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Introduction: Heart failure is a complex, debilitating condition and despite advances in treatment, it remains a significant cause of morbidity and mortality worldwide. Therefore, the need for alternative treatment strategies is essential. In this review, we explore the therapeutic strategies of augmenting natriuretic peptide receptors (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) in heart failure., Areas Covered: We aim to provide an overview of the evidence of preclinical and clinical studies on novel heart failure treatment strategies. Papers collected in this review have been filtered and screened following PubMed searches. This includes epigenetics, modulating enzyme activity in natriuretic peptide (NP) synthesis, gene therapy, modulation of downstream signaling by augmenting soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) inhibition, nitrates, c-GMP-dependent protein kinase, synthetic and designer NP and RNA therapy., Expert Opinion: The novel treatment strategies mentioned above have shown great potential, however, large randomized controlled trials are still lacking. The biggest challenge is translating the results seen in preclinical trials into clinical trials. We recommend a multi-disciplinary team approach with cardiologists, geneticist, pharmacologists, bioengineers, researchers, regulators, and patients to improve heart failure outcomes. Future management can involve telemedicine, remote monitoring, and artificial intelligence to optimize patient care.

Heart failure with reduced ejection fraction (HFrEF) is the inability of the heart to adequately contract or eject blood. This heart is unable to produce adequate cardiac output to perfuse vital tissues. At a fundamental level, it is known that the cardioprotective pathway of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate is impaired in heart failure patients. Vericiguat is a novel, orally used, small molecule, and direct stimulator of the soluble guanylate cyclase, and thus, it enhances the production of cyclic guanosine monophosphate. Vericiguat was approved by the FDA in January of 2021 to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic heart failure and ejection fraction less than 45%. In this review, we describe the chemical and mechanistic aspects, pharmacokinetics, adverse effects, and contraindications of vericiguat so as to facilitate its optimal therapeutic use., Competing Interests: The authors declare no conflict of interest with the work being reported here., (Copyright © 2022 Raquel Chiles and Rami A. Al-Horani.)

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Doses of sacubitril/valsartan (Sac/Val) achieved in clinical trials of heart failure with reduced ejection fraction (HFrEF) are often not reached in clinical practice., Objectives: The purpose of this study was to investigate associations among Sac/Val doses and changes in prognostic biomarkers, health status, and cardiac remodeling among individuals with HFrEF through 12 months of treatment with Sac/Val administered per usual care., Methods: A total of 794 persons with HFrEF (ejection fraction [EF] ≤40%) were categorized according to average daily doses of Sac/Val divided into tertiles. Change from baseline to 12 months in biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, soluble ST2, atrial natriuretic peptide, urinary cyclic guanosine monophosphate), Kansas City Cardiomyopathy Questionnaire-23 scores, and parameters of cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, and E/e') were assessed., Results: The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose), and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed in all dose tertiles. Gains in Kansas City Cardiomyopathy Questionnaire-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute left ventricular EF improvement across HF dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e' were also observed across dose categories., Conclusions: Among patients with HFrEF, similar improvement in prognostic biomarkers, health status, and cardiac remodeling were observed across various Sac/Val doses. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183., Competing Interests: Funding Support and Author Disclosures The PROVE-HF study was funded by Novartis Pharmaceuticals. Dr Mohebi is supported by a Barry fellowship. Dr Piña has participated on advisory boards for Vifor and AstraZeneca; and has served as a steering committee member for Novartis. Drs Prescott and Ward are employees of Novartis Pharmaceuticals. Dr Butler is a consultant for Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide, and Vifor. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer, Merck, Cytokinetics, and Myokardia; has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, and Sequana; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr Januzzi is supported in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a Board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Prevencio, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, Takeda and Vifor. Dr Liu has reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: β3-AR (β3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the β3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF., Methods: In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III-IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week's treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure., Results: We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07-0.75] L/min/BSA; P =0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (-1.6 [CI, -0.4 to -2.8] Wood units; P =0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated., Conclusions: Oral treatment with the β3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: 2016-002367-34.

Importance: Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death., Observations: Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology, and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial hypertension is further divided into subgroups based on underlying etiology, consisting of idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the newborn, as well as PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists of drugs that enhance the nitric oxide-cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil), and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current treatment consists of combination drug therapy that targets more than 1 biological pathway, such as the nitric oxide-cyclic guanosine monophosphate and endothelin pathways (eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and mortality compared with the previous conventional single-pathway targeted monotherapy., Conclusions and Relevance: Pulmonary arterial hypertension affects an estimated 10.6 per 1 million adults in the US and, without treatment, typically progresses to right heart failure and death. First-line therapy with drug combinations that target multiple biological pathways are associated with improved survival.

Treatment of hypertension until now has been directed at inhibition of vasoconstriction, of cardiac contractility and of blood volume regulation. Despite the arsenal of drugs available for this purpose, the control of target blood pressure is still a difficult goal to reach in outpatients. The nitric oxide-cyclic guanosine monophosphate signaling is one of the most important mediators of vasodilation. It might therefore be a potential and most welcome drug target for optimization of the treatment of hypertension. In this chapter we review the problems that can occur in this signaling system, the attempts that have been made to correct these problems, and those that are still under investigation. Recently developed, clinically safe medicines that are currently approved for other applications, such as myocardial infarction, await to be tested for essential systemic hypertension. We conclude that despite many years of research without translation, stimulation of nitric oxide-cyclic guanosine monophosphate is still a viable strategy in the prevention of the health risk posed by chronic hypertension., Competing Interests: Conflict of interest AJMR has received financial support for preclinical studies from Intracellular Therapies, USA, and Sulfateq BV, The Netherlands., (Copyright © 2022 Elsevier Inc. All rights reserved.)