Falls et al. J Transl Med (2017) 15:172 DOI 10.1186/s12967-017-1271-z Journal of Translational Medicine PROTOCOL Open Access Inorganic nitrate as a treatment for acute heart failure: a protocol for a single center, randomized, double‑blind, placebo‑controlled pilot and feasibility study Roman Falls1,2, Michael Seman1,2, Sabine Braat2,4, Joshua Sortino1, Jason D. Allen1,3 and Christopher J. Neil1,2,3,5* Abstract Background: Acute heart failure (AHF) is a frequent reason for hospitalization worldwide and efective treatment options are limited. It is known that AHF is a condition characterized by impaired vasorelaxation, together with reduced nitric oxide (NO) bioavailability, an endogenous vasodilatory compound. Supplementation of inorganic sodium nitrate ­(NaNO3) is an indirect dietary source of NO, through bioconversion. It is proposed that oral sodium nitrate will favorably afect levels of circulating NO precursors (nitrate and nitrite) in AHF patients, resulting in reduced systemic vascular resistance, without signifcant hypotension. Methods and outcomes: We propose a single center, randomized, double-blind, placebo-controlled pilot trial, evaluating the feasibility of sodium nitrate as a treatment for AHF. The primary hypothesis that sodium nitrate treat- ment will result in increased systemic levels of nitric oxide pre-cursors (nitrate and nitrite) in plasma, in parallel with improved vasorelaxation, as assessed by non-invasively derived systemic vascular resistance index. Additional sur- rogate measures relevant to the known pathophysiology of AHF will be obtained in order to assess clinical efect on dyspnea and renal function. Discussion: The results of this study will provide evidence of the feasibility of this novel approach and will be of inter- est to the heart failure community. This trial may inform a larger study. Keywords: Heart failure, Acute heart failure, Acute decompensated heart failure, Sodium nitrate, Nitric oxide, Non- invasive cardiovascular monitoring Background and rationale to fuid overload, raised ventricular flling pressures and/ Acute heart failure: incidence and current treatment or pulmonary congestion [4]. In the United States, acute heart failure (AHF), also Although contemporary medical and device-based known as acute decompensated heart failure, is responsi- therapies (including non-invasive ventilation and ven- ble for over 1 million hospital admissions annually [1] and tricular assist devices) have substantially improved the is the leading reason for hospitalization among patients outlook for patients with chronic heart failure, the lack over 65 years of age. AHF refers to the heterogeneous of established efective treatment strategies for patients syndrome of the gradual or rapid onset of worsening presenting with AHF has been identifed as a major need signs and/or symptoms of heart failure [2, 3], attributed [5]. Tis, together with (i) the re-emerging role of vaso- dilators in AHF, (ii) evidence for acutely impaired nitric oxide (NO) bioavailability and (iii) the potential thera- *Correspondence: [email protected] peutic beneft of inorganic sodium nitrate, will be dis- 5 Western Health Cardiology, Footscray Hospital, Gordon St, Locked Bag 2, cussed as background to this protocol. Footscray, VIC 3011, Australia Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Falls et al. J Transl Med (2017) 15:172 Page 2 of 9 Vascular resistance in the hemodynamics of AHF have been associated with increased mortality [16]. In A discussion of typical hemodynamic profles in the regards to high dose intravenous organic nitrates (e.g. spectrum of AHF presentations is crucial to understand isosorbide dinitrate, glyceryltrinitrate), despite their the re-emerging role of vasodilators in this context. availability and apparent beneft in several relatively small Patients with AHF generally present with an elevated phase II studies [17–19], use is hampered by the develop- pulmonary capillary wedge pressure (PCWP), result- ment of tolerance [20], as well as the generation of reac- ing in congestion (interstitial and/or alveolar pulmonary tive oxygen species [21] and impaired biotransformation edema), present in the majority of cases of AHF. On the in heart failure patients [22]. other hand, cardiac output/cardiac index (CI) can vary Several novel neurohumoral therapeutic strategies, substantially within the AHF population. Te majority including recombinant B-type natriuretic peptide infu- of AHF patients (69%) actually present with a CI in the sion, adenosine receptor antagonism and vasopressin normal range, as illustrated by the work of Nohria et al. receptor antagonism, have not demonstrated an advan- [6]. Furthermore, the majority of patients with AHF are tage over standard therapy [23–25]. Mechanical diuresis known to present with hypertension (50%), rather than via ultrafltration has likewise not demonstrated supe- normotension (47%) or hypotension (3%) [7]. By infer- riority to standard medical diuresis, in fact demonstrat- ence, given that such patients are typically not hyperdy- ing an increased incidence of adverse events [26]. More namic, systemic vascular resistance (SVR) is likely to be recently, serelaxin, a recombinant vasodilating peptide, generally and markedly elevated at the time of acute pres- has shown some promise in a study by Teerlink et al. entations in this group. Elevated SVR was found to be the [27]. Whilst there was a signifcant beneft seen in dysp- most consistent hemodynamic abnormality in a cross- nea relief during treatment and biomarker endpoints, the sectional study employing non-invasive cardiac output 30-day readmission rate was not reduced. Intriguingly, measurements in a large cohort of AHF patients [8]. however, the mortality at 6 months was improved over Acute elevation of SVR has several implications in placebo. Tis fnding has focused interest on vasodilation the context of AHF. Increased SVR would generally be in AHF, as well as informed a large phase III study [28]. attributed to impaired vasorelaxation (or failure of vaso- dilation) at an arteriolar level, as a net result of neuroen- Nitric oxide bioavailability in AHF docrine and paracrine signals, in addition to the infuence Te normal physiology of vascular relaxation involves the of vasoactive drugs. Importantly, activation of the sym- generation of NO via endothelial nitric oxide synthase, pathetic nervous system, with arteriolar vasoconstriction from l-arginine; NO freely difuses to adjacent smooth and reduced venous capacitance, is thought to promote muscle cells to activate soluble guanylate cyclase (sCG), the centralization of blood volume, in the genesis of pul- which induces vasorelaxation via a second messenger monary congestion [9, 10]. Te efects of high SVR on cyclic guanylate monophosphate. Heart failure is associ- afterload are also likely to be crucial in the pathophysiol- ated with decreased NO bioavailability and dysfunction ogy of AHF, which has been conceptualized as a condi- of endothelial NOS [29]. In acute decompensation, there tion of afterload mismatch, as reviewed by Cotter et al. is decreased overall NO production, as refected by a 38% [8, 11]. In respect to afterload, it should be noted that decrease in systemic nitrate and nitrite [30]. An addi- there are pulsatile and non-pulsatile elements of afterload tional mechanism by which NOS function may be acutely and both are known to be abnormal in AHF [12, 13]. All impaired is a substantial increase in levels of circulating of the above considerations are components of an emerg- asymmetric dimethylarginine (ADMA), an endogenous ing vasculocentric model of AHF [14]. inhibitor of NOS, which was measured simultaneously with reduced nitrate and nitrite levels, by Saitoh and Current therapeutics in AHF colleges [30]. Tus, in the AHF context, impaired NOS Te primary therapeutic objective during AHF hospitali- function may be at the nexus of poor NO biosynthesis/ zation is decongestion, whilst avoiding the complications bioavailability and elevated SVR. Methods to therapeuti- of hypotension and worsening renal function (WRF). cally circumvent this defciency may result in therapeutic Currently, loop diuretic is universally recommended in beneft. international guidelines, with the directed use of nonin- Te concept of a circulating pool of inorganic nitrite NO− NO− vasive ventilation, nitrovasodilators and inotropic sup- ( 2 ) and nitrate ( 3 ) as an efective NO donor, port, in more severe cases [3, 15]. With the exception of independent of endothelial NOS function, has received noninvasive ventilation, this basic therapeutic tool kit has increasing attention over the past decade [31]. Nitrite lev- been consistent for over 30 years. Unfortunately, despite els can be increased via direct administration (e.g. intra- substantial efort, no novel pharmacological strategy has venous or inhaled), or by oral intake of nitrate (typically thus