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      Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

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          Abstract

          Aims

          Heart failure with preserved ejection fraction ( HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate ( cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐ 5A ( PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.

          Methods and results

          Zucker diabetic fatty ( ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular ( LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G ( PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.

          Conclusions

          We report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.

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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.

          Margaret M. Redfield, Horng Chen, Barry Borlaug … (2013)
          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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            Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways.

            Karina Huynh, Bianca C. Bernardo, Julie McMullen … (2014)
            Cardiovascular disease is the primary cause of morbidity and mortality among the diabetic population. Both experimental and clinical evidence suggest that diabetic subjects are predisposed to a distinct cardiomyopathy, independent of concomitant macro- and microvascular disorders. 'Diabetic cardiomyopathy' is characterized by early impairments in diastolic function, accompanied by the development of cardiomyocyte hypertrophy, myocardial fibrosis and cardiomyocyte apoptosis. The pathophysiology underlying diabetes-induced cardiac damage is complex and multifactorial, with elevated oxidative stress as a key contributor. We now review the current evidence of molecular disturbances present in the diabetic heart, and their role in the development of diabetes-induced impairments in myocardial function and structure. Our focus incorporates both the contribution of increased reactive oxygen species production and reduced antioxidant defenses to diabetic cardiomyopathy, together with modulation of protein signaling pathways and the emerging role of protein O-GlcNAcylation and miRNA dysregulation in the progression of diabetic heart disease. Lastly, we discuss both conventional and novel therapeutic approaches for the treatment of left ventricular dysfunction in diabetic patients, from inhibition of the renin-angiotensin-aldosterone-system, through recent evidence favoring supplementation of endogenous antioxidants for the treatment of diabetic cardiomyopathy. Novel therapeutic strategies, such as gene therapy targeting the phosphoinositide 3-kinase PI3K(p110α) signaling pathway, and miRNA dysregulation, are also reviewed. Targeting redox stress and protective protein signaling pathways may represent a future strategy for combating the ever-increasing incidence of heart failure in the diabetic population. Copyright © 2014 Elsevier Inc. All rights reserved.
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              PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.

              Anindita Das, David Durrant, Fadi Salloum … (2015)
              The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients.
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                Author and article information

                Contributors
                Csaba Mátyás: csaba.matyas@gmail.com
                Journal
                Journal ID (nlm-ta): Eur J Heart Fail
                Journal ID (iso-abbrev): Eur. J. Heart Fail
                Journal ID (doi): 10.1002/(ISSN)1879-0844
                Journal ID (publisher-id): EJHF
                Title: European Journal of Heart Failure
                Publisher: John Wiley & Sons, Ltd (Oxford, UK )
                ISSN (Print): 1388-9842
                ISSN (Electronic): 1879-0844
                Publication date (Electronic): 19 December 2016
                Publication date (Print): March 2017
                Volume: 19
                Issue: 3 ( doiID: 10.1002/ejhf.2017.19.issue-3 )
                Pages: 326-336
                Affiliations
                [ 1 ] Experimental Research Laboratory, Heart and Vascular CenterSemmelweis University Városmajor u. 68 1122 BudapestHungary
                [ 2 ] Department of Cardiac SurgeryUniversity of Heidelberg HeidelbergGermany
                [ 3 ] Institute of PathophysiologySemmelweis University BudapestHungary
                [ 4 ] Department of PhysiologySemmelweis University BudapestHungary
                [ 5 ] Division of Clinical Physiology, Faculty of MedicineUniversity of Debrecen DebrecenHungary
                Author notes
                [*] [* ]Corresponding Author. Tel: +36 1 458 6810, Fax: +36 1 458 6842, Email: csaba.matyas@ 123456gmail.com
                Article
                Publisher ID: EJHF711
                DOI: 10.1002/ejhf.711
                PMC ID: 5347963
                PubMed ID: 27995696
                SO-VID: 35e7a2ee-fa54-4dd0-94db-5defeb17a479
                Copyright © © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 20 July 2016
                Date revision received : 21 October 2016
                Date accepted : 09 November 2016
                Page count
                Figures: 5, Tables: 1, Pages: 11, Words: 5322
                Funding
                Funded by: Hungarian Scientific Research Fund
                Award ID: OTKA‐PD100245
                Award ID: OTKA‐K 109083
                Funded by: János Bolyai Research Scholarship of the Hungarian Academy of Sciences
                Funded by: European Social Fund in the framework of TÁMOP 4.2.4. A/1‐11‐1‐2012‐0001 ‘National Excellence Program’
                Funded by: scholarship of Human Resource Support Office
                Award ID: NTP‐NFTÖ‐16‐0081
                Categories
                Subject: Research Article
                Subject: Pathophysiology
                Subject: Research Article
                Custom metadata
                source-schema-version-number 2.0
                component-id ejhf711
                cover-date March 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.8 mode:remove_FC converted:13.03.2017

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: vardenafil,cgmp,diabetic cardiomyopathy,diastolic dysfunction,cardiomyocyte stiffness
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: vardenafil, cgmp, diabetic cardiomyopathy, diastolic dysfunction, cardiomyocyte stiffness

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