Introduction: heart failure progression and general mechanisms

Heart failure remains a major healthcare problem as hospitalisation rates for this condition continue to increase, and outcomes remain poor [1]. Heart failure can result from various underlying conditions, including acute and chronic ischaemic heart disease, cardiomyopathies, myocarditis and pressure overload, resulting in a mismatch between the load applied to the heart and the energy needed for contraction (mechanoenergetic uncoupling). After an initial insult, a complex interplay of secondary mediators such as angiotensin II, endothelin, proinflammatory cytokines [e.g. tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6)], in concert with oxidative stress and peroxynitrite, activate downstream effectors [e.g. poly(ADP-ribose) polymerase-1 (PARP-1) or matrix metalloproteinases (MMP)]. These effectors act directly on the myocardium or indirectly via changes in haemodynamic loading conditions [2]. The net effect of these processes is to cause endothelial and myocardial dysfunction, cardiac and vascular remodelling with hypertrophy, fibrosis, cardiac dilation and myocardial necrosis, leading eventually to heart failure. Adverse remodelling increases peripheral resistance, further aggravating heart failure (Fig. 1) [2–4].

Fig. 1
figure 1

General mechanisms involved in heart failure

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Acute decompensated heart failure (ADHF) broadly represents new or worsening symptoms or signs of dyspnoea, fatigue or oedema that lead to hospital admission or unscheduled medical care and that are consistent with an underlying worsening of left ventricular function [5]. Current therapies for ADHF include loop diuretics to reduce intravascular volume, vasodilators to reduce vascular resistance and inotropic agents/calcium sensitisers to increase cardiac contractility [6–8]. There has, however, been little change in drug therapy for several decades, with novel agents such as the calcium sensitiser levosimendan failing in pivotal studies [9], and the novel vasodilator nesiritide being associated with kidney dysfunction [10]. While the short-term use of inotropes can improve haemodynamic parameters and symptoms in patients with ADHF their use remains somewhat controversial [5]. For example, a registry of patients hospitalised with ADHF associated higher in-hospital mortality rates with intravenous inotropes than with nitroglycerin or nesiritide therapy [11]. Moreover, the long-term administration of inotropes other than digoxin is consistently associated with increased mortality in patients with heart failure [12–14]. Even traditional therapy with diuretics can have uncertain effects on treatment outcomes [15]. Thus, there is an urgent need for new drug therapies, with attention recently focusing on guanylate cyclase pathways in addition to other therapeutic targets.

Guanylate cyclase pathways

Cyclic guanosine-3′,5′-monophosphate (cGMP) regulates complex signalling cascades through immediate downstream effectors, including cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases and cyclic nucleotide-gated ion channels [16]. These enable cGMP to play a central role in regulating many physiological processes, including cardiovascular homeostasis, cellular growth and contractility, inflammation, sensory transduction, and neuronal plasticity and learning [17].

cGMP is the second messenger of several important signalling pathways based on distinct guanylate cyclases in the cardiovascular system [18]. Intracellular cGMP is synthesised by guanylate cyclases, either by particulate (membrane-bound) or soluble (cytosolic) forms in response to compounds such as nitric oxide (NO) and natriuretic peptides (NPs), respectively [16, 19]. There is a growing evidence-base that particulate guanylate cylase (pGC) and soluble guanylate cylase (sGC) have distinct mechanisms and differential effects, as explored in several cell types [20, 21]. Moreover, both the NO/sGC as well as the NP/pGC systems are disordered in a range of cardiovascular conditions, including ADHF [2, 18]. The NO/sGC pathway, for example, is disrupted because of impaired NO production or excessive NO degradation or neutralisation by oxidants such as superoxide [2, 18]. Furthermore, the NP/pGC system serves as an important compensatory mechanism against neurohumoral activation in heart failure [22]. For example, NPs bind to type-A NP receptors (expressed in the heart and other organs), and which have an intracellular guanylate cyclase domain. Activation of these receptors generates an increase in cGMP mediating natriuresis, inhibition of renin and aldosterone, plus vasorelaxant, anti-fibrotic, anti-hypertrophic and lusitropic effects [22]. However, the response to NPs is blunted in advanced stages of heart failure [23]. Thus, there is a clear rationale for the therapeutic augmentation of NO/sGC and/or NP/pGC systems in patients with ADHF [18, 22].

In this review, we will discuss particulate and soluble cGMP pathways involved in heart failure, with a particular focus on three emerging drugs that modify these pathways: nesiritide and ularitide/urodilatin are NPs with vasodilating, natriuretic and diuretic effects, and as such act on pGC; and cinaciguat (BAY 58-2667), a novel sGC activator. All of these agents have potential as therapies for ADHF. A summary of some key concepts in cGMP signalling in the mammalian cardiovascular system is shown in Fig. 2. While it is beyond the scope of this article to review all agents that increase intracellular cGMP levels other recent reports cover other drugs/ligands that have such an effect [17, 18].

Fig. 2
figure 2

cGMP signalling in the mammalian cardiovascular system. cGMP (small circles) is generated from membrane-bound particulate guanylate cyclases (pGCs) and cytosolic soluble guanylate cyclases (sGCs), in response to natriuretic peptides (NPs) and nitric oxide (NO), respectively. cGMP acts through a number of distinct pathways: cGMP effectors include cGMP-dependent protein kinases (cGKs), cGMP-modulated cation channels and cGMP-regulated phosphodiesterases (PDEs) that hydrolyse cyclic nucleotides. The molecular mechanisms of cGMP-mediated smooth muscle relaxation and cell growth are not fully understood (indicated by question marks). Growth regulation may involve protein phosphorylation through cGKs as well as modulation of cAMP levels through cGMP-regulated cAMP-PDEs. Potential future effects are shown in parentheses. cAMP cyclic adenosine 3′,5′-monophosphate; cGMP cyclic guanosine-3′,5′-monophosphate; GDP guanosine diphosphate; GTP guanosine triphosphate; IRAG inositol 1,4,5-trisphosphate receptor associated cGMP kinase substrate; RTK receptor tyrosine kinase. From Ref. [17]. Reprinted with permission from AAAS

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pGC pathways and NPs: nesiritide and urodilatin/ularitide

NPs play an important role in maintaining cardiac and renal function, regulating fluid volume, pressure and sodium concentration [24]. The best known members of this family are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), both secreted by the heart, and C-type natriuretic peptide (CNP), which is secreted by the endothelium [25]. These peptides represent less than 5% of the total amount of circulating peptides: the great majority (95%) of peptides are the less familiar, long-acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide [26].

The physiological effects of NPs include vasodilation, natriuresis and diuresis, and regulation of sodium and water homeostasis [27, 28]. They are endogenous antagonists of the renin–angiotensin–aldosterone system (RAAS), as well as the endothelin and sympatoadrenal systems, and so are promising potential therapeutic agents for use in patients with cardiovascular and renal dysfunction. The majority of the physiological effects of NPs can be ascribed to pGC activation, because the ANP/BNP receptor (NP receptor (NPR)-A) has an intracellular guanylyl cyclase domain [25].

There are three types of NP receptors: NPR-A, NPR-B and NPR-C. The first two of these are expressed at high levels in cardiac tissues [22], while NPR-C (which lacks an intracellular guanylate cyclase domain and probably functions mainly as a clearance receptor, removing excess NP from circulation) is highly expressed in renal tissues [29]. NPR-A and NPR-B are highly homologous transmembrane proteins with an extracellular binding domain, transmembrane domain and intracellular domains with kinase and guanylate cyclase activity. The guanylate cyclase domain catalyses the generation of cGMP, which mediates most of the physiological effects of NPs [25].

Nesiritide is a 32-amino-acid-peptide preparation of human B-type natriuretic peptide manufactured using recombinant technology. Similar to endogenous BNP, the effects of nesiritide include natriuresis, vasodilation, inhibition of the renin–angiotensin–aldosterone system (RAAS), and antimitotic effects on endothelial, smooth muscle and myocardial cells [30]. Because clinical heart failure, in part, is a state of decreased responsiveness to BNP, nesiritide may overcome the deficiency of active BNP or resistance to BNP [31].

Nesiritide is a balanced arterial and venous vasodilator devoid of inotropic or chronotropic activity. The haemodynamic effects of nesiritide include reductions in left and right heart filling pressures, systemic vascular resistance (SVR), systolic blood pressure (SBP) and pulmonary capillary wedge pressure (PCWP) [32]. Infusions also counteract the effects of neurohormonal activation of the RAAS by reducing circulating amounts of renin, angiotensin, aldosterone, endothelin and norepinephrine [28, 33, 34]. Infusions of BNP in normal subjects have demonstrated increased natriuresis with increased urine output and glomerular filtration rates (GFR), but studies evaluating this strategy in patients with ADHF have varied [4, 35].

Urodilatin is a 32-amino-acid peptide found in urine, and is produced by differential processing of the pro-atrial ANP precursor peptide in distal renal tubule cells. In patients with chronic heart failure, urinary urodilatin synthesis is increased, apparently to counteract antinatriuresis and fluid retention [36]. In contrast to ANP and BNP (produced in the heart), and CNP (produced in the endothelium), endogenous urodilatin is synthesised in renal distal tubular cells, and following luminal secretion, binds downstream NPR-A receptors in the inner medullary collecting duct, regulating renal sodium and water excretion [36–38].

Ularitide is a synthetic version of urodilatin, and is undergoing clinical development for the treatment of acute heart failure syndromes [38]. Effects of ularitide are largely mediated by binding to NPR-A, leading to increased intracellular cGMP levels. Consistent with this mode of action, dose-dependent ularitide induced increases in plasma cGMP levels have been observed in healthy volunteers and patients with ADHF [39].

Nesiritide: clinical utility

The aims when managing ADHF are to improve clinical symptoms (e.g. dyspnoea, fatigue, global state), to stabilise haemodynamics (PCWP < 15 mmHg, increased GFR and oxygenation) and, finally, to improve short- and long-term outcome (reduce mortality, morbidity and length of stay in hospital). However, current pharmacological therapeutic options (e.g. diuretics, vasodilators and positive inotropic agents) have well-known clinical limitations, as mentioned previously, leading to the search for more effective drugs. NPs such as nesiritide, a recombinant form of human BNP, have been used for the treatment of patients with acute heart failure [40]. Although nesiritide improves dyspnoea, and reduces PCWP as well as systemic arterial pressure, its use is associated with clinical drawbacks. Data from meta-analyses have raised concerns about an increased risk of renal deterioration and potentially an increase in premature mortality in patients with ADHF who are given nesiritide [10, 41]. Moreover, nesiritide is not approved in most European countries [6].

Nesiritide has been studied in several studies in ADHF, chronic heart failure and even cardiac surgery. However, the approved indication in the United States and some other countries for nesiritide is in ADHF, largely based on the Vasodilation in the Management of Acute CHF (VMAC) trial [40]. VMAC was a double-blind, randomised clinical trial of 489 patients that evaluated short-term haemodynamic and clinical effects of nesiritide added to standard care compared with placebo added to standard care [40]. In the group with catheterised patients, the primary endpoint of PCWP was significantly reduced in the nesiritide group compared with the placebo or nitroglycerin group at 3 h, and significantly reduced compared with nitroglycerin at 6, 9, 12 and 24 h. By 36 and 48 h there were no significant differences in PCWP reduction between the nesiritide and nitroglycerin groups. Overall, the nesiritide group had significant improvement in self-assessed dyspnoea compared with placebo at 3 h (P = 0.03); however, there was no significant difference in self-assessed dyspnoea between the nesiritide and nitroglycerin groups at 3 h (P = 0.56).

Nesiritide has been studied in patients with chronic advanced heart failure administered as out-patient serial infusions in the Follow-up Serial Infusions of Nesiritide I (FUSION I) and II (FUSION II) studies. The FUSION II study enrolled 920 patients who were randomised to receive nesiritide (2 μg/kg bolus plus 0.01 μg/kg/min infusion for 4–6 h) or placebo infused once or twice weekly for 12 weeks [42]. Whilst there were no significant differences in rates of the primary endpoint of all-cause mortality or cardiovascular or cardiorenal hospitalisation or in rates of its individual component events, there were also no significant safety concerns raised in this study regarding renal function or mortality.

Nesiritide has been evaluated in patients undergoing non-transplant cardiac surgery. The NAPA (Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery) trial prospectively randomised 279 patients to receive fixed-dose nesiritide (0.01 μg/kg/min infusion without bolus) or placebo beginning at the time of anaesthesia [43]. The mean duration of infusion was 39.4 ± 21.6 h. Although mean serum creatinine (Scr) increased postoperatively in both groups, mean levels returned to baseline by 12 h after intensive care unit admission and remained so throughout the remainder of the hospitalisation in the nesiritide group. In placebo patients, mean Scr levels were elevated significantly from baseline and this elevation persisted throughout the hospitalisation. The peak increase in Scr was 0.15 ± 0.29 mg/dl in the nesiritide group compared with 0.34 ± 0.48 mg/dl in the placebo group (P < 0.001). In this study, nesiritide was associated with a smaller reduction in GFR compared with placebo (−10.8 ± 19.3 ml/min/1.73 m2 vs −17.2 ± 21.9 ml/min/1.73 m2; P = 0.001) during hospital stay or by day 14. These effects were most pronounced in patients with renal dysfunction at baseline (defined as Scr >1.2 mg/dl). Urine output in the first 24 h after surgery was significantly greater in the nesiritide group compared with the placebo group, including the subset of patients with renal dysfunction at baseline. Whilst mortality data were not available for all patients, 30-day mortality data were available for 259 patients and did not differ significantly between groups (2.8% nesiritide group vs 5.9% placebo group; P = 0.219). More interesting is the mortality at 180 days available for 189 patients surprisingly showed significantly improved in the nesiritide group (6.6% nesiritide group vs 14.7% placebo group; P = 0.046).

While existing controlled trials have suggested that nesiritide is safe and effective in reducing cardiac filling pressures and improving symptoms of dyspnoea in patients with ADHF; there has not been a large trial powered to assess long-term safety or mortality associated with nesiritide. In an attempt to address the safety of nesiritide, a meta-analysis of randomised, double-blind, controlled trials of nesiritide in patients with ADHF was performed [10]. Five unique trials were pooled to examine the renal effects and three trials were used to examine mortality. The renal analysis included 1,269 patients and showed significant increases in Scr levels across the different dosing strategies, indicative of worsening renal function. In the three trials pooled to analyze mortality rates, 485 patients were randomly assigned to receive nesiritide and 377 patients were randomly assigned to receive control therapy [41]. Adjusted survival analysis produced similar results with an 80% greater probability of death by day 30 (HR 1.80; 95% CI 0.98, 3.31; P = 0.057). Because of some of the concerns with higher doses, the standard dosing for nesiritide is generally 0.01 μg/kg/min, although it may be increased in increments of 0.005 μg/kg/min to a maximum infusion rate of 0.03 μg/kg/min.

Although the more recent studies of FUSION II and NAPA appear to demonstrate general safety of nesiritide at usual doses, there remain questions regarding the safety and magnitude of effect in a diverse, heterogeneous ADHF population. To address these questions a 7000 patient randomised clinical trial is underway that will examine the extent of benefit and carefully exclude safety risks including renal dysfunction and mortality [44]. This study, known as ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Subjects with Decompensated Heart Failure) trial is planned to be completed by June 2011.

Ularitide: clinical utility in acute decompensated heart failure

Physiologically, ularitide restores fluid haemostasis by inducing diuresis, natriuresis and vasodilation [37]. In healthy volunteers, ularitide increased the renal filtration fraction by increasing GFR, reducing effective renal plasma flow and increasing the fractional excretion of sodium and thus urinary sodium excretion [45]. This preservation of renal function is particularly desirable in patients with ADHF, as about one-quarter experience substantial deterioration of their renal dysfunction and this is associated with worse clinical outcomes [46]. Moreover, ularitide given to healthy volunteers or patients with decompensated heart failure can also reduce plasma concentrations of renin, aldosterone and angiotensin II, so this agent may also downregulate the RAAS [47, 48]. In healthy volunteers, ularitide infusion led to reduced cardiac preload, pulmonary arterial pressure and PCWP, increased cardiac index and reduced systemic vascular resistance, suggesting a potential benefit to patients with ADHF characterised by elevated left and right ventricular filling pressures and neuroendocrine activation [49].

The clinical efficacy of ularitide in patients with ADHF was first investigated in a pilot study (SIRIUS I) [39], followed by SIRIUS II, a double-blind, parallel-dose study in 221 patients given placebo or one of three doses of ularitide (24-h intravenous infusions at 7.5, 15 or 30 ng/kg/min) [38]. Compared with placebo, all three ularitide doses were associated with significantly greater reductions in mean PCWP and right atrial pressure, suggesting improvement of left and right ventricular and diastolic pressure. Furthermore, ularitide reduced SVR and increased cardiac index for the 15 and 30 ng/kg/min groups (Fig. 3). Dyspnoea, a cardinal symptom of ADHF, was also improved in each ularitide dose group compared with placebo. Adverse effects of ularitide include increased sweating, dizziness and hypotension [38]. As hypotension is a recognised safety risk of vasodilators, this adverse event deserves particular attention. In SIRIUS II, ularitide infusions were temporarily interrupted because SBP had fallen to below 80 mmHg in 2 (3.3%), 4 (7.5%) and 7 (10.9%) patients in the 7.5, 15 and 30 ng/kg/min ularitide groups, respectively [38]. For the same reason, only one patient (1.7–1.9%) in each ularitide group required permanent discontinuation of study drug. Time to complete resolution of hypotension was approximately 0.5–1 h in most cases and lasted up to 4 h in four cases and 8 h in two cases. All patients recovered completely either by discontinuation of ularitide infusion or by elevation of legs and saline infusion.

Fig. 3
figure 3

Changes from baseline in a pulmonary capillary wedge pressure, b cardiac index and c systemic vascular resistance in patients (n = 221) with decompensated heart failure given a 24-h continuous infusion of ularitide or placebo. Adapted from Ref. [38], by permission of Oxford University Press

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Renal function, as determined by Scr levels, was maintained during the infusion and the 48 h thereafter [38]. This lack of evidence of deleterious renal effects induced by ularitide is particularly important because renal function often deteriorates in patients with ADHF, and predicts a worsening clinical outcome [50]. Recent results have also suggested that infusions of ularitide can preserve renal function in patients with heart failure (Fig. 4), possibly by both elevating cardiac output and maintaining the mean arterial pressure–right atrial pressure gradient [48]. Hence, ularitide has potential as a treatment for ADHF, particularly when worsening renal function is of concern, though further studies in larger numbers of patients are required to prove these benefits.

Fig. 4
figure 4

a Mean (±SEM) changes from baseline in serum blood urea nitrogen (BUN) levels 24 h after treatment with ularitide and b percentage of patients with >25% and <25% changes in BUN from baseline 24 h after treatment with ularitide, showing that a 24-h infusion of ularitide, 15 ng/kg/min, may preserve short-term renal function in patients with decompensated heart failure. * P ≥ 0.05. Adapted from Ref. [48], by permission of Oxford University Press

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sGC pathways: cinaciguat

There are differential signalling pathways in operation during activation of pSGs and sGCs, and there is growing evidence that cGMP produced by these two generation systems has different effects, possibly because of spatial compartmentalisation of cGMP within cardiac cells (Fig. 5) [19]. Hence, therapeutic agents that target sGC (e.g. cinaciguat) may be expected to have somewhat different effects compared to drugs such as ularitide or nesiritide that target pGC.

Fig. 5
figure 5

Potential differential signalling pathways during activation of particulate and soluble guanylate cyclases (pGC and sGC, respectively). After stimulation with C-type natriuretic peptide (CNP) binding to its receptor, pGC-produced cGMP accumulates near the sarcolemma as diffusion may be restricted, perhaps via cytostolic distribution of phosphodiesterases. Once activated by cGMP, the cGMP protein kinase phosphorylates an array of target proteins such as L-type Ca2+ channels and phospholamban (PLB), decreasing intracellular Ca2+ levels. In contrast, sGC-produced cGMP may result in the accumulation of cGMP near myofilaments, some of whose components (e.g. troponins) may be phosphorylated by activated cGMP protein kinase to decrease Ca2+ sensitivity. Both signalling pathways lead to reduced cardiac function. cGMP cyclic guanosine-3′,5′- monophosphate; GTP guanosine triphosphate; NO nitric oxide; PDE phosphodiesterase; PKG protein kinase G; SR sarcoplasmic reticulum. From Ref. [19], by permission of Experimental Biology and Medicine

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NO is a key signalling molecule, and reduced bioavailability and/or responsiveness to endogenous NO contributes to the development of cardiovascular diseases, some of which are currently treated with organic nitrates (such as glyceryl trinitrate) and other NO donors or ‘nitrovasodilator’ drugs that release NO to activate sGC [18]. Organic nitrates and other NO-donor drugs have been used to relieve cardiovascular symptoms for many decades [18]. However, the limitations of traditional nitrates are well-known (e.g. potential lack of response due to insufficient biometabolism, development of tolerance and non-specific interactions of NO with other biological molecules) [18, 51]. Furthermore, despite symptomatic improvements in patients with cardiovascular disease treated with organic nitrates, there is no clear evidence of an overall reduction in mortality rates [18].

It is worthwhile noting that one major prerequisite for the NO-induced activation of sGC is the presence of the reduced Fe2+ haem moiety: its removal abolishes NO-induced enzyme activation [52, 53]. Aberrant NO–sGC–cGMP signalling and an associated loss in the potency of NO-based therapeutic agents is observed in several disease states such as hypertension, atherosclerosis and diabetes, in which oxidative stress has a central role [54]. Such NO–sGC–cGMP dysfunction may arise as a consequence of reactive oxygen species mediating decreases in NO bioavailability and an impairment of sGC activity through the oxidation of its prosthetic haem moiety [54]. However, a new generation of NO- and haem-independent sGC activators (cinaciguat and HMR-1766) has been developed that may offer considerable advantages over current therapies [55, 56]. Cinaciguat is an example of an sGC activator, stimulating cGMP synthesis and targeting sGC in its NO-insensitive, oxidised ferric (Fe3+) or haem-free state (Fig. 6) [17, 18, 54, 56]. Other novel agents known as sGC stimulators (YC-1, BAY 41-2272, CFM-1571, A-350619 and riociguat) have also been developed which enhance the sensitivity of sGC to very low levels of NO, thus acting in synergy with NO [18].

Fig. 6
figure 6

Soluble guanylate cyclase (sGC) redox equilibrium. The equilibrium can be shifted by reactive oxygen species to the oxidised (ferric; Fe3+) state or to the reduced (ferrous; Fe2+) by postulated (but undiscovered) reductases. The equilibrium may be shifted towards the oxidised, nitric oxide (NO)-unresponsive enzyme during various pathophysiological conditions associate with oxidative stress. The haem-independent sGC activators (e.g. BAY 58-2667; cinaciguat) can activate the oxidised or haem-independent form of sGC. In contrast, haem-dependent stimulators (e.g. BAY 63-2521; riociguat) activate the reduced sGC and act independently and/or synergistically with NO

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Extensive preclinical data have shown that cinaciguat is a potent activator of NO-unresponsive oxidised or haem-free sGC [56–58]. Furthermore, oxidative stress (which occurs during various vascular disease states) interferes with signalling via NO–sGC–cGMP pathways through scavenging of NO and formation of the strong oxidant peroxynitrite, making vasodilator therapy with NO donors less effective [59]. Under these conditions, cinaciguat not only activated the NO-insensitive sGC variant in vitro and in vivo, but also preferentially induced vasodilation in diseased vessels without the development of tolerance [59, 60].

Cinaciguat: clinical utility in ADHF

Cinaciguat is currently at an early stage of clinical development as a therapy for ADHF, but preclinical data and the limited clinical data available indicate it has potential as an effective drug treatment. The cardiorenal effects of intravenous cinaciguat, 0.1 or 0.3 μg/kg/min, have been assessed in an experimental canine model of tachypacing-induced severe chronic heart failure [61, 62]. Cinaciguat potently unloaded the heart (reduced mean arterial pressure, right atrial pressure, pulmonary artery pressure and PCWP), increased cardiac output and renal blood flow, and preserved GFR, sodium and water excretion.

A further strong rationale for future clinical effectiveness of cinaciguat in cardiovascular disease states is provided by cinaciguat’s ability to activate sGC in its NO-unresponsive oxidised or haem-free state. Initial studies in healthy volunteers (n = 59) demonstrated the clinical usefulness of cinaciguat, administered for up to 4 h at doses of 50–250 μg/h, documenting a favourable safety and tolerability profile [63]. Cinaciguat decreased diastolic blood pressure without clinically obvious ECG deviations or rhythm abnormalities or relevant effects on haematology or clinical chemistry parameters. [63]. Plasma levels of cGMP also increased in a dose-dependent manner in the 4-h infusion groups (P < 0.0001) [63].

A phase II, non-randomised, unblinded, uncontrolled multicentre study in patients with ADHF investigated the effect of different doses of cinaciguat using initial dose-finding studies (cinaciguat, 50, 100, 200 and 400 μg/h), and subsequently evaluated cinaciguat in patients using the optimised starting dose of 100 μg/h, which could be titrated after 2, 4 and 6 h to doses between 50 and 400 μg/h depending on haemodynamic response [60]. Of 33 patients who enrolled and were treated in this study, 30 completed the trial. These first clinical results in patients with ADHF demonstrate the therapeutic potential of cinaciguat. Continuous parenteral administration was well-tolerated and induced potent venous and arterial dilation, which led to significant reductions in cardiac pre- and after-load and an increase in cardiac index. Specifically, cinaciguat resulted in reductions from baseline in PCWP, right atrial pressure, systemic and pulmonary vascular resistance, and increases in cardiac output (Fig. 7) [64–66]. Furthermore, the proportion of patients responding to cinaciguat (PCWP reduced by ≥4 mmHg vs baseline) was 53% after 2 h, 83% after 4 h and 90% after 6 h, and the proportion of patients reporting improvements in dyspnoea scores increased during and after 6 h of cinaciguat intravenous infusion [60]. Of the 33 patients included in the safety population, a total of 11 adverse events were reported by six patients, and three of these events (hypotension and unspecified sickness) were judged to be related to the study drug. Of the two hypotensive events, one was mild and the other moderate in severity, and both adverse events completely resolved. There was no evidence of tachyphylaxis. It may be inferred from these results that a pool of oxidised or haem-free sGC is present in patients with ADHF, and that these forms may be preferentially activated by cinaciguat [60, 66].

Fig. 7
figure 7

The effect of an intravenous infusion of cinaciguat on a pulmonary capillary wedge pressure and b cardiac output in patients (n = 30) with acute decompensated heart failure [64]. * P < 0.0001 vs baseline. Adapted from Ref. [65], by permission of Wolters Kluwer Health

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Conclusions

In mammals, intracellular cGMP is produced either by pGC or sGC, and subsequent effects occur via distinct pathways involving a range of cGMP effectors. Disruption of these pathways is intimately involved in various cardiovascular disorders. Different endogenous and exogenous molecules modulate pGC and sGC (e.g. NO, NPs), and it is possible that stimulation of pGC and sGC may have different effects in cardiovascular tissues. Thus, new therapeutic agents targeting each of these guanylate cyclases may have distinct effects.

Synthetic NPs, nesiritide and ularitide, acting on pGC and increasing intracellular plasma cGMP levels, either are already approved (in US) (nesiritide) or have potential for the treatment of ADHF (ularitide). Preliminary results suggest that ularitide may preserve short-term renal function in these patients. However, long-term effects still await investigation in further studies. For nesiritide, administration has been associated with long-term renal dysfunction.

Among the sGC activators, cinaciguat may offer advantages over traditional NO-based sGC stimulators. Usefulness of the latter ones may be limited through its tolerance, limited bio-metabolism, non-specific interactions and lack of sGC activation when the sGC haem moiety is either absent or in an oxidised state. In addition, for these compounds a reduction in mortality has not been demonstrated yet in large randomised trials. Cinaciguat stimulates cGMP synthesis and targets sGC in its NO-insensitive, oxidised ferric (Fe3+) or haem-free state, and thus may also be effective under conditions of oxidative stress, as found in various cardiovascular conditions. Despite limited clinical data for cinaciguat in individuals with ADHF, preliminary studies in this patient group show substantial haemodynamic benefits and improvements in symptoms. Cinaciguat may be useful in patients with ADHF, especially as this group may have oxidised or haem-free sGC which cannot be activated by traditional organic nitrate therapies. Thus, further studies are required to evaluate cinaciguat, in particular, because of its novel and promising mode of action. These should focus principally on determining whether cinaciguat can confer symptomatic and mortality benefits in large numbers of patients with ADHF.