BACKGROUND: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (-12 mm Hg [95% CI, -22 to -1]; P = .03) and right ventricular end-diastolic area (-5.6 cm2 [95% CI, -11 to -0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.

2nd Department of Medicine Public Hospital Elisabethinen Linz Austria

Bayer HealthCare Pharmaceuticals Milan Italy

Bayer HealthCare Pharmaceuticals Wuppertal Germany

Clinic 3 for Internal Medicine Heart Center at the University Hospital of Cologne Cologne Germany

Clinical Department of Cardiology and Angiology of the 1st Faculty of Medicine and General Teaching Hospital Prague Czech Republic

Department of Internal Medicine 2 Paracelsus Medical University Salzburg Salzburg Austria

From the Department of Internal Medicine 2 Medical University of Vienna Vienna Austria

National University Health System Singapore

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Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251-259 PubMed

McMurray JJ, Adamopoulos S, Anker SD, et al. ; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787-1847 PubMed

Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350(19):1953-1959 PubMed

Borlaug BA, Olson TP, Lam CS, et al. . Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010;56(11):845-854 PubMed PMC

Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003;107(5):714-720 PubMed

Bursi F, McNallan SM, Redfield MM, et al. . Pulmonary pressures and death in heart failure: a community study. J Am Coll Cardiol. 2012;59(3):222-231 PubMed PMC

Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol. 2009;53(13):1119-1126 PubMed PMC

Akiyama E, Sugiyama S, Matsuzawa Y, et al. . Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2012;60(18):1778-1786 PubMed

Galiè N, Hoeper MM, Humbert M, et al. ; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-2537 PubMed

Katz SD, Hryniewicz K, Hriljac I, et al. . Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation. 2005;111(3):310-314 PubMed

Lam CS, Brutsaert DL. Endothelial dysfunction: a pathophysiologic factor in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2012;60(18):1787-1789 PubMed

Mathier MA, Rose GA, Fifer MA, et al. . Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1998;32(1):216-224 PubMed

Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263-2273 PubMed PMC

van Heerebeek L, Hamdani N, Falcão-Pires I, et al. . Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012;126(7):830-839 PubMed

Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs. 2011;20(4):567-576 PubMed

Grimminger F, Weimann G, Frey R, et al. . First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009;33(4):785-792 PubMed

Sharkovska Y, Kalk P, Lawrenz B, et al. . Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models. J Hypertens. 2010;28(8):1666-1675 PubMed

Stasch JP, Hobbs AJ. NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol. 2009;(191):277-308 PubMed

Ghofrani HA, Galiè N, Grimminger F, et al. ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340 PubMed

Ghofrani HA, D’Armini AM, Grimminger F, et al. ; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-329 PubMed

Bonderman D, Ghio S, Felix SB, et al. ; Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT) Study Group. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013;128(5):502-511 PubMed

Rooke GA, Feigl EO. Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circ Res. 1982;50(2):273-286 PubMed

Lang RM, Bierig M, Devereux RB, et al. ; American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7(2):79-108 PubMed

Ogunyankin KO, Liu K, Lloyd-Jones DM, Colangelo LA, Gardin JM. Reference values of right ventricular end-diastolic area defined by ethnicity and gender in a young adult population: the CARDIA study. Echocardiography. 2011;28(2):142-149 PubMed PMC

Boilson BA, Schirger JA, Borlaug BA. Caveat medicus! Pulmonary hypertension in the elderly: a word of caution. Eur J Heart Fail. 2010;12(1):89-93 PubMed

Yin N, Kaestle SM, Kuppe H, et al. . Iloprost inhalation causes lung edema in overperfused heart failure lungs [abstract]. Am J Respir Crit Care Med. 2009;179:A3376

Paulus WJ, Tschöpe 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(4):263-271 PubMed

Buys ES, Sips P, Vermeersch P, et al. . Gender-specific hypertension and responsiveness to nitric oxide in sGCalpha1 knockout mice. Cardiovasc Res. 2008;79(1):179-186 PubMed

Cawley SM, Kolodziej S, Ichinose F, Brouckaert P, Buys ES, Bloch KD. sGCalpha1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling. Am J Physiol Heart Circ Physiol. 2011;301(1):H157-H163 PubMed PMC

Ramos-Espiritu LS, Hess KC, Buck J, Levin LR. The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms in INS-1E cells. J Pharmacol Exp Ther. 2011;338(3):925-931 PubMed PMC

Münzel T, Daiber A, Mülsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005;97(7):618-628 PubMed

Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA, Borlaug BA. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol. 2012;59(5):442-451 PubMed

Guazzi 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(2):164-174 PubMed

Redfield MM, Chen HH, Borlaug BA, et al. ; 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(12):1268-1277 PubMed PMC

Ghofrani HA, Grimminger F. Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy. Eur Respir Rev. 2009;18(111):35-41 PubMed

Gerges C, Gerges M, Lang MB, et al. . Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out-of-proportion” pulmonary hypertension. Chest. 2013;143(3):758-766 PubMed

Mycology-Nanotechnology Interface: Applications in Medicine and Cosmetology

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ClinicalTrials.gov
NCT01172756