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Nitroxyl donors for acute heart failure: promising newcomers

2017; Elsevier BV; Volume: 19; Issue: 10 Linguagem: Inglês

10.1002/ejhf.793

1879-0844

John Parissis, Vasiliki Bistola, Ignatios Ikonomidis, Filippos Triposkiadis,

Cardiovascular Function and Risk Factors

European Journal of Heart FailureVolume 19, Issue 10 p. 1333-1334 Editorial commentFree Access Nitroxyl donors for acute heart failure: promising newcomers John Parissis, Corresponding Author John Parissis jparissis@yahoo.com Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GreeceCorresponding author. Email: jparissis@yahoo.comSearch for more papers by this authorVasiliki Bistola, Vasiliki Bistola Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GreeceSearch for more papers by this authorIgnatios Ikonomidis, Ignatios Ikonomidis Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GreeceSearch for more papers by this authorFilippos Triposkiadis, Filippos Triposkiadis Department of Cardiology, Larissa University Hospital, Larissa, GreeceSearch for more papers by this author John Parissis, Corresponding Author John Parissis jparissis@yahoo.com Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GreeceCorresponding author. Email: jparissis@yahoo.comSearch for more papers by this authorVasiliki Bistola, Vasiliki Bistola Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GreeceSearch for more papers by this authorIgnatios Ikonomidis, Ignatios Ikonomidis Heart Failure Unit, Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, GreeceSearch for more papers by this authorFilippos Triposkiadis, Filippos Triposkiadis Department of Cardiology, Larissa University Hospital, Larissa, GreeceSearch for more papers by this author First published: 14 August 2017 https://doi.org/10.1002/ejhf.793Citations: 8 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.897 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 'A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics, and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction' by C. Tita et al., published in this issue on pages 1321–1332. Acute heart failure (AHF) constitutes a heterogeneous clinical syndrome, which remains a significant challenge for everyday clinical practice, clinical research, and drug development. From the clinical perspective, AHF is characterized by high mortality rates reaching 30% within 1 year following the acute event and the increased need for repeated hospitalizations (20% within 30 days and 50% within 6 months).1 Currently available treatment modalities for AHF offer symptomatic relief in a substantial number of cases, but have failed to improve short and long term outcomes.2 Meanwhile, advances in therapeutic management of AHF have been extremely limited, with several new molecules failing to result in meaningful clinical benefits. Possible reasons for these treatment failures include diverse syndrome pathophysiology [patients with acute decompensation of chronic heart failure (ADCHF) or de novo heart failure with preserved or reduced left ventricular ejection fraction (LVEF)], heterogeneity in patient demographic and clinical characteristics, and inappropriate therapeutic targets/molecules or trial design.3 Regardless of the specific underlying pathophysiology, common contributors to AHF development include impaired cardiac mechanics, cardiac injury, vasoconstriction, endothelial dysfunction, excess neurohormonal activation, and renal dysfunction.4 Clinical manifestations in this setting are predominantly due to a combination of reduced cardiac output, increased left and right heart pressures, and systemic (venous and arterial) vasoconstriction, causing cardiac overload and venous congestion. Although AHF phenotypes share common pathophysiological pathways, the individual contribution of these pathways and the complex interplays among them result in diverse AHF phenotypes, requiring individualized management. In this regard, ADCHF with preserved or reduced LVEF is observed as part of the natural course of the syndrome, may develop during early or advanced clinical stages in patients receiving or not neurohormonal antagonists, and may be precipitated by specific factors (i.e. infection, uncontrolled hypertension, non-adherence to drugs or diet). Unfortunately, treatment is usually empirical and in most cases includes diuretics with or without vasodilators following the 'one size fits all' model. The situation is slightly different in de novo AHF, which is frequently precipitated by an acute ischaemic, arrhythmic, inflammatory or mechanical cardiac event. In this setting, diuretics and vasodilators usually supplement the eradication of the underlying cause. In any case, individualized, phenotype-based management should be pursued in all patients with AHF.5 In this issue of the European Journal of Heart Failure, Tita et al.6 present the results of a phase 2a study of a novel molecule, BMS-986231, given in a specific AHF patient subgroup comprising patients with ADCHF and reduced LVEF. BMS-986231 is a second-generation nitroxyl donor that releases HNO, a molecule shown in pre-clinical studies to produce a variety of beneficial effects on cardiac function, including enhancement of inotropy, lusitropy, and vasodilation.7 Inotropic and lusitropic effects are mediated through the post-translational modification of calcium-regulating cardiomyocyte proteins, including SERCA-2a, phospholamban and ryanodine receptors, while arterial and venous vasodilation have been attributed to the activation of soluble guanylate cyclase.8, 9 Meanwhile, BMS-986231 does not affect L-type calcium channel current or total sarcoplasmic reticulum calcium load, an unwanted effect caused by traditional inotropic agents that has been associated with arrhythmogenesis. The study by Tita et al. is a dose–response study, designed to test the safety, tolerability, and haemodynamic effects of BMS-986231 (n = 46). Four sequentially escalated drug-dosing schemes (3, 5, 7, or 12 µg/kg/min) were administered in four patient groups and compared against placebo. Study results with respect to the haemodynamic effects of the active comparator confirm the beneficial haemodynamic effects of BMS-986231 in the clinical setting of ADCHF, which resulted in unloading of the left and possibly the right ventricle. BMS-986231 reduced pulmonary capillary wedge pressure by a mean of 18% across all dosing groups throughout the duration of the 6 h infusion, and similar reductions were detected in pulmonary artery systolic and diastolic pressures, and in high doses for right atrial pressure. Moreover, although the cardiac index (CI) measured by the Fick method (primary end-point) did not show a clear pattern of effect, non-invasively measured CI was consistently increased by all dosing schemes of BMS-986231, significance achieved by the two highest dose regimens. Additionally, systemic vascular resistance was reduced by the active drug, and, as expected, arterial systolic and diastolic blood pressure were also reduced. However, the most prominent increase of CI produced by the highest dosing scheme of the active drug (12 µg/kg/min) counteracted the effects of systemic vasodilation on systolic blood pressure, which did not actually decrease in this dosing regimen. A limitation of this study is that the potential direct effects of BMS-986231 on cardiac function were not assessed. It is not known, therefore, whether the improved haemodynamic patient profile was due to vasodilation per se or vasodilation acting on top of the potential positive inotropic and/or lusitropic effects of the drug. However, this study has re-confirmed the favourable haemodynamic, tolerability, and safety profile of BMS-986231. Regarding safety, the neutral effect of the active drug on the heart rate, which contrasts with the detrimental increase in heart rate caused by most of the conventional inotropic agents, justifies the optimism that a non-arrhythmogenic profile will be revealed in future large-scale testing. The latter is also required to acquire data regarding the effect of BMS-986231 on markers of myocardial injury (i.e. troponins), also increased by the currently used conventional inotropic agents. Overall, these preliminary findings regarding the use of BMS-986231 in patients with ADCHF and reduced LVEF are encouraging. Therefore, further large-scale testing is strongly encouraged to assess the effect of this drug on outcomes in this patient population. Conflict of interest: J.P. reports honoraria from Novartis, Servier, Pfizer and Orion Pharma. V.B. reports honoraria from Novartis. I.I. and F.T. report no conflict of interest. References 1Dharmarajan K, Hsieh AF, Kulkarni VT, Lin Z, Ross JS, Horwitz LI, Kim N, Suter LG, Lin H, Normand SL, Krumholz HM. Trajectories of risk after hospitalization for heart failure, acute myocardial infarction, or pneumonia: retrospective cohort study. BMJ 2015; 350: h411. 2Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH and van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016; 18: 891– 975. 3McDonagh TA, Komajda M, Maggioni AP, Zannad F, Gheorghiade M, Metra M, Dargie HJ. Clinical trials in acute heart failure: simpler solutions to complex problems. Consensus document arising from a European Society of Cardiology cardiovascular round-table think tank on acute heart failure, 12 May 2009. Eur J Heart Fail 2011; 13: 1253– 1260. 4Mentz RJ, O'Connor CM. Pathophysiology and clinical evaluation of acute heart failure. Nat Rev Cardiol 2016; 13: 28– 35. 5Marti CN, Georgiopoulou VV, Kalogeropoulos AP. Acute heart failure: patient characteristics and pathophysiology. Curr Heart Fail Rep 2013; 10: 427– 433. 6Tita C, Gilbert EM, Van Bakel AB, Grzybowski J, Haas GJ, Jarrah M, Dunlap SH, Gottlieb SS, Klapholz M, Patel PC, Pfister R, Seidler T, Shah KB, Zieliński T, Venuti RP, Cowart D, Foo SY, Vishnevsky A, Mitrovic V. A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics, and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction. Eur J Heart Fail 2017;19:1321–1332. 7Sabbah HN, Tocchetti CG, Wang M, Daya S, Gupta RC, Tunin RS, Mazhari R, Takimoto E, Paolocci N, Cowart D, Colucci WS, Kass DA. Nitroxyl (HNO): A novel approach for the acute treatment of heart failure. Circ Heart Fail 2013; 6: 1250– 1258. 8Tocchetti CG, Wang W, Froehlich JP, Huke S, Aon MA, Wilson GM, Di Benedetto G, O'Rourke B, Gao WD, Wink DA, Toscano JP, Zaccolo M, Bers DM, Valdivia HH, Cheng H, Kass DA, Paolocci N. Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. Circ Res 2007; 100: 96– 104. 9Zhu G, Groneberg D, Sikka G, Hori D, Ranek MJ, Nakamura T, Takimoto E, Paolocci N, Berkowitz DE, Friebe A, Kass DA. Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl (HNO) in the mouse. Hypertension 2015; 65: 385– 392. Citing Literature Volume19, Issue10October 2017Pages 1333-1334 ReferencesRelatedInformation