediate (range 41–68 mmol/L), or low (range 69–139 mmol/L) IRSA. Linear mixed effect models and ANCOVA were used to assess the relation with decongestive effectiveness measured by: (i) weight change, (ii) visual analogue scale (VAS) improvement, (iii) N-terminal pro-B-type natriuretic peptide (NT-proBNP) change, (iv) natriuretic response (UNa in mmol/L), (v) 72 h natriuresis (mmol), (vi) oedema resolution, and (vii) length of stay. High IRSA patients had less improvement in decongestive metrics, including weight loss (p = 0.028), VAS improvement, NT-proBNP decrease, natriuretic response (p-time interaction 24 h, resulted in an increase in natriuretic response in the high IRSA group, however cumulative natriuresis still remained lower at 72 h (p < 0.001). Longitudinal UNa profiling of patients with low IRSA showed physiologic breaking in the UNa pattern, associated with attaining decongestion and slight increase in creatinine and cystatin C, forming a potential signal of complete decongestion. Conclusions: A simple random UNa sample at the time of AHF, gives insight into IRSA which is consistently associated with decongestive effectiveness across multiple metrics, offering an opportunity for early AHF care improvement.

Background: cGMP MANP (M-atrial natriuretic peptide) is a best-in-class activator of the pGC-A (particulate guanylyl cyclase A) receptor. Furosemide increases the effectiveness of antihypertensive agents, but activates renin-angiotensin-aldosterone system. We aimed to investigate for the first time cardiorenal and neurohumoral actions of MANP in a genetic model of hypertension in spontaneously hypertensive rats. We also assessed how MANP would potentiate the blood pressure (BP)–lowering actions of furosemide while reducing the production of aldosterone. Methods: Spontaneously hypertensive rats (N=60) were randomized in vehicle, MANP, furosemide, or MANP+furosemide groups. Furosemide (1, 5, 10 mg/kg) was given as a single bolus which in MANP+furosemide groups was followed by a 60-minute infusion of MANP. Results: BP was reduced in MANP300 (300 pmol/[kg·min]) and MANP600 (600 pmol/[kg·min]) groups ( P P Conclusions: We provide novel evidence that MANP potentiates the BP-lowering actions of furosemide, suppresses the activation of renin-angiotensin-aldosterone system, and preserves renal function. These data are highly relevant to clinical needs in the treatment of hypertension and heart failure.

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Objectives To delineate the impact of diabetes mellitus (DM) on the development of cardiovascular diseases in a community population. Patients & Methods Cross-sectional survey of residents randomly selected through the Rochester Epidemiology Project, 45 years or older, of Olmsted County as of June 1, 1997, through September 30, 2000. Responders (2042) underwent assessment of systolic and diastolic function using echocardiography. The current analyses included all participants with DM and were compared with a group of participants without DM matched 1:2 for age, sex, hypertension, and coronary artery disease. Baseline characteristics and laboratory and echocardiography findings between groups were compared along with rates of mortality due to various cardiovascular conditions. Results We identified 116 participants with DM and 232 matched participants without DM. Those with DM had a higher body mass index and plasma insulin and serum glucose levels. Although left ventricular ejection fractions were similar, E/e' ratio (9.7 vs 8.5; P=.001) was higher in DM vs non-DM. During a follow-up of 10.8 (interquartile range, 7.8-11.7) years, participants with DM had a higher incidence of heart failure (HF); hazard ratio, 2.1; 95% confidence limits, 1.2-3.6; P=.01) and 10-year Kaplan-Meier rate of 21% (22 of 116) vs 12% (24 of 232) compared with those without DM. We also examined the subgroup of participants without diastolic dysfunction. In this subgroup, those with DM had an increased risk for HF; hazard ratio, 2.5; 95% confidence limits, 1.0-6.3; P=.04). Conclusion In this cohort, participants with DM have an increased incidence of HF over a 10-year follow-up period even in the absence of underlying diastolic dysfunction. These findings suggest that DM is an independent risk factor for the development of HF and supports the concept of DM cardiomyopathy.

Objective To classify subjects in a general population per their renal function and characterize the cardiac biomarker levels, left ventricular function and cardiovascular outcomes over a 10.2 year follow-up period (interquartile range, 5.1–11.4 years). Methods This was a retrospective review of a population-based random sample of residents aged ≥45 years. Data were collected between January 1, 1997, and December 31, 2000. One thousand nine hundred eighty-one individuals were classified based on estimated glomerular filtration rate (eGFR) into group I (>90 mL/min/1.73 m2), group II (60 to 89 mL/min/1.73 m2) and group III ( Results Eight hundred nineteen patients were classified as group I, 1036 as group II, and 126 of 1981 (6.4%) as group III or CKD. Subjects in group III were older and had a higher incidence of hypertension, diabetes, and MI at baseline. Over a 10.2-year follow-up period, CKD was associated with an increased risk of MI (hazard ratio, 1.95; 95% CI, 1.2-3.14; P=.006) and composite cardiovascular outcomes including MI, congestive heart failure, stroke, and all-cause mortality (hazard ratio, 1.38; 95% CI, 1.05-1.83 ;P=.02). Subjects with NT-proBNP or hs-TnT in the third tertile were at greater risk of cardiovascular events without significant interactions between eGFR and levels of NT-proBNP and hs-TnT. Conclusion Subjects with CKD had significantly elevated cardiac biomarkers and were at an increased risk of MI and adverse cardiovascular events. This warrants future studies to investigate whether these cardiac biomarkers could identify high-risk CKD patients for aggressive management of cardiovascular risk factors.

AIMS: To identify prevalence and predictors of undetected pre-clinical diastolic dysfunction (PDD) in a cohort of adult Hispanic patients with type 2 diabetes (T2D), and compare variations in epidemiology and echocardiographic characteristics between categorization based on the 2009 versus 2016 guidelines. METHODS: From 2013 to 2016, a cross-sectional cohort study of adults with T2D was performed. Patients without signs/symptoms of heart failure (HF) underwent 2D/Doppler echocardiographic screening, and were grouped into two subcohorts: 1) normal diastolic function, and 2) PDD, defined by the 2009 or 2016 ASE/EACVI criteria. RESULTS: Among 307 Hispanic subjects, by 2009 criteria, 193 (62.9%) had normal diastolic function, 113 (36.8%) diastolic dysfunction and 1 (0.3%) indeterminate. Those that had diastolic dysfunction (DD) were older (mean age 59.1±12.7 vs 52.2±12.2 years, p

Objectives This study sought to characterize urinary and plasma C-type natriuretic peptide (CNP) in acute decompensated heart failure (ADHF) to define their relationship with clinical variables and to determine whether urinary and plasma CNP together add prognostic value. Background CNP is a protective hormone that is synthesized in the kidney and endothelium and possesses antiremodeling properties. Urinary and plasma CNP levels are elevated in pathophysiological conditions; however, their regulation and prognostic value in heart failure (HF) is unclear. Methods Urinary and plasma CNP were measured in 109 healthy subjects and 208 patients with ADHF; the 95th percentile of CNP values from healthy subjects established the normal contemporary cutoffs. Patients with ADHF were stratified based on urinary and plasma CNP levels for clinical characterization and the assessment of risk for adverse outcomes. Results There was no significant correlation between urinary and plasma CNP in both cohorts. Urinary and plasma CNP were significantly elevated in patients with ADHF, and both increased with disease severity and were positively correlated with plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP). Of the patients with ADHF, 23% had elevations in both urinary and plasma CNP, whereas 24% had normal CNP levels. During a median follow-up of 3 years, patients with elevated urinary and plasma CNP had a significantly higher risk of rehospitalization and/or death (HR: 1.79; P = 0.03) and rehospitalization (HR: 2.16; P = 0.01) after adjusting for age, sex, left ventricular ejection fraction, renal function, and plasma NT-proBNP. The C-statistic and integrated discrimination analyses further supported that the addition of urinary and plasma CNP to established risk models improved the prediction of adverse outcomes in patients with ADHF. Conclusions Urinary and plasma CNP are differentially regulated in ADHF, and elevations in both provided independent prognostic value for predicting adverse outcomes.

Background: The aims of this study are to evaluate the rate of progression of preclinical (Stage A and B) heart failure, identify associated characteristics, and evaluate long-term outcomes. Methods: Retrospective review of the Olmsted County Heart Function Study. Individuals categorized as Stage A or B heart failure at initial visit that returned for a second visit 4 years later were included. Logistic regression analyses evaluated group differences with adjustment for age and sex. Results: At visit 1, 413 (32%) individuals were classified as Stage A and 413 (32%) as Stage B. By visit 2, 146 (35%) individuals from Stage A progressed with the vast majority (n=142) progressing to Stage B. In comparison, a total of 23 (6%) individuals progressed from Stage B. A greater rate of progression was seen for Stage A compared with Stage B (8.7 per 100 person-years [95% CI, 7.4–10.2] versus 1.4 per 100 person-years [95% CI, 0.9–2.1]; P P =0.01), but not for Stage A ( P =0.39). A multivariate model found female sex (odds ratio, 1.65 [95% CI, 1.05–2.58]; P =0.03), increased E/e’ (odds ratio, 1.13 [95% CI, 1.02–1.26], P =0.02), and beta blocker use (odds ratio, 2.19 [95% CI, 1.25–3.82], P =0.006) were associated with progression for Stage A. There was a signal that cardiovascular mortality was higher in individuals who progressed, although not statistically significant ( P =0.06 for Stage A and P =0.05 for Stage B). Conclusions: There is significant progression of preclinical heart failure in a community population, with progression rates higher for Stage A. NT-proBNP correlated with progression for Stage B, but not for Stage A. No statistically significant differences in long-term outcomes were seen. Study results have clinical implications important to help guide future heart failure screening and prevention strategies.

Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. Methods and results This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS‐HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter‐quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P

The natriuretic peptide (NP) system is composed of 3 distinct peptides (atrial natriuretic peptide or ANP, B-type natriuretic peptide or BNP, and C-type natriuretic peptide or CNP) and 3 receptors (natriuretic peptide receptor-A or NPR-A or particulate guanynyl cyclase-A natriuretic peptide receptor-B or NPR-B or particulate guanynyl cyclase-B, and natriuretic peptide receptor-C or NPR-C or clearance receptor). ANP and BNP function as defense mechanisms against ventricular stress and the deleterious effects of volume and pressure overload on the heart. Although the role of NPs in cardiovascular homeostasis has been extensively studied and well established, much remains uncertain about the signaling pathways in pathological states like heart failure, a state of impaired natriuretic peptide function. Elevated levels of ANP and BNP in heart failure correlate with disease severity and have a prognostic value. Synthetic ANP and BNP have been studied for their therapeutic role in hypertension and heart failure, and promising trials are under way. In recent years, the expression of ANP and BNP in human adipocytes has come to light. Through their role in promotion of adipocyte browning, lipolysis, lipid oxidation, and modulation of adipokine secretion, they have emerged as key regulators of energy consumption and metabolism. NPR-A signaling in skeletal muscles and adipocytes is emerging as pivotal to the maintenance of long-term insulin sensitivity, which is disrupted in obesity and reduced glucose-tolerance states. Genetic variants in the genes encoding for ANP and BNP have been associated with a favorable cardiometabolic profile. In this review, we discuss several pathways that have been proposed to explain the role of NPs as endocrine networkers. There is much to be explored about the therapeutic role of NPs in improving metabolic milieu.

ObjectiveB-type natriuretic peptide (BNP) has favourable effects on left ventricular remodelling, including antifibrotic and antiapoptotic properties. We tested the hypothesis that infusion of BNP after an acute myocardial infarction would reduce left ventricular systolic and diastolic volumes and improve left ventricular ejection fraction compared with placebo.MethodsA total of 58 patients who underwent successful revascularisation for an acute ST elevation anterior myocardial infarction were randomised to receive 72-hour infusion of BNP at 0.006 µg/kg/min or placebo. Left ventricular end diastolic and systolic volumes and left ventricular ejection fraction were measured at baseline and at 30 days by multigated acquisition scan. Left ventricular infarction size was measured by cardiac MRI.ResultsBNP infusion led to significantly higher BNP levels and plasma cyclic guanosine monophosphate at 72 hours. No significant difference in change of left ventricular volumes or ejection fraction from baseline to 30 days was observed between groups. Although left ventricular infarction size measured by cardiac MRI was not significantly different between BNP infusion versus placebo (p=0.39), there was a trend towards reduced infarction size in patients with a baseline ejection fraction of ConclusionsInfusion of BNP in patients with an anterior myocardial infarction did not affect parameters of left ventricular remodelling. Patients treated with BNP who had a baseline left ventricular ejection fraction of Trial registration numberNCT00573144.

Objective To determine the risks of acute kidney injury development and long-term clinical outcomes of patients with hypertensive crisis. Patients and Methods This was a population study of Olmsted County residents with hypertensive crisis between January 1, 2000, and December 31, 2008, with follow-up until June 30, 2016. Results The results demonstrated that those with underlying chronic kidney disease upon admission for hypertensive crisis, defined as a systolic blood pressure above 180 mm Hg or diastolic blood pressure above 120 mm Hg, were more likely to develop acute kidney injury during hospitalization (odds ratio, 6.04; 95% CI, 1-26; P=.02). Hospitalization length of stay was increased when patients developed acute kidney injury during hypertensive crisis hospitalization (7.6±9 vs 3.4±4 days; P=.04). Furthermore, those who developed acute kidney injury had increased cardiac rehospitalization frequency over 10 years (87% vs 46%; P=.009). These results suggest that those with poor renal reserve are more likely to have further acute kidney damage in the setting of hypertensive crisis, likely due to decreased renal perfusion and neurohormonal dysregulation. Conclusion In patients hospitalized for hypertensive crisis, chronic renal insufficiency was a risk factor associated with acute kidney injury development during hospitalization. Those who developed acute kidney injury had longer hospitalizations with increased rehospitalization frequency. Future studies are warranted to further investigate whether the preservation of renal function will improve clinical outcomes in hospitalized patients with hypertensive crisis.

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N -acetyl-β- d -glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation–Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300–815 mg), which induced a urine output of 8425 mL (interquartile range, 6341–10 528 mL) over the 72-hour intervention period. Levels of N -acetyl-β- d -glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P >0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (−8.7 ng/mg; interquartile range, −169 to 35 ng/mg; P P =0.21), N -acetyl-β- d -glucosaminidase ( P =0.46), or kidney injury molecule 1 ( P =0.22). Increases in neutrophil gelatinase-associated lipocalin, N -acetyl-β- d -glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69–0.91; P =0.001). Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

Aims Chronic kidney disease (CKD) is prevalent and is associated with increased cardiovascular morbidity and mortality. The interaction between diastolic dysfunction (DD) and CKD in subjects with preserved systolic function is not well defined. This study sought to determine the association between renal function and DD in subjects with preserved ejection fraction. Methods and results Through the Rochester Epidemiology Project, subjects who underwent echocardiography over 2 years with EF ≥50% were identified and the clinical data were obtained. Glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease equation. Linear regression was used to test for association of GFR and DD. DD was defined as follows: Grade 2 or pseudonormal pattern (0.75 140 ms, ΔE/A ≥ 0.5, and PV S 1.5, E/e′ ≥ 10, DT

Based on the cardiac hormone atrial natriuretic peptide (ANP) and its seminal role in blood pressure (BP) homeostasis, we investigated the chronic BP lowering actions of a novel ANP analog currently entering clinical trials for hypertension. Previous reports demonstrate that this analog MANP activates the guanylyl cyclase A receptor (GC-A) and results in more potent biological actions compared with ANP; thus, it may represent a new therapeutic drug for hypertension. A major goal of this study was to establish that chronic subcutaneous delivery of MANP is feasible and hypotensive together with cGMP effects. We investigated the BP-lowering and cGMP-activating actions of acute and chronic subcutaneous delivery in normal and hypertensive rats. Furthermore, we explored vascular mechanisms of MANP in human aortic smooth muscle cells (HASMC) and ex vivo in isolated arteries. In normal rats with a single subcutaneous injection, MANP promoted robust dose-dependent BP-lowering actions and natriuresis, together with cGMP activation. Most importantly in hypertensive rats, once-a-day subcutaneous injection of MANP for 7 days induced cGMP elevation and long-term BP reduction compared with vehicle. Mechanistically, in HASMC, MANP activated cGMP and attenuated angiotensin II-mediated increases in intracellular Ca2+levels while directly vasorelaxing arterial rings. Our study demonstrates for the first time the effectiveness of subcutaneous administration of MANP for 7 days and provides innovative, vascular mechanisms of BP regulation supporting its continued development as a novel therapeutic for hypertension.

OBJECTIVES: The study sought to identify the role of Annexin A1 as a congestion marker in acute heart failure, and to identify its putative role in predicting clinical outcomes. BACKGROUND: Annexin A1 (AnxA1) is a protein that inhibits inflammation following ischemia-reperfusion (I-R) injury in cardiorenal tissues. Since acute heart failure (AHF) is a state of tissue hypoperfusion, we hypothesized that plasma AnxA1 levels are altered in AHF. METHODS: In The Renal Optimization Strategies Evaluation (ROSE) trial, patients hospitalized for AHF with kidney injury were randomized to receive dopamine, nesiritide, or placebo for 72 hours in addition to diuresis. In a sub-analysis, plasma AnxA1 levels were measured at baseline and at 72 hours in 275 patients. Participants were divided into three tertiles based on their baseline AnxA1 levels. RESULTS: The prevalence of peripheral edema 2+ increased with increasing AnxA1 levels (p < 0.007). Cystatin C, blood urea nitrogen, and kidney injury molecule-1 plasma levels were higher among participants in tertile 3 vs tertiles 1 or 2 (p < 0.05). Patients with a congestion score of 4 had a mean baseline AnxA1 level 8.63 units higher than those with a congestion score of 0 (p= 0.03). Patients in tertiles 2 and 3 were twice as likely to experience creatinine elevation as patients in tertile 1 (p= 0.03). Patients in tertiles 2 and 3 were at a higher risk of 60-day all-cause mortality or heart failure hospitalization and 180-day all-cause mortality (p

Aims Guided by predictive characteristics of cardiovascular biomarkers, we explored the clinical implications of a simulated biomarker-guided heart failure (HF) and major adverse cardiovascular events (MACE) prevention strategy in the community. Methods and results In a community cohort (n = 1824), the predictive characteristics for HF and MACE of galectin-3 (Gal-3), ST2, high-sensitivity cardiac troponin I (hscTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) were established. We performed number needed to screen (NNS) and treat (NNT) with the intervention analyses according to biomarker screening strategy and intervention efficacy in persons with at least one cardiovascular risk factor. In the entire cohort, for both HF and MACE, the predictive characteristics of NT-proBNP and hscTnI were superior to other biomarkers; alone, in a multimarker model, and adjusting for clinical risk factors. An NT-proBNP-guided preventative intervention with an intervention effect size (4-year hazard ratio for intervention in biomarker positive cohort) of ≤0.7 would reduce the global burden of HF by ≥20% and MACE by ≥15%. From this simulation, the NNS to prevent one HF event or MACE in 4 years would be ≤100 with a NNT to prevent one HF event of ≤20 and one MACE of ≤10. Conclusions The predictive characteristics of NT-proBNP and hscTnI for HF or MACE in the community are superior to other biomarkers. Biomarker-guided preventative interventions with reasonable efficacy would compare favourably to established preventative interventions. This data provides a framework for biomarker selection which may inform design of biomarker-guided preventative intervention trials.

Objectives This study sought to investigate relationships between insulin-like growth factor–binding protein-7 (IGFBP7) and parameters of diastolic function or functional capacity in patients with heart failure and preserved ejection fraction (HFpEF) who were randomized to receive sildenafil or placebo. Background IGFBP7 was previously found to be associated with diastolic function in heart failure with reduced ejection fraction, but it is unclear whether these associations are present in HFpEF. Methods At baseline and 24 weeks, IGFBP7, imaging studies, and peak oxygen consumption (Vo2max) were obtained and compared in 160 patients with HFpEF who were randomized to receive sildenafil or placebo. Results Patients with supramedian baseline IGFBP7 concentrations were older, had signs of systemic congestion and worse renal function, and had higher concentrations of prognostic heart failure biomarkers including amino-terminal pro-B-type natriuretic peptide (p Conclusions In patients with HFpEF, IGFBP7 may be a novel biomarker of diastolic function and exercise capacity.

To define the natural history of patients with isolated metabolic syndrome (MS).Metabolic syndrome is associated with increased risk of cardiovascular mortality. Patients with isolated MS are a subset of patients with MS who do not meet the diagnostic criteria of hypertension (HTN) and diabetes mellitus (DM). Data were collected prospectively on a population-based random sample of 1042 Olmsted County, Minnesota, residents aged 45 years or older who underwent clinical evaluation, medical record abstraction, and echocardiography (visit 1: January 1,1997, to December 31, 2000). The cohort was subdivided into healthy controls, those with isolated MS, and those with MS with HTN and/or DM groups. After 4 years, patients returned for visit 2 (September 1, 2001, to December 30, 2004). After visit 2, we have a median of 8.3 years of follow-up.There was a higher incidence of HTN, DM, and obesity in the isolated MS group at visit 2 (P.001) than in healthy controls. Patients with isolated MS did not have significantly higher rates of cardiovascular mortality (hazard ratio [HR], 0.85; 95% CI, 0.23-3.13; P=.80) or development of heart failure (HR, 1.29; 95% CI, 0.58-2.73; P=.53) compared with healthy controls over 8 years of follow-up after visit 2. However, patients with MS with HTN and/or DM had higher rates of cardiovascular mortality (HR, 2.40; 95% CI, 1.00-5.83; P=.02) and heart failure (HR, 2.24; 95% CI, 1.16-4.32; P=.02) compared with healthy controls over 8 years of follow-up after visit 2.Isolated MS was associated with increased risk for the development of HTN, DM, and obesity, but not increased mortality or heart failure over an 8-year period compared with healthy controls. Future studies should determine whether aggressive management of risk factors in isolated MS will prevent progression to MS.

The cardiac natriuretic peptides (NPs) ANP and BNP are natriuretic and aldosterone suppressing via the activation of the pGC-A receptor. CNP is a fibro-inhibiting peptide through the activation of the pGC-B receptor. We engineered a novel dual pGC-A/pGC-B activator, Cenderitide (CD) that contains

The native particulate guanylyl cyclase B receptor (pGC-B) activator, C-type natriuretic peptide (CNP), induces anti-remodeling actions in the heart and kidney through the generation of the second messenger 3', 5' cyclic guanosine monophosphate (cGMP). Indeed fibrotic remodeling, particularly in cardiorenal disease states, contributes to disease progression and thus, has been a key target for drug discovery and development. Although the pGC-B/cGMP system has been perceived as a promising anti-fibrotic pathway, its therapeutic potential is limited due to the rapid degradation and catabolism of CNP by neprilysin (NEP) and natriuretic peptide clearance receptor (NPRC). The goal of this study was to bioengineer and test in vitro and in vivo a novel pGC-B activator, C53. Here we established that C53 selectively generates cGMP via the pGC-B receptor and is highly resistant to NEP and has less interaction with NPRC in vitro. Furthermore in vivo, C53 had enhanced cGMP-generating actions that paralleled elevated plasma CNP-like levels, thus indicating a longer circulating half-life compared to CNP. Importantly in human cardiac fibroblasts (HCFs) and renal fibroblasts (HRFs), C53 exerted robust cGMP-generating actions, inhibited TGFβ-1 stimulated HCFs and HRFs proliferation chronically and suppressed the differentiation of HCFs and HRFs to myofibroblasts. The current findings advance innovation in drug discovery and highlight C53 as a novel pGC-B activator with sustained in vivo activity and anti-fibrotic actions in vitro. Future studies are warranted to explore the efficacy and therapeutic opportunity of C53 targeting fibrosis in cardiorenal disease states and beyond.

Importance There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF. Objective To determine the effect of 4 weeks’ administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018. Interventions Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks. Main Outcomes and Measures The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks. Results Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, −0.20 [95% CI, −0.56 to 0.16];P = .27). There were no significant between–treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, −15 [95% CI, −264 to 234];P = .91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, −1.4 to 3.5];P = .39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, −0.1 to 0.2];P = .43), echocardiographic E/e′ ratio (16.4 vs 16.6; difference, 0.1 [95% CI, −1.2 to 1.3];P = .93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, −53 to 75];P = .74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase. Conclusions and Relevance Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity. Trial Registration ClinicalTrials.gov Identifier:NCT02742129

Introduction The prevalence and predictors of undetected pre-clinical diastolic dysfunction (PDD), Stage B heart failure, in the Hispanic population with type 2 diabetes (T2D) is not well defined. In 2016, the American Society of Echocardiography (ASE) recommended a revised diastolic dysfunction categorization guideline. Objectives To identify prevalence and predictors of PDD in Hispanic adults with T2D, and compare differences in clinical and echocardiographic characteristics utilizing 2009 versus 2016 ASE diastolic function guidelines. Methods A cross-sectional study of Hispanic adults with T2D from 2013 to 2016 was performed. Subjects without signs or symptoms of heart failure (HF) underwent 2D/Doppler echocardiography and grouped into two sub-cohorts: 1) normal diastolic function, and 2) PDD, defined by 2009 or 2016 ASE criteria. Univariable and multivariable logistic analysis were performed to identify characteristics associated with PDD. Results Among 307 subjects, by 2009 criteria, 63% and 37% had normal diastolic function and PDD, respectively. By 2016 criteria, 85%, 7%, and 8% had normal diastolic function, PDD, and indeterminate diastolic function, respectively. Those with PDD were older (mean age 59.1±12.7 vs 52.2±12.2 years, p Conclusions By utilizing 2016 versus 2009 diastolic function criteria to a Hispanic population with T2D, the prevalence of PDD decreased from 37% to 7%, consistent with the new guidelines being more specific and less sensitive for diagnosing PDD.

Background The acute heart failure (AHF) Syndromes International Working Group proposed that dyspnea be assessed under standardized, incrementally provocative maneuvers and called for studies to assess the feasibility of this approach. We sought to assess the feasibility and statistical characteristics of a novel provocative dyspnea severity score (pDS) versus the traditional dyspnea visual analog scale (DVAS) in an AHF trial. Methods At enrollment, 24, 48 and 72hours, 230 ROSE-AHF patients completed a DVAS. Dyspnea was then assessed with 5-point Likert dyspnea scales administered during 4 stages (A: upright-with O 2 , B: upright-without O 2 , C: supine-without O 2 and D: exercise-without O 2 ). Patients with moderate or less dyspnea were eligible for the next stage. Results At enrollment, oxygen withdrawal and supine provocation were highly feasible (≥97%), provoking more severe dyspnea (≥1 Likert point) in 24% and 42% of eligible patients, respectively. Exercise provocation had low feasibility with 38% of eligible patients unable to exercise due to factors other than dyspnea. A pDS was constructed from Likert scales during the 3 feasible assessment conditions (A-C). Relative to DVAS, the distribution of the pDS was more skewed with a high "ceiling effect" at enrollment (23%) limiting sensitivity to change. Change in pDS was not related to decongestion or 60-day outcomes. Conclusions Although oxygen withdrawal and supine provocation are feasible and elicit more severe dyspnea, exercise provocation had unacceptable feasibility in this AHF cohort. The statistical characteristics of a pDS based on feasible provocation measures do not support its potential as a robust dyspnea assessment tool in AHF.

Aims We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. Methods and results We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (−39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. Conclusion Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.

Objectives This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains. Background Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. Methods Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. Results Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). Conclusions In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF.

BACKGROUND Cardiac resynchronization therapy (CRT) reverses left ventricular remodeling and improves left ventricular systolic function. However, little is known about whether CRT improves ventricular conduction. OBJECTIVE To determine the relationship between CRT response and QRS narrowing. METHODS The study included consecutive patients who underwent CRT with defibrillator (CRT-D) implantation between January 2002 and December 2012 and had subsequent generator replacement (GR). At the time of GR, super-responder was defined as those who had left ventricular ejection fraction (LVEF) of 50% or more; patients who had an LVEF of 36-49% with an increase of more than 5% were considered responders, and the others were nonresponders. All patients were assessed 6 months after CRT-D implantation and at the time of GR. RESULTS Of 114 study patients, 58 (50.9%) were nonresponders, 29 (25.4%) responders, and 27 (23.7%) super-responders. QRS narrowing at 6 months was significant in super-responders (175.4 ± 21.4 to 159.7 ± 20.7 ms, P = 0.001) and responders (169.0 ± 21.3 to 157.7 ± 17.6 ms, P = 0.008). At time of GR, only super-responders had further QRS narrowing (159.7 ± 20.7 to 146.3 ± 19.2 ms, P

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.

Purpose of review Acute heart failure (AHF) is a major health problem worldwide, with no proven therapy. Low-dose dopamine has been used in this entity to improve renal outcomes in the past decades. The aim of this article is to review the former and recent clinical trials about the use of low-dose dopamine in AHF. Recent findings The Dopamine in Acute Decompensated Heart Failure II study enrolled 161 patients with AHF and found no improvement in clinical outcomes with the addition of dopamine. Similarly, the Renal Optimization Strategies Evaluation in Acute Heart Failure trial, which included 360 patients with AHF and renal dysfunction, evaluated the efficacy of 72-h infusion of either low-dose nesiritide or low-dose dopamine versus placebo in addition to standardized diuretic treatment. No differences were found between both treatment groups and placebo with regard to the coprimary endpoints of cumulative urine volume and change from baseline in plasma cystatin C. Summary On the basis of the current data, there is no role for the routine use of low-dose dopamine in nonhypotensive patients with AHF. Further studies are needed to define the role of low-dose dopamine in patients with AHF and hypotension. Until the availability of more data, the use of dopamine in AHF should be individualized.

Nesiritide and dopamine have been recognized for some time as potential renal adjunct therapies in the management of patients with acute heart failure (AHF). Several studies have yielded conflicting evidence of the efficacy of both medications in enhancing the renal function of patients with AHF. The Renal Optimization Strategies Evaluation (ROSE) study was a multicenter double-blind placebo controlled trial designed to assess the potential renoprotective effects of low-dose nesiritide and dopamine in AHF patients with renal dysfunction. This article will focus on previous research, summary of results, and lessons learned from the ROSE-AHF trial as well as future directions for clinical research and applications.

Essential physiological homeostatic processes such as vascular tone, fluid balance, cardiorenal function, and sensory processes are regulated by the second messenger cyclic guanosine 3', 5'-monophosphate (cGMP). Dysregulation of cGMP-dependent pathways plays an important role in cardiovascular diseases such as hypertension, pulmonary hypertension, heart failure, or erectile dysfunction. Thus, the cGMP pathway consisting of the cGMP-generating guanylyl cyclases, protein kinases, and phosphodiesterases (PDE) has evolved to an important drug target and is the focus of a wide variety of research fields ranging from unraveling mechanisms on the molecular level to understanding the regulation of physiological and pathophysiological processes by cGMP. Based on the results from basic and preclinical research, therapeutic drugs have been developed which modulate the cGMP pathway and are investigated in clinical trials. Riociguat, a nitric oxide (NO)-independent soluble guanylyl cyclase stimulator; recombinant B-type natriuretic peptide (BNP); or recombinant atrial natriuretic peptide (ANP) and PDE5 inhibitors are cGMP-modulating drugs that are already available for the treatment of pulmonary hypertension, acute heart failure, and erectile dysfunction, respectively. The latest results from basic to clinical research on cGMP were presented on the 6th International Conference on cGMP in Erfurt, Germany, and are summarized in this article.