The multifaceted mechanisms of nitroxyl in heart failure: inodilator or ‘only’ vasodilator?

This article refers to 'Haemodynamic effects of the nitroxyl donor cimlanod (BMS-986231) in chronic heart failure: a randomized trial' by N.N. Lang et al., published in this issue on pages 1147–1155. Heart failure (HF) is a leading cause for hospital admissions in developed countries, and its incidence further increases with the prolonged average life expectancy. While in recent decades the prognosis of patients with chronic HF with reduced ejection fraction (HFrEF) improved by various pharmacological and device-based approaches, the prognosis of acute HF (AHF) remains poor.1 AHF is commonly associated with congestion, elevated cardiac afterload and/or decreased cardiac output,1, 2 and these factors contribute to variable degrees depending on the aetiology of AHF.3 An important clinical sign is peripheral hypoperfusion, which predicts in-hospital mortality2 and is mainly caused by decreased cardiac output.3, 4 While decongestion with intravenous loop diuretics and reduction of pre- and afterload with vasodilators (e.g. nitroglycerin, NTG) provide clinical benefits in AHF (with class I and IIa recommendations in the current HF guidelines,1 respectively), attempts to develop treatments that increase cardiac output were so far less successful. Despite favourable acute effects on haemodynamics, the use of catecholamines and phosphodiesterase inhibitors is associated with increased mortality3, 4 and therefore, restricted to patients with AHF and peripheral hypoperfusion.1 Catecholamines and phosphodiesterase inhibitors have in common that they increase myocardial oxygen consumption, predispose to fatal arrhythmias and activate pro-hypertrophic and pro-apoptotic signalling pathways, mainly driven by cyclic adenonise monophosphate (cAMP)/protein kinase A (PKA) as well as Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent signalling.4, 5 Hence, more recent approaches to improve systolic function aimed to avoid the activation of cAMP/PKA/CaMKII pathways and the consequent Ca2+ entry into cardiomyocytes, for instance by targeting sarcomeres directly (i.e. with levosimendan, omecamtiv mecarbil or danicamtiv).4, 5 Another compound with a favourable mode of action to optimize systolic and diastolic function in cardiac myocytes is nitroxyl (HNO), the one electron reduction sibling of nitric oxide (NO).6 HNO is highly electrophilic and reacts avidly with negatively charged thiols, converting these reversibly to disulfide residues or, less reversibly, to sulfinamides. In isolated cardiac myocytes, HNO increases the activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) and the open probability of ryanodine receptors through such redox modifications, accelerating sarcoplasmic reticulum Ca2+ reuptake (hastening relaxation) and release (enhancing systolic force development) (Figure 1). In addition, HNO modifies sarcomeric proteins to increase their Ca2+ sensitivity and, thereby, systolic force generation7 (Figure 1). Since HNO mediates these effects without increasing cAMP or trans-sarcolemmal Ca2+ influx,8 adverse PKA- and CaMKII-dependent signalling is avoided and, haemodynamically, β-blockers do not blunt the effects of HNO.4, 5, 9 Similar to NO, HNO also triggers peripheral vasodilatation via endothelial soluble guanylate cyclase, but opposite to NO, does not induce tachyphylaxis in peripheral vessels.4, 5, 9 In large HF animal models, HNO donors directly improved myocardial contractility and relaxation, reducing preload and afterload without increasing heart rate or myocardial oxygen consumption.10-12 Despite its short half-life, the first animal studies used the prototypical HNO donor Angeli's salt (AS, Na2N2O3), which derived its name of the Florentine chemist Angelo Angeli, who characterized this molecule in 1896.5 Since AS is also a co-generator of NO2−, these studies required proper controls to exclude this potential confounding effect. Other compounds tested were Piloty's acid and its derivatives, isopropylamine-NO•, and acyloxy nitroso compounds, such as 1-nitrosocyclohexyl acetate (also known as the 'blue compound').9 However, all these compounds are unstable at room temperature. Therefore, novel and pure HNO donors were generated, including CXL-1020, a congener of Piloty's acid that decomposes to HNO and an inactive organic by-product.12 For clinical application, cimlanod (BMS-986231) was developed, which is a pro-drug of CXL-1020 and produced venous and arteriolar dilatation with inotropic effects in hospitalized patients with advanced HF.13 In the StandUP-AHF trial, cimlanod at a dose of 6 mg/kg/min was reasonably well-tolerated and reduced markers of congestion, but this effect did not last beyond the 48 h treatment period.14 From these clinical data, however, it cannot be clearly distinguished whether the favourable haemodynamic effects of cimlanod in patients are related to its inotropic and lusitropic, or rather its vasodilatory effects. In fact, the redox reactivity of HNO that accounts for its inotropic effects can be both a blessing and a curse, since by its capacity to react with reactive oxygen species to form NO, the HNO molecule is rather unstable in oxidizing conditions5, 9 (Figure 1). Therefore, to address this issue in the clinical scenario, in the current issue of this Journal, Lang and colleagues15 present the randomized, double-blind, phase II StandUP-Imaging trial, in which they compared the haemodynamic effects of cimlanod with those of NTG or placebo in 45 patients with – of note – stable chronic HFrEF. Participants were subjected to a continuous 5 h intravenous infusion of cimlanod, NTG, or placebo in a crossover design. The main results are that compared to placebo, both cimlanod and NTG modestly decreased stroke volume index, and slightly reduced left ventricular and left atrial volumes, without any differences between cimlanod and NTG. Similar to NTG, cimlanod reduced systolic blood pressure by 15 mmHg (placebo-corrected), and 24% of patients developed headache. The authors conclude that in patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar, and that therefore the effects of cimlanod are best explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. The authors are to be congratulated to performing a smart and important study, which has been thoroughly executed and adequately interpreted. The important question that emerges now is whether cimlanod is indeed 'only' a vasodilator as NTG, or whether its unique mode of action as an inodilator (Figure 1) unfolds better under different conditions. In fact, one possible explanation is that in patients with HFrEF, a rather pro-oxidative milieu may have favoured the decomposition of HNO towards NO,9 thereby fostering vasodilatation at the cost of inotropy and lusitropy (Figure 1). This, however, would be expected to be even more pronounced in patients with acute (and therefore, more advanced/severe) HF, rendering cimlanod even more likely to behave as a vasodilator instead of an inotrope. Another important consideration, however, is that the expression and activity of SERCA is substantially reduced in cardiac myocytes of patients with HFrEF, a key mechanism for both systolic and diastolic dysfunction.4 However, treatment of HFrEF patients with β-blockers upregulates SERCA mRNA expression, which correlates with an improvement of left ventricular ejection fraction.16 In the current StandUP-Imaging trial, 96% of the stable HFrEF patients were treated with β-blockers and were haemodynamically stable, and therefore improvements of SERCA activity may have been less pronounced compared to patients with AHF, where also more severe pro-oxidative modifications of SERCA could further compromise SERCA function.17 As discussed previously,4 similar issues may underlie the lack of benefit of SERCA gene therapy in more stable patients with HFrEF treated with β-blockers. Furthermore, since the current study was conducted in stable and non-congested HFrEF patients (half of them did not take diuretics), the observed reduction in stroke volume index is likely related to diminished preload (due to venous dilatation) in these patients with already relatively low filling pressures.15 In patients with more severe HF and high left ventricular end-diastolic pressures, however, cardiac index rather increases when afterload is reduced, despite a reduction in intra-cardiac filling pressures.13 In fact, in patients after myocardial infarction, intravenous NTG increased cardiac output in patients with high left ventricular filling pressures, but decreased it in those with normal left ventricular filling pressures.18 In addition, cimlanod may reduce preload by increasing diuresis or diuretic sensitivity, effects that are specifically assessed in the ongoing StandUP-Renal study.7 Finally, with respect to HNO effects on cardiac load, it needs to be considered that both an increase of pre- and afterload increase inotropy via sarcomeric and/or redox- and Ca2+/CaMKII-dependent mechanisms, conceptualized by the Frank–Starling19 and Anrep effects,20 respectively. Therefore, by lowering pre- and afterload through vasodilatation, HNO may to some extent counterbalance its own direct effects on excitation–contraction coupling in cardiac myocytes (Figure 1). To conclude, while the present StandUP-Imaging trial provides clear data and conclusions in patients with stable HFrEF, it will be important to further evaluate the effects of cimlanod in its actual target population, i.e. patients with AHF, for which so far no treatment has evolved to safely improve haemodynamics without deteriorating long-term prognosis.4 Conflict of interest: C.G.T. has received funding from Amgen, outside the submitted work; has a patent Canadian Patent No. 2613477, issued on Dec 3, 2013. Inventors: Nazareno Paolocci, David A Kass, Carlo G Tocchetti. Owner: Johns Hopkins University. Entitled: Thiol-sensitive positive inotropes. JHU Ref.: C04755-P04755-05 with royalties paid, and a patent P75NTR Antagonists and treatment of acute and chronic cardiac disease. Inventors: Paolocci; Nazareno; (Baltimore, MD); Feng; Ning; (Baltimore, MD); Tocchetti; Carlo G.; (Baltimore, MD); Takahashi; Cyrus; (Baltimore, MD); Carter; Bruce; (Nashville, TN). 2020. Source of the Document: United States Patent and Trademark Office Granted Publication. Patent number US10786543, Publication date: Sep 29, 2020. V.M. reports no conflict of interest. C.M. has received honoraria for lectures or consulting from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Servier, Novartis, NovoNordisk, Berlin Chemie, and Bayer.

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