The prevalence of heart failure (HF) in the USA is predicted to increase by 46% between 2012 and 2030.1 In Portugal, mortality rates remain at approximately 50% within five years of diagnosis.2 It is therefore essential to explore the main pathophysiological pathways of HF and to review current therapies.

HF is a complex clinical syndrome that can be defined as an abnormality of cardiac structure or function affecting ventricular filling and ejection,3 in which there is evidence of imbalances in redox status and nitric oxide (NO) production that can be redressed by appropriate therapy.4

In Portugal, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins (Figure 1) account for 90% of lipid-lowering drugs prescribed,5 but it is not known what proportion are prescribed in HF. Although various observational studies suggest that statins may reduce the morbidity and mortality associated with HF, due in part to their antioxidant properties,6–8 and that coronary artery disease (CAD), in which the value of statin therapy is well established, is responsible for around two-thirds of cases of systolic HF,3 the benefit of statins specifically for HF has been called into question by the results of randomized clinical trials. Their use is also limited by cardiac cachexia and by the paradoxical association of low serum cholesterol with worse HF prognosis.9

HMG-CoA reductase inhibitors (statins) (adapted from94). Lovastatin, simvastatin and pravastatin are of fungal origin, while more recent statins are completely synthetic. Statins of fungal origin are structurally related and have a hydronaphthalene ring in common. Lovastatin and simvastatin are administered as inactive prodrugs while pravastatin is given in the active form. Totally synthetic statins have different structures that may account for their solubility differences in water.'> HMG-CoA reductase inhibitors (statins) (adapted from94). Lovastatin, simvastatin and pravastatin are of fungal origin, while more recent statins are completely synthetic. Statins of fungal origin are structurally related and have a hydronaphthalene ring in common. Lovastatin and simvastatin are administered as inactive prodrugs while pravastatin is given in the active form. Totally synthetic statins have different structures that may account for their solubility differences in water.' title='Chemical structure of HMG-CoA reductase inhibitors (statins) (adapted from94). Lovastatin, simvastatin and pravastatin are of fungal origin, while more recent statins are completely synthetic. Statins of fungal origin are structurally related and have a hydronaphthalene ring in common. Lovastatin and simvastatin are administered as inactive prodrugs while pravastatin is given in the active form. Totally synthetic statins have different structures that may account for their solubility differences in water.'/>

Figure 1.

Chemical structure of HMG-CoA reductase inhibitors (statins) (adapted from94).

Lovastatin, simvastatin and pravastatin are of fungal origin, while more recent statins are completely synthetic. Statins of fungal origin are structurally related and have a hydronaphthalene ring in common. Lovastatin and simvastatin are administered as inactive prodrugs while pravastatin is given in the active form. Totally synthetic statins have different structures that may account for their solubility differences in water.

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Statins’ main mechanism of action is inhibition of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Inhibition of this enzyme interferes with the synthesis of mevalonate and isoprenoid intermediates, particularly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are responsible for the isoprenylation of a wide range of proteins including small proteins associated with guanosine triphosphate (GTP) such as Ras, Rho and Rac (Figure 2). Isoprenylation of these molecules is essential for the covalent attachment, subcellular localization, and intracellular trafficking of membrane-associated proteins.10 Inhibition of the synthesis of isoprenoid intermediates may underlie many of statins’ pleiotropic effects (Table 1),11 including their antioxidant and anti-inflammatory action.

eNOS: endothelial nitric oxide synthase; ET-1: endothelin-1; HMG-CoA: hydroxymethylglutaryl-coenzyme A; PAI-1: plasminogen activator inhibitor-1; PP: pyrophosphate; t-PA: tissue plasminogen activator.'> eNOS: endothelial nitric oxide synthase; ET-1: endothelin-1; HMG-CoA: hydroxymethylglutaryl-coenzyme A; PAI-1: plasminogen activator inhibitor-1; PP: pyrophosphate; t-PA: tissue plasminogen activator.' title='Effects of statins on the mevalonate pathway (adapted from95,96). ↑: increased; ↓: decreased; eNOS: endothelial nitric oxide synthase; ET-1: endothelin-1; HMG-CoA: hydroxymethylglutaryl-coenzyme A; PAI-1: plasminogen activator inhibitor-1; PP: pyrophosphate; t-PA: tissue plasminogen activator.'/>

Figure 2.

Effects of statins on the mevalonate pathway (adapted from95,96). ↑: increased; ↓: decreased; eNOS: endothelial nitric oxide synthase; ET-1: endothelin-1; HMG-CoA: hydroxymethylglutaryl-coenzyme A; PAI-1: plasminogen activator inhibitor-1; PP: pyrophosphate; t-PA: tissue plasminogen activator.

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The main aim of this review is to analyze the role of oxidative stress in HF and the molecular mechanisms underlying statins’ antioxidant properties. It also examines current scientific evidence on the use of these drugs as a specific treatment for HF.

Several experimental and clinical studies in recent years have demonstrated the importance of oxidative stress in the pathogenesis of HF. Oxidative stress is defined as an imbalance between the synthesis of reactive oxygen species (ROS) and their elimination by antioxidant defense systems, with a prevailing pro-oxidant status that results in macromolecular damage and disrupts cellular redox signaling.12 The ROS family includes free radicals such as superoxide (O2−) and the hydroxyl radical (HO) as well as non-radical oxidants such as hydrogen peroxide (H2O2) and hypochlorous acid (HClO).13

Cardiomyocytes, endothelial cells and neutrophils all produce ROS in the heart.14 The principal enzymes involved in this process are mitochondrial oxidases, nicotinamide adenine dinucleotide phosphate oxidases (Nox), xanthine oxidase (XO), endothelial nitric oxide synthase (eNOS), monoamine oxidase (MAO) and myeloperoxidase (MPO).14–16

Mitochondria are the main source of ROS. More than 90% of the total oxygen (O2) consumed by aerobic organisms is utilized by mitochondrial oxidases to produce adenosine triphosphate in a process coupled to the reduction of cellular O2 to water. About 1–4% of the O2 used in these reactions is converted to O2− and H2O2, which can be detrimental to mitochondrial function if not adequately detoxified.13 Cardiomyocytes contain the greatest density of mitochondria in the body, due to the energy requirements of the heart. Cardiac mitochondria in animal models of HF produce more O2− than normal mitochondria.14

Nox are enzyme complexes that catalyze O2 reduction using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the electron donor. This process produces ROS such as O2− and H2O2.17 These enzymes were originally identified in neutrophils. The structure of Nox in these cells includes a membrane complex made up of the catalytic subunit, gp91phox and the subunit p22phox, the cytoplasmic proteins p47phox, p67phox and p40phox, and Rac, a low molecular weight G protein.17,18 Several homologs of the gp91phox subunit, now known as Nox2, have been identified, and there are seven Nox isoforms, Nox1–5 and the dual oxidases Duox1 and Duox2, which differ in expression, molecular composition, subcellular location and tissue distribution.7,19 Nox1–3 require cytosolic subunits to be translocated to form a membrane complex in order to produce ROS,17 while Nox4 is constitutively active and Nox5 remains inactive until stimulated by calcium.11,17 The most important Nox in CVD are Nox1, Nox2, Nox4 and Nox5.20 The activity of Nox1 and Nox2 can be increased by angiotensin II, growth hormones and cytokines.11,17 In terms of distribution, endothelial cells express Nox2, Nox4 and Nox5, vascular smooth muscle cells express Nox1, Nox4 and Nox5, phagocytes mainly express Nox2,11 and cardiomyocytes mainly produce Nox2 and Nox4.19 The Nox family has been implicated in the pathogenesis of HF due to pressure overload, doxorubicin-induced HF and ischemic and diabetic cardiomyopathy.19

eNOS synthesizes NO and citrulline from O2 and l-arginine. However, in conditions of oxidative stress or reduced availability of the substrate (l-arginine) or the cofactor tetrahydrobiopterin (BH4), eNOS can become uncoupled and produce O2− instead of NO (Figure 3).21 In the heart, eNOS is expressed in endothelial cells and cardiomyocytes. Uncoupling of eNOS appears to contribute to endothelial dysfunction in hypertensive diastolic HF and to ventricular hypertrophy due to pressure overload.14,22

eNOS requires the presence of a cofactor, BH4. When BH4 binds to eNOS, the enzyme is coupled. Degradation of BH4 by ROS, particularly ONOO− leads to the uncoupling of the enzyme and hence the production of O2− instead of NO. In turn, O2− reacts with NO, producing ONOO− and oxidizing BH4, leading to a vicious cycle of eNOS uncoupling. Akt: protein kinase B; AMPK: adenosine monophosphate-activated protein kinase; mRNA: messenger ribonucleic acid; BH4: tetrahydrobiopterin; Poly(A): polyadenylate; Cav-1: caveolin-1; eNOS: endothelial nitric oxide synthase; GTPCH-1: guanosine triphosphate cyclohydrolase; NO: nitric oxide; O2: oxygen; O2−: superoxide; ONOO−: peroxynitrite; P: phosphate; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; ROS: reactive oxygen species; Ser633: serine 633; Ser1177: serine 1177.'> eNOS requires the presence of a cofactor, BH4. When BH4 binds to eNOS, the enzyme is coupled. Degradation of BH4 by ROS, particularly ONOO− leads to the uncoupling of the enzyme and hence the production of O2− instead of NO. In turn, O2− reacts with NO, producing ONOO− and oxidizing BH4, leading to a vicious cycle of eNOS uncoupling. Akt: protein kinase B; AMPK: adenosine monophosphate-activated protein kinase; mRNA: messenger ribonucleic acid; BH4: tetrahydrobiopterin; Poly(A): polyadenylate; Cav-1: caveolin-1; eNOS: endothelial nitric oxide synthase; GTPCH-1: guanosine triphosphate cyclohydrolase; NO: nitric oxide; O2: oxygen; O2−: superoxide; ONOO−: peroxynitrite; P: phosphate; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; ROS: reactive oxygen species; Ser633: serine 633; Ser1177: serine 1177.' title='Effects of oxidative stress on endothelial nitric oxide synthase. The synthesis of NO by eNOS requires the presence of a cofactor, BH4. When BH4 binds to eNOS, the enzyme is coupled. Degradation of BH4 by ROS, particularly ONOO− leads to the uncoupling of the enzyme and hence the production of O2− instead of NO. In turn, O2− reacts with NO, producing ONOO− and oxidizing BH4, leading to a vicious cycle of eNOS uncoupling. Akt: protein kinase B; AMPK: adenosine monophosphate-activated protein kinase; mRNA: messenger ribonucleic acid; BH4: tetrahydrobiopterin; Poly(A): polyadenylate; Cav-1: caveolin-1; eNOS: endothelial nitric oxide synthase; GTPCH-1: guanosine triphosphate cyclohydrolase; NO: nitric oxide; O2: oxygen; O2−: superoxide; ONOO−: peroxynitrite; P: phosphate; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; ROS: reactive oxygen species; Ser633: serine 633; Ser1177: serine 1177.'/>

Figure 3.

Effects of oxidative stress on endothelial nitric oxide synthase.

The synthesis of NO by eNOS requires the presence of a cofactor, BH4. When BH4 binds to eNOS, the enzyme is coupled. Degradation of BH4 by ROS, particularly ONOO− leads to the uncoupling of the enzyme and hence the production of O2− instead of NO. In turn, O2− reacts with NO, producing ONOO− and oxidizing BH4, leading to a vicious cycle of eNOS uncoupling. Akt: protein kinase B; AMPK: adenosine monophosphate-activated protein kinase; mRNA: messenger ribonucleic acid; BH4: tetrahydrobiopterin; Poly(A): polyadenylate; Cav-1: caveolin-1; eNOS: endothelial nitric oxide synthase; GTPCH-1: guanosine triphosphate cyclohydrolase; NO: nitric oxide; O2: oxygen; O2−: superoxide; ONOO−: peroxynitrite; P: phosphate; PI3K: phosphoinositide 3-kinase; PKA: protein kinase A; ROS: reactive oxygen species; Ser633: serine 633; Ser1177: serine 1177.

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XO is involved in purine metabolism, catalyzing the conversion of hypoxanthine to xanthine and thence to uric acid. O2 is used as an electron donor in these reactions, producing O2− and H2O2.13 Increased expression and activity of XO has been described in HF, while administration of allopurinol, an XO inhibitor, increased cardiac contractility in an animal model of HF and reduced adverse cardiac remodeling in an experimental model of myocardial infarction (MI).14

The MAO family of enzymes catalyzes the oxidative degradation of neutrotransmitters such as noradrenaline, adrenaline and dopamine, and in the process generates H2O2. When the heart is subjected to neurohormonal and/or chronic hemodynamic stress, the abundance of circulating/tissue monoamines can increase MAO-derived H2O2 production,15 with significant contributions from both isoforms. MAO-A may establish a link with the renin-angiotensin system in the pathophysiology of diabetic cardiomyopathy,23 and there is evidence of cardiomyocyte necrosis when it is over-expressed,24 while MAO-B predominates in chronic hemodynamic overload.25

MPO is an enzyme secreted by activated neutrophils and monocytes in inflammatory conditions and uses H2O2 to produce several oxidizing molecules, including HClO, chloramines and nitrogen dioxides, that cause tissue damage in the heart and blood vessels and contribute to endothelial dysfunction.13 Plasma MPO is elevated in HF patients compared to controls, and its activity is increased in severe chronic HF compared to mild to moderate HF.16,26

Oxidative stress can result not only from increased ROS production but also from dysfunctional antioxidant defenses.21 The most important antioxidant enzymes are superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx).13 Conversion of O2− to H2O2 is catalyzed by SOD isoforms found in the cytoplasm and organelles (Cu,Zn-SOD and SOD-1), mitochondria (SOD-2)' alt='manganese-dependent superoxide dismutase (mitochondrial isoform; SOD-2)'>MnSOD and SOD-2) or extracellularly (extracellular superoxide dismutase [EC-SOD] or SOD-3). H2O2 can then be converted to H2O and O2 by catalase in peroxisomes or by GPx in the cytoplasm and mitochondria.13 Other antioxidant enzymes include glutathione reductase, glutathione-S-transferase, the peroxiredoxins and the thioredoxins. The latter regulate the thiol-disulfide status of proteins, affecting their structure and function, and thioredoxin 1 binds directly to and metabolize ROS.27 Heme oxygenase 1 (HO-1) also has antioxidant properties; as ROS formation can be catalyzed by an excess of heme, degradation of this compound by HO-1 reduces oxidative stress.28 The human body also has non-enzyme antioxidant defenses, including glutathione (GSH), vitamins C and E, carotenoids, uric acid, bilirubin and albumin.13 High-density lipoprotein (HDL) is another antioxidant molecule; functional HDL has high levels of antioxidant and anti-inflammatory proteins and enzymes, notably paraoxonase-1, which appears to be involved in inhibition of low-density lipoprotein (LDL) oxidation.29

Although reduced antioxidant enzyme activity has been reported in animal models of HF,30 there are conflicting results in HF patients, with increases, decreases, and no change in antioxidant enzyme activity.31–33 Reductions in vitamin C and carotenoid levels have also been seen in patients with chronic HF.34

ROS are involved in several processes that affect cardiac structure and function, contributing to the genesis and progression of HF.

Oxidative stress is associated with aging and the development of many diseases, including CVD.14 Several studies over the last 10 years have assessed the effects of statins on markers of oxidative stress and endothelial function in cardiovascular, renal and metabolic disorders.

In HF patients with reduced left ventricular ejection fraction (LVEF), one month of simvastatin or atorvastatin therapy reduced ROS production and systemic concentrations of malondialdehyde (MDA), a marker of lipid peroxidation, increased EC-SOD activity, and improved endothelial function and functional capacity.67,68 In another study, of patients with systolic HF, one month's treatment with rosuvastatin also significantly reduced plasma MPO and oxLDL levels.69

In individuals with CAD undergoing coronary artery bypass grafting, prospective treatment with atorvastatin or pravastatin for four weeks significantly reduced mRNA expression and activity of Rac1 in myocardial tissue samples, as well as angiotensin II-induced Nox activity.70 In a study of patients undergoing cardiac surgery who were monitored until discharge, a strong association was observed between O2− and peroxynitrite production and postoperative complications during hospital stay. Preoperative atorvastatin therapy for three days significantly reduced Nox activity and O2− and peroxynitrite production in myocardial tissue, while ex-vivo incubation of myocardium with atorvastatin induced mevalonate-reversible and Rac1-mediated inhibition of Nox.71 A similar study showed that preoperative administration of atorvastatin increased BH4 availability and reduced both basal and uncoupled eNOS-derived O2− production in samples of internal mammary artery.72 Statin therapy also appears to reduce plasma MPO concentrations in patients with acute coronary syndrome but not in those with stable CAD.73

Statins’ redox effects have been assessed in individuals with hyperlipidemia, in whom they have various protective effects, including reduced ROS production and increased platelet NO synthesis, decreased urinary and platelet isoprostanes, diminished platelet Rac1 activation, inhibiting of serum and platelet Nox2, increasing adiponectin levels and thereby reducing gp91phox and Nox activity, raised serum vitamin E levels, and decreased DNA damage in hypercholesterolemic individuals with the C242T polymorphism of the p22phox gene, which is associated with risk for developing CAD.47,74–78

Oxidative stress is also linked to the pathogenesis of atrial fibrillation (AF). In a study assessing the effects of statins on ROS production in patients who developed AF following cardiac surgery or with permanent AF, atorvastatin reduced Rac1 and Nox activity in right atrial samples from those who developed postoperative AFF, but did not affect ROS, eNOS uncoupling, or BH4 in those with permanent AF. These results suggest that Nox upregulation is an early but transient event in the natural history of AF.79

Statins also appear to have a protective effect in diabetes. Rosuvastatin treatment for six months in patients with diabetic nephropathy improved renal function and significantly reduced serum lipid peroxidation products and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of DNA oxidation.80 In diabetic polyneuropathy, rosuvastatin for 12 months led to improvements in severity, symptoms and nerve conduction parameters, as well as reductions in lipid peroxidation.81

Despite the growing evidence of statins’ antioxidant effects in cardiovascular and metabolic disorders, these effects are not seen in some studies. In patients at high risk for cardiovascular disease, atorvastatin and simvastatin did not significantly alter plasma MDA or MPO concentrations or urinary 8-OHdG,82 while in another study of patients with diabetic nephropathy, atorvastatin did not increase NO availability.83

In addition to their effects on cholesterol synthesis, statins have pleiotropic properties, notably antioxidant action. These effects appear to result from inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway.

There is widespread recognition of the role of oxidative stress in the pathogenesis of many diseases, including HF. ROS interfere with various processes that affect cardiac structure and function, contributing to apoptosis and mitochondrial dysfunction in cardiomyocytes, contractile dysfunction, myocardial fibrosis and hypertrophy, endothelial dysfunction and atherosclerosis. Statins reduce ROS levels and increase NO synthesis, thereby improving cardiac redox balance. These effects are mainly mediated by inhibition of pro-oxidant enzymes such as Nox and by stimulation of the expression, activity and stability of eNOS. In addition, statins stimulate other antioxidant enzymes and help control inflammatory processes. Statins thus have effects on various molecules that are central to both oxidative stress and inflammation, notably by stimulating the synthesis of 15-epi-LXA4, which has pro-resolving, anti-inflammatory and antioxidant properties. Their antioxidant effects have been demonstrated in several cardiovascular conditions, including HF, CAD and AF, mainly in the early stages of these diseases (Table 3).

With regard to the effects of statins in reducing cardiovascular events and mortality in HF, although various observational studies have shown reduced mortality with statin therapy, two large clinical trials – CORONA and GISSI-HF – did not demonstrate such a benefit. The ESC and the ACC do not currently recommend statins in HF in the absence of other indications for their use. Given the lack of consensus, further clinical trials are needed to clarify the clinical value of statins in subgroups of HF patients and its relation with their effects on redox state.

T. Sousa acknowledges support from Fundação para a Ciência e a Tecnologia (FCT) (SFRH/BPD/112005/2015).

The authors have no conflicts of interest to declare.