Portal de Periódicos da CAPES

Phosphodiesterase‐5 inhibition in heart failure with preserved ejection fraction: trading therapy for prevention

2017; Elsevier BV; Volume: 19; Issue: 3 Linguagem: Inglês

10.1002/ejhf.742

1879-0844

Marco Guazzi, Loek van Heerebeek, Walter J. Paulus,

Heart Failure Treatment and Management

European Journal of Heart FailureVolume 19, Issue 3 p. 337-339 Editorial commentFree Access Phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction: trading therapy for prevention Marco Guazzi, Corresponding Author Marco Guazzi marco.guazzi@unimi.it IRCCS Policlinico San Donato Hospital, University of Milan, Milan, ItalyCorresponding author. University of Milan, Department of Biomedical Sciences for Health, Heart Failure Unit-Cardiology, IRCCS Policlinico San Donato, Piazza E. Malan 2, 20097 San Donato Milanese, Milan, Italy. Tel/Fax: +39 02 52774966, Email: marco.guazzi@unimi.itSearch for more papers by this authorLoek van Heerebeek, Loek van Heerebeek VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorWalter J. Paulus, Walter J. Paulus VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this author Marco Guazzi, Corresponding Author Marco Guazzi marco.guazzi@unimi.it IRCCS Policlinico San Donato Hospital, University of Milan, Milan, ItalyCorresponding author. University of Milan, Department of Biomedical Sciences for Health, Heart Failure Unit-Cardiology, IRCCS Policlinico San Donato, Piazza E. Malan 2, 20097 San Donato Milanese, Milan, Italy. Tel/Fax: +39 02 52774966, Email: marco.guazzi@unimi.itSearch for more papers by this authorLoek van Heerebeek, Loek van Heerebeek VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this authorWalter J. Paulus, Walter J. Paulus VU University Medical Center, Amsterdam, The NetherlandsSearch for more papers by this author First published: 19 January 2017 https://doi.org/10.1002/ejhf.742Citations: 6 The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. doi: 10.1002/ejhf.711 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat This article refers to ‘Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes,’ by C. Mátyás et al., published in this issue on pages 326–336. Heart failure with preserved ejection fraction (HFpEF) is rapidly becoming a major burden to healthcare systems in Western societies, with a 1% annual rise in prevalence relative to heart failure with reduced ejection fraction (HFrEF) and, despite numerous efforts, no established therapeutic intervention with prognostic benefit are available.1 Although a myriad of mechanisms contribute to low exercise tolerance in HFpEF, diastolic LV dysfunction remains pivotal to the pathophysiology of HFpEF and reflects both cardiomyocyte stiffness and myocardial fibrosis.2 Correction of diastolic LV dysfunction remains a compelling challenge in modern cardiovascular medicine and was addressed in the study by Mátyás et al.3 published in the current issue of the journal. The NO–cGMP–PKG pathway and heart failure with preserved ejection fraction In 2013, a new theoretical framework was proposed for HFpEF, based on a continuum of evidence in experimental preparations and human LV biopsies. This new paradigm for HFpEF postulated a central role for coronary microvascular endothelial dysfunction, and inflammation as a result of multiple mainly metabolic co-morbidities. Microvascular endothelial inflammation is presumed to trigger an unfavourable molecular cascade ultimately leading to diastolic LV dysfunction because of stiff and hypertrophied cardiomyocytes and interstitial collagen deposition.4 The major player in this cascade was identified to be loss of nitric oxide (NO) bioavailability, which resulted in cardiomyocyte deprivation of cyclic guanosine monophosphate (cGMP) and lower activity of protein kinase G (PKG).5 The new paradigm triggered a tremendous interest in the association between HFpEF and the NO–cGMP–PKG pathway as evident from a PubMed search using HFpEF and NO–cGMP–PKG pathway as key words, which revealed >100 published articles since the launch of the new paradigm. Three primary mechanisms may impair cGMP signalling in HFpEF myocardium: (i) enhanced degradation through up-regulation of cardiac phosphodiesterases (PDEs), especially PDE5; (ii) decreased NO stimulation and/or responsiveness of soluble guanylate cyclase; and (iii) reduced synthesis via impaired natriuretic peptide activation of transmembrane particulate guanylate cyclase receptors.6 PDE5 is the isoenzyme that breaks down cGMP into its inactive 5'-GMP form.7 In the last decade, in vitro8 and in vivo9, 10 studies have claimed that PDE5 inhibition by sildenafil effectively protects against unfavourable LV remodelling by targeting inhibition of hypertrophic and profibrotic stimuli and modulation of cardiomyocyte stiffness (Figure 1). However, overexpression of PDE5, the key substrate for efficacy of PDE5 inhibitors, has not been an unequivocal finding.5, 11 Figure 1Open in figure viewerPowerPoint Drugs effective on NO-cGMP-PKG pathway with special emphasis on phosphodiesterase-5 (PDE5) inhibition and its cardiac substrate targets. GC, guanilate cyclase; cGMP, cyclic guanosine monophosphate; PKG, protein kinase G. ‘Lifelong’ phosphodiesterase-5 inhibition in Zucker diabetic fatty rats In the present issue of the journal, Mátyás et al.3 report on the myocardial effects of almost lifelong (from week 7 to week 32) administration of the PDE5 inhibitor vardenafil in Zucker diabetic fatty (ZDF) rats, an established model of metabolically induced HFpEF. Vardenafil is more cGMP specific than sildenafil, the most widely used PDE5 inhibitor, and is less likely to interfere with the PDE–cAMP axis. The authors confirmed diastolic LV dysfunction to be mediated by myocardial microvascular inflammation and convincingly demonstrated deranged molecular pathways involved in the NO–cGMP–PKG axis such as overexpression of PDE5. Vardenafil improved both active LV relaxation and diastolic LV stiffness. The latter was achieved by lower cardiomyocyte passive tension and by reduced interstitial fibrosis. Vardenafil not only enhanced PKG activity as evident from an increased p-VASP/VASP (vasodilator-stimulated phosphoprotein) ratio, but also affected endothelial inflammation, nitro-oxidative stress, cardiomyocyte hypertrophy, and apoptosis.12 Vardenafil induced these late-life, ‘pleiotropic’ beneficial effects through preventive actions in early life when the ZDF rats were in a pre-diabetic stage. The positive findings of Mátyás et al.3 clearly contrast with the neutral outcome of some previous clinical attempts to treat HFpEF patients with sildenafil, and suggest myocardial responsiveness to PDE5 inhibition to differ between early pre-clinical risk factor exposure and late clinically manifest HFpEF. Trading therapy for prevention A time-dependent difference in myocardial responsiveness to sildenafil is also supported by other expertimental and clinical observations. In the ZSF1 rat (a cross between a ZDF and a spontaneously hypertensive rat), treatment with sildenafil from week 16 to 20 improved diastolic LV dysfunction, albeit less than in the study of Mátyás et al.,3 probably because of the later onset of treatment.13 In the ZSF1 rat, myocardial fibrosis was absent at 20 weeks of age and diastolic LV dysfunction could be attributed to hypophosphorylation of titin at PKG-specific sites,14 an ideal target for PDE5 inhibition. Myocardial responsiveness to PDE5 inhibition in the incipient stages of concentric LV remodelling and HFpEF was also reported in clinical studies. In a placebo-controlled study of 59 men with early features of diabetic cardiomyopathy, i.e. concentric LV hypertrophy, preserved LV EF but impaired MRI measures of LV torsion and strain, 3 months of sildenafil treatment reversed LV remodeling, evident from a significant improvement of the LV mass to volume ratio.15 Similarly, in hypertensive patients with recent-onset dyspnoea, 1 year treatment with sildenafil improved diastolic LV distensibility, evident from lower LV filling pressures at larger LV internal dimension.16 The successful outcome of PDE5 inhibition in early concentric LV remodelling or early HFpEF contrasts sharply with the neutral outcome of the RELAX trial,17 which was unfortunately planned in the ‘pre-phenotyping’ era of HFpEF and probably addressed a population of advanced HFpEF patients presenting with a high rate of co-morbidities such as anaemia and COPD, by definition unresponsive to a NO-overexperessing intervention. The advanced stage of HFpEF was probably evident from the mean plasma NT-proBNP level, which equalled 700 pg/mL, a value 10 times higher than in the aforementioned early-stage diabetic cardiomyopathy patients.15 Conclusion The study by Mátyás et al.3 ‘resuscitates’ use of PDE5 inhibitors for the prevention of HFpEF. In line with the recent emphasis on phenotype-specific treatment of HFpEF,2 their study supports resumption of clinical investigations on the use of PDE5 inhibitors in early pre-clinical metabolic risk factor exposure and in early HFpEF. If these investigations live up to the expectations, the course of PDE5 inhibition in HFpEF would fit the quote of Dante Alighieri: ‘The path to paradise begins in hell’. Conflict of interest: none declared. References 1Triposkiadis F, Giamouzis G, Parissis J, Starling RC, Boudoulas H, Skoularigis J, Butler J, Filippatos G. Reframing the association and significance of co-morbidities in heart failure. Eur J Heart Fail 2016; 18: 744– 758. 2Shah SJ, Kitzman DW, Borlaug BA, van Heerebeek L, Zile MR, Kass DA, Paulus WJ. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation 2016; 134: 73– 90. 3Mátyás C, Németh BT, Oláh A, Török M, Ruppert M, Kellermayer D, Barta BA, Szabó G, Kökény G, Horváth EM, Bódi B, Papp Z, Merkely B, Radovits T. Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes. Eur J Heart Fail 2017; 19:XXX–XXX. 4Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62: 263– 271. 5van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, van der Velden J, Stienen GJ, Laarman GJ, Somsen A, Verheugt FW, Niessen HW, Paulus WJ. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012; 126: 830– 839. 6Greene SJ, Gheorghiade M, Borlaug BA, Pieske B, Vaduganathan M, Burnett JC Jr, Roessig L, Stasch JP, Solomon SD, Paulus WJ, Butler J. The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction. J Am Heart Assoc 2013; 2:e000536. 7Guazzi M. Clinical use of phosphodiesterase-5 inhibitors in chronic heart failure. Circ Heart Fail 2008; 1: 272– 280. 8Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5a prevents and reverses cardiac hypertrophy. Nat Med 2005; 11: 214– 222. 9Zhang M, Takimoto E, Hsu S, Lee DI, Nagayama T, Danner T, Koitabashi N, Barth AS, Bedja D, Gabrielson KL, Wang Y, Kass DA. Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. J Am Coll Cardiol 2010; 56: 2021– 2030. 10Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail 2011; 4: 8– 17. 11Degen CV, Bishu K, Zakeri R, Ogut O, Redfield MM, Brozovich FV. The emperor's new clothes: PDE5 and the heart. PLoS One 2015; 10:e0118664. 12Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 2014; 142: 375– 415. 13Oliveira-Pinto I V-NF, Cerqueira R, Leite S, Fontoura D, Falcao-Pires I, Lourenco AP, Leite-Moreira AF, Paulus WJ. Chronic treatment with sildenafil in experimental metabolic syndrome associated to heart failure with preserved ejection fraction. Eur J Heart Fail 2014; 16 Suppl 2: 111. 14Hamdani N, Franssen C, Lourenco A, Falcao-Pires I, Fontoura D, Leite S, Plettig L, Lopez B, Ottenheijm CA, Becher PM, Gonzalez A, Tschope C, Diez J, Linke WA, Leite-Moreira AF, Paulus WJ. Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circ Heart Fail 2013; 6: 1239– 1249. 15Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, Naro F, Morano S, Fedele F, Lenzi A. Chronic inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation 2012; 125: 2323– 2333. 16Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 2011; 124: 164– 174. 17Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E, RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013; 309: 1268– 1277. Citing Literature Volume19, Issue3March 2017Pages 337-339 FiguresReferencesRelatedInformation