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      Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure

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          Significance

          The morbidity and mortality associated with heart failure (HF) are unacceptably high. Cyclic guanosine-3′,5′-monophosphate (cGMP) plays a key role in preserving cardiac structure and function, and therapeutically targeting cGMP in HF has shown promise in experimental models and patients. Phosphodiesterases (PDEs) metabolize and curtail the actions of cGMP (and cAMP), and increased PDE activity is thought to contribute to HF pathogenesis. Herein, we show that inhibition of one specific isoform, PDE2, enhances the salutary effects of cGMP in the context of HF, and that this beneficial action facilitates a distinct pathway, driven by nitric oxide, that is impaired in this disorder. These observations validate PDE2 inhibitors as a demonstrable means of boosting cardiac cGMP and advancing HF therapy.

          Abstract

          Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3′,5′-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α −/−) or natriuretic peptide-responsive GC-A (GC-A −/−), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A −/− mice but is absent in animals null for GC-1α or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy.

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          Most cited references73

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          Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

          Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. clinicaltrials.gov Identifier: NCT00763867.
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            Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

            Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.
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              Role of oxidative stress in cardiac hypertrophy and remodeling.

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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                31 July 2018
                16 July 2018
                16 July 2018
                : 115
                : 31
                : E7428-E7437
                Affiliations
                [1] aWilliam Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London , EC1M 6BQ London, United Kingdom;
                [2] bPfizer, Inc. , St. Louis, MO 63198
                Author notes
                2To whom correspondence should be addressed. Email: a.j.hobbs@ 123456qmul.ac.uk .

                Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved June 26, 2018 (received for review January 18, 2018)

                Author contributions: R.S.B., M.E.J.P., M.S.D., S.M.C., A.A.A., K.J.B., A.J.M., M.A.T., and A.J.H. designed research; R.S.B., M.E.J.P., M.S.D., S.M.C., A.A.A., K.J.B., A.J.M., and M.A.T. performed research; M.A.T. contributed new reagents/analytic tools; R.S.B., M.E.J.P., M.S.D., S.M.C., A.A.A., K.J.B., A.J.M., M.A.T., and A.J.H. analyzed data; and R.S.B., M.E.J.P., M.S.D., S.M.C., A.A.A., K.J.B., A.J.M., M.A.T., and A.J.H. wrote the paper.

                1R.S.B. and M.E.J.P. contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-4712-9421
                http://orcid.org/0000-0002-3589-7108
                Article
                201800996
                10.1073/pnas.1800996115
                6077693
                30012589
                4334700a-db75-45f7-b9a6-d65a5d360938
                Copyright © 2018 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 10
                Funding
                Funded by: British Heart Foundation (BHF) 501100000274
                Award ID: PG/10/077/28554
                Award Recipient : Reshma S Baliga Award Recipient : Michael EJ Preedy Award Recipient : Mathew S Dukinfield Award Recipient : Sandy M Chu Award Recipient : Aisah A Aubdool Award Recipient : Kristen J Bubb Award Recipient : Amie J Moyes Award Recipient : Adrian J Hobbs
                Categories
                PNAS Plus
                Biological Sciences
                Pharmacology
                PNAS Plus

                nitric oxide,natriuretic peptide,cyclic gmp,phosphodiesterase,heart failure

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