Heart failure: Novel therapeutic approaches

Abstract

Heart failure (HF) is a complex clinical syndrome that can result from any structural or functional cardiac disorders that impairs the ability of the ventricle to fill with or eject blood. Despite effective medical interventions, mortality and morbidity remain substantial. There have been significant advances in the therapy of HF in recent decades, such as the introduction of beta-blockers and antagonists of the renin–angiotensin system but still there is a major unmet need for better therapies for HF. In the present era, pathophysiology of HF has been explored. Various novel pathways, molecular sites have been identified, which contribute to the progression of the disease. By targeting these sites, newer pharmacological agents have been developed, which can play a promising role in the treatment of HF. This article focuses on recent advancements in pharmacotherapy of HF, which include agents targeting myocardial contractility, cytokines and inflammation, fibrosis and remodeling, myocardial metabolism, oxidative stress, and other newly defined pathways.

Introduction

Heart failure (HF) is a complex and heterogeneous clinical syndrome considered as a global epidemic due to rising incidence and prevalence. It is characterized by progressive loss of contractility and ejection fraction, ventricular dilatation, ventricular wall thinning, increased peripheral vascular resistance and dysregulated fluid homeostasis, neurohumoral and cytokine activation, and increased arrhythmias.[1] Increased myocardial wall stress induces an orchestrated cascade of remodeling stimuli within the heart with progressive loss of function. It should be noted that abnormalities of systolic and/or diastolic function can result in similar symptoms and they might share some common underlying mechanisms. Within the clinical HF spectrum, the severity of symptoms often fluctuates considerably. Acute episodes of HF due to cardiac decompensation often in the setting of an acute intercurrent illness, such as myocardial infarction, arrhythmia, or sepsis — are also well recognized and require distinct forms of clinical management.[2]

There have been considerable advances in the pharmacological management of HF over the past 20 years. β-Blockers, angiotensin converting enzyme (ACE) inhibitors, ARBs(angiotensin receptor blockers), and aldosterone antagonists improve survival in HF patients. Despite effective medical interventions, mortality and morbidity remain substantial. The observation that HF continues to progress in patients receiving optimal therapy has raised the possibility of the contribution of other biological pathways to ventricular remodeling and HF.[3,4] Various pharmacological target sites have been identified and implicated in pathogenesis of HF. Novel therapies have emerged from improved understanding of the pathophysiology of HF.

This article attempts to review some of these pathological processes and to provide a focus to the often overlooked contribution of the alternative pathways in the progression of HF and their potential role as a target for therapy in HF. Agents targeting myocardial contractility, cytokines and inflammation, fibrosis and remodeling, myocardial metabolism, oxidative stress, arginine vasopressin receptor antagonists, natriuretic peptides, neutral endopeptidase (NEP) inhibitors, vasopeptidase inhibitors, endothelin receptor antagonists, agents interfering with catecholamine synthesis and release, agents interfering with catecholamine synthesis and release, and agents acting through other pathways are important in the therapy of HF.

Novel Therapeutic Approaches in HF

Agents improving myocardial contractility

Abnormal handling of intracellular Ca²⁺ in cardiomyocytes is responsible for reduced cardiac contractility in HF. Ca²⁺ homeostasis is maintained in the heart by certain membrane proteins. In HF, the amount of triggered Ca²⁺ that enters the myocyte during depolarization is reduced and the rate of diastolic decay of Ca²⁺ transient is prolonged. There is protein kinase A(PKA)-mediated hyperphosphorylation of the ryanodine receptor, which causes diastolic Ca²⁺ leak and impaired reuptake of Ca²⁺ by sarcoplasmic reticulum (SR) due to reduced expression of the SR Ca²⁺ ATPase (SERCA) and relative upregulation of its inhibitory partner phospholamban.

In failing heart, RyR2 is hyperphosphorylated by PKA resulting in defective channel function due to increased sensitivity to Ca²⁺-induced activation. K201 stabilizes the closed state of RyR2 by increasing its affinity for the FKBP12.6, which prevents the Ca²⁺ leak. K201 inhibits spontaneous diastolic Ca²⁺ release during Ca²⁺ overload by dual inhibitory action on SR Ca²⁺-ATPase (SERCA2a) and RyR2 without significantly affecting the transient Ca²⁺ amplitude. Because of its favorable effects on Ca²⁺ homeostasis, it has beneficial effect in systolic and diastolic dysfunction with antiarrythmic effect.

A novel approach to improve cardiac left ventricular (LV) systolic function is via activation of the force-generating protein cardiac myosin. Myosin activators such as omecamtiv mecarbil accelerate the rate-limiting step of the myosin enzymatic cycle and shift the cycle in favor of the force-producing state. It increases cardiac contractility by accelerating the transition of the actin–myosin complex from weakly bound to strongly bound without changing intracellular Ca²⁺ homeostasis and therefore it improves LV systolic function without increasing energy demand or arrhythmogenesis.[5] It does not increase the velocity of contraction but instead, it lengthens the systolic ejection time, which results in increased contractility and cardiac function in a potentially more oxygen-efficient manner.[6] Preliminary reports for a clinical Phase II trial show that omecamtiv mecarbil increases LV systolic ejection time, stroke volume, and cardiac output while reducing heart rate in a concentration-dependent manner. Even when systolic heart failure(sHF) was developed in the presence of severe left ventricular hypertrophy(LVH), omecamtiv mecarbil still improved LV systolic function along with preload reduction and without alteration in oxygen consumption. Oral formulation of omecamtiv mecarbil shows high bioavailability and it is safe and effective inotropic agent.[5]

Istaroxime is the agent with both inotropic and lusitropic effects. It inhibits the sarcolemmal Na⁺–K⁺ ATPase, thus increasing cytosolic Ca²⁺. It also enhances the action of SERCA2a increasing Ca²⁺ reuptake by the SR, favoring myocardial relaxation. Greater SR Ca²⁺ reuptake during diastole increases Ca²⁺ available for release at the next systole, thus it has a positive inotropic effect. It does not increase myocardial oxygen consumption, improves diastolic parameters, and is devoid of arrythmogenicity. This drug is in phase II clinical trials in acute heart failure. Novel analogs of istaroxime are being developed having greater potency.[7]

Levosimendan, an ionotropic vasodilator, has been approved for the treatment of acute decompensated heart failure(ADHF). It enhances cardiac contractility primarily by binding to troponin C and increasing myofilament sensitivity to Ca²⁺. It does not impair relaxation so having positive lusitropic effect. Additional effects include vasodilation mediated via activation of potassium-dependent ATP channels and (at high concentrations) inhibition of enzyme phosphodiesterase III.[8] It has short elimination half-life of 1 h in human beings and it is converted to long-acting active metabolites, namely, OR-1855 and OR-1896. Its actions are mainly mediated through its active metabolite OR-1896. Both levosimendan and OR-1896 have been shown to be effective in preventing postinfarct HF and cardiac remodeling in spontaneously diabetic rats.[9]

During hypertrophy and HF, the activity of the Na⁺–H⁺ exchanger-1 (NHE-1) is upregulated, which results in elevated [Na⁺]_i and consequently leads to increased [Ca²⁺]_i. This causes development of hypertrophy and remodeling. Treatment with NHE-1 inhibitor cariporide caused regression of hypertrophy and HF, restored sodium and Ca²⁺ handling, and incidence of Ca²⁺ after-transients even when substantial hypertrophy and signs of HF were already present. It not only preserves contractile function but also has antiarrhythmic potential.[10]

Abnormal SR Ca²⁺ cycling in HF is partly responsible for abnormalities of LV systolic and diastolic function. Nitroxyl (HNO) donors are compounds that improve cardiomyocyte function by directly enhancing SR Ca²⁺ cycling. In an experimental study, it is shown that acute intravenous infusion of CXL-1020, a nitroxyl (HNO) donor, exerts positive ionotropic effect and improves LV systolic function without increasing oxygen consumption. This novel HNO donor may be useful in patients with acute HF syndromes.[11] This agent is currently in Phase II clinical trial.[12]

Other novel approaches, such as phospholamban inhibition or augmentation in SERCA2 level to improve contractility are also promising.[1]

Drugs targeting cytokines and inflammation

HF is associated with rise in inflammatory cytokines, including TNFα, interleukins (IL-1β, IL-2, IL-6, IL-12, IL-17, and IL-18), and several chemokines, for example, monocyte chemoattractant peptide (MCP)-1, IL-8, and macrophage inflammatory protein (MIP)-1a. Conventional agents have little effect on the cytokine network. Several animal and clinical studies have shown that downregulation of inflammation improves cardiac performance. So immunomodulatory therapy has emerged as a possible new treatment modality in HF.

TNFα plays a significant role in the progression of HF and its raised level is associated with myocyte hypertrophy, remodeling of the extracellular matrix(ECM) with increased fibrosis and apoptosis.[13] Two important agents inhibiting TNFα activity, etanercept (TNFα receptor antagonist) and infliximab (chimeric anti TNFα antibody) are widely studied in clinical trials. But none of these studies showed a beneficial effect. There may be several explanations for the failure of anti-TNFα therapy trials in HF. First, infliximab treatments have resulted in detrimental effects on TNFα-expressing cardiomyocytes and induction of apoptosis via antibody-dependent cellular toxicity, complement-dependent cytotoxic effector mechanisms. Second, low physiological levels of TNFα may be required for tissue remodeling and repair. Infliximab may have reduced TNFα concentrations to below the levels required for physiologically beneficial effects. So, future research should clarify the best type of anti-TNFα therapy, the optimal dosage and which subgroups of chronic HF to treat before any firm conclusions regarding its efficacy in chronic HF can be drawn.[4]

Another anti-TNFα treatment strategy in HF includes inhibition of its synthesis by anti-TNF-α converting enzyme (anti-TACE). TACE is required for processing of pro-TNFα into its mature form. MPIs and aprotinin have been shown to decrease TNFα processing by inhibiting TACE nonselectively. Selective inhibitors such as DPH-067517 and GM 6001 are developed, which may be potential candidates for evaluation in HF.[14]

Pentoxifylline (PTX), a xanthine-derived agent is a phosphodiesterase inhibitor, which downregulates TNFα synthesis by suppressing gene transcription of TNFα. PTX is also documented to possess TNFα-independent immunomodulatory effects. By preventing cell death, PTX might preserve the myocardium, protecting it from apoptosis and subsequently delaying the progression of HF. Although certain small clinical trials demonstrated that PTX therapy in HF improved clinical symptoms, some studies failed to report a beneficial effect.[15] Lysofylline, a LPAAT (lysophosphatidic acid acyl transferase) inhibitor, decreases lipopolysaccharide-induced TNFα synthesis. It is under investigation as anti-TNFα therapy for patients with sepsis and its role in HF needs to be evaluated.[14]

Activation of p38 MAPK pathway by TNFα depresses contractility and enhances matrix remodeling and the inflammation. The proinflammatory effects of p38 are mediated by several cytokines in addition to TNFα, including IL-1β and IL-6, which play an important role in progression of HF. Two inhibitors of p38, namely, SB203580 and FR167653, have been shown to reduce apoptosis, fibrosis, hypertrophy, LV dilatation and increased ejection fraction and contractility in experimental studies.[13]

The detrimental effects of IL-6 and some other cytokines are mediated via gp130 through upregulation of mannose-binding lectin (MBL), involved in complement activation. Intervention on the downstream MBL complement pathway may represent a novel target in HF.

IL-18 is upregulated in the myocardium in HF. It increases production of proinflammatory mediators, such as IL-1β, IL-8, TNFα, and iNOS. These mediators have been implicated in decreased myocardial contractile function, increased remodeling, and apoptosis. So IL-18 inhibition can be a potential target for the treatment of HF.[3]

Cardiac dysfunction is associated with cardiac inflammation in experimental diabetic cardiomyopathy that is attenuated after treatment with interleukin converting enzyme inhibitor (ICEI). Pralnacasan, a selective and reversible inhibitor of ICE, is found beneficial in diabetic cardiomyopathy.[16]

IL-1 receptor antagonists, activators of peroxisome proliferated activated receptors(PPARs) (which impair endotoxin-stimulated TNFα expression), and a mast cell stabilizing agent (tranilast) are also found to be beneficial in HF.

Therapy with intravenous immunoglobulin (IVIg) decreases the level of certain inflammatory mediators (eg, IL-8 and IL-1) and upregulates anti-inflammatory mediators (eg, IL-10 and IL-1Ra). IVIg therapy has been shown to increase left ventricular ejection fraction (LVEF) significantly and improve some hemodynamic variables (eg, pulmonary capillary wedge pressure and exercise capacity). Incidence of adverse effects with IVIg therapy is very low. However, shortage of supply and high cost may limit the use of this medication in HF.[17]

Celacade immune modulation therapy (IMT) has been described in which a sample of patient's blood is exposed ex vivo to oxidative stress and is reintroduced to the patient by intramuscular injection. This therapy results in the downregulation of proinflammatory cytokines and upregulation of anti-inflammatory cytokines. The results of phases II and III clinical trial of celacade therapy are encouraging. The effectiveness of this therapy has been proved with various drugs for HF.[18]

Drugs targeting myocardial fibrosis and remodelling

Myocardial fibrosis is a major pathological finding that may be involved in both systolic and diastolic dysfunction of the failing heart. Matrix metalloproteinases (MMPs) play an important role in the process of fibrosis and remodeling through direct digestion of matrix components as well as release of biologically active factors from the ECM (including TGFβ, IL-GF, and FGF). Various experimental studies have also shown that increased expression of TNFα and IL-1β is associated with increased gelatinolytic activity of MMPs. Therefore, modulation of the myocardial remodeling and function could be achieved by changing the activity of MMPs either by direct inhibition or by anticytokine treatment.[19]

Batimastat, ilomastat, marimastat, and prinomastat are inhibitors of MMP, which have been developed for HF. PG-53072, a selective inhibitor of MMP, has attenuated LV dysfunction and cardiac remodeling in experimental HF. In a study done to evaluate semi-selective inhibitors (PY-2 and 1, 2-HOPO-2) and two broad-spectrum inhibitors (PD166793 and CGS27023A) in the setting of ischemia reperfusion injury, semi-selective inhibitors were found to be more effective. Based on these findings, semi-selective Matrix metalloproteinase inhibitors warrant further studies to check their ability to protect ischemic myocardium in the in vivo setting.[20]

Alterations in the heart's ECM can also contribute to a structural remodeling of the myocardium that leads to ventricular dysfunction during either diastolic or systolic phases of the cardiac cycle. Members of the (MMP) family targeting ECM-like cathepsins and their inhibitors (ie, cystatins) are important agents having growing role in the same.[21]

Angiotensin II-mediated collagen synthesis is inhibited by adenosine. Recently, it has been shown that adenosine activates the A₂ R-Gs-adenylyl cyclase pathway and resultant increased cyclic AMP(cAMP) reduces collagen synthesis via a PKA-independent, Epac-dependent pathway that feeds through PI3K.

This pathway provides the framework for new targets to regulate collagen synthesis. Knowledge of this pathway may permit manipulation of collagen synthesis particularly in postinfarction cardiac remodeling so that wound healing occurs but collagen deposition does not progress to excessive levels.

TGFβ plays a major role in physiology, including suppression of the immune system and normal tissue repair. It also induces fibroblasts to produce and remodel ECM. So, broad targeting of TGFβ signaling pathway as an anti-fibrotic approach may also interfere with its physiological roles. Additional pathways and receptors that contribute to TGFβ-induced fibrosis are TGFβ/TGFβ type I and type II receptor/Smad axis, including syndecan 4, ras/MEK/ERK, CTGF, and ET-1. By targeting these ancillary pathways, selective antifibrotic effects might be achieved.[22]

In rat model of HF, locally generated angiotensin II correlates with TGFβ expression and synthesis. Early induction of TGFβ via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis. So ACE inhibitors may decrease the induction of profibratory TGFβ.[19]

The antifibrotic action of thalidomide has been studied in postinfarction myocardial remodeling in rats and the attenuation of fibrosis could be due to a direct effect of thalidomide on myocardial TGF-h1 gene expression resulting in lower levels of a major stimulus for ECM remodeling. It may also directly affect fibroblast proliferation and survival. In addition, the immunostimulatory effect of thalidomide may prove beneficial by contributing to decreased accumulation of ECM as Th1-type immune response promoted by it may inhibit collagen biosynthesis. This antifibrotic effect could potentially contribute to limit development and progression of HF.[23]

Protein kinase C(PKC) isozymes were found to regulate a number of cardiac responses and exert beneficial and harmful effects in acute and chronic HF. PKCα, PKCβ, and PKCγ comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. In transgenic animal studies it is observed that PKCα has a predominant role in the pathogenesis of HF than PKCβ and PKCγ. PKCα results in altered phosphatase-1 activity, which in turn regulates phospholamban phosphorylation. This controls Ca²⁺ loading and the magnitude of the Ca²⁺ transient through SERCA2 function. Thus, pharmacological inhibition of PKCα activity would function at the level of SR Ca²⁺ handling to augment contractility.[24] PKCβ is an attractive target as a number of key circulating neurohormones signal, at least in part, mediated through this enzyme, including the α-adrenergic system, endothelin, and angiotensin II. Ruboxistaurin was initially suggested as a PKCβ-selective inhibitor but now it is proved that it is equally selective toward PKCα and PKCγ. The beneficial effects of ruboxistaurin on cardiac contractility are mediated through the inhibition of PKCα. It also inhibits PKCβ-mediated remodeling and pathological fibrosis.[25] Similarly, Ro-31-8220 and Ro-32-0432 are nonselective PKC inhibitors, which showed beneficial effect in cardiac remodeling as well as contractile dysfunction in an experimental study.[24]

Diastolic HF is characterized by an increase in advanced glycation end-products (AGEs). Serum concentration of AGEs has been correlated with echocardiographic indices of cardiac stiffness. The AGE crosslink breaker alagebrium (ALT711) has been demonstrated to reduce myocardial stiffness in animal models.[26]

Neuregulin-1 (NRG-1) is a cardioactive growth factor released from endothelial cells. It plays an important role in cardiac development, structural maintenance, and functional integrity of the heart. In clinical trials recombinant human neuregulin-1 (rhNRG-1) treatment improved cardiac function and reversed remodeling of the heart. Thus rhNRG-1 may represent a novel therapeutic mechanism.[27]

Modulators of metabolism in HF

It is well established that cardiac metabolism is abnormal in HF. HF severity, substrate availability, hormonal status, and coexisting insulin resistance contribute to the metabolic changes seen in HF. During LV dysfunction, fatty acid oxidation dominates as a source of energy production. High rates of this oxidation inhibit glucose oxidation via the Randle Cycle phenomenon. This uncoupling of glucose oxidation from glycolysis eventually leads to proton overload and intracellular acidosis which further decreases cardiac efficiency. Evidence exists that altered myocardial metabolism itself may contribute to HF disease pathogenesis. Based on increasing knowledge of the role of substrate metabolism in HF, optimizing myocardial energy metabolism has been studied as a novel form of therapy.[28]

Myocardial substrate metabolism pathways can be modulated at several steps:

Manipulation of circulating substrate levels (nicotinic acid, glucose-insulin-potassium), CPT inhibitors (perhexiline maleate, etomoxir), MCD inhibitor, 3-KAT inhibitors (trimetazidine, ranolazine), and PDK inhibitor (dichloroacetate), incretins (glucagon-like peptide-1), and thiazolidinediones (peroxisome proliferator-activated receptor-γ ligands).

CPT-1 is an important enzyme in fatty acid metabolism, which catalyzes the rate-limiting step in mitochondrial uptake of long chain fatty acids. The agents which inhibit this enzyme are etomoxir, oxfenicine, and perhexiline. They limit fatty acid oxidation and favoring glucose oxidation.

Etomoxir is powerful and irreversible FFA oxidation inhibitors (FOXi). In animal studies, etomoxir has been shown to improve glucose oxidation and reduce myocardial oxygen consumption while sustaining contractile function. In one clinical study, etomoxir was shown to improve LVEF, cardiac output at peak exercise, and clinical status of HF patients.[28] Perhexiline, inhibitor of CPT-1 improves peak exercise oxygen consumption, LVEF, and quality of life in ischemic and nonischemic HF patients. Inhibition of CPT-1 by perhexiline results in accumulation of phospholipids, which lead to hepatotoxicity and peripheral neuropathy that can be reduced by reducing plasma concentrations.[29]

Trimetazidine is a 3-KAT inhibitor with weak CPT-1 inhibitory property. Studies have shown that long-term treatment with trimetazidine(TMZ) improves ejection fraction, enhances LV diastolic function, reverses LV remodeling, significantly improves clinical status, cardiac function, and survival rate in patients with ischemic HF. The clinical efficacy of TMZ has been demonstrated and it remains a potential treatment for the future.[29] Ranolazine is a substituted piperazine compound similar to but less potent. Early studies with ranolazine suggested that its protection was mediated by stimulation of glucose oxidation, secondary to partial inhibition of fatty acid oxidation through inhibition of 3-KAT. But recent studies have suggested that the cardioprotection seen with may be due at least in part to inhibition of the late sodium current, thereby preventing the sodium-dependent Ca²⁺ overload in ischemic injury associated HF.[30]

Dichloroacetate acts by inhibiting PDK, an enzyme that inactivates mitochondrial PDH. Activation of PDH increases glucose oxidation, improves coupling between glycolysis and glucose oxidation, and minimizing intracellular acidosis and contractile dysfunction. In a small clinical study, it was shown to increase myocardial lactate metabolism, stroke volume with simultaneous reduction in myocardial oxygen consumption resulting in increased mechanical efficiency in patients with ischemic HF. However, its use is limited by a short half-life and the need for high doses and IV administration. Novel PDK inhibitors are currently being investigated.[28]

Malonyl CoA decarboxylase (MCD) is a major regulator of cardiac fatty acid oxidation, secondary to modifying intracellular malonyl CoA levels. Inhibition of MCD increases malonyl CoA concentration in the heart and has inhibitory effect on CPT-1 decreasing fatty acid oxidation. CBM-301940 by inhibiting MCD decreases the rate of fatty acid oxidation and accelerates glucose oxidation.[31]

CVT-4325, a novel pFOXi (its precise mechanism of action is as yet unclear), improves cardiac work without increasing cardiac oxygen consumption, implying an increase in myocardial efficiency[32].

Drugs reducing oxidative stress

Oxidative stress plays an important role in the development and/or progression of chronic HF and it has been well established in both clinical and experimental studies that there is excessive production of reactive oxygen species (ROS). The potential sources of ROS production in HF include xanthine oxidase, NADPH oxidase, cyclooxygenase, lipooxygenase, cytochrome 450, and uncoupled NOS.[33] ROS can damage cardiac tissue via oxidation of lipids, proteins, and DNA producing diverse effects, such as reduced cardiac contractility, malfunction of ion transporters, and Ca²⁺ cycling. In addition, ROS can also act as an intracellular signaling mechanism, affecting transcription factors, such as NFκB and activator protein-1. Their deleterious effects are limited by free radical scavengers, such as super oxide dismutase(SOD) which catalyzes glutathione peroxidase, catalase, and other nonenzymatic antioxidants such as vitamin E, C, and β-carotene, ubiquinone (coenzyme Q10), lipoic acid, and urate.

Studies testing the effects of classical antioxidants, such as vitamin C, vitamin E, or folic acid, in combination with vitamin E have been disappointing. Ubiquinone (coenzyme Q10), a natural antioxidant essential for mitochondrial electron chain transport activity, is depleted in HF. It is an independent predictor of mortality in HF. Many clinical studies with ubiquinone have been small, underpowered and showed small but significant improvement in ventricular function. But its role as adjunctive therapy in HF is being tested in a large clinical trial. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, has been shown to be beneficial in conditions with oxidative stress. Its antioxidant role needs to be evaluated in HF.[34]

In experimental models it has been shown that XO inhibitors allopurinol or oxypurinol restored XO activity to baseline levels and improved myocardial function. These agents reduce the levels of ROS and enhance SERCA2a levels while decreasing the expression of the sodium — Ca²⁺ exchanger to increase myocardial contractility. XO inhibition also has anti-inflammatory effect. Acute and chronic administration of allopurinol shows variable effects in HF. Acute intravenous administration of allopurinol has been shown to improve LV function and ameliorate endothelial dysfunction. Chronic oral administration failed to show any improvement in exercise capacity. So, large-scale clinical trials are needed to evaluate the effects of this treatment strategy and to elucidate whether targeted XO inhibition will benefit only selected subsets of patients with congestive HF specifically those who are hyperuricemic or will be efficacious in a larger population.[35,36]

A recent clinical trial in HF patients used hydralazine and isosorbide dinitrate, both reported to have beneficial antioxidant effects.[35] Probucol, a clinically used cholesterol-lowering drug, has been shown to attenuate oxidative stress, reduce cardiac remodeling, and improve ventricular function experimentally.[37] ACE inhibitors, ARBs, β-adrenoceptor blockers (β1), carvedilol, nebivolol, and statins also reduce oxidative stress, which may be beneficial in HF.

Other agents

Apart from these novel targets, other pharmacological sites have been implicated in pathogenesis, which could be potential targets.

Arginine vasopressin receptor antagonists

Newer drug therapy being developed for use in HF is based on vasopressin antagonism at the V_1A and V₂ receptor. V_1A receptor antagonism causes vasodilation and reduces afterload. V₂ receptor antagonism increases free water excretion (aquaresis) excretion with little or no sodium loss. The vasopressin antagonists, conivaptan (a dual V_1A and V₂ antagonist), and tolvaptan (a selective V₂ receptor antagonist) are approved for the treatment of hyponatremia in HF patients. Tolvaptan (OPC-41061), a synthetic analog of OPC-31260 has produced diuresis and reduced edema, dyspnea, jugular venus pressure(JVP), and relieved systemic congestion in HF. Conivaptan has been shown to inhibit pressor response and stimulate aquaresis in rats and dogs. In patients with severe symptomatic HF, conivaptan has significantly reduced pulmonary capillary wedge pressure(PCWP) and right atrial pressure. Thus arginine vasopressin(AVP) antagonists may be useful in patients with volume-overload HF.[2,38]

Natriuretic peptides

Among three major isoforms, atrial natriuretic peptide(ANP) and brain natriuretic peptide(BNP) are circulating peptides produced principally by right atrium and ventricles, respectively, whereas C type natriuretic peptide(CNP) is produced by endothelial cells. A fourth member of natriuretic peptide, namely, dendroaspis natriuretic peptide (DNP) has been also reported to be present in human plasma and atrial myocardium. The production of these cardiac hormones is stimulated after myocardial infarction(MI), cardiac hypertrophy, and HF. BNP causes natriuresis, diuresis, vasodilation, and neurohormonal modulation by decreasing the activation of renin angiotensin aldosterone system(RAAS) and sympathetic nervous system. In clinical trials, nesiritide, a synthetic analog of BNP has been shown to decrease cardiac filling pressures, increase cardiac index(CI), and improve the clinical status of patients with ADHF. Compared with other available intravenous agents for HF, nesiritide is effective, well tolerated with few adverse effects, and does not require invasive monitoring. Nesiritide has proven efficacy as new treatment in decompensated HF. The major problems with this group are peptidic nature and short half-life.[39,40]

Neutral endopeptidase inhibitors

The natriuretic peptides are degraded in the body by the enzyme called NEP and inhibition of this enzyme produces a sustained increase in plasma natriuretic peptide level. Candoxatril and ecadotril are two highly specific inhibitors of NEP, which are prodrugs. Candoxatrilat is the active metabolite of candoxatril causing induced diuresis, natriuresis, decreases pulmonary capillary wedge pressure, and improves exercise capacity. It does not cause any discernable increments in plasma renin activity, which is usually associated with diuretic therapy. Ecadotril is converted to its active congener, S-thiorphan which raises plasma natriuretic peptides and decreases both plasma renin activity and PCWP. But ecadotril has been reported to produce pancytopenia and death in patients of HF. Hence the development of NEP inhibitors has been discouraged.[41]

Vasopeptidase inhibitors

They have dual inhibitory effect on two key enzymes involved in metabolism of vasoactive peptides, namely, NEP and ACE and produce vasodilation, diuresis, and enhancement of myocardial function. Omapatrilat, sampatrilat, gemopatrilat, fasidotrilat, MDL 100 240, Z13752A, BMS 189921, and mixanpril are the inhibitors developed for the treatment of HF. Among all, omapatrilat has been extensively studied. It increases glomerular filtration rate(GFR) and sodium excretion and decreases PCWP. But the largest clinical trial comparing omapatrilat with enalapril has failed to demonstrate any additional benefit of omapatrilat over ACE inhibitors.[41]

Endothelin receptor antagonists

Although these agents showed promising results in experimental studies, clinical trials have not supported the findings. In HF, ET-1 level is elevated, which produces vasoconstriction, cardiac remodeling through ET_A receptors, and induces vasodilation through ET_B receptors by generating NO and prostacyclin. Selective ET_A receptor antagonist FR 139317(code name) has been shown to decrease cardiac pressures and increased cardiac output, GFR and renal blood flow but another agent darusentan did not show any improvement and it has increased the mortality. ET_B receptor antagonist RES-701-1 has increased cardiac pressures and decreased cardiac output as well as renal blood flow. Thus, blockade of ET_B receptors may not be useful in HF. Similarly, bosentan and tezosentan, nonselective ET_A/ET_B receptor antagonist did not demonstrate any improvement in HF.[42]

Agents interfering with catecholamine synthesis and release

Nolomirole [selective dopamine2-alpha2 (DA2-α2) receptor agonist] inhibits catecholamine release from sympathetic nerve endings and inhibits the release of TNFα to improve ventricular function. This agent significantly reduces cardiac hypertrophy, attenuates clinical symptoms of monocrotaline-induced HF.[43]

Nepicastat is a dopamine β-hydroxylase) inhibitor, which reduces norepinephrine synthesis. It attenuates ventricular remodeling and prevents systolic dysfunction. Moreover, it may augment the levels of dopamine(DA) that act via dopamine receptors to produce renal vasodilation.[44]

Other target sites for HF

Treatment with a 5-HT₄ receptor blocker SB207266 reduces LV remodeling, diastolic dysfunction, and partially restores neurohormonal signaling to normal in a postinfarction rat model, whereas other parameters remained unchanged. The possible beneficial effects observed could imply a role for 5-HT₄ receptor blockers in CHF.[45]

Inhibition of Rho-kinase, poly (ADP-ribose) polymerase and caspase-3 prevent remodeling and improve the LV function in rats subjected to pressure overload induced by partial aortic constriction.

Ularitide is a synthetic form of urodilatin, a natriuretic peptide produced in the kidney with vasodilating, natriuretic, and diuretic effects. Infusion of ularitide in ADHF resulted in prompt, consistent lowering of PCWP and LV pump function with relief of dyspnea, resolution of HF signs, and postdischarge clinical outcomes without apparent early deleterious effects on renal function.[46]

Relaxin is a natural human peptide that affects multiple vascular control pathways. In a clinical study in patients with acute HF and normal-to-increased blood pressure, it reduced clinical symptoms, hospitalization, and overall mortality. It also increases BNP or N-terminal prohormone of BNP. It has an acceptable safety profile with no adverse renal effects. It may play a role in decompensated HF.[47]

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase (sGC) activator in clinical development for ADHF. In preclinical studies, it has been shown to act on NO-nonresponsive soluble guanylyl cyclase(sGC) and to induce vasodilation preferentially in diseased vessels. In a clinical study in ADHF, it showed potent preload- and afterload-reducing effects and improvement in cardiovascular function. Further studies of the agent for HF are warranted.[48]

Experimental studies suggest that A1-receptor antagonism induces diuresis and natriuresis without exerting adverse effects on cardiac and renal functions, providing a potential therapeutic tool for ADHF. Adenosine receptor antagonists block the adenosine-mediated TGF and appear to increase the diuretic effect of furosemide while ameliorating the adverse effects on GFR. Rolofylline (KW-3902), BG9719, BG9928, and SLV320 increased urine output, sodium excretion, and GFR. But a recent trial of rolofylline did not show any benefit on either renal function or clinical outcomes in ADHF. So the future development of this class of agents for HF is uncertain.[42]

A1-agonism appears to represent another potential therapeutic avenue in HF. In an experimental model of cardiac hypertrophy induced by pressure overload, activation of the A1-receptor was shown to attenuate myocardial hypertrophy and myocardial dysfunction. So, adenosine might have beneficial effects on LV hypertrophy attenuation and heart function improvement. Studies on renal function should therefore use A1-receptor blockade and evaluate heart function and heart size.[2,42]

Inhibition of aldosterone synthase could be an alternative strategy for mineralocorticoid-receptor antagonists in congestive HF. FAD286, LCI699, SL125 are novel agents inhibiting the enzyme. In experimental CHF, FAD286 improved LV hemodynamics, remodeling, and normalized LV redox status.[49]

Direct sinus node inhibitor, ivabradine is a specific and selective I_f current inhibitor in the sinus node available for clinical use. It slows heart rate by decreasing the velocity of diastolic depolarization (ie, by reducing the “steepness” of the I_f current slope of diastolic depolarization). Heart rate reduction by ivabradine significantly reduced cardiovascular deaths and hospital admissions due to HF when combined with standard treatments.[50,51]

Direct renin inhibitor (DRI), aliskiren offers an alternative and complementary strategy of upstream RAAS blockade to these existing therapies. In preclinical trials, aliskiren therapy resulted in the improvement in ventricular function and reduced cardiac remodeling. Clinical trials with aliskiren show that combining a DRI with an ACE inhibitor (and/or one other RAAS blocker) might provide significant additional benefit in systolic chronic HF without a clinically significant increase in side effects and adverse events. Other ongoing clinical trials will further evaluate the role.[52]

In addition, other agents for treatment of HF are under development such as calcineurin inhibitors (AKAP1, atrogin, MCIP1), CaMKII inhibitors (KN93), histone deacetylase inhibitors (trichostatin A, SAHA), PI3K inhibitors (LY294002), matricellularproteins (thrombospondins, osteopontin, periostin, tenascins), V₂ antagonists (Lixivaptan, Mozavaptan, RWJ-351647, Satavaptan), V_1A (OPC-21268, Relcovaptan, SR-49059), V_1A and V₂ (CL-385004, JTV-605, RWJ-676070), and so on.

In summary, the current treatment of HF with established agents may reduce mortality and morbidity but it cannot retard the disease process completely. Other pathways play a significant role in the progression of the disease. Better understanding of these alternative pathways and development of newer agents to modulate these pathways may improve the therapy of the millions of patients living with HF.