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Investigations into the mixed muscle–secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones — the natriuretic peptides — referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.The heart is an endocrine organ, producing atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in a regulated manner. In this Review, the authors discuss the physiological regulation and actions of the cardiac natriuretic peptides and their clinical use as powerful diagnostic and prognostic biomarkers of heart disease.

Nesiritide was approved by the FDA on the basis of small clinical trials for the treatment of acute heart failure. In this large clinical trial, nesiritide did not improve outcomes in patients with acute heart failure, and it can no longer be recommended for this condition. Acute decompensated heart failure is a major health problem that is associated with several million hospitalizations worldwide each year, poor short-term outcomes, and high costs. 1 – 3 Despite the magnitude of the problem, rates of early death and rehospitalization have not improved over the past several decades. 3 Nesiritide, a recombinant B-type natriuretic peptide (BNP) with vasodilatory properties, 4 – 7 was approved in 2001 for use in patients with acute heart failure on the basis of studies showing a reduction in pulmonary-capillary wedge pressure and improvement in dyspnea at 3 hours. 5 , 6 , 8 However, subsequent pooled analyses of data from small, randomized trials . . .

Patients with pulmonary arterial hypertension were randomly assigned to receive sotatercept at a dose of 0.3 mg per kilogram or 0.7 mg per kilogram or placebo, in addition to standard therapy. At 24 weeks, both sotatercept groups had a greater reduction in pulmonary vascular resistance than the placebo group.

Elevated filling pressure of the left ventricle (LV) defines diastolic dysfunction. The gold standard for diagnosis is represented by the measurement of LV end-diastolic pressure (LVEDP) during cardiac catheterization, but it has the disadvantage of being an invasive procedure. This study aimed to investigate the correlation between LVEDP and cardiac serum biomarkers such as natriuretic peptides (mid-regional pro-atrial natriuretic peptide [MR-proANP], B-type natriuretic peptide [BNP], and N-terminal prohormone BNP [NT-proBNP]), soluble ST2 (sST2), galectin-3 and mid-regional pro-adrenomedullin (MR-proAMD). Consecutive patients hospitalized in a tertiary center and undergoing left cardiac catheterization were included in the study. Diastolic dysfunction was considered present if the end-expiratory LVEDP was ≥ 15 mmHg. Cardiac biomarkers were determined from pre-procedural peripheral venous blood samples. A total of 110 patients were included, of whom 76 (69.0%) were males, with a median age of 65 (55–71) years. Median LVEDP was 13.5 (8–19) mmHg and diastolic dysfunction was present in 50 (45.4%) of the patients. LVEDP correlated with BNP (p < 0.0001, r = 0.39 [0.20–0.53]), NT-proBNP (p < 0.0001, r = 0.40 [0.22–0.55]), MR-proANP (p = 0.001, r = 0.30 [0.11–0.46]), sST2 (p < 0.0001, r = 0.47 [0.30–0.60]), but not with MR-proAMD (p = 0.77) or galectin-3 (p = 0.76). In the final stepwise multivariable binary logistic regression model, diastolic dysfunction was predicted by NT-proBNP, mitral average E/e’, sST2, atrial fibrillation, and left atrium reservoir strain. BNP, NT-proBNP, MR-proANP, and sST2 had predictive value for diastolic dysfunction. In contrast, galectin-3 and MR-proAMD were not associated with increased filling pressures. Furthermore, NT-proBNP and sST2 significantly improved diastolic dysfunction prediction in the final multivariable model.

ObjectivesTwo identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C).MethodsAdults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting ≥30% reduction from baseline in worst abdominal pain plus an increase of ≥1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥6 of 12 treatment weeks). Safety was assessed by adverse events (AEs).ResultsOverall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for ≥2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0).ConclusionsPlecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability.

Background and Objective Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study ( N = 35 patients aged 5–14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study ( N = 60 patients aged 5–18 years randomized to receive daily subcutaneous injections for 52 weeks). Methods Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. Results The exposure–response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5–18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration ( C max ) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure ( C max and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. Conclusions The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. Clinical Trials Registration NCT02055157, NCT03197766, and NCT01603095.

Vosoritide is a biologic analogue of C-type natriuretic peptide, a stimulator of endochondral ossification, which is disordered in achondroplasia. In this phase 2 dose-finding study and extension study involving children with achondroplasia, once-daily administration of vosoritide resulted in a sustained increase in the annualized growth velocity.

PurposeMyocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects.MethodsTwo cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values.ResultsLevosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43–2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers.ConclusionAdding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

Patients with acute decompensated heart failure were randomly assigned to receive sacubitril–valsartan or enalapril. At 8 weeks, the sacubitril–valsartan group had a greater reduction in the N-terminal pro–B-type natriuretic peptide concentration than the enalapril group.

The natriuretic peptides (NPs) ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide) mediate their widespread effects by activating the natriuretic peptide receptor-A (NPR-A), while C-type natriuretic peptide (CNP) acts via natriuretic peptide receptor-B (NPR-B). NPs are removed from the circulation by internalization via the natriuretic peptide clearance receptor natriuretic peptide receptor-C (NPR-C). In addition to their well-known functions, for instance on blood pressure, all three NPs confer significant cardioprotection and renoprotection. Since neither the NP-mediated renal functions nor the renal target cells of renoprotection are completely understood, we performed systematic localization studies of NP receptors using in situ hybridization (RNAscope) in mouse kidneys. NPR-A mRNA is highly expressed in glomeruli (mainly podocytes), renal arterioles, endothelial cells of peritubular capillaries, and PDGFR-receptor β positive (PDGFR-β) interstitial cells. No NPR-A mRNA was detected by RNAscope in the tubular system. In contrast, NPR-B expression is highest in proximal tubules. NPR-C is located in glomeruli (mainly podocytes), in endothelial cells and PDGFR-β positive cells. To test for a possible regulation of NPRs in kidney diseases, their distribution was studied in adenine nephropathy. Signal intensity of NPR-A and NPR-B mRNA was reduced while their spatial distribution was unaltered compared with healthy kidneys. In contrast, NPR-C mRNA signal was markedly enhanced in cell clusters of myofibroblasts in fibrotic areas of adenine kidneys. In conclusion, the primary renal targets of ANP and BNP are glomerular, vascular, and interstitial cells but not the tubular compartment, while the CNP receptor NPR-B is highly expressed in proximal tubules. Further studies are needed to clarify the function and interplay of this specific receptor expression pattern.