Open access peer-reviewed chapter

The Role of Neurohormonal Systems, Inflammatory Mediators and Oxydative Stress in Cardiomyopathy

Written By

Ronald Zolty

Submitted: 15 October 2020 Reviewed: 19 March 2021 Published: 27 October 2021

DOI: 10.5772/intechopen.97345

From the Edited Volume

Cardiomyopathy - Disease of the Heart Muscle

Edited by Gustav Mattsson and Peter Magnusson

Chapter metrics overview

360 Chapter Downloads

View Full Metrics


Cardiomyopathy and more specifically the dilated cardiomyopathy, regardless of severity, is associated with activation of neuro-hormonal, cytokine and oxidative stress signaling pathways that alter the structure and function of cardiac myocytes and non-myocyte cells. These cellular alterations culminate in the morphological changes in cardiac structure termed as cardiac remodeling, a maladaptive process that contributes to further left ventricular dysfunction and heart failure development. This pathological progression is mainly driven by circulating mediators, in particular angiotensin II and norepinephrine. Natriuretic peptides, endothelin-1, vasopressin play also an important role in the progression of the cardiomyopathy. Cardiac inflammation, mediated by cytokines such as tumor necrosis factor-α (TNF-α), interleukins 1 (IL-1) and 6 (IL-6), as well as the oxidative stress were also shown to worsen the cardiac function. Although these pathways have been described separately, they are critically inter-dependent in the response to the development and progression of the dilated cardiomyopathy. This chapter reviews the cellular basis for cardiac remodeling and the mechanisms that contribute to these cellular abnormalities and, more broadly, to the pathophysiology of dilated cardiomyopathy, its progression and its potential treatments.


  • Angiotensin II
  • Adrenergic signaling
  • Natriuretic peptides
  • Vasopressin
  • Prostaglandin
  • Endothelin
  • Nitric Oxide
  • Cytokines
  • ROS
  • Oxidative stress

1. Introduction

Cardiomyopathy is a group of diseases that affect the heart muscle [1]. As the disease worsens, symptoms of heart failure will occur including shortness of breath, fatigue, and fluid retention with pulmonary congestion and peripheral edema.

The majority of patients with heart failure have an underlying cardiomyopathy as the causative etiology. In the US, the most common cause of heart failure (HF) is a primary or secondary dilated cardiomyopathy [1, 2] encompassing approximately 60% of the HF cases.

Whether the etiology of the cardiomyopathy is idiopathic, inflammatory, viral, or ischemic, the pathological processes leading to the clinical syndrome of heart failure begin with myocardial injury. The hemodynamic consequences of the initial injury will lead to a decline in myocardial contractility. The reduction of cardiac output will elicit a complex humoral and inflammatory response. The humoral response comprises two major components, the renin-angiotensin-aldosterone (RAA) pathway [3] and the sympathetic nervous (SN) system and is referred as neuro-hormonal activation [4]. Additional circulating mediators, such as natriuretic peptides, nitric oxide, endothelin and vasopressin also play a role in the circulatory adaptation to the heart failure state. Furthermore, the initial myocardial injury leading to the development of cardiomyopathy stimulates the production of cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) [5]. Finally, oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, is enhanced in HF [6, 7, 8, 9].

For neuro-hormonal and cytokine activation, these pathways are initially compensatory in response to acute injury but have ultimately maladaptive consequences on the long term, leading to cardiac remodeling and worsening heart failure.

Cardiac remodeling refers to changes in the size, shape, structure and function of the heart. Ventricular remodeling involves hypertrophy and apoptosis of myocytes, regression to a fetal phenotype, as well as modification of the extracellular matrix (Figure 1).

Figure 1.

Schematic representation of cardiac remodeling in dilated cardiomyopathy and HF.


2. Neuro-hormonal activation in cardiomyopathy and heart failure

Heart failure associated with cardiomyopathy is a highly complex syndrome in which the insufficient cardiac output leads to neuro-hormonal activation and subsequent ventricular remodeling [10]. The characteristic hemodynamic abnormalities in patients with HF are a reduction in stroke volume with concomitant increase in systemic vascular resistance. In the early phase of heart failure, neuro-hormonal activation, with the stimulation of the SN and RAA systems, helps maintaining adequate cardiac output and peripheral perfusion. Sustained neuro-hormonal activation, however, will result in increased cardiac wall stress, ventricular dilatation and adverse remodeling effects [11, 12]. A variety of endogenously produced mediators, including norepinephrine, angiotensin II, aldosterone, endothelin and vasopressin have been implicated as biologically active molecules which will contribute to disease progression of the failing heart.

Stimulation of these neuro-hormones and their receptors influences myocardial contractility, heart rate and conduction, cardiac metabolism, and cellular growth. Therefore, these cardiac neuro-mediator and neuro-receptors play a key role in cardiac physiology and myocyte function in healthy and diseased heart. For example, cardiac hypertrophy is produced by a combination of increased myocyte stretch, neurotransmitter release, and several types of autocrine, paracrine, and hormonal stimulation that mediate myocyte growth. In this context, the α-1 receptor pathway, the angiotensin II AT1 receptor pathway, the endothelin 1 receptor pathway, and the β-adrenergic receptor pathway have all been implicated in the pathogenesis of myocyte hypertrophy.

Activation of the adrenergic nervous system and the renin-angiotensin systems appears to be of primary importance in producing major adaptive cardiac receptor-signal transduction changes in the failing heart.

The most important modulated function mechanisms responsible for the stimulation of cardiac function appears to be the adrenergic signaling pathway. In addition to the adrenergic stimulation, an increase in plasma volume will take place, resulting in an increased ventricular preload as well as an increase in cardiac myocyte hypertrophy, which results in more contractile elements, increased wall thickness with a subsequent decrease in wall tension. The plasma volume increase is associated with stimulation of the RAA system and production of angiotensin II and aldosterone which will enhance sodium and water reabsorption in both the proximal and distal renal tubules [13].

2.1 Activation of the renin-angiotensin system with LV dysfunction

When the heart fails, the RAA system is activated as demonstrated with increased of the renin activity with production of angiotensin II and aldosterone [14, 15, 16, 17, 18].

The RAA system consists of a cascade of enzymatic reactions involving three components, angiotensinogen, renin and angiotensin-converting enzyme (ACE), which generate angiotensin (Ang) II as the biologically active product. Ang II binds to two types of specific receptors, angiotensin type-1 (AT1R) and type-2 (AT2R). Both receptor belong to the family of seven transmembrane domain heterotrimeric G protein-coupled receptors (GPCR). The majority of the deleterious mitogenic and hypertrophic actions of Ang II have been attributed to interaction with the AT1 receptor, which is the predominant receptor, while AT2 generally produces beneficial effects.

The deleterious effects of the activation of the RAA system are mediated primarily through increased circulating and tissue levels of the neuro-hormonal angiotensin II (Figure 2). Ang II is an extremely potent vasoconstrictor, acting directly on vascular smooth muscles and indirectly by increasing sympathetic tone [19, 20]. In addition, it produces sodium retention (through aldosterone and renal vasoconstriction), as well as fluid retention through anti-diuretic hormone [21, 22]. At the cellular level, Ang II promotes migration, proliferation, and hypertrophy, thus producing numerous adverse effects, including remodeling of the left ventricle, and development of endothelial dysfunction [23, 24].

Figure 2.

Deleterious pathophysiologic effects of angiotensin II in dilated cardiomyopathy and heart failure. MMP: Matrix metalloproteinases, ROS: Reactive oxygen species.

Ang II promotes cardiac remodeling in several ways. By increasing arterial smooth muscle tone and causing salt and water retention, it increases cardiac preload and afterload. Also, increased wall stress is a potent stimulus for remodeling. In addition, Ang II has direct effects on the myocardium; it causes hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts as well as an increase in extracellular matrix deposition, [25] and stimulates the release of other growth factors, including norepinephrine and endothelin, which in turn stimulate cardiac remodeling [26]. These actions of Ang II are largely mediated through the angiotensin type 1 (AT1) receptor. Thus RAA system inhibition by ACE inhibitors or by angiotensin receptor blockers, attenuates many of the key hemodynamic, mechanical and functional disturbances crucial to the pathophysiology of cardiac dysfunction. ACE inhibitors are therefore a mainstay of therapy in patients with symptomatic and asymptomatic LV systolic dysfunction.

2.2 Sympathetic nervous system activation with LV dysfunction

Similarly to the RAA system, when the cardiac function fails, the adrenergic nervous system is activated. Numerous studies have documented elevated circulating norepinephrine levels with LV myocardial dysfunction [14, 15, 16, 17, 27]. Even in asymptomatic patients with left ventricular dysfunction, an 35% increase in plasma norepinephrine was demonstrated [18]. In the failing heart, the increase of adrenergic activity seems to occur as a consequence of increased central sympathetic release at the pre-synaptic level [28].

Pre-synaptic facilitation of norepinephrine release by angiotensin II may also play an important role in adrenergic activation, [29] thus demonstrating a positive feedback of angiotensin II on cardiac adrenergic activity. Conversely, the adrenergic nervous system provides a major stimulus for activation of the RAA system, as activation of renal nerves by the SN system results in renal renin release [30, 31]. Thus activation of the adrenergic and renin-angiotensin systems appears to be co-regulated with cardiac dysfunction. Activation of one system stimulates the other and maneuvers that decrease the activity of one system may inhibit the other [32]. For example, administration of an ACE inhibitor to patients with heart failure with reduced ejection fraction (HFrEF) results not only in a decrease in plasma angiotensin II levels but also in a fall in circulating norepinephrine [33, 34].

Activation of cardiac β-adrenergic receptor (AR) represents the body’s most powerful principle to increase cardiac contractility and heart rate [35] (Figure 3). Adrenergic receptors are a family of G-protein-coupled receptors with nine members, three α1, three α2, and three β: β1, β2 and β3. When the first subdivision of adrenergic receptors was defined on the basis of pharmacological experiments, [36] the α-subtype was defined as the one that causes smooth muscle contraction, whereas the β-subtype mediates smooth muscle relaxation. Twenty years later, the β-receptors were subdivided again, into the β1-subtype, which stimulates cardiac muscle, and the β2-subtype, which relaxes smooth muscle [37].

Figure 3.

Shematic representation of the cascade of reactions to increase cardiomyocyte contractility by the sympathetic nervous activation.

The mammalian heart expresses all three β-adrenergic receptor subtypes [38, 39, 40]. In the healthy heart, the majority (i.e. 60–80%) of receptors are the β1-subtype in most species, while the β2-subtype accounts for a minor fraction of total βARs. A third β-adrenergic receptor subtype, the β3-subtype, was initially thought to be limited to adipose tissue, [40] but was later also detected in the heart [39]. This subtype is generally perceived as less important due to its very low expression level and relatively minor functional effects. There is evidence that the β1-subtype is preferentially located on cardiac myocytes, whereas the β2-subtype is expressed to a significant extent on non-cardiomyocyte cells, including vascular smooth muscle cells and synaptic nerve endings.

β1- and β2-adrenergic receptors are potent stimulators of cardiac contraction and relaxation in the human heart [35, 41]. As direct effectors of the sympathetic nervous system, they serve to rapidly adapt cardiac performance to an increased hemodynamic demand. Both β1 and β2 receptors couple to the stimulatory G protein Gs, thereby activating adenylyl cyclase. The formation of the second messenger cAMP then leads to activation of PKA (cAMP protein kinase A), which phosphorylates several key regulators of the cardiac excitation-contraction machinery. This includes phospholamban, [42] the L-type Ca-channel, [42, 43] the ryanodine receptor, [44] troponin T and I, [45] myosin binding protein C [46] and the small protein phosphatase inhibitor-1 [47]. These events lead to rapid changes of the cardiomyocyte calcium transient and enhanced myofilament sensitivity for calcium, resulting in a potent inotropic effect.

Data indicate that sustained stimulation of the β1-receptor system, which is ideally suited to provide short-term increases in cardiac function, causes marked structural and functional damage to the heart on the long term. Thus the chronic activation by the adrenergic system in heart failure represents a maladaptive response.

Also, the β-adrenergic signaling in dilated cardiomyopathy is characterized by the fact that it is desensitized in failing human hearts. In HF, there is a reduction of the density of β1ARs in in failing human myocardium, [48] a decrease of norepinephrine-re-uptake [49] and ultimately an increase in Ginhibitory (Gi) protein expression [50] and in GRK2 (βARK)-activity [51], a receptor kinase that phosphorylates and thereby inactivates βARs. The observed desensitization of βAR receptors represents an adaptation process to the highly increased levels of catecholamines in heart failure. This phenomenon is considered a beneficial readjustment of the signaling cascade to minimize the detrimental effects of chronic stimulation of the myocardium by catecholamines.

β-adrenergic receptor blockade is now regarded as one of the most effective therapeutic principle in dilated cardiomyopathy and heart failure [52].

Several large clinical trials with carvedilol, metoprolol succinate and bisoprolol have demonstrated a significant benefit in large placebo-controlled trial [53, 54, 55]. On the contrary, two β-blockers (xamoterol and bucindolol) have failed to significantly reduce mortality or even increased mortality [56, 57]. The most likely explanation for the failure of xamoterol is the pronounced partial agonism exerted by this agent [58]. Bucindolol led to a non-significant reduction of mortality in the BEST trial. Two main reasons might account for this finding. First, the study population differed markedly from the other large heart failure trials. It included a high percentage of African-Americans and of women, and both of these groups are underrepresented in other trials [56]. In the other trials, the beneficial effects of β-blockade were less pronounced compared with the effects in Caucasians [56]. Second bucindolol might display some degree of partial agonism.

2.3 Aldosterone

The pivotal role played by aldosterone in the pathogenesis of dilated cardiomyopathy and HF is well-recognized. Activation of the RAA system leads to marked elevations in plasma aldosterone levels, which have been shown to correlate with increased mortality [59]. Elevated aldosterone levels lead to excessive sodium retention, with expansion of the extracellular volume, worsening hemodynamic conditions, and a fall in cardiac output. Decreased renal blood flow further stimulates the RAA system, causing secondary hyperaldosteronism and further sodium retention. In addition, by contributing to hypokalemia and hypomagnesemia, aldosterone increases the sensitivity of cardiac tissue to arrhythmias, with a resultant increase in sudden death [60, 61].

A growing body of evidence suggests that aldosterone may contribute to endothelial dysfunction, possibly through reduced nitric oxide bioavailability [62]. Since the endothelium plays a critical role in the regulation of vascular tone, platelet aggregation and thrombosis, endothelial dysfunction predicts subsequent cardiovascular events [63]. Furthermore, aldosterone contributes to the development of HF by promoting myocardial fibrosis. In vitro studies have demonstrated that administration of aldosterone to cardiac fibroblasts significantly enhances collagen synthesis, [64] a finding that has been confirmed in rat models [65]. Another potentially harmful effect of aldosterone is its ability to blunt baroreflex response. Administration of aldosterone to dogs [66] and to healthy human volunteers [67] resulted in an elevation in the threshold for baroreflex activation and a reduction in peak discharge rate. Finally aldosterone has been shown to promote the activation and aggregation of platelets and to enhance arteriolar constriction [68].

The clinical trial Randomized Aldosterone Evaluation Study (RALES) demonstrated the benefits of aldosterone receptor blockade in HF. 1633 patients with NYHA Class III-IV chronic HF, already receiving ACEIs, were randomized to spironolactone versus placebo [69]. The relative risk of death was reduced by 30% over two years (RR 0.7, 95% CI 0.60–0.82; p < 0.001) with a 35% reduction in HF hospitalizations and an improvement in functional class.

2.4 Endothelin

Endothelin is a potent vasoconstrictor peptide and its synthesis is stimulated by hypoxia, ischemia, neurohormones (norepinephrine, angiotensin II, arginine vasopressin), and inflammatory cytokines [70, 71, 72].

Tissue and plasma levels of endothelin-1 and its precursor (big endothelin-1) are elevated in patients with cardiomyopathy and HF [73, 74, 75, 76, 77, 78]. These increases are due to increased endothelin synthesis primarily in the pulmonary vascular bed [79] and the myocardium [80]. The vascular distension seen in HF (especially in the pulmonary vascular bed) appears to a stimulus for increased endothelin-1 production [81]. Another potential contributor to the increased endothelin-1 concentration in HF, is the downregulation of endothelin-B receptors, which has been observed in the lung tissue of experimental animals with HF [82, 83]. Endothelin B receptors appear to play a role in the clearance of endothelin-1. Pulmonary vascular tone in HF are largely mediated by endothelin-A receptor [84, 85]. Increased levels of endothelin-1 are associated with increased angiotensin II levels, more advanced HF symptoms, worse hemodynamics, and decreased survival [70, 75, 78, 81, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94].

Endothelin-A receptor antagonists prevent remodeling, improve LV function, and prolong survival in rats [95, 96, 97].

The Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study (VERITAS), the largest clinical trial of an endothelin receptor antagonist for ADHF, enrolled 1435 patients. Patients treated with tezosentan experienced significant reduction in pulmonary arterial pressures and pulmonary capillary wedge pressures as well as an increase in cardiac index. Despite these significant improvements in hemodynamics, use of tozosentan did not improve the composite primary end point of dyspnea at 24 hours, worsening HF or death at 7 days [98].

The Resource utilization Among Congestive Heart Failure Study (REACH) was another clinical trial investigating the effects of bosentan in 370 patients with advanced HF and an LVEF <35%. The trial was stopped prematurely due to elevations in liver transaminases. At the time of the study termination, there was no significant differences in outcomes between the bosentan compared to the placebo group. Nevertheless, a post-hoc analysis of 174 patients who completed the 6-month follow up demonstrated significant clinical improvement (p = 0.045) [99].

Finally, the Enrasentan Cooperative Randomized Evaluation (ENCOR) trial studied enrasentan, a dual A/B endothelin receptor antagonist in 419 patients with stable NYHA Class II and II with LVEF ≤35%. There was no significant improvement in the primary endpoint of clinical HF score with the active drug [100].

2.5 Vasopressin

Arginine vasopressin (AVP) is a peptide hormone that is elevated in heart failure, and associated with a poor prognosis [18, 101]. AVP contributes to fluid retention and hyponatremia [102, 103]. AVP exerts its cardiao-vascular effects trough two receptors subtypes V1a and V2. V1a is found on vascular smooth muscle cells and cardiac myocytes. Whereas, vasopressin V1A receptors mediate vasoconstriction, positive inotropic and mitogenic effects, the V2 receptors inhibit free water clearance [104, 105, 106]. Stimulation of the V1a-receptor, initially leads to increased myocardial protein synthesis resulting in myocardial hypertrophy [107, 108]. V2-receptors are found in the distal tubule of the kidney, and their activation results in water retention via upregulation of aquaporin channels [104, 109].

The control of Vasopressin secretion is complex and involves both osmotic and nonosmotic stimuli [110]. Factors causing vasopressin release include plasma osmolality, intra-cardiac and arterial pressures, as well as Angiotensin II levels [111]. Under most circumstances, Vasopressin is coupled to osmolality levels, making osmo-receptor the major determinant of Vasopressin release.

When the pressure within the heart or arterial vessels decreases, tonic inhibitory restraint of vasopressin is diminished and plasma vasopressin levels rise. Inversely, elevated blood pressure leads to decrease plasma vasopressin level [112, 113, 114].

Despite their hypo-osmolar hyponatremia state, patients with HF have inappropriately elevated plasma vasopressin levels [101, 115, 116].

Agents that antagonize V1A receptor reduce vascular tone and the mitogenic myocardial effects of AVP. Because V2 antagonists increase aquaresis, the addition of an AVP V2 antagonist improves free water clearance, and reduces hyponatremia.

Conivaptan is a dual V1a/V2 receptor antagonist that has been investigated in the treatment of HF. One hundred and forty-two patients with NYHA class III or IV HF were randomized to either a single IV dose of conivaptan or placebo and evaluated over 12 hours for changes in hemodynamics. Both capillary wedge pressure and right atrial pressure were significantly reduced in the treatment group compared to placebo. However, cardiac index did not improve [117].

The EVEREST study investigated whether short term and long term blockade of the V2 receptor with Tolvaptan is beneficial in patients with HF. The results confirmed that Tolvapatan when added to standard therapy improved symptoms and signs of HF, however no benefit was observed on all-cause mortality or the combined endpoint of cardiovascular mortality or hospitalization for worsening HF The drug had no significant effect on long term LV remodeling in patient with LVEF <30% [118].

2.6 Natriuretic peptides

While the activation of the RAA and SN system is detrimental in HF, other counter-regulatory pathways are activated in HF, including the natriuretic peptide (NP) system. The NP system consists of atrial (ANP) [119]. B-type (BNP) [120] and C-type (CNP) NPs. These hormones regulate blood pressure and fluid homeostasis [121, 122, 123]. ANP is synthesized and secreted in atria. BNP is secreted from the ventricles in response to mechanical stretch and increased intra-cardiac volume and pressure, while CNP mostly originates from endothelial and renal cells and is secreted in response to endothelium-dependent agonists and pro-inflammatory cytokines [121, 122, 124].

NPs activate three transmembrane receptors: natriuretic peptide receptor (NPR)-A, NPR-B and NPR-C.27 The binding of NPs to type A (NPR-A) and type B (NPR-B) receptors activates guanylate cyclase, increasing levels of the second messenger cyclic guanosine monophosphate (cGMP) and its effector molecule protein kinase G. This induces natriuresis, diuresis, vasodilation and inhibition of the RAA and the SN systems, as well as antifibrotic, antiproliferative and antithrombotic effects [121, 122, 124].

Blockade of NP breakdown by neprilysin inhibitors has, therefore, been investigated [125]. Oral neprilysin inhibitors, such as candoxatril, produced clinical benefit in patients with chronic HF [126, 127]. However, candoxatril has no effect on, or increases, systolic BP (SBP) in normotensives, an effect prevented by enalapril, and does not reduce BP in hypertensive subjects, probably because its vasodilatory effect may be offset by an increased activity of the RAAS and sympathetic nervous system and/or by downregulation of NP receptors [128, 129]. In addition, since neprilysin acts on numerous physiological targets, the effect of candoxatril was broader than anticipated [128].

Neprilysin inhibition results in activation of the RAAS, therefore, in order to be clinically beneficial, neprilysin inhibition requires concomitant inhibition of the RAAS [130]. Vasopeptidase inhibitors are dual inhibitors of ACE and neprilysin and, therefore, emerged as a new therapeutic option in HF and hypertension, but their pharmacological profile is complex [131]. Omapatrilat was more effective than either lisinopril or amlodipine in reducing BP, [131] but in patients with chronic HF it was not more effective than enalapril in reducing the combined risk of death or hospitalization for HF requiring intravenous treatment [132]. However, omapatrilat was discontinued due to the risk of angioedema, possibly due to excessive inhibition of bradykinin degradation (presumably via neprilysin, ACE and aminopeptidase P) [133, 134].

Sacubutril/Valsartan is an oral combination medication consisting of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is called angiotensin receptor-neprilysin inhibitor (ARNi). The PARADIGM-HF trial compared sacubitril/valsartan to enalapril [37] in heart failure patients with reduced LVEF. The trial was stopped early after a prespecified interim analysis revealed a significant reduction in the primary endpoint of cardiovascular death or heart failure in the sacubitril/valsartan group compared to enalapril [135].


3. Inflammation

Ample evidence exists that dilated cardiomyopathy and HF are associated with the activation of the immune system resulting in elevated levels of pro-inflammatory cytokines. In patients with cardiomyopathy and HF, elevated levels of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) are found [136, 137, 138]. The best characterized inflammatory molecule in DCM and HF is TNF-α.

The importance in understanding the role of inflammation in the pathogenesis of dilated cardiomyopathy arises from the observation that many aspects of the development of dilated cardiomyopathy can be explained by the biological effects of pro-inflammatory cytokines. Cytokines, when expressed at sufficiently high concentrations, can mimic the development of the dilated cardiomyopathy phenotype features, which include left ventricular remodeling and dysfunction with myocyte hypertrophy, changes in fetal gene expression, alteration of the extracellular matrix, and cardiac myocyte apoptosis [139, 140, 141, 142, 143]. As it is the case with neuro-hormonal activation, overexpression of cytokines results in cardiac direct toxicity [144, 145].

Clinically, the progressive increase in inflammatory cytokine levels is in direct relation with NYHA functional class deterioration. Also, data from the VEST trial demonstrated a strong correlation between survival and TNF-α levels [146]. Similar findings were observed with levels of IL-6 [146].

One of the marks of pro-inflammatory cytokines is their ability to depress LV function. Preclinical studies in rodents showed that circulating levels of TNF-α that correspond with those observed in patients with HF were sufficient to produce negative inotropic effects [139]. Also, transgenic mice with TNF-α overexpression studies resulted in depressed LV function [140, 147].

The cytokine hypothesis proposes that cardiomyopathy progression is an inflammatory process and that amplification of pro-inflammatory cytokines worsens left ventricular dysfunction and facilitates the development of HF [10, 148].

There is significant cross-talk between the neuro-hormonal and the cytokine systems [144]. Data have shown that these cytokine signaling pathways augment local neuro-hormonal activation, which in turn promotes the enhanced expression of these same cytokines [144]. For instance adrenergic stimulation as seen in HF, induces myocardial TNF-α expression, [149] which in turn attenuates beta-adrenergic responsiveness. Also, Angiotensin II is known to activate nuclear factor-kappa B (NF-kB), a redox-sensitive transcription factor that is important in stimulating the myocardial inflammatory response, [150] including activation of inflammatory cytokines, NO, chemokines and cell adhesion molecules [150, 151].

Clinical studies that have examined the effect of ACE-inhibitors have shown that while ACE inhibitors have mixed results in terms of inhibiting pro-inflammatory cytokines, Angiotensin Receptor Blockers (ARBs) have consistently led to significant decrease in circulating levels of inflammatory mediators such as TNF-α in patients with cardiomyopathy and HF [152, 153]. Similar findings have been reported with the use of beta-blockers in experimental animal models and clinical heart failure studies. Beta-adrenergic blockade with a beta-1-selective adrenergic antagonist has demonstrated partial inhibition of the expression of pro-inflammatory mediators in an experimental model of post-infarct LV heart failure remodeling model [55]. In sub-group analysis of the MERIT-HF, treatment with metoprolol did not lead to a decrease in the level of pro-inflammatory mediators, whereas in a different trial, the use of carvedilol, a non-selective beta-1 and beta-2 adrenergic antagonist with anti-oxidant properties resulted in a significant reduction in the production of TNF-α [154, 155, 156]. These data suggest that here are interactions between the renin-angiotensin and adrenergic systems with pro-inflammatory cytokines.

3.1 Tumor necrosis factor-α (TNF-α)

TNF-α is recognized as a cytokine with pleiotropic biologic capacities [157, 158]. TNF affects growth, differentiation and function of every cell type, including cardiomyocytes.

TNF-α binds to a lower affinity the type 1 receptor called TNFR1 and a higher affinity type 2 receptor called TNFR2. Intracellular signaling occurs as a result of TNF-induced cross-linking (oligomerization) of the receptors. Previous studies have identified the presence of both types of TNF receptors in the non-failing and failing heart [159, 160]. Normal myocardium does not contain TNF-α. In the failing heart, with the increased expression of TNF-α, the receptors for TNF-α, TNFR1 and TNFR2, are downregulated, [159] similar to the β1 adrenergic receptor downregulation and the SN system in heart failure.

The majority of the deleterious effects of TNF-α are coupled to activation of TNFR1, whereas activation of TNFR2 appears to exert protective effects. Activation of TNFR1 is responsible for mediating negative inotropic effects, and cardiac myocyte apopotosis [142, 159, 161]. In contrast activation of the type 2 TNF receptor appears to protect the cardiomyocyte against hypoxic stress and ischemic injury [159, 162]. Previous studies have shown that both TNFR1 and TNFR2 exist in the circulation as circulating soluble receptors and are referred as sTNFR1 and sTNFR2. Elevated levels of sTNFR1 and sTNFR2 have been shown to be strong independent predictors of adverse outcomes in hospitalized HF patients [146, 163, 164].

Early in the disease process, much of circulating TNF-α is derived from immune cell line such as activated macrophages. However, late in disease progression much of the TNF-α is produced by the cardiac myocytes themselves [165]. Transgenic mice overexpressing TNF will develop an early inflammatory myocarditis that later progresses to myocyte hypertrophy, left ventricular dilatation, and progressive left ventricular dysfunction [140]. In this model, TNF also activate expression of matrix metalloproteinases, [166] which contribute to LV remodeling and dilatation. Administration of TNF in experimental animal models at concentrations comparable to those observed in clinical heart failure, produces significant declines in myocardial contractility with worsening left ventricular function [139]. In another rat model, the infusion of TNF, caused progressive left ventricular enlargement with significant degradation of the extra-cellular matrix [167].

The negative inotropic effects of TNF-α on cardiac myocytes are mediated through increased expression of iNOS with production of nitric oxide [168, 169] and activation of norepinephrine and angiotensinogen II. TNF-α was shown to increase the expression of the AT1 receptor in cardiac fibroblasts by a mechanism dependent on NF-ϏB, thereby augmenting Ang II effects on cells via an increase in AT1 receptor density [170]. Increase of Ang II stimulates the synthesis of cardiac fibroblasts and the inhibition of MMP2 activity. Ang II activates NF-ϏB, via the AT1 receptor and thus increases the production of pro-inflammatory cytokines [171]. Transgenic mice with TNF-α overexpression demonstrate increased levels of both ACE and Ang II [172]. These different studies support the presence of cross-talk between the RAA and cytokine signaling pathways. TNF-α also augments sympathetic activation. Isoproterenol administration in rodents increases the expression of TNF-α, IL-1β, and IL-6 [163, 173]. These studies support that the sympathetic nervous system regulates positively the cytokine gene expression, while cytokines potentiate the effects of catecholamines on the myocardium.

3.2 Interleukin-1 (IL-1)

There are three members of the interleukin-1 (IL-1) family: IL-1α, IL-β, and IL-1 receptor antagonist (IL-1Ra) [158]. IL-1α and IL-β are agonist and IL-1 Ra is a specific receptor antagonist. Similar to TNF-α, IL-1β appears to be activated in response to stressful environmental stimuli [136, 174].

IL-1β expression is elevated in the myocardium of failing hearts and is present at high circulating concentrations in patients with dilated cardiomyopathy. The primary sources of IL-1β within the myocardium are macrophages and cardiac fibroblasts [175, 176]. Similar to TNF-α and IL-6, IL-1β inhibits fibroblast-mediated production of collagen and suppresses proliferation of fibroblasts [177, 178]. IL-1β also increases the expression and activity of MMP’s which cause destruction of the fibrillary collagen network. Moreover, IL-1β induces the expression of nitric oxide synthase. Furthermore, IL-1β causes cardiac myocytes hypertrophy and inhibits the expression of the fetal genes, β-MHC and skeletal α-actin. In summary, IL-1β alters the phenotype and genotype of cardiac myocytes, [177, 178] while also disrupting the composition of the extracellular matrix.

3.3 Interleukin IL-6

Similar to TNF-α and IL-1β, levels of IL-6 are elevated in patients with dilated cardiomyopathy and HF. The degree of IL-6 elevation correlates to heart failure severity and prognosis [179]. IL-6 signals through its receptor, IL-6R, associates with the gp130 cytokine receptor, and forms a membrane complex that activates downstream signaling pathways. The source of IL-6 production are cardiac myocytes, fibroblasts and mononuclear inflammatory cells [175]. IL-6 stimulation of fibroblasts decreases collagen synthesis and increases MMP activity, contributing to disintegration of extracellular matrix [175]. Transgenic mice expressing both IL-6 and IL-6R develop LV hypertrophy, resulting from activation of the gp130 receptor. Other cytokines within the IL-6 family, including cardiotropin 1 and leukemia inhibitor factor, induce cardiomyocyte hypertrophy [180, 181, 182]. Thus IL-6 participates to the alterations of the extracellular matrix and cardiomyocyte hypertrophy.

3.4 Nitric oxide synthases

While the contributions of neuro-hormonal and cytokine signaling pathways to ventricular remodeling are well-established, cytokine-mediated increase in inducible nitric oxide synthase may be an important downstream pathway that contributes significantly to the cardiac remodeling [183, 184]. There are three known members of the nitric oxide synthase (NOS) family, [183] neuronal NOS (nNOS or NOS 1), inducible NOS (iNOS or NOS II) and endothelial NOS (eNOS or NOS III). Cardiac myocytes in the normal heart express mainly eNOS [185]. However, studies have shown that iNOS is expressed at high levels in the myocardium of failing hearts [186, 187, 188].

Evidence from in vivo studies supports a detrimental effect of iNOS in the failing heart. Cardiac specific over-expression of iNOS in transgenic mice leads to cardiac fibrosis, dilatation and premature death, [189] although Heger et all reported no demonstrable phenotype accompanying iNOS overexpression in the mouse heart [190]. Sam et al. demonstrated that 6 months after an MI, the extent of LV dysfunction and myo-cardiac apoptosis was significantly diminished in iNOS knockout mice, supporting a detrimental role of iNOS in this ischemic cardiomyopathy model [191]. These data suggest that iNOS may play an important role in ventricular remodeling and cardiac myocyte apoptosis. Supporting this concept, iNOS expression in end-stage failing heart normalized after placement of ventricular assist device [188].

3.5 Anti-inflammation treatment in cardiomyopathy and heart failure

Despite an abundance of evidence implicating the inflammatory pathway in HF and cardiomyopathy, and numerous examples of anti-inflammatory therapies improving HF in experimental animal models, these agents have been largely unsuccessful in treating human cardiomyopathy and HF.

3.5.1 Prednisone

Prednisone was shown to suppress TN-Fα biosynthesis at the translational and transcriptional levels. Parrillo et al. randomized 102 patients to prednisone versus placebo to 102 patient with dilated cardiomyopathy. Following three months of therapy, an increase in LVEF of >5% was observed in 53% of patients receiving prednisone. All patients were categorized prospectively in two separately randomized subgroups. “Reactive” patients (n = 60) were those who had fibroblastic (n = 36) or lymphocytic (n = 2) infiltration or immunoglobulin deposition (n = 16) on endomyocardial biopsy, a positive gallium scan (n = 7), or an elevated erythrocyte sedimentation rate (n = 18). Nonreactive patients (n = 42) had none of these features. At three months, 67 percent of the reactive patients who received prednisone had LVEF improvement, as compared with 28 percent of the reactive controls (P = 0.004) [192]. The data of this study suggested that patients with idiopathic dilated cardiomyopathy may have some improvement when given a high dose of prednisone. However, the increase in the ejection fraction was overall small with limited duration, and the side effects were important. In conclusion, prednisone was judged to have only a marginal clinical benefit, and should not be administered as standard therapy for dilated cardiomyopathy.

3.5.2 Etarnecept

TNF-α inhibitors are immunomodulators that are used in a wide variety of rheumatological/autoimmune diseases including RA, [193, 194], inflammatory bowel disease, [195] and psoriasis/psoriatic arthritis [196].

Etanercept is a human recombinant TNF-α receptor that binds and inactivates circulating TNF-α molecules.

Preclinical experimental studies have demonstrated that etanercept reversed the deleterious negative inotropic effect of TNF-α [139, 197].

A series of phase I clinical studies in patients with moderate to advanced HF showed improvements in 6 –minute walk distance, quality of life and LV cardiac function following treatment with etanercept for up to 3 months [198, 199]. Subsequently, two large multicenter quality of life clinical trials RENAISSANCE (Randomized Etanercept North American Strategy to Study Antogonism of Cytokines) and RECOVER (Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction) were conducted in HF patients with NYHA class II-IV and demonstrated no clinical benefit [200]. The RENEWAL (Randomized Etanercept World-wide EvALuation) clinical trial with all cause mortality and hospitalization for HF as primary end-point, did not reveal any benefit either with etarnecept [201].

3.5.3 Infliximab

Infliximab is a chimeric monoclonal antibody that binds and inactivates circulating TNF-α that has been shown to be effective in the treatment of Crohn disease and rheumatoid arthritis. The ATTACH clinical trial (Anti-TNF-α Therapy Against CHF), a phase II study enrolled 150 patients with NYHA class III-IV HF. The results of this trial revealed no beneficial effects on clinical status with infliximab. There was even a dose related increase in mortality and HF hospitalizations with infliximab when compared to placebo at 14 and 28 weeks, resulting in early termination of the trial [202].

3.5.4 Intravenous immunoglobulin

Although the exact mechanism of intravenous immunoglobulin (IVIg) therapy is not known, IVig therapy is being used in a wide range of immune-mediated disorders, such as dermatomyosis, Kawasaki and multiple sclerosis [203, 204]. Based on an initial report that IVIg was beneficial in acute cardiomyopathy, [205] Gullestad et al. conducted a double-blind clinical trial with IVIg for 26 weeks in 47 patients with Class II-III HF, who were receiving standard HF therapy including ACE inhibitors and β-blockers. In this study, IVIg induced a marked rise in plasma levels of the anti-inflammatory mediators (IL-10, IL-1 receptor antagonist and soluble TNF receptors) and was associated with a significant increase in LVEF [206]. Thus in this small study, therapy with IVIg was potentially effective in patients with cardiomyopathy and HF, but these results should be confirmed in a larger subset of patients and also needs to examine the effect on morbidity and mortality of this therapy.


4. Oxydative Stress

Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense (Figure 4), has been shown to play an important role in the pathophysiology of cardiac remodeling in HF, [6, 7, 8, 9, 207]. Specifically, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases (MMPs), leading to the extracellular matrix remodeling. Moreover, ROS can directly impair the cardiac contractile function by modifying proteins involved in excitation-contraction coupling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure.

Figure 4.

Source of reactive oxygen species (ROS) and their pathophysiological role in heart failure. NOS: Nitric oxide synthase.

Oxidation products of several organic molecules including lipids, proteins, and nucleic acids have been implicated in the pathogenesis of dilated cardiomyopathy and their levels are found to be increased in heart failure. The severity of heart failure and levels of oxidative stress increase concurrently, which suggests that oxidative stress could be utilized as a biomarker for dilated cardiomyopathy progression.

Oxidative stress is associated with increased production of ROS and reactive nitrogen species (RNS), diminished nitric oxide (NO) bioavaibility and reduced superoxide dismutase (SOD), glutathione peroxidase and catalase activity. ROS are formed as products of oxidation–reduction reactions and include free radical molecules such as superoxide (O2−), hydroxyl radical (OH−), lipid peroxyl and non-free radical species like hydrogen peroxide (H2O2). RNS like (ONOO−) are formed by the reaction between nitric oxide (NO) and O2− [208]. Cellular ROS are generated predominantly as by-products of mitochondrial respiration, NADPH oxidase, endothelial nitric oxide synthase (eNOS) [209] and xanthine oxidase activity [210].

Clinically, oxydative stress markers have prognostic values as they correlate with worsening NYHA functional class and cardiac dysfunction [211, 212]. Several studies have demonstrated that the lipid peroxidation products such as malondialdehyde [MDA] [211] and 4-hydroxynonenal [213] are increased in patients with dilated cardiomyopathies compared to normal controls. Myeloperoxidase, a peroxidase enzyme present in granulocytes is increased in the serum of patients with dilated cardiomyopathy. Increased myeloperidase levels correlate with HF severity. Finally, plasma myeloperidase appears also to be an independent predictor of mortality and HF hospitalization [212]. Uric acid, produced by the ubiquitous ROS-generating xanthine oxidase, is considered as a marker for oxidative stress in the cardiovascular system. It is released from the failing human heart, with an inverse correlation between the level of uric acid and left ventricular ejection fraction [214]. Increased serum uric acid levels are associated with increased filling pressures, reduced cardiac index and plasma NT-proBNP [215]. Uric acid is also a strong independent predictor of mortality in patients with dilated cardiomyopathy [216].

One consequence of myocardial oxidative stress is myocardial remodeling, including myocyte hypertrophy, myocyte apoptosis and alteration of the extracellular matrix.

Oxidative stress has direct effects on cellular structure and function and activates integral signaling molecules leading to myocardial remodeling and failure (Figure 5). Oxidative stress stimulates myocardial growth, matrix remodeling, and cellular dysfunction, which involve the activation of several downstream signaling pathways. First, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors [217]. Oxidative stress stimulates the tyrosine kinase Src, GTP-binding protein Ras, protein kinase C, mitogen-activated protein kinases (MAPK), Jun-nuclear kinase (JNK) and p38. Second, Oxidative stress induces apoptosis, another important contributor to remodeling and dysfunction, which is induced by ROS-mediated DNA and mitochondrial damage and activation of pro-apoptotic signaling kinases [218]. Third, Oxidative stress causes DNA strand breaks, activating the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 regulates the expression of a variety of inflammatory mediators, which facilitate the progression of cardiac remodeling [219]. Fourth, oxidative stress can activate matrix metalloproteinases (MMPs), a family of proteolytic enzymes [220]. MMPs play a pivotal role in normal tissue remodeling processes, such as cell migration, invasion, proliferation, and apoptosis. MMP activity has been shown to be increased in the failing hearts [220, 221]. MMPs are generally produced in an inactive form and are activated by reactive oxygen species (ROS). Because MMP can be activated by ROS, one mechanism of LV remodeling is the activation of MMPs secondary to increased ROS [222]. Sustained MMP activation will lead to extracellular matrix remodeling. Fifth, ROS mediate growth responses in ventricular myocytes by stimulating the activity of several growth factors including transforming growth factor-β1 (TGF-β1), [223, 224] VEGF, [225] fibroblast growth factor-2 (FGF-2), [226], and PDGF [227]. Sixth, oxidative stress promotes vasoconstriction by increasing the production of endothelin-1 [228] and angiotensin II by increased production of 02- via the NADPH oxidase [229]. Seventh, oxidative stress upregulates the transcription of the factors HIF-1α and HIF-2α expression, [230] factors that are also implicated in the development of cardiomyopathy and HF. Eighth, increased oxidative stress leads to inflammation and cell injuries due to oxidation of proteins, lipids and DNA [209]. Finally, ROS directly influence myocyte contractile function by modifying proteins involved in excitation-contraction coupling. Zima and Blatter [231] including the ryanodine receptor, the L-type calcium channel, and the Ca2 + ATPase.

Figure 5.

Oxidative stress and heart failure. MAPK: Mitogen-activated protein kinases; JNK: Jun-nuclear kinase; PARP-1: Poly(ADP-ribose) polymerase-1; MMP: Matrix metalloproteinases; AP-1: Activator protein-1.

4.1 Oxidative stress and mitochondrial DNA damage

In addition to the role of mitochondria as a source of reactive oxygene species (ROS), the mitochondria themselves can be damaged by ROS. Increased generation of ROS in the failing hearts was associated with mitochondrial damage and dysfunction, characterized by an increased lipid peroxidation in the mitochondria, a reduction in the number of the mitochondrial DNA copy, a decrease in the number of mitochondrial RNA transcripts and a reduced oxidative capacity due to low complex enzyme activities [232]. They thus can lead to a catastrophic cycle of mitochondrial functional decline, further ROS generation, and cellular injury.

4.2 Therapies targeting oxidative stress

To date, there are no positive large-scale clinical trials of antioxidant therapy in cardiomyopathy and heart failure.

4.2.1 Coenzyme Q

Coenzyme Q (CoQ) is an antioxidant via the redox cycle. CoQ inhibits both the initiation and the propagation of lipid and protein oxidation.

Preclinical data has provided information across a variety of models supporting the pathophysiological role of CoQ10 depletion in HF and the concept of improved outcomes with CoQ10 supplementation [233].

There have been a large number of trials examining the effect of CoQ10 in HF. Two meta-analyses have examined the potential benefit of CoQ10. Fotino et al. [234] analysis from 13 trials and 395 patients demonstrated an improvement in LVEF of 3.67% (95% CI, 1.6%–5.74%) in those receiving CoQ10 versus placebo. The majority of benefit of LVEF improvement was in trials published before 1993. The other meta-analysis by Madmani et al. [235] looked at 7 studies data with 914 patients and did not show any significant improvement in LVEF or exercise capacity. Given the significant heterogeneity of the data, it was not possible to make any significant conclusion.

The most recent clinical trial with CoQ10l, Q-SYMBIO (Coenzyme Q10 as Adjunctive Treatment of Chronic Heart Failure: A Randomized, Double-blind, Multicenter Trial With Focus on Symptoms, Biomarker Status) enrolled 420 patients and demonstrated that compared with placebo, CoQ10 reduced the primary 2-year end point of cardiovascular death, hospital stays for HF, or mechanical support or cardiac transplant (P = 0.005; hazard ratio, 0.5; 95% CI, 0.32–0.80) [236]. Although having limitations, this study has renewed interest in evaluating CoQ10 supplementation in patients with HF. The results of the trial warrants future adequately powered randomized controlled trials of CoQ10 supplementation in patients with HF.

4.2.2 Allopurinol

Under normal conditions, the enzyme xanthine oxidase (XO) exists primarily in its dehydrogenase form, serving as the rate-limiting step in purine degradation to uric acid. Xanthine oxidase catalyzes the transformation of hypoxanthine to xanthine and then to uric acid with the associated production of four superoxide anions [237]. Xanthine oxidase is therefore a potential major regulator of cellular oxidative stress [238].

A large body of experimental and clinical data suggests that oxidative stress contributes to ventricular and vascular remodeling and disease progression in HF. XO is a potent source of oxidative stress, and therefore an obvious target for therapy.

Significant hyperuricemia is present in ≈25% of patients with HF with reduced ejection fraction, [215, 216] and it is associated with worsening symptoms, exercise intolerance, and reduced survival [239, 240, 241].

Under conditions of tissue hypoxia similar to HF in an experimental model, [242] the breakdown of ATP to AMP to hypoxanthine provides substrate to XO. Subsequently, XO uses oxygen rather than NAD as an oxidant. As a result, XO produces superoxide and hydrogen peroxide (H2O2) rather than NADH [243, 244]. Increased vascular O2• − production has been attributed in major part to XO, which has been found to adversely impact endothelial function by impairing nitric oxide (NO) signaling [245] and to directly contribute to experimental cardiac remodeling.

The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study, a randomized trial with 243 HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol compared to placebo failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction after 24 weeks.of treatment [246].

In summary, oxidative stress appears to play an important role in the pathophysiology of cardiac remodeling and cardiomyopathy. Thus therapeutic strategies to modulate this maladaptive oxidative stress response as seen in cardiomyopathy and HF should become a target for future extensive investigation.


5. Conclusions

Cardiac remodeling represents the culmination of complex interactions between neuro-hormonal, stress activated cytokine and oxidative stress signaling pathways. These different signaling pathways feedback positively on one another and act in concert to initiate and propagate the cellular changes taking place within the remodeling ventricle. These pathways stimulate myocyte hypertrophy, increase the rate at which myocytes undergo hypertrophy, apoptotic cell death as well as proliferation of fibroblasts, some of which may differentiate into contractile myofibroblasts.

This constellation of cellular changes ultimately leads to gross morphological features of cardiac dilatation, progressive cardiac dysfunction and worsening heart failure. In this manner, these complex series of signaling events that lead to cardiac remodeling may very well represent the central pathophysiological mechanisms underlying cardiomyopathy progression.


  1. 1. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O'Connell J, et al .Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies.Circulation. 1996 Mar 1;93(5):841-842. doi: 10.1161/01.cir.93.5.841
  2. 2. Bristow MR, Mestroni L, Bohlmeyer T, Gilbert EM. Chapter 66. Dilated Cardiomyopathies. Hurst’s the Heart, 10th Edition, McGraw-Hill NY, 2001: 1947-1966
  3. 3. Dzau VJ Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med. 1993 Apr 26;153(8):937-42.PMID: 8386920
  4. 4. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992 Jul;20(1):248-54. doi: 10.1016/0735-1097(92)90167-l. PMID: 1351488 DOI: 10.1016/0735-1097(92)90167-l
  5. 5. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002 Nov 29;91(11):988-98. doi: 10.1161/01.res.0000043825.01705.1b.PMID: 12456484
  6. 6. Belch JJ, Bridges AB, Scott N, Chopra M.Oxygen free radicals and congestive heart failure.Br Heart J. 1991; 65: 245-248
  7. 7. Hill MF, Singal PK. Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol 1996; 148: 291-300
  8. 8. Hill MF, Singal PK. Right and left myocardial antioxidant responses during heart failure subsequent to myocardial infarction. Circulation 1997; 96:2414-2420
  9. 9. Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A. Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 1998; 97: 1536-1539
  10. 10. Klein L, O'Connor CM, Gattis WA, Zampino M, de Luca L, Vitarelli A, et al. M.Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations. Am J Cardiol. 2003 May 8;91(9A):18F–40F. doi: 10.1016/s0002-9149(02)03336-2. PMID: 12729848
  11. 11. Sutton MG, Sharpe. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000 Jun 27;101(25):2981-2988. doi: 10.1161/01.cir.101.25.2981
  12. 12. Weber KT. Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation. Circulation. 1997 Dec 2;96(11):4065-4082. doi: 10.1161/01.cir.96.11.4065
  13. 13. Shchekochikhin D, Schrier RW, Lindenfeld J. Cardiorenal syndrome: pathophysiology and treatment. Curr Cardiol Rep. 2013 Jul;15(7):380. doi: 10.1007/s11886-013-0380-4. PMID: 23700289
  14. 14. Levine TB , Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol. 1982 May;49(7):1659-1666. doi: 10.1016/0002-9149(82)90243-0
  15. 15. Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986 Apr;73(4):615-621. doi: 10.1161/01.cir.73.4.615
  16. 16. Davis D, Baily R, Zelis R. Abnormalities in systemic norepinephrine kinetics in human congestive heart failure.Am J Physiol. 1988 Jun;254(6 Pt 1):E760–E766. doi: 10.1152/ajpendo.1988.254.6.E760. PMID: 3377075
  17. 17. Abraham WT, Hensen J, Schrier RW. Elevated plasma noradrenaline concentrations in patients with low-output cardiac failure: dependence on increased noradrenaline secretion rates Clin Sci (Lond). 1990 Nov;79(5):429-435. doi: 10.1042/cs0790429
  18. 18. Francis GS , Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 1990 Nov;82(5):1724-1729. doi: 10.1161/01.cir.82.5.1724
  19. 19. Folkow B, Johansson B, Mellander S. The comparative effects of angiotensin and noradrenaline on consecutive vascular sections. Acta Physiol Scand. 1961; 53:99-104 PMID: 13893844
  20. 20. Zimmerman BG, Sybertz EJ, Wong PC. Interaction between sympathetic and renin-angiotensin system. J Hypertens. 1984 Dec;2(6):581-587. doi: 10.1097/00004872-198412000-00002
  21. 21. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001 Dec 6;345(23):1689-1697. doi: 10.1056/NEJMra000050
  22. 22. Brown JJ, Fraser R, Leckie B, Lever AF, Morton JJ, Padfield PL, Semple PF, Robertson JI. Significance of renin and angiotensin in hypertension. Cardiovasc Clin. 1978;9(1):55-89. PMID: 352522
  23. 23. Williams B. Angiotensin II and the pathophysiology of cardiovascular remodeling. Am J Cardiol. 2001 Apr 19;87(8A):10C-17C. doi: 10.1016/s0002-9149(01)01507-7.PMID: 11334763
  24. 24. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998 Apr 14;97(14):1411-1420. doi: 10.1161/01.cir.97.14.1411. PMID: 9577953
  25. 25. Sadoshima J, Izumo S. Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 1993 Sep;73(3):413-423. doi: 10.1161/01.res.73.3.413
  26. 26. Greenberg BH. Effects of angiotensin converting enzyme inhibitors on remodeling in clinical trials.J Card Fail. 2002 Dec;8(6 Suppl):S486-90. doi: 10.1054/jcaf.2002.129251.PMID: 12555162
  27. 27. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978 Feb;41(2):233-243. doi: 10.1016/0002-9149(78)90162-5. PMID: 203177
  28. 28. Meredith IT, Eisenhofer G, Lambert GW, Dewar EM, Jennings GL, Esler MD. Cardiac sympathetic nervous activity in congestive heart failure. Evidence for increased neuronal norepinephrine release and preserved neuronal uptake. Circulation. 1993 Jul;88(1):136-145. doi: 10.1161/01.cir.88.1.136. PMID: 8391399
  29. 29. Abraham WT, Lowes BD, Rose CP, Larrabee P, Bristow MR. Angiotensin II selectively increases cardiac adrenergic activity in patients with heart failure. J Am Coll Cardiol 1994; 23: 215A
  30. 30. Berl T, Henrich WL, Erickson AL, Schrier RW. Prostaglandins in the beta-adrenergic and baroreceptor-mediated secretion of renin. Am J Physiol. 1979 May;236(5):F472–F477. doi: 10.1152/ajprenal.1979.236.5.F472. PMID: 220882
  31. 31. Weber F, Brodde OE, Anlauf M, Bock KD. Subclassification of human beta-adrenergic receptors mediating renin release.Clin Exp Hypertens A. 1983;5(2):225-238. doi: 10.3109/10641968309048823. PMID: 6131758
  32. 32. Bristow MR, Abraham WT. Anti-adrenergic effects of angiotensin converting enzyme inhibitors. Eur Heart J. 1995 Nov;16 Suppl K:37-41. doi: 10.1093/eurheartj/16.suppl_k.37. PMID: 8869134
  33. 33. Cody RJ, Franklin KW, Kluger J, Laragh JH. Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril. Am J Med. 1982 May;72(5):791-7. doi: 10.1016/0002-9343(82)90547-2.PMID: 7044120
  34. 34. Gilbert EM, Sandoval A, Larrabee P, Renlund DG, O'Connell JB, Bristow MR. Lisinopril lowers cardiac adrenergic drive and increases beta-receptor density in the failing human heart. Circulation. 1993 Aug;88(2):472-480. doi: 10.1161/01.cir.88.2.472. PMID: 8393389
  35. 35. Brodde OE, Michel MC. Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev. 1999 Dec;51(4):651-90.PMID: 10581327
  36. 36. Ahlquist RP A study of the adrenotropic receptors. Am J Physiol. 1948 Jun;153(3):586-600. doi: 10.1152/ajplegacy.1948.153.3.586. PMID: 18882199
  37. 37. Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown TG Jr.Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967 May 6;214(5088):597-598. doi: 10.1038/214597a0. PMID: 6036174
  38. 38. Brodde OE. Beta-adrenoceptors in cardiac disease. Pharmacol Ther. 1993 Dec;60(3):405-430. doi: 10.1016/0163-7258(93)90030-h. PMID: 7915424
  39. 39. Gauthier C, Langin D, Balligand JL. Beta3-adrenoceptors in the cardiovascular system.Trends Pharmacol Sci. 2000 Nov;21(11):426-31. doi: 10.1016/s0165-6147(00)01562-5.PMID: 11121573
  40. 40. Arch JR, Ainsworth AT, Cawthorne MA, Piercy V, Sennitt MV, Thody VE, et al. Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature. 1984 May 10-16;309(5964):163-5. doi: 10.1038/309163a0. PMID: 6325935
  41. 41. Kaumann A, Bartel S, Molenaar P, Sanders L, Burrell K, Vetter D, et al. Activation of beta2-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failure. Circulation. 1999 Jan 5-12;99(1):65-72. doi: 10.1161/01.cir.99.1.65. PMID: 9884381
  42. 42. Zhao XL, Gutierrez LM, Chang CF, Hosey MM. The alpha 1-subunit of skeletal muscle L-type Ca channels is the key target for regulation by A-kinase and protein phosphatase-1C. Biochem Biophys Res Commun. 1994 Jan 14;198(1):166-173. doi: 10.1006/bbrc.1994.1024. PMID: 8292020
  43. 43. Gerhardstein BL, Puri TS, Chien AJ, Hosey MM. Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the beta 2 subunit of L-type voltage-dependent calcium channels. Biochemistry. 1999 Aug 10;38(32):10361-10370. doi: 10.1021/bi990896o. PMID: 10441130
  44. 44. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000 May 12;101(4):365-376. doi: 10.1016/s0092-8674(00)80847-8
  45. 45. Sulakhe PV, Vo XT. Regulation of phospholamban and troponin-I phosphorylation in the intact rat cardiomyocytes by adrenergic and cholinergic stimuli: roles of cyclic nucleotides, calcium, protein kinases and phosphatases and depolarization. Mol Cell Biochem. 1995 Aug-Sep;149-150:103-26. doi: 10.1007/BF01076569. PMID: 8569720
  46. 46. Kunst G, Kress KR, Gruen M, Uttenweiler D, Gautel M, Fink RH. Myosin binding protein C, a phosphorylation-dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2.Circ Res. 2000 Jan 7-21;86(1):51-8. doi: 10.1161/01.res.86.1.51. PMID: 10625305
  47. 47. Zhang ZY, Zhou B, Xie L. Modulation of protein kinase signaling by protein phosphatases and inhibitors. Pharmacol Ther. 2002 Feb-Mar;93(2-3):307-317. doi: 10.1016/s0163-7258(02)00199-7. PMID: 12191622
  48. 48. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, et al .Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982 Jul 22;307(4):205-211. doi: 10.1056/NEJM198207223070401. PMID: 6283349
  49. 49. Böhm M, La Rosée K, Schwinger RH, Erdmann E . Evidence for reduction of norepinephrine uptake sites in the failing human heart. J Am Coll Cardiol. 1995 Jan;25(1):146-153. doi: 10.1016/0735-1097(94)00353-r. PMID: 7798493
  50. 50. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, et al. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res. 1986 Sep;59(3):297-309. doi: 10.1161/01.res.59.3.297. PMID: 2876788
  51. 51. Ungerer M, Böhm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation. 1993 Feb;87(2):454-463. doi: 10.1161/01.cir.87.2.454. PMID: 8381058
  52. 52. Bristow MR. beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000 Feb 8;101(5):558-569. doi: 10.1161/01.cir.101.5.558. PMID: 10662755
  53. 53. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55. doi: 10.1056/NEJM199605233342101.PMID: 8614419
  54. 54. CIBIS II Investigators and Committees: The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13. PMID: 10023943
  55. 55. MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failureEffect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999 Jun 12;353(9169):2001-7. PMID: 10376614
  56. 56. Beta-Blocker Evaluation of Survival Trial Investigators, Eichhorn EJ, Domanski MJ, Krause-Steinrauf H, Bristow MR, Lavori PW. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.N Engl J Med. 2001 May 31;344(22):1659-67. doi:10.1056/NEJM200105313442202.PMID: 11386264
  57. 57. Xamoterol in severe heart failure. The Xamoterol in Severe Heart Failure Study Group. Lancet. 1990 Jul 7;336(8706):1-6. PMID: 1694945
  58. 58. Engelhardt S, Grimmer Y, Fan GH, Lohse MJ. Constitutive activity of the human beta(1)-adrenergic receptor in beta(1)-receptor transgenic mice. Engelhardt S, Grimmer Y, Fan GH, Lohse MJ. Mol Pharmacol. 2001 Oct;60(4):712-717. PMID: 11562432
  59. 59. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study GroupCirculation. 1990 Nov;82(5):1730-1736. doi: 10.1161/01.cir.82.5.1730
  60. 60. Tsuji H, Venditti FJ Jr, Evans JC, Larson MG, Levy D. The associations of levels of serum potassium and magnesium with ventricular premature complexes (the Framingham Heart Study). Am J Cardiol. 1994 Aug 1;74(3):232-235. doi: 10.1016/0002-9149(94)90362-x. PMID: 7518645
  61. 61. Gottlieb SS, Baruch L, Kukin ML, Bernstein JL, Fisher ML, Packer M. Prognostic importance of the serum magnesium concentration in patients with congestive heart failure.J Am Coll Cardiol. 1990 Oct;16(4):827-831. doi: 10.1016/s0735-1097(10)80329-8. PMID: 2212365
  62. 62. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation. 2000 Feb 15;101(6):594-597. doi: 10.1161/01.cir.101.6.594. PMID: 10673249
  63. 63. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001 Nov 27;104(22):2673-2678. doi: 10.1161/hc4601.099485. PMID: 11723017
  64. 64. Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol. 1994 Jul;26(7):809-820. doi: 10.1006/jmcc.1994.1098. PMID: 7966349
  65. 65. Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res. 1990 Dec;67(6):1355-1364. doi: 10.1161/01.res.67.6.1355. PMID: 1700933
  66. 66. Wang W. Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension. 1994 Nov;24(5):571-575. doi: 10.1161/01.hyp.24.5.571. PMID: 7960015
  67. 67. Yee KM, Struthers AD. Aldosterone blunts the baroreflex response in man. Clin Sci (Lond). 1998 Dec;95(6):687-692. doi: 10.1042/cs0950687. PMID: 9831693
  68. 68. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest. 1995 Mar;95(3):995-1001. doi: 10.1172/JCI117809. PMID: 7884001
  69. 69. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators N Engl J Med. 1999 Sep 2;341(10):709-717. doi: 10.1056/NEJM199909023411001
  70. 70. Clavell AL, Mattingly MT, Stevens TL, Nir A, Wright S, Aarhus LL, et al. Angiotensin converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction. J Clin Invest. 1996 Mar 1;97(5):1286-1292. doi: 10.1172/JCI118544. PMID: 8636441
  71. 71. Noll G, Wenzel RR, Lüscher TF. Endothelin and endothelin antagonists: potential role in cardiovascular and renal disease. Mol Cell Biochem. 1996 Apr 12-26;157(1-2):259-67. doi: 10.1007/BF00227908. PMID: 8739256
  72. 72. Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994 Mar 30;199(3):1461-1465. doi: 10.1006/bbrc.1994.1395. PMID: 8147891
  73. 73. Fukuchi M, Giaid A. Expression of endothelin-1 and endothelin-converting enzyme-1 mRNAs and proteins in failing human hearts. J Cardiovasc Pharmacol. 1998;31 Suppl 1:S421–S423. doi: 10.1097/00005344-199800001-00120. PMID: 9595501
  74. 74. Genth-Zotz S, Zotz RJ, Cobaugh M, van Veldhuisen DJ, Netzer T, Meyer J, Darius H. Changes of neurohumoral parameters and endothelin-1 in response to exercise in patients with mild to moderate congestive heart failure. Int J Cardiol. 1998 Sep 30;66(2):137-142. doi: 10.1016/s0167-5273(98)00225-3. PMID: 9829325
  75. 75. Kiowski W, Sütsch G, Hunziker P, Müller P, Kim J, Oechslin E et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet. 1995 Sep 16;346(8977):732-736. doi: 10.1016/s0140-6736(95)91504-4. PMID: 7658874
  76. 76. Good JM, Nihoyannopoulos P, Ghatei MA, Crossman D, Bloom SR, Clark P, et al. Elevated plasma endothelin concentrations in heart failure; an effect of angiotensin II? Eur Heart J. 1994 Dec;15(12):1634-1640. doi: 10.1093/oxfordjournals.eurheartj.a060446. PMID: 7698133
  77. 77. Pacher R, Stanek B, Hülsmann M, Koller-Strametz J, Berger R, Schuller M, et al .Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure. J Am Coll Cardiol. 1996 Mar 1;27(3):633-641. doi: 10.1016/0735-1097(95)00520-x. PMID: 8606275
  78. 78. Tsutamoto T, Wada A, Maeda Y, Adachi T, Kinoshita M. Relation between endothelin-1 spillover in the lungs and pulmonary vascular resistance in patients with chronic heart failure. J Am Coll Cardiol. 1994 May;23(6):1427-1433. doi: 10.1016/0735-1097(94)90387-5. PMID: 8176102
  79. 79. Sakai S, Miyauchi T, Sakurai T, Kasuya Y, Ihara M, Yamaguchi I, et al. Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heart. Circulation. 1996 Mar 15;93(6):1214-1222. doi: 10.1161/01.cir.93.6.1214. PMID: 8653844
  80. 80. Cody RJ, Haas GJ, Binkley PF, Capers Q , Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation. 1992 Feb;85(2):504-509. doi: 10.1161/01.cir.85.2.504. PMID: 1735147
  81. 81. Takeda S, Takano T, Ogawa R. The effect of nasal continuous positive airway pressure on plasma endothelin-1 concentrations in patients with severe cardiogenic pulmonary edema. Anesth Analg. 1997 May;84(5):1091-1096. doi: 10.1097/00000539-199705000-00025. PMID: 9141937
  82. 82. Kobayshi T, Miyauchi T, Sakai S, Maeda S, Yamaguchi I, Goto K, Sugishita Y Down-regulation of ET(B) receptor, but not ET(A) receptor, in congestive lung secondary to heart failure. Are marked increases in circulating endothelin-1 partly attributable to decreases in lung ET(B) receptor-mediated clearance of endothelin-1?Life Sci. 1998;62(2):185-93. doi: 10.1016/s0024-3205(97)01064-3. PMID: 9488116
  83. 83. Ooi H, Colucci WS, Givertz MM. Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan. Circulation. 2002 Sep 24;106(13):1618-1621. doi: 10.1161/01.cir.0000034444.31846.f4. PMID: 12270852
  84. 84. Fleisch M, Sütsch G, Yan XW, Wenzel RR, Binggeli C, Bianchetti MG, et al Systemic, pulmonary, and renal hemodynamic effects of endothelin ET(A/B)-receptor blockade in patients with maintained left ventricular function J Cardiovasc Pharmacol. 2000 Sep;36(3):302-309. doi: 10.1097/00005344-200009000-00004. PMID: 10975586
  85. 85. Rodeheffer RJ, Lerman A, Heublein DM, Burnett JC Jr. Increased plasma concentrations of endothelin in congestive heart failure in humans. Mayo Clin Proc. 1992 Aug;67(8):719-24. doi: 10.1016/s0025-6196(12)60795-2.PMID: 1434909
  86. 86. Wei CM, Lerman A, Rodeheffer RJ, McGregor CG, Brandt RR, Wright S, et al. Endothelin in human congestive heart failure. Circulation. 1994 Apr;89(4):1580-1586. doi: 10.1161/01.cir.89.4.1580. PMID: 8149524
  87. 87. Tsutamoto T, Hisanaga T, Fukai D, Wada A, Maeda Y, Maeda K, Kinoshita M. Prognostic value of plasma soluble intercellular adhesion molecule-1 and endothelin-1 concentration in patients with chronic congestive heart failure. Am J Cardiol. 1995 Oct 15;76(11):803-808. doi: 10.1016/s0002-9149(99)80231-8. PMID: 7572659
  88. 88. Krum H, Goldsmith R, Wilshire-Clement M, Miller M, Packer M. Role of endothelin in the exercise intolerance of chronic heart failure. Am J Cardiol. 1995 Jun 15;75(17):1282-1283. doi: 10.1016/s0002-9149(99)80783-8. PMID: 7778560
  89. 89. Omland T, Lie RT, Aakvaag A, Aarsland T, Dickstein K. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation. 1994 Apr;89(4):1573-1579. doi: 10.1161/01.cir.89.4.1573. PMID: 8149523
  90. 90. Pousset F, Isnard R, Lechat P, Kalotka H, Carayon A, Maistre G, et al. Prognostic value of plasma endothelin-1 in patients with chronic heart failure. Eur Heart J. 1997 Feb;18(2):254-258. doi: 10.1093/oxfordjournals.eurheartj.a015228. PMID: 9043842
  91. 91. Hülsmann M, Stanek B, Frey B, Sturm B, Putz D, Kos T, et al. Value of cardiopulmonary exercise testing and big endothelin plasma levels to predict short-term prognosis of patients with chronic heart failure. J Am Coll Cardiol. 1998 Nov 15;32(6):1695-1700. doi: 10.1016/s0735-1097(98)00437-9. PMID: 9822098
  92. 92. Frey B, Pacher R, Locker G, Bojic A, Hartter E, Woloszczuk W, Stanek B. Prognostic value of hemodynamic vs big endothelin measurements during long-term IV therapy in advanced heart failure patients. Chest. 2000 Jun;117(6):1713-1719. doi: 10.1378/chest.117.6.1713. PMID: 10858407
  93. 93. Stanek B, Frey B, Hülsmann M, Koller-Strametz J, Hartter E, Schuller M, et al .Validation of big endothelin plasma levels compared with established neurohumoral markers in patients with severe chronic heart failure. Transplant Proc. 1997 Feb-Mar;29(1-2):595-6. doi: 10.1016/s0041 1345(96)00097-8. PMID: 9123146
  94. 94. Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature. 1996 Nov 28;384(6607):353-355. doi: 10.1038/384353a0. PMID: 8934519
  95. 95. Spinale FG, Walker JD, Mukherjee R, Iannini JP, Keever AT, Gallagher KP. Concomitant endothelin receptor subtype-A blockade during the progression of pacing-induced congestive heart failure in rabbits. Beneficial effects on left ventricular and myocyte function. Circulation. 1997 Apr 1;95(7):1918-1929. doi: 10.1161/01.cir.95.7.1918. PMID: 9107181
  96. 96. Borgeson DD, Grantham JA, Williamson EE, Luchner A, Redfield MM, Opgenorth TJ, Burnett JC Jr. Chronic oral endothelin type A receptor antagonism in experimental heart failure. Hypertension. 1998 Mar;31(3):766-770. doi: 10.1161/01.hyp.31.3.766. PMID: 9495259
  97. 97. Moe GW, Albernaz A, Naik GO, Kirchengast M, Stewart DJ. Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure. Cardiovasc Res. 1998 Sep;39(3):571-579. doi: 10.1016/s0008-6363(98)00169-2. PMID: 9861299
  98. 98. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol. 2002 Oct;85(2-3):195-197. doi: 10.1016/s0167-5273(02)00182-1. PMID: 12208583
  99. 99. Cosenzi A. Enrasentan, an antagonist of endothelin receptors. Cardiovasc Drug Rev. 2003 Spring;21(1):1-16. doi: 10.1111/j.1527-3466.2003.tb00102.x. PMID: 12595914
  100. 100. Anand I, McMurray J, Cohn JN, Konstam MA, Notter T, Quitzau K, et al; EARTH investigators.Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet. 2004 Jul 24-30;364(9431):347-54. doi: 10.1016/S0140-6736(04)16723-8. PMID: 15276394
  101. 101. Goldsmith SR, Francis GS, Cowley AW Jr, Levine TB, Cohn JN. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol. 1983 Jun;1(6):1385-1390. doi: 10.1016/s0735-1097(83)80040-0. PMID: 6343460
  102. 102. Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation. 1989 Aug;80(2):299-305. doi: 10.1161/01.cir.80.2.299. PMID: 2752558
  103. 103. Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure J Am Coll Cardiol. 2005 Nov 15;46(10):1785-1791. doi: 10.1016/j.jacc.2005.02.095. Epub 2005 Oct 21
  104. 104. Walker BR, Childs ME, Adams EM. Direct cardiac effects of vasopressin: role of V1- and V2-vasopressinergic receptors. Am J Physiol. 1988 Aug;255(2 Pt 2):H261–H265. doi: 10.1152/ajpheart.1988.255.2.H261. PMID: 2970231
  105. 105. Kaygisiz Z, Kabadere TE, Dernek S, Erden SH.The effects of vasopressin in isolated rat hearts. Indian J Physiol Pharmacol. 2001 Jan;45(1):54-62. PMID: 11211571
  106. 106. Briner VA, Tsai P, Choong HL, Schrier RW. Comparative effects of arginine vasopressin and oxytocin in cell culture systems. Am J Physiol. 1992 Aug;263(2 Pt 2):F222–F227. doi: 10.1152/ajprenal.1992.263.2.F222. PMID: 1510120
  107. 107. Nakamura Y, Haneda T, Osaki J, Miyata S, Kikuchi K. Hypertrophic growth of cultured neonatal rat heart cells mediated by vasopressin V(1A) receptor Eur J Pharmacol. 2000 Mar 10;391(1-2):39-48. doi: 10.1016/s0014-2999(99)00775-x. PMID: 10720633
  108. 108. Fukuzawa J, Haneda T, Kikuchi K. Arginine vasopressin increases the rate of protein synthesis in isolated perfused adult rat heart via the V1 receptor. Mol Cell Biochem. 1999 May;195(1-2):93-98. doi: 10.1023/a:1006980517557. PMID: 10395073
  109. 109. Xu DL, Martin PY, Ohara M, St John J, Pattison T, Meng X, et al. Upregulation of aquaporin-2 water channel expression in chronic heart failure rat. J Clin Invest. 1997 Apr 1;99(7):1500-1505. doi: 10.1172/JCI119312. PMID: 9119993
  110. 110. Schrier RW, Berl T, Anderson RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol. 1979 Apr;236(4):F321–F332. doi: 10.1152/ajprenal.1979.236.4.F321. PMID: 373467
  111. 111. Share L. Role of vasopressin in cardiovascular regulation. Physiol Rev. 1988 Oct;68(4):1248-1284. doi: 10.1152/physrev.1988.68.4.1248. PMID: 3054948
  112. 112. Goldsmith SR. Baroreflex loading maneuvers do not suppress increased plasma arginine vasopressin in patients with congestive heart failure. J Am Coll Cardiol. 1992 May;19(6):1180-1184. doi: 10.1016/0735-1097(92)90321-d. PMID: 1532971
  113. 113. Goldsmith SR, Francis GS, Cowley AW, Cohn N. Response of vasopressin and norepinephrine to lower body negative pressure in humans. Am J Physiol 1982; 243: H970
  114. 114. Goldsmith SR, Cowley AW, Francis GS, Cohn N. Effects of increased intracardiac and arterial pressure on plasma vasopressin in humans. Am J Physiol 1984; 246: H647
  115. 115. Szatalowicz VL, Arnold PE, Chaimovitz C, Bichet D, Berl T, Schrier RW. Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N Engl J Med. 1981 Jul 30;305(5):263-266. doi: 10.1056/NEJM198107303050506. PMID: 7242616
  116. 116. Riegger GA, Liebau G, Kochsiek K. Antidiuretic hormone in congestive heart failure. Am J Med. 1982 Jan;72(1):49-52. doi: 10.1016/0002-9343(82)90576-9. PMID: 7058822
  117. 117. Udelson JE, Smith WB, Hendrix GH, Painchaud CA, Ghazzi M, Thomas I, et al . Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation. 2001 Nov 13;104(20):2417-2423. doi: 10.1161/hc4501.099313. PMID: 11705818
  118. 118. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-1331. doi: 10.1001/jama.297.12.1319. Epub 2007 Mar 25. PMID: 17384437
  119. 119. de Bold AJ, Borenstein HB, Veress AT, et al. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci. 1981;28:89-94
  120. 120. Sudoh T, Kangawa K, Minamino N, et al. A new natriuretic peptide in porcine brain. Nature. 1988;332:78-81
  121. 121. Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006;27:47-72
  122. 122. Boerrigter G, Burnett JC., Jr Recent advances in natriuretic peptides in congestive heart failure. Expert Opin Investig Drugs. 2004;13:643-652
  123. 123. Zois NE, Bartels ED, Hunter I, et al. Natriuretic peptides in cardiometabolic regulation and disease. Nat Rev Cardiol. 2014;11:403-412. DOI: 10.1038/nrcardio.2014.64
  124. 124. Mangiafico S, Costello-Boerrigter LC, Andersen IA, et al. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J. 2013;34:886-93c. DOI: 10.1093/eurheartj/ehs262
  125. 125. Chen HH, Burnett JC., Jr Therapeutic potential for existing and novel forms of natriuretic peptides. Heart Fail Clin. 2006;2:365-373
  126. 126. Northridge DB, Newby DE, Rooney E, et al. Comparison of the short-term effects of candoxatril, an orally active neutral endopeptidase inhibitor, and frusemide in the treatment of patients with chronic heart failure. Am Heart J. 1999;138:1149-1157
  127. 127. Westheim AS, Bostrøm P, Christensen CC, et al. Hemodynamic and neuroendocrine effects for candoxatril and frusemide in mild stable chronic heart failure. J Am Coll Cardiol. 1999;34:1794-1801
  128. 128. Ando S, Rahman MA, Butler GC, et al. Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. Hypertension. 1995;26:1160-1166. DOI: 10.1161/01.HYP.26.6.1160
  129. 129. Corti R, Burnett JC, Jr, Rouleau JL, et al. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation. 2001;104:1856-1862. DOI: 10.1161/hc4001.097191
  130. 130. Margulies KB, Perrella MA, McKinley LJ, et al. Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure. J Clin Invest. 1991;88:1636-1642
  131. 131. Nathisuwan S, Talbert RL. A review of vasopeptidase inhibitors: a new modality in the treatment of hypertension and chronic heart failure. Pharmacotherapy. 2002;22:27-42
  132. 132. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106:920-926
  133. 133. Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema, Hypertension. 2008;51:141-147
  134. 134. Messerli FH, Nussberger J. Vasopeptidase inhibition and angio–oedema. Lancet. 2000;356:608-609
  135. 135. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30. PMID: 25176015
  136. 136. Francis SE, Holden H, Holt CM, Duff GW. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol. 1998 Feb;30(2):215-223. doi: 10.1006/jmcc.1997.0592. PMID: 9514998
  137. 137. Munger MA, Johnson B, Amber IJ, Callahan KS, Gilbert EM. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1996 Apr 1;77(9):723-727. doi: 10.1016/s0002-9149(97)89206-5. PMID: 8651123
  138. 138. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure N Engl J Med. 1990 Jul 26;323(4):236-241. doi: 10.1056/NEJM199007263230405. PMID: 2195340
  139. 139. Bozkurt B, Kribbs SB, Clubb FJ Jr, Michael LH, Didenko VV, Hornsby PJ, et al Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats Circulation. 1998 Apr 14;97(14):1382-1391. doi: 10.1161/01.cir.97.14.1382. PMID: 9577950
  140. 140. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, et al Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha Circ Res. 1997 Oct;81(4):627-635. doi: 10.1161/01.res.81.4.627. PMID: 9314845
  141. 141. Yokoyama T, Nakano M, Bednarczyk JL, McIntyre BW, Entman M, Mann DL Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes Circulation. 1997 Mar 4;95(5):1247-1252. doi: 10.1161/01.cir.95.5.1247. PMID: 9054856
  142. 142. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death J Clin Invest. 1996 Dec 15;98(12):2854-2865. doi: 10.1172/JCI119114. PMID: 8981934
  143. 143. Thaik CM, Calderone A, Takahashi N, Colucci WS.Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest. 1995 Aug;96(2):1093-1099. doi: 10.1172/JCI118095. PMID: 7635944
  144. 144. Sekiguchi K, Li X, Coker M, Flesch M, Barger PM, Sivasubramanian N, Mann DL Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure Cardiovasc Res. 2004 Aug 15;63(3):433-442. doi: 10.1016/j.cardiores.2004.02.005. PMID: 15276468
  145. 145. Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, et al Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alphaCirculation. 1998 Apr 14;97(14):1375-1381. doi: 10.1161/01.cir.97.14.1375. PMID: 9577949
  146. 146. Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation. 2001 Apr 24;103(16):2055-2059. doi: 10.1161/01.cir.103.16.2055. PMID: 11319194
  147. 147. Franco F, Thomas GD, Giroir B, Bryant D, Bullock MC, Chwialkowski MC, et al. Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation. 1999 Jan 26;99(3):448-454. doi: 10.1161/01.cir.99.3.448. PMID: 9918534
  148. 148. Seta Y, Shan K, Bozkurt B, Oral H, Mann DL. Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail. 1996 Sep;2(3):243-249. doi: 10.1016/s1071-9164(96)80047-9. PMID: 8891862
  149. 149. Murray DR, Prabhu SD, Chandrasekar B. Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation. 2000 May 23;101(20):2338-2341. doi: 10.1161/01.cir.101.20.2338. PMID: 10821806
  150. 150. Hernández-Presa M, Bustos C, Ortego M, Tuñon J, Renedo G, Ruiz-Ortega M, Egido J. Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis Circulation. 1997 Mar 18;95(6):1532-41. doi: 10.1161/01.cir.95.6.1532. PMID: 9118522
  151. 151. Brasier AR, Jamaluddin M, Han Y, Patterson C, Runge MS. Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-kappaB (NF-kappaB) transcription factor. Mol Cell Biochem. 2000 Sep;212(1-2):155-169. PMID: 11108147
  152. 152. Gullestad L, Aukrust P, Ueland T, Espevik T, Yee G, Vagelos R, et al Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol. 1999 Dec;34(7):2061-2067. doi: 10.1016/s0735-1097(99)00495-7. PMID: 10588224
  153. 153. Gurlek A, Kilickap M, Dincer I, Dandachi R, Tutkak H, Oral D. Effect of losartan on circulating TNFalpha levels and left ventricular systolic performance in patients with heart failure. J Cardiovasc Risk. 2001 Oct;8(5):279-282. doi: 10.1177/174182670100800506. PMID: 11702033
  154. 154. Prabhu SD, Chandrasekar B, Murray DR, Freeman GL. beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation. 2000 May 2;101(17):2103-9. doi: 10.1161/01.cir.101.17.2103.PMID: 10790354
  155. 155. Gullestad L, Ueland T, Brunsvig A, Kjekshus J, Simonsen S, Frøland SS, Aukrust P. Effect of metoprolol on cytokine levels in chronic heart failure--a substudy in the Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure (MERIT-HF). Am Heart J. 2001 Mar;141(3):418-421. doi: 10.1067/mhj.2001.112785. PMID: 11231439
  156. 156. Tsutamoto T, Wada A, Matsumoto T, Maeda K, Mabuchi N, Hayashi M, et al. Relationship between tumor necrosis factor-alpha production and oxidative stress in the failing hearts of patients with dilated cardiomyopathy.J Am Coll Cardiol. 2001 Jun 15;37(8):2086-92. doi: 10.1016/s0735-1097(01)01299-2. PMID: 11419892
  157. 157. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666-3670. doi: 10.1073/pnas.72.9.3666. PMID: 1103152
  158. 158. Old LJ. Tumor necrosis factor (TNF).Science. 1985 Nov 8;230(4726):630-632. doi: 10.1126/science.2413547. PMID: 2413547
  159. 159. Torre-Amione G, Kapadia S, Lee J, Bies RD, Lebovitz R, Mann DL. Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation. 1995 Sep 15;92(6):1487-1493. doi: 10.1161/01.cir.92.6.1487. PMID: 7664431
  160. 160. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation. 1996 Feb 15;93(4):704-711. doi: 10.1161/01.cir.93.4.704. PMID: 8640999
  161. 161. Oral H, Dorn GW 2nd, Mann DL. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte.J Biol Chem. 1997 Feb 21;272(8):4836-4842. doi: 10.1074/jbc.272.8.4836. PMID: 9030540
  162. 162. Nakano M, Knowlton AA, Dibbs Z, Mann DL. Tumor necrosis factor-alpha confers resistance to hypoxic injury in the adult mammalian cardiac myocyte. Circulation. 1998 Apr 14;97(14):1392-1400. doi: 10.1161/01.cir.97.14.1392. PMID: 9577951
  163. 163. Ferrari R, Bachetti T, Confortini R, Opasich C, Febo O, Corti A, et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation. 1995 Sep 15;92(6):1479-1486. doi: 10.1161/01.cir.92.6.1479. PMID: 7664430
  164. 164. Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation. 2000 Dec 19;102(25):3060-3067. doi: 10.1161/01.cir.102.25.3060. PMID: 11120695
  165. 165. Kubota T, Miyagishima M, Alvarez RJ, Kormos R, Rosenblum WD, Demetris AJ, et al. Expression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failure Heart Lung Transplant. 2000 Sep;19(9):819-824. doi: 10.1016/s1053-2498(00)00173-x. PMID: 11008069
  166. 166. Sivasubramanian N, Coker ML, Kurrelmeyer KM, MacLellan WR, DeMayo FJ, Spinale FG, Mann DL.Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation. 2001 Aug 14;104(7):826-831. doi: 10.1161/hc3401.093154. PMID: 11502710
  167. 167. Bradham WS, Bozkurt B, Gunasinghe H, Mann D, Spinale FG. Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective. Cardiovasc Res. 2002 Mar;53(4):822-830. doi: 10.1016/s0008-6363(01)00503-x. PMID: 11922892
  168. 168. Funakoshi H, Kubota T, Machida Y, Kawamura N, Feldman AM, Tsutsui H, et al. Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha. Am J Physiol Heart Circ Physiol. 2002 Jun;282(6):H2159–H2166. doi: 10.1152/ajpheart.00872.2001. PMID: 12003824
  169. 169. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res. 2000 Aug 4;87(3):241-247. doi: 10.1161/01.res.87.3.241. PMID: 10926876
  170. 170. Gurantz D, Cowling RT, Villarreal FJ, Greenberg BH. Tumor necrosis factor-alpha upregulates angiotensin II type 1 receptors on cardiac fibroblasts. Circ Res. 1999 Aug 6;85(3):272-279. doi: 10.1161/01.res.85.3.272. PMID: 10436170
  171. 171. Cowling RT, Gurantz D, Peng J, Dillmann WH, Greenberg BH. Transcription factor NF-kappa B is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factor-alpha or interleukin-1 beta. J Biol Chem. 2002 Feb 22;277(8):5719-5724. doi: 10.1074/jbc.M107515200. Epub 2001 Oct 12. PMID: 11600498
  172. 172. Flesch M, Höper A, Dell'Italia L, Evans K, Bond R, Peshock R,et al. Activation and functional significance of the renin-angiotensin system in mice with cardiac restricted overexpression of tumor necrosis factor. Circulation. 2003 Aug 5;108(5):598-604. doi: 10.1161/01.CIR.0000081768.13378.BF. Epub 2003 Jul 21. PMID: 12874189
  173. 173. Jaffré F, Callebert J, Sarre A, Etienne N, Nebigil CG, Launay JM, et al. Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts. Circulation. 2004 Aug 24;110(8):969-974. doi: 10.1161/01.CIR.0000139856.20505.57. Epub 2004 Aug 9. PMID: 15302781
  174. 174. Herskowitz A, Choi S, Ansari AA, Wesselingh S Cytokine mRNA expression in postischemic/reperfused myocardium Am J Pathol. 1995 Feb;146(2):419-28.PMID: 7856752
  175. 175. Siwik DA, Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium. Heart Fail Rev. 2004 Jan;9(1):43-51. doi: 10.1023/B:HREV.0000011393.40674.13. PMID: 14739767
  176. 176. Long CS. The role of interleukin-1 in the failing heart. Heart Fail Rev. 2001 Mar;6(2):81-94. doi: 10.1023/a:1011428824771. PMID: 11309527
  177. 177. Patten M, Hartogensis WE, Long CS. Interleukin-1beta is a negative transcriptional regulator of alpha1-adrenergic induced gene expression in cultured cardiac myocytes. J Biol Chem. 1996 Aug 30;271(35):21134-21141. doi: 10.1074/jbc.271.35.21134. PMID: 8702883
  178. 178. Palmer JN, Hartogensis WE, Patten M, Fortuin FD, Long CS Interleukin-1 beta induces cardiac myocyte growth but inhibits cardiac fibroblast proliferation in culture J Clin Invest. 1995 Jun;95(6):2555-2564. doi: 10.1172/JCI117956. PMID: 7769098
  179. 179. Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol. 1998 Feb;31(2):391-398. doi: 10.1016/s0735-1097(97)00494-4. PMID: 9462584
  180. 180. Nicol RL, Frey N, Pearson G, Cobb M, Richardson J, Olson EN. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. EMBO J. 2001 Jun 1;20(11):2757-2767. doi: 10.1093/emboj/20.11.2757. PMID: 11387209
  181. 181. Kato T, Sano M, Miyoshi S, Sato T, Hakuno D, Ishida H, et al Calmodulin kinases II and IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats Circ Res. 2000 Nov 10;87(10):937-945. doi: 10.1161/01.res.87.10.937. PMID: 11073891
  182. 182. Wollert KC, Taga T, Saito M, Narazaki M, Kishimoto T, Glembotski CC, et al Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways J Biol Chem. 1996 Apr 19;271(16):9535-9545. doi: 10.1074/jbc.271.16.9535. PMID: 8621626
  183. 183. Balligand JL, Cannon PJ. Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):1846-58. doi: 10.1161/01.atv.17.10.1846 PMID: 9351345
  184. 184. Sawyer DB, Colucci WS. Nitric oxide in the failing myocardium. Cardiol Clin. 1998 Nov;16(4):657-664, viii. doi: 10.1016/s0733-8651(05)70042-4. PMID: 9891595
  185. 185. Feron O, Belhassen L, Kobzik L, Smith TW, Kelly RA, Michel T. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem. 1996 Sep 13;271(37):22810-22814. doi: 10.1074/jbc.271.37.22810. PMID: 8798458
  186. 186. Fukuchi M, Hussain SN, Giaid A. Heterogeneous expression and activity of endothelial and inducible nitric oxide synthases in end-stage human heart failure: their relation to lesion site and beta-adrenergic receptor therapy Circulation. 1998 Jul 14;98(2):132-9. doi: 10.1161/01.cir.98.2.132.PMID: 9679719
  187. 187. Haywood GA, Tsao PS, von der Leyen HE, Mann MJ, Keeling PJ, Trindade PT, et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation. 1996 Mar 15;93(6):1087-1094. doi: 10.1161/01.cir.93.6.1087. PMID: 8653828
  188. 188. Patten RD, Denofrio D, El-Zaru M, Kakkar R, Saunders J, Celestin F, et al. Ventricular assist device therapy normalizes inducible nitric oxide synthase expression and reduces cardiomyocyte apoptosis in the failing human heart. J Am Coll Cardiol. 2005 May 3;45(9):1419-1424. doi: 10.1016/j.jacc.2004.05.090. PMID: 15862412
  189. 189. Mungrue IN, Gros R, You X, Pirani A, Azad A, Csont T, et al. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest. 2002 Mar;109(6):735-743. doi: 10.1172/JCI13265. PMID: 11901182
  190. 190. Heger J, Gödecke A, Flögel U, Merx MW, Molojavyi A, Kühn-Velten WN, Schrader J. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res. 2002 Jan 11;90(1):93-99. doi: 10.1161/hh0102.102757. PMID: 11786524
  191. 191. Sam F, Sawyer DB, Xie Z, Chang DL, Ngoy S, Brenner DA,et ak. Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction. Circ Res. 2001 Aug 17;89(4):351-356. doi: 10.1161/hh1601.094993. PMID: 11509452
  192. 192. Parrillo JE, Cunnion RE, Epstein SE, Parker MM, Suffredini AF, Brenner M, et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med. 1989 Oct 19;321(16):1061-1068. doi: 10.1056/NEJM198910193211601. PMID: 2677721
  193. 193. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340:253-259
  194. 194. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999;130:478-486
  195. 195. Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:644-659
  196. 196. Mease PJ. Tumor necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors. Ann Rheum Dis. 2002;61:298-304
  197. 197. Kapadia S, Torre-Amione G, Yokoyama T, Mann DL. Soluble TNF binding proteins modulate the negative inotropic properties of TNF-alpha in vitro. Am J Physiol. 1995 Feb;268(2 Pt 2):H517–H525. doi: 10.1152/ajpheart.1995.268.2.H517. PMID: 7864177
  198. 198. Deswal A, Bozkurt B, Seta Y, Parilti-Eiswirth S, Hayes FA, Blosch C, Mann DL Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure Circulation. 1999 Jun 29;99(25):3224-6. doi: 10.1161/01.cir.99.25.3224.PMID: 10385494
  199. 199. Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure Circulation . 2001 Feb 27;103(8):1044-1047. doi: 10.1161/01.cir.103.8.1044. PMID: 11222463
  200. 200. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure.J Card Fail. 2001 Jun;7(2):176-182. doi: 10.1054/jcaf.2001.25652. PMID: 11420770
  201. 201. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, et al Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004 Apr 6;109(13):1594-1602. doi: 10.1161/01.CIR.0000124490.27666.B2. Epub 2004 Mar 15. PMID: 15023878
  202. 202. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003 Jul 1;107(25):3133-40. doi: 10.1161/01.CIR.0000077913.60364.D2. Epub 2003 Jun 9. PMID: 12796126
  203. 203. Dwyer JM. Manipulating the immune system with immune globulin.N Engl J Med. 1992;326:107-116
  204. 204. Mobini N, Sarela A, Ahmed AR. Intravenous immunoglobulins in thetherapy of autoimmune and systemic inflammatory disorders.Ann AllergyAsthma Immunol. 1995;74:119-128
  205. 205. McNamara DM, Holubkov R, Starling RC, Dec GW, Loh E, Torre-Amione G, et al .Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy.Circulation. 2001 May 8;103(18):2254-2259. doi: 10.1161/01.cir.103.18.2254. PMID: 11342473
  206. 206. Gullestad L, Aass H, Fjeld JG, Wikeby L, Andreassen AK, Ihlen H, et al. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation. 2001 Jan 16;103(2):220-225. doi: 10.1161/01.cir.103.2.220. PMID: 11208680
  207. 207. Takimoto E, Kass DA.Role of oxidative stress in cardiac hypertrophyand remodeling.Hypertension 49: 241-248, 2007
  208. 208. Beckman JS, Beckman TW, J. Chen J, et al. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620-1624. doi: 10.1073/pnas.87.4.1620
  209. 209. Chen CA, Wang TY, Varadharaj S, et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature. 2010 Dec 23;468(7327):1115-1118.doi: 10.1038/nature09599
  210. 210. Elahi MM, Kong YX, Matata BM. Oxidative stress as a mediator of cardiovascular disease. Oxid Med Cell Longev. Nov-Dec 2009;2(5):259-269. doi: 10.4161/oxim.2.5.9441
  211. 211. Díaz-Vélez CR, García-Castiñeiras S, Mendoza-Ramos E, Hernández-López E. Increased malondialdehyde in peripheral blood of patients with congestive heart failure. Am Heart J. 1996 Jan;131(1):146-152. doi: 10.1016/s0002-8703(96)90063-0
  212. 212. Tang WH, Brennan ML, Philip K, Tong W, Mann S, Van Lente F, et al. Plasma myeloperoxidase levels in patients with chronic heart failure. Am J Cardiol. 2006 Sep 15;98(6):796-799. doi: 10.1016/j.amjcard.2006.04.018. Epub 2006 Jul 28
  213. 213. Mak S, Lehotay DC, Yazdanpanah M, Azevedo ER, Liu PP, Newton GE.Unsaturated aldehydes including 4-OH-nonenal are elevated in patients with congestive heart failure. J Card Fail. 2000 Jun;6(2):108-14.PMID: 10908084
  214. 214. Sakai H, Tsutamoto T, Tsutsui T, Tanaka T, Ishikawa C, Horie M. Serum level of uric acid, partly secreted from the failing heart, is a prognostic marker in patients with congestive heart failure. Circ J. 2006 Aug;70(8):1006-1011. doi: 10.1253/circj.70.1006. PMID: 16864933
  215. 215. Kittleson MM, St John ME, Bead V, Champion HC, Kasper EK, Russell SD, et al. Increased levels of uric acid predict haemodynamic compromise in patients with heart failure independently of B-type natriuretic peptide levels. Heart. 2007 Mar;93(3):365-367. doi: 10.1136/hrt.2006.090845. PMID: 17322514
  216. 216. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation. 2003 Apr 22;107(15):1991-1997. doi: 10.1161/01.CIR.0000065637.10517.A0. Epub 2003 Apr 21. PMID: 12707250
  217. 217. Sabri A, Hughie HH, Lucchesi PA.Regulation of hypertrophic andapoptotic signaling pathways by reactive oxygen species in cardiacmyocytes.Antioxid Redox Signal 5: 731-740, 2003
  218. 218. Cesselli D, Jakoniuk I, Barlucchi L, Beltrami AP, Hintze TH, Nadal-Ginard B, Kajstura J, Leri A, Anversa P.Oxidative stress-mediatedcardiac cell death is a major determinant of ventricular dysfunction andfailure in dog dilated cardiomyopathy. Circ Res. 2001; 89: 279-286
  219. 219. Xiao CY, Chen M, Zsengellér Z, Li H, Kiss L, Kollai M, Szabó C. Poly(ADP-Ribose) polymerase promotes cardiac remodeling, contractile failure, and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure. J Pharmacol Exp Ther. 2005 Mar;312(3):891-898. doi: 10.1124/jpet.104.077164. Epub 2004 Nov 2. PMID: 15523000
  220. 220. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R,Hebbar L.Time-dependent changes in matrix metalloproteinase activityand expression during the progression of congestive heart failure: relationto ventricular and myocyte function.Circ Res. 1998; 82: 482-495
  221. 221. Creemers EE, Cleutjens JP, Smits JF, Daemen MJ.Matrix metallo-proteinase inhibition after myocardial infarction: a new approach toprevent heart failure? Circ Res. 2001; 89: 201-210
  222. 222. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS.Reactive oxygen species produced by macrophage-derived foam cellsregulate the activity of vascular matrix metalloproteinases in vitro.Implications for atherosclerotic plaque stability.J Clin Invest. 1996; 98: 2572-2579
  223. 223. Lim H, Zhu YZ. Role of transforming growth factor-beta in the progression of heart failure. Cell Mol Life Sci. 2006 Nov;63(22):2584-96. doi: 10.1007/s00018-006-6085-8.PMID: 17013566
  224. 224. Purnomo Y, Piccart Y, Coenen T, Prihadi JS, Lijnen PJ. Oxidative stress and transforming growth factor-beta1-induced cardiac fibrosis.Cardiovasc Hematol Disord Drug Targets. 2013 Aug;13(2):165-72. doi: 10.2174/1871529x11313020010.PMID: 23988004
  225. 225. Luo G, Wang R, Zhou H, Liu X. ALDOA protects cardiomyocytes against H/R-induced apoptosis and oxidative stress by regulating the VEGF/Notch 1/Jagged 1 pathway. Mol Cell Biochem. 2020 Oct 21. doi: 10.1007/s11010-020-03943-z. Online ahead of print. PMID: 33089381
  226. 226. Moore JB 4th, Zhao J, Fischer AG, Keith MCL, Hagan D, Wysoczynski M, Bolli R. Histone Deacetylase 1 Depletion Activates Human Cardiac Mesenchymal Stromal Cell Proangiogenic Paracrine Signaling Through a Mechanism Requiring Enhanced Basic Fibroblast Growth Factor Synthesis and Secretion. J Am Heart Assoc. 2017 Jul 5;6(7):e006183. doi: 10.1161/JAHA.117.006183.PMID: 28679560
  227. 227. Belviso I, Angelini F, Di Meglio F, Picchio V, Sacco AM, Nocella C,et al .The Microenvironment of Decellularized Extracellular Matrix from Heart Failure Myocardium Alters the Balance between Angiogenic and Fibrotic Signals from Stromal Primitive Cells. Int J Mol Sci. 2020 Oct 24;21(21):7903. doi: 10.3390/ijms21217903.PMID: 33114386
  228. 228. Cheng TH, Shih NL, Chen SY, et al. Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells. J. Mol. Cell. Cardiol. 2001;33:1805-1814. doi: 10.1006/jmcc.2001.1444
  229. 229. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000 Mar 17;86(5):494-501. doi: 10.1161/01.res.86.5.494. PMID: 10720409
  230. 230. Packer M. Mutual Antagonism of Hypoxia-Inducible Factor Isoforms in Cardiac, Vascular, and Renal Disorders. JACC Basic Transl Sci. 2020 Sep 28;5(9):961-968. doi: 10.1016/j.jacbts.2020.05.006. eCollection 2020 Sep.PMID: 33015417
  231. 231. Zima AV, Blatter LA.Redox regulation of cardiac calcium channelsand transporters.Cardiovasc Res. 2006; 71: 310-321
  232. 232. Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K,Utsumi H, Hamasaki N, Takeshita A. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 88: 529-535, 2001
  233. 233. Schmelzer C, Döring F. Micronutrient special issue: coenzyme Q(10) requirements for DNA damage prevention. Mutat Res. 2012;733:61-68. doi: 10.1016/j.mrfmmm.2011.09.004
  234. 234. Fotino AD, Thompson-Paul AM, Bazzano LA. Effect of coenzyme Q10 supplementation on heart failure: a meta-analysis. Am J Clin Nutr. 2013;97:268-275. doi: 10.3945/ajcn.112.040741
  235. 235. Madmani ME, Yousuf SA, Tamr AK, Madmani Y, Shahrour Y, Essali A, Kadro W. Coenzyme Q10 for heart failure (Review). Cochrane Review. 2013:1-35
  236. 236. Mortensen SA, Rosenfeldt F, Kumar A, Dolliner P, Filipiak KJ, Pella D, Alehagen U, Steurer G, Littarru GP; Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2014;2:641-649. doi: 10.1016/j.jchf.2014.06.008
  237. 237. Archer SL, Nelson DP, Weir EK. Detection of activated O2 species in vitro and in rat lungs by chemiluminescence. J Appl Physiol (1985). 1989;67:1912-1921. doi: 10.1152/jappl.1989.67.5.1912
  238. 238. Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006;58:87-114
  239. 239. Ogino K, Kato M, Furuse Y, Kinugasa Y, Ishida K, Osaki S, Kinugawa T, Igawa O, Hisatome I, Shigemasa C, Anker SD, Doehner W. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail. 2010;3:73-81. doi: 10.1161/CIRCHEARTFAILURE.109.868604
  240. 240. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J. 1997;18:858-865
  241. 241. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, Anand I, Maggioni A, Burton P, Sullivan MD, Pitt B, Poole-Wilson PA, Mann DL, Packer M. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113:1424-1433. doi: 10.1161/CIRCULATIONAHA.105.584102
  242. 242. Poss WB, Huecksteadt TP, Panus PC, et al. Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia. Am J Physiol Lung Cell Mol Physiol. 1996; 270: L941–L946
  243. 243. Engerson TD, McKelvey TG, Rhyne DB, et al. Conversion of xanthine dehydrogenase to oxidase in ischemic rat tissues. J Clin Invest. 1987; 79: 1564-1570
  244. 244. Pritsos CA. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. Chem Biol Interact. 2000; 129: 195-208
  245. 245. Houston M, Estevez A, Chumley P, et al. Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem. 1999; 274: 4985-4994
  246. 246. Givertz MM, Anstrom KJ, Redfield MM et al Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure PatientsThe Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study. Circulation. 2015;131:1763-1771. DOI: 10.1161/CIRCULATIONAHA.114.014536

Written By

Ronald Zolty

Submitted: 15 October 2020 Reviewed: 19 March 2021 Published: 27 October 2021