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Importance: Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency., Objective: To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF., Design, Setting, and Participants: CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019., Interventions: Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90)., Main Outcomes and Measures: The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs)., Results: Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group)., Conclusions and Relevance: Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF., Trial Registration: ClinicalTrials.gov Identifier: NCT03254485.

Background: Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine 3',5'-monophosphate signaling, is being investigated for the treatment of patients with HFpEF., Methods: CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency: diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO 2 by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire., Conclusions: The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Drugs facilitating the cardioprotective effects of natriuretic peptides are introduced in heart failure treatment. ANP and BNP also stimulate lipolysis and increase circulating concentrations of free fatty acids (FFAs); an aspect, however, thought to be confined to primates. We examined the lipolytic effect of natriuretic peptide infusion in healthy young men and evaluated the effect in a porcine model of myocardial ischemia and reperfusion. Six young healthy normotensive men underwent infusion with ANP, BNP, or CNP for 20 min. Blood samples were collected before, during, and after infusion for measurement of FFAs. In a porcine model of myocardial ischemia and reperfusion, animals were infused for 3 h with either BNP (n = 7) or saline (n = 5). Blood samples were collected throughout the infusion period, and cardiac tissue was obtained after infusion for lipid analysis. In humans, ANP infusion dose-dependently increased the FFA concentration in plasma 2.5-10-fold (baseline vs. 0.05 μg/kg/min P < 0.002) and with BNP 1.6-3.5-fold (P = 0.001, baseline vs. 0.02 μg/kg/min) 30 min after initiation of infusion. Infusion of CNP did not affect plasma FFA. In pigs, BNP infusion induced a 3.5-fold increase in plasma FFA (P < 0.0001), which remained elevated throughout the infusion period. Triglyceride content in porcine right cardiac ventricle tissue increased ∼5.5 fold in animals infused with BNP (P = 0.02). Natriuretic peptide infusion has similar lipolytic activity in human and pig. Our data suggest that short-term infusion increases the cardiac lipid content, and that the pig is a suitable model for studies of long-term effects mediated by natriuretic peptides., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The natriuretic peptides (NPs) family, including atrial, B-type, and C-type NPs, is a group of hormones possessing relevant haemodynamic and anti-remodelling actions in the cardiovascular (CV) system. Due to their diuretic, natriuretic, vasorelaxant, anti-proliferative, and anti-hypertrophic effects, they are involved in the pathogenic mechanisms leading to major CV diseases, such as heart failure (HF), coronary artery disease, hypertension and left ventricular hypertrophy, and cerebrovascular accidents. Blood levels of NPs have established predictive value in the diagnosis of HF, as well as for its prognostic stratification. In addition, they provide useful clinical information in hypertension and in both stable and unstable coronary artery disease. Structural abnormalities of atrial natriuretic peptide gene (NPPA), as well as genetically induced changes in circulating levels of NPs, have a pathogenic causal link with CV diseases and represent emerging markers of CV risk. Novel NP-based therapeutic strategies are currently under advanced clinical development, as they are expected to contribute to the future management of hypertension and HF. The present review provides a current appraisal of NPs' clinical implications and a critical perspective of the potential therapeutic impact of pharmacological manipulation of this class of CV hormones.

Objectives: This study sought to investigate plasma levels of circulating cardiac natriuretic peptides, atrial natriuretic peptide (ANP) and B-type or brain natriuretic peptide (BNP), in the general community, focusing on their relative differences in worsening human hypertension., Background: Although ANP and BNP are well-characterized regulators of blood pressure in humans, little is known at the population level about their relationship with hypertension. The authors hypothesized that hypertension is associated with a lack of activation of these hormones or their molecular precursors., Methods: The study cohort (N = 2,082, age >45 years) was derived from a random sample from Rochester, Minnesota, and each subject had a medical history, clinical examination, and assessment of different plasma forms of ANP and BNP. Patients were stratified by blood pressure. Multivariable linear regression was used to assess differences in natriuretic peptide levels in worsening hypertension., Results: Compared to normotensive, BNP(1-32) and N-terminal proBNP(1-76) (NT-proBNP(1-76)) were significantly decreased in pre-hypertension (p < 0.05), with BNP(1-32) significantly decreased in stage 1 as well (p < 0.05). Although proBNP(1-108) remained unchanged, the processed form was significantly increased only in stage 2 hypertension (p < 0.05). ANP(1-28) remained unchanged, while NT-ANP(1-98) was reduced in pre-hypertension (p < 0.05)., Conclusions: The authors demonstrated the existence of an impaired production and/or release of proBNP(1-108) along with a concomitant reduction of BNP(1-32) and NT-proBNP(1-76) in the early stages of hypertension, with a significant elevation only in stage 2 hypertension. Importantly, they simultaneously demonstrated a lack of compensatory ANP elevation in advanced hypertension., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Radiocontrast-induced nephropathy (RCIN), a leading cause of in-hospital acute renal failure, is an acute decrease in renal function related to intravascular administration of iodinated radiocontrast agents. Though RCIN is relatively uncommon in patients without predisposing factors, patients with preexisting renal dysfunction, diabetes mellitus and severe congestive heart failure are at increased risk for acute renal failure following radiocontrast. Three recently developed animal models have provided important insights into the pathophysiology of RCIN. Specifically, these studies have implicated transient renal ischemia, direct renal tubular toxicity and changes in glomerular capillary permeability as possible mediators of RCIN, and these pathophysiologic mechanisms are not mutually exclusive. There is currently no effective treatment for RCIN. Assuring adequate hydration may reduce the risk of RCIN. In addition, synthetic atrial natriuretic factor and/or mannitol are promising, but as yet unproven, approaches to the prophylaxis of RCIN.