Atrial fibrillation (AF), a common arrhythmia, can cause many serious consequences, including stroke and even death. The pathological mechanism of AF is very complicated. Epigenetic mechanisms, especially DNA methylation, contribute to the pathogenesis and maintenance of AF. DNA methylation is an important part of epigenetic and plays a significant role in human physiology and pathology. AF patients possess specific methylation sites (e.g., Pitx2c, RASSF1A, SURs, SERCA2a, and LINC00472), which have potential values of being biomarkers and underlie the diagnosis and prognosis of AF. These methylation sites can also benefit accurate treatment of AF. With deeper understanding into the epigenetic mechanisms of AF, the precision medicine for AF has also developed rapidly. In the future, DNA methylation omics and other research methods will be integrated to explore the epigenetic mechanisms in AF.

Myocardial fibrosis is a critical event during septic shock. Upregulation in the fibrosis signaling cascade proteins such as fibroblast growth factor (FGF), urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA) and activation of matrix metalloproteinases (MMPs) are widely associated with the development of myocardial infarction, dilated cardiomyopathy, cardiac fibrosis and heart failure. However, evidences suggest that the common upstream mediators of fibrosis cascade play little role in cardiac fibrosis induced by LPS; further, it is unknown if LPS directly triggers the expressions and/or activity of FGF-2, uPA, tPA, MMP-2 and MMP-9 in cardiac fibroblasts. In the present study, we treated primary cultures of cardiac fibroblasts with LPS to explore whether LPS upregulates FGF-2, uPA, tPA, MMP-2, MMP-9 and enhance cellular migration. Further the precise molecular and cellular mechanisms behind these LPS induced responses were identified. Inhibition assays on MAPKs using U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor) and QNZ (NFκB inhibitor) show that LPS-induced upregulation of FGF-2, uPA, MMP-2 and MMP-9 in cardiac fibroblasts was mediated through ERK1/2 signaling. Collectively, our results provide a link between LPS-induced cardiac dysfunction and ERK1/2 signaling pathway and thereby implies ERK1/2 as a possible target to regulate LPS induced upregulation of FGF-2, uPA, MMP-2, MMP-9 and cellular migration in cardiac fibroblasts.

To evaluate the effect of norepinephrine on inflammatory cytokine expression in ex vivo human monocytes and monocytic THP-1 cells.

For human monocyte studies, cells were isolated from 12 chronic heart failure (HF) (66 ± 12 years, New York Heart Association functional class III-IV, left ventricular ejection fraction 22% ± 9%) and 14 healthy subjects (66 ± 12 years). Monocytes (1 × 106/mL) were incubated with lipopolysaccharide (LPS) 100 ng/mL, LPS + norepinephrine (NE) 10-6 mol/L or neither (control) for 4 h. Tumor necrosis factor-alpha (TNFα) and interleukin-10 (IL-10) production were determined by ELISA. Relative contribution of α- and β-adrenergic receptor subtypes on immunomodulatory activity of NE was assessed in LPS-stimulated THP-1 cells incubated with NE, the α-selective agonist phenylephrine (PE), and the β-selective agonist isoproterenol (IPN). NE-pretreated THP-1 cells were also co-incubated with the β-selective antagonist propranolol (PROP), α2-selective antagonist yohimbine (YOH) or the α1-selective antagonist prazosin (PRAZ).

Basal TNFα concentrations were higher in HF vs healthy subjects (6.3 ± 3.3 pg/mL vs 2.5 ± 2.6 pg/mL, P = 0.004). Norepinephrine's effect on TNFα production was reduced in HF (-41% ± 17% HF vs -57% ± 9% healthy, P = 0.01), and proportionately with NYHA FC. Increases in IL-10 production by NE was also attenuated in HF (16% ± 18% HF vs 38% ± 23% healthy, P = 0.012). In THP-1 cells, NE and IPN, but not PE, induced a dose-dependent suppression of TNFα. Co-incubation with NE and antagonists revealed a dose-dependent inhibition of the NE suppression of TNFα by PROP, but not by YOH or PRAZ. Dose-dependent increases in IL-10 production were seen with NE and IPN, but not with PE. This effect was also antagonized by PROP but not by YOH or PRAZ. Pretreatment of cells with IPN attenuated the effects of NE and IPN, but did not induce a response to PE.

NE regulation of monocyte inflammatory cytokine production may be reduced in moderate-severe HF, and may be mediated through β-adrenergic receptors.

Venous congestion and endothelial and neurohormonal activation are known to occur in acute decompensated heart failure (ADHF), yet the temporal role of these processes in the pathophysiology of decompensation is not fully understood. Conventional wisdom presumes congestion to be a consequence of worsening cardiovascular function; however, the biomechanically driven effects of venous congestion are biologically plausible contributors to ADHF that remain largely unexplored in vivo. Recent experimental evidence from human models suggests that fluid accumulation and venous congestion are not simply consequences of poor cardiovascular function, but rather are fundamental pro-oxidant, pro-inflammatory, and hemodynamic stimuli that contribute to acute decompensation. The latest advances in the monitoring of volume status using implantable devices allow for the detection of venous congestion before symptoms arise. This may ultimately lead to improved treatment strategies including not only diuretics, but also specific, adjuvant interventions to counteract endothelial and neurohormonal activation during early preclinical decompensation.

Volume overload and venous congestion are typically viewed as a consequence of advanced and of acute heart failure (HF) and renal failure (RF) although it is possible that hypervolaemia itself might be a critical intermediate in the pathophysiology of these diseases. This study aimed at elucidating whether peripheral venous congestion is sufficient to promote changes in inflammatory, neurohormonal, and endothelial phenotype similar to those observed in HF and RF.

To experimentally model peripheral venous congestion, we developed a new method (so-called venous stress test) and applied the methodology on 24 healthy subjects (14 men, age 35 ± 2 years). Venous arm pressure was increased to ∼30 mmHg above the baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 min of venous congestion, using angiocatheters and endovascular wires. Magnetic beads coated with EC-specific antibodies were used for EC separation; amplified mRNA was analysed by Affymetrix HG-U133 Plus 2.0 Microarray.

Plasma interleukin-6 (IL-6), endothelin-1 (ET-1), angiotensin II (AII), vascular cell adhesion molecule-1 (VCAM-1), and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. A total of 3437 mRNA probe sets were differentially expressed (P < 0.05) in venous ECs before vs. after testing, including ET-1, VCAM-1, and CXCL2.

Peripheral venous congestion causes release of inflammatory mediators, neurohormones, and activation of ECs. Overall, venous congestion mimicked, notable aspects of the phenotype typical of advanced and of acute HF and RF.

Toll-like receptors (TLRs) are important in a variety of inflammatory diseases including acute cardiac disorders. TLR4 innate signaling regulates the synthesis of anti-inflammatory cytokine, interleukin-10 (IL-10) upon TLR4 agonists' re-stimulation. Anti-apoptotic action of IL-10 in cardiac dysfunction is generally accepted but its protective mechanism through TLR4 is not yet understood. We studied the effect of IL-10 in the activation of TLR4 downstream signals leading to cardiomyocytes survival. IL-10 caused a significant increase in the expression of CD14, MyD88 and TLR4. TLR4 activation led to the translocation of the interferon regulatory factor 3 (IRF3) into the nucleus. Phosphorylation of IRF3 enhanced mRNA synthesis for IL-1β but not TNF-α and was elevated even after removal of IL-10 stimulation. Furthermore, degradation of inhibitory kappa B (IκB) kinase (Ikk) suggested that IκBβ was the main activating kinase for IRF3-regulated NF-κB activation and phosphorylation of p65. Phosphorylated NF-κB p65 was translocated into the nucleus. Concomitantly, an increase in Bcl-xL activity inhibited Bax and the proteolytic activity of caspase 3 as well as a decrease in PARP cleavage. An inhibition of MyD88, modulated the above listed responses to IL-10 as there was a decrease in TLR4 and IRF3 and an increase in TNF-α mRNA. This was associated with a decrease in NF-κB p65, Bcl-xL mRNA and protein levels as well as there was an activation of Bax and PARP cleavage independent of caspase 3 activation. These data in cardiomyocytes suggest that IL-10 induced anti-apoptotic signaling involves upregulation of TLR4 through MyD88 activation.

We have already reported that TNF-α increases cardiomyocyte apoptosis and IL-10 treatment prevented these effects of TNF-α. Present study investigates the role of Akt and Jak/Stat pathway in the IL-10 modulation of TNF-α induced cardiomyocyte apoptosis.

Cardiomyocytes isolated from adult Sprague Dawley rats were exposed to TNF-α (10 ng/ml), IL-10 (10 ng/ml) and TNF-α+IL-10 (ratio 1) for 4 h. Exposure to TNF-α resulted in an increase in cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay. IL-10 by itself had no effect, but it prevented TNF-α induced apoptosis. IL-10 treatment increased Akt levels within cardiomyocytes and this change was associated with an increase in Jak1 and Stat3 phosphorylation. Pre-exposure of cells to Akt inhibitor prevented IL-10 induced Stat3 phosphorylation. Furthermore, in the presence of Akt or Stat3 inhibitor, IL-10 treatment was unable to block TNF-α induced cardiomyocyte apoptosis.

It is suggested that IL-10 modulation of TNF-α induced cardiomyocyte apoptosis is mediated by Akt via Stat3 activation.

This study was designed to assess the effects of dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) from fish oil on the response of doxorubicin-induced chronic heart failure in rats. Male Sprague-Dawley rats were treated daily for 8 weeks with normal saline or n-3 PUFA intragastrically after induction of myocardial injury by intraperitoneal injection of doxorubicin 2 mg/kg once weekly for 8 weeks. Cardiac function was assessed by echocardiography. The cytoprotective role of n-3 PUFA against doxorubicin-induced myocardial injury was demonstrated by light microscopy, and serum cytokines (tumour necrosis factor-alpha and interleukin-10) were analysed by enzyme-linked immunosorbent assay. Doxorubicin induced death, alterations in echocardiography parameters and histological damage, all of which are features that characterize heart failure. There were significant differences between the doxorubicin-induced heart failure group and the n-3 PUFA-treated group in terms of echocardiography parameters and cytokine changes. Thus, dietary supplementation with n-3 PUFA attenuated doxorubicin-induced cardiac dysfunction, an effect that might be associated with recovery from an imbalance of the cytokine network.

Severe and potentially fatal hypotension and cardiac contractile dysfunction are common symptoms in patients with sepsis. In our previous study, we found that estradiol and estrogen-receptor alpha have cardio-protective effects in myocardial cells exposed to LPS. Estradiol supplementation has been shown to induce breast and cervical cancers. Flos Carthami, the flower of Carthamus tinctorius L. (Compositae) is an important traditional Chinese medicine used for the treatment of heart disease and inflammation, and therefore might be a potential alternative to Estradiol in the prevention of heart damage. This study investigated the effect of Flos Carthami (FC(EtOH)) ethanolic extract on LPS-induced apoptosis in H9c2 cardiomyoblast cells.

H9c2 cells induced apoptosis with LPS administration (1 microg/mL). H9c2 cells were divided into five groups: Control, LPS (1 microg/mL), and three FC(EtOH) (31.25, 62.5,and 125 microg/mL). We detected apoptosis using MTT, LDH, TUNEL assay. JC-1 staining and Western blot were used to detect pro-apoptosis proteins, anti-apoptosis proteins, MAPK proteins (JNK, ERK, and P38), and NFkappaB expression.

FC(EtOH) (62.5 microg/mL) inhibited LPS-induced apoptosis by suppressing JNK1/2 activity, which resulted in the reduction of both IkappaB degradation and NFkappaB activation. In addition, FC(EtOH) led to the activation of anti-apoptotic proteins, Bcl-2 and Bcl-xL, the stabilization of the mitochondria membrane and the down-regulation of extrinsic and intrinsic pro-apoptotic proteins, such as TNFalpha, active caspase-8, t-Bid, Bax, active caspases-9, and -3.

Carthamus tinctorius L. possesses the ability to suppress JNK activity and inhibit LPS-induced TNFalpha activation and apoptosis in H9c2 cardiomyoblast cells. Carthamus tinctorius L could potentially serve as a cardio-protective agent against LPS-induced apoptosis.

Sarcoplasmic reticulum Ca-ATPases (SERCA2a) plays an essential role in the Ca homeostasis and cardiac functions. Tumor necrosis factor-alpha (TNF-alpha) decreases the SERCA2a, which may underlie cardiac dysfunction during sepsis and heart failure. Because the promoter region of SERCA2a contains CpG islands, gene methylation should be critical in regulating SERCA2a. The present study was to evaluate whether TNF-alpha can modulate SERCA2a via enhancing methylation and to investigate the underlying mechanisms.

Controlled laboratory experiment.

University research laboratory.

HL-1 cardiomyocytes.

TNF-alpha (1-50 ng/mL) was administered in HL-1 cardiomyocytes with and without co-administration of an NF-kappaB inhibitor (SN-50, 50 microg/mL), antioxidant agents (ascorbic acid, 100 microM, or coenzyme Q10, 10 microM), or methylation inhibitor (5-aza-2'-deoxycytidine, 0.1, 1 microM).

TNF-alpha (50 ng/mL) decreased the SERCA2a RNA and protein by quantitative polymerase chain reaction and immunoblot. Furthermore, TNF-alpha (50 ng/mL) increased the methylation in the SERCA2a promoter region, which was not influenced by the co-administration of SN-50, ascorbic acid, or coenzyme Q10, but was attenuated by 5-aza-2'-deoxycytidine (0.1 microM). Additionally, TNF-alpha (50 ng/mL) increased the expression of DNA methyltransferase 1.

TNF-alpha increased DNA methyltransferase levels, thus enhancing the methylation in the SERCA2a promoter region with a result of reducing SERCA2a. These findings suggest that inhibition of hypermethylation may be a novel treatment strategy for cardiac dysfunction.

Cardiomyocyte death caused by proinflammatory cytokines, such as Tumor necrosis factor alpha (TNF-alpha), is one of the hot topics in cardiovascular research. TNF-alpha can induce multiple cell processes that are dependent on the treatment time although the long-term treatment definitely leads to cell death. The ability to intervene in cell death will be invaluable to reveal the effects of short-term TNF-alpha treatment to cardiomyocytes. However, a real-time monitoring technique is needed to guide the intervention of cell responses. In this work, we employed the impedance-sensing technique to real-time monitor the equivalent cell-substrate distance of cardiomyocytes via electrochemical impedance spectroscopy (EIS) and electrical cell-substrate impedance sensing (ECIS). In the stabilized cardiomyocyte culture, the sustained TNF-alpha treatment caused strengthened cell adhesion in the first 2 h which was followed by the transition to cell detachment afterwards. Considering cell detachment was an early morphological evidence of cell death, we removed TNF-alpha from the cardiomyocyte culture before the transition to achieve the intervention of cell responses. The result of this intervention showed that cell adhesion was continuously strengthened before and after the removal of TNF-alpha, indicating the short-term treated cardiomyocytes did not undergo death processes. It was also demonstrated in TUNEL and TBE tests that the percentages of apoptosis and cell death were both lowered.

Heart failure (HF) is a complex clinical syndrome with multiple aetiologies. Current treatment options can slow the progression to HF, but overall the prognosis remains poor. Clinical studies suggest that high dietary intake of the omega-3 polyunsaturated fatty acids (omega-3PUFA) found in fish oils (eicosapentaenoic and docosahexaenoic acids) may lower the incidence of HF, and that supplementation with pharmacological doses prolongs event-free survival in patients with established HF. The mechanisms for these potential benefits are complex and not well defined. It is well established that fish oil supplementation lowers plasma triglyceride levels, and more recent work demonstrates anti-inflammatory effects, including reduced circulating levels of inflammatory cytokines and arachidonic acid-derived eicosanoids, and elevated plasma adiponectin. In animal studies, fish oil favourably alters cardiac mitochondrial function. All of these effects may work to prevent the development and progression of HF. The omega-3PUFA found in plant sources, alpha-linolenic acid, may also be protective in HF; however, the evidence is not as compelling as for fish oil. This review summarizes the evidence related to use of omega-3PUFA supplementation as a potential treatment for HF and discusses possible mechanisms of action. In general, there is growing evidence that supplementation with omega-3PUFA positively impacts established pathophysiological targets in HF and has potential therapeutic utility for HF patients.

Nutrition impairment commonly occurs in patients with heart failure and affects disease progression. Vitamin and mineral deficiencies are associated with early mortality, particularly in patients classified as cachectic. Guideline-based therapies approved for heart failure, such as loop diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aldosterone antagonists, and beta-adrenergic blockers, can lead to electrolyte abnormalities and predispose to some vitamin and micronutrient deficits. Clinical trial evidence in support of supplementary vitamin and mineral therapies for heart failure patients is limited with the exception of documented calcium and possibly vitamin D, thiamine, and coenzyme Q10 deficiencies. This area is gaining significant attention, and research is ongoing. The clinician can help minimize morbidity from nutrition impairment through appropriate monitoring and correction of baseline and medication-induced electrolyte imbalances, in addition to vitamin and mineral supplementation when appropriate.

We have recently reported that tumour necrosis factor-alpha (TNF-alpha) increases oxidative stress and apoptosis in cardiomyocytes by upregulating p38 mitogen-activated protein (MAP) kinase (MAPK) phosphorylation. Interleukin-10 (IL-10) blocked these effects of TNF-alpha by upregulating extracellular signal-regulated kinase 1/2 (ERK 1/2) MAPK phosphorylation. However, the precise site of this IL-10 action is still unknown, and this is investigated in the present study.

Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to TNF-alpha (10 ng/mL), IL-10 (10 ng/mL), and IL-10+TNF-alpha (ratio 1) for 4 h. Hydrogen peroxide and antioxidant trolox were used as positive controls. Exposure to TNF-alpha resulted in an increase in the production of reactive oxygen species, the number of apoptotic cells, caspase-3 activation, and poly-ADP ribose polymerase (PARP) cleavage. Increased oxidative stress by using hydrogen peroxide also caused apoptosis. The changes due to TNF-alpha were associated with an increase in the inhibitor of kappaB kinase (IKK) and nuclear factor kappa-B (NF kappaB) phosphorylation. IL-10 by itself had no effect, but it prevented the above mentioned TNF-alpha-induced changes. Trolox also mitigated TNF-alpha induced changes. Pre-exposure of cells to an IKK inhibitor (PS-1145) prevented TNF-alpha-induced caspase-3 and PARP cleavage. Inhibition of ERK 1/2 MAPK with PD98059 attenuated the protective role of IL-10 against TNF-alpha-induced activation of IKK and NF kappaB as well as cardiomyocyte apoptosis.

The present study shows that TNF-alpha-induced activation of the NF kappaB pathway plays a critical role in cardiomyocyte apoptosis. IL-10 prevents TNF-alpha-induced NF kappaB activation and pro-apoptotic changes in cardiomyocytes by inhibiting IKK phosphorylation through the activation of ERK 1/2 MAPK.

Upregulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is associated with the development of myocardial infarction (MI), dilated cardiomyopathy, cardiac fibrosis, and heart failure (HF). Evidences suggest that lipopolysaccharide (LPS) participates in the inflammatory response in the cardiovascular system; however, it is unknown if LPS is sufficient to upregulate expressions and/or activity of uPA, tPA, MMP-2, and MMP-9 in myocardial cells. In this study, we treated H9c2 cardiomyoblasts with LPS to explore whether LPS upregulates uPA, tPA, MMP-2, and MMP-9, and further to identify the precise molecular and cellular mechanisms behind this upregulatory responses. Here, we show that LPS challenge increased the protein levels of uPA, MMP-2 and MMP-9, and induced the activity of MMP-2 and MMP-9 in H9c2 cardiomyoblasts. However, LPS showed no effects on the expression of tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor), and QNZ (NFkappaB inhibitor), the LPS-upregulated expression and/or activity of uPA, MMP-2, and MMP-9 in H9c2 cardiomyoblasts are markedly inhibited only by ERK1/2 inhibitors, U0126. Collectively, these results suggest that LPS upregulates the expression and/or activity of uPA, MMP-2, and MMP-9 through ERK1/2 signaling pathway in H9c2 cardiomyoblasts. Our findings further provide a link between the LPS-induced cardiac dysfunction and the ERK1/2 signaling pathway that mediates the upregulation of uPA, MMP-2 and MMP-9.

The study of biomarkers and their signalling pathways has allowed the development of new therapeutic strategies in a range of disorders. The aim of the present systematic review is to provide an overview of different biomarkers in patients with hypertrophic cardiomyopathy that could give some insight into the pathophysiologic mechanism(s) underlying the typical clinical and histological manifestations of the disease. Several pathophysiological models are presented and discussed, including studies that have investigated these biomarkers for diagnostic and prognostic reasons, in relation to disease progression and/or mortality.

Peripartum cardiomyopathy (PPCM) is a disorder of unknown aetiology in which heart failure due to left ventricular dysfunction occurs between the last month of pregnancy and first five months post-partum. Theories abound concerning the specific cause and risk factors for PPCM, but none have been accepted universally. The primary objective of this review was to summarize the state of knowledge on the pathogenesis of PPCM, especially in light of recent studies.

We searched MEDLINE (January 1966-September 2007), OVID, and reference lists of articles for studies containing information on the aetiology and risk factors for PPCM, and published in English.

The literature reveals a wealth of articles proposing various mechanisms for aetiology and risk factors of PPCM. There is conflicting evidence on the pathogenetic role of viral myocarditis, abnormal immune response to pregnancy, abnormal response to the haemodynamic stress of pregnancy, accelerated myocyte apoptosis, cytokine-induced inflammation, malnutrition, genetic factors, excessive prolactin production, abnormal hormonal function, increased adrenergic tone, and myocardial ischaemia. A number of factors are postulated to increase the risk of the development of PPCM. These include non-Caucasian ethnicity, advanced maternal age, multiparity, poor socioeconomic status, multiple pregnancy and prolonged tocolytic use. The authors call for a strict definition of PPCM that excludes known causes of heart failure, such as the pregnancy-induced hypertensive spectrum of disorders.

The aetiology and risk factors for PPCM are poorly defined. There is a need for large-scale multi-centre epidemiological studies and registries to delineate the aetiology and pathogenesis of PPCM.

Evidences suggest that lipopolysaccharide (LPS) participates in the inflammatory response in the cardiovascular system; however, it is unknown if LPS is sufficient to cause the cardiac hypertrophy. In the present study, we treated H9c2 myocardiac cells with LPS to explore whether LPS causes cardiac hypertrophy, and to identify the precise molecular and cellular mechanisms behind hypertrophic responses. Here we show that LPS challenge induces pathological hypertrophic responses such as the increase in cell size, the reorganization of actin filaments, and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in H9c2 cells. LPS treatment significantly promotes the activation of GATA-4 and the nuclear translocation of NFAT-3, which act as transcription factors mediating the development of cardiac hypertrophy. After administration of inhibitors including U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor), FK506 (calcineurin inhibitor), and QNZ (NFkappaB inhibitor), LPS-induced hypertrophic characteristic features, such as increases in cell size, actin fibers, and levels of ANP and BNP, and the nuclear localization of NFAT-3 are markedly inhibited only by calcineurin inhibitors, CsA and FK506. Collectively, these results suggest that LPS leads to myocardiac hypertrophy through calcineurin/NFAT-3 signaling pathway in H9c2 cells. Our findings further provide a link between the LPS-induced inflammatory response and the calcineurin/NFAT-3 signaling pathway that mediates the development of cardiac hypertrophy.

The study objective is to prove an association among plasma concentration of big endothelin and endothelin-1, other clinical parameters and two frequent polymorphisms - G8002A and -3A/-4A - in the endothelin-1 (EDN-1) coding gene (6p21-23), and among plasma concentration of TNF alpha and gene polymorphisms TNF alpha -308 A/G, -238 A/G, TNF beta Ncol and 3'TACE (tumour necrosis factor alpha converting enzyme) in patients with chronic heart failure (CHF). The second objective is to find an association between polymorphisms G8002A and -3A/4A EDN-1 with diabetes mellitus (DM), peripheral artery disease (PAD) and myocardial infarction (MI) in patients with chronic heart failure (CHF). The study population included 266 patients with symptomatic CHF and proven dysfunction of the left ventricle (LV). Genotyping and plasma concentrations of humoral substances were examined in 224 patients with ejection fraction (EF) below 40%. No associations between plasma concentrations of endothelin-1 and big endothelin and polymorphisms G8002A (p=0.87, p=0.81) and -3A/-4A (p=0.871, p=0.749) in the gene coding endothelin-1 were found. No associations were observed between plasma concentration of TNF alpha and genotypes in four polymorphisms in TNF alpha, beta and TACE genes. A significant correlation was seen between plasma concentration of big endothelin and pulmonary congestion. Patients with ischemic heart disease (IHD) and previous MI showed a difference in the distribution of genotype G8002A for endothelin-1: allele G 0.718 and A 0.282 vs those without MI: allele G 0.882 and A 0.118, (p<0.05). Patients with IHD and DM had allele G in 0.67 and A 0.33, while those without DM had allele G in 0.790 and A in 0.209 (p<0.03). Patients with IHD and concomitant PAD had allele G in 0.718 and A in 0.282 vs those without PAD allele G in 0.882 and A in 0.118 (p<0.0004). Patients with dilative cardiomyopathy (DCMP) showed no differences in genotype G8002A and presence of DM or PAD. It might be speculated that in the case of endothelin-1 and TNF alpha in CHF the genetic determination is not important, and plasma concentrations are influenced more by the disease severity. Ischemics with previous MI, concomitant DM or PAD showed more frequently allele A and less often allele G than those without these diseases. A genotype with allele A is associated with higher risk of concomitant diseases.

Inflammation and abnormal calcium homeostasis play important roles in atrial fibrillation. Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, can induce cardiac arrhythmias. Pulmonary veins (PVs) are critical in initiating paroxysmal atrial fibrillation. This study was designed to investigate whether TNFalpha may change the calcium handling and arrhythmogenic activity of PV cardiomyocytes. We used whole-cell patch clamp and indo-1 fluorimetric ratio technique to investigate the action potentials, ionic currents and intracellular calcium in isolated rabbit single PV cardiomyocytes with and without (control) incubation with TNFalpha (25 ng/ml) for 7-10 h. The expression of sarcoplasmic reticulum ATPase in the control and TNFalpha-treated PV cardiomyocytes was evaluated by confocal micrographs and Western blot. We found that the spontaneous beating rates were similar between the control (n=45) and TNFalpha-treated (n=28) PV cardiomyocytes. Compared with the control PV cardiomyocytes, the TNFalpha-treated PV cardiomyocytes had significantly a larger amplitude of the delayed afterdepolarizations (6.0+/-1.7 vs. 2.6+/-0.8 mV, P<0.05), smaller L-type calcium currents, larger transient inward currents, larger Na(+)-Ca(2+) exchanger currents, a smaller intracellular calcium transient, smaller sarcoplasmic reticulum calcium content, larger diastolic intracellular calcium, a longer decay portion of the calcium transient (Tau), and a decreased sarcoplasmic reticulum ATPase expression. In conclusion, TNFalpha can increase the PV arrhythmogenicity and induce an abnormal calcium homeostasis, thereby causing inflammation-related atrial fibrillation.

Statin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure-a physiologic state characterized by systemic inflammation and endothelial dysfunction.

This review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF.

Preliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic.

Following ischemia-reperfusion, there is a sustained increase of TNF-alpha both locally in the heart as well as in circulating levels in blood. While TNF-alpha has been implicated in cardiomyocyte apoptosis which occurs in several cardiomyopathies, the molecular pathways by which TNF-alpha induces apoptosis in these cells are not fully elucidated. We investigated the role of the two families of cysteine proteases, caspases and calpains, which are known to participate in apoptotic cell death. The effect of the highly specific calpain inhibitor, Z-LLY-fmk, and the caspase pathways involved in TNF-alpha-mediated apoptosis of the HL-1 cardiomyocyte cell line were examined. Activation of the downstream caspase-3, and the cleavage of poly ADP-ribose polymerase (PARP) were observed in a time-dependent manner upon treatment with TNF-alpha. Caspase-12, but not caspase-9, was activated in response to TNF-stimulation, indicating that an endoplasmic reticulum (ER)/calcium-dependent pathway may be involved. In HL-1 cardiomyocytes, TNF-alpha-induced apoptosis appears to be mediated by calpain as apoptotic changes were abrogated in the presence of the highly specific calpain inhibitor, Z-LLY-fmk. In conclusion, our results suggest that TNF-alpha-mediated apoptosis in HL-1 cardiomyocytes follows the caspase-12 apoptotic pathway that involves calpain.

Tamoxifen is the most commonly used antiestrogen for the treatment of breast cancer. Several clinical trials demonstrate that tamoxifen reduces the risk of heart disease and osteoporosis. However, the mechanism by which tamoxifen causes cardioprotection is unclear. Because increased levels of tumor necrosis factor alpha (TNFalpha) in tissue and/or plasma have been observed in virtually all forms of cardiac injury, we investigated whether tamoxifen prevents cardiac injury in a murine model of acute TNFalpha challenge. Five- to six-week-old female mice were injected (ip) with tamoxifen at 0.25 mg/kg daily for 3 or 7 days before receiving an injection of TNFalpha. Ultrastructural examination of cardiac tissues revealed remarkable protection against TNFalpha-induced mitochondrial damage in tamoxifen pretreated mice. Tamoxifen treatment significantly improved the mitochondrial respiratory function and enhanced superoxide-scavenging activity of mitochondria. These findings reveal a novel mitochondria-mediated mechanism by which tamoxifen exerts its cardiac protection effect against acute TNFalpha-induced heart injury.

Renal dysfunction is a constant feature of congestive heart failure and is a stronger predictor of mortality than left ventricular ejection fraction or New York Heart Association classification. In heart failure, a reduction of glomerular filtration rate and renal plasma flow occurs, although the filtration fraction increases. There are many reason for this pattern. A reduction in effective circulating volume stimulates sympathetic activity and the renin-angiotensin-aldosterone system, and it is associated with increased concentrations of atrial natriuretic peptide, brain natriuretic peptide, and tumor necrosis factor alpha. Because in chronic kidney disease heart dysfunction commonly is present, an efficient cardiologist-nephrologist interaction should be promoted.

The specific antagonists of tumor necrosis factor-alpha (TNF-alpha), infliximab and etanercept, are established therapeutic agents for inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although the importance of TNF-alpha in chronic inflammatory diseases is well established, little is known about its implications in the cardiovascular system. Because proliferation of arteriolar connections toward functional collateral arteries (arteriogenesis) is an inflammatory-like process, we tested in vivo the hypothesis that infliximab and etanercept have antiarteriogenic actions. Sixty-three New Zealand White rabbits underwent femoral artery occlusion and received infliximab, etanercept, or vehicle according to clinical dosage regimes. After 1 wk, collateral conductance, assessed with fluorescent microspheres, revealed significant inhibition of arteriogenesis (collateral conductance): 52.4 (SD 8.1), 35.2 (SD 7.7), and 33.3 (SD 10.1) ml x min(-1) x 100 mmHg(-1) with PBS, infliximab, and etanercept, respectively (P < 0.001). High-resolution angiography showed no significant differences in number of collateral arteries, but immunohistochemical analysis demonstrated a decrease in mean collateral diameter, proliferation of vascular smooth muscle cells, and reduction of leukocyte accumulation around collateral arteries in treated groups. Infliximab and etanercept bound to infiltrating leukocytes, which are important mediators of arteriogenesis. Infliximab induced monocyte apoptosis, and neither substance affected monocyte expression of the adhesion molecule Mac-1. We demonstrated that TNF-alpha serves as a pivotal modulator of arteriogenesis, which is attenuated by treatment with TNF-alpha inhibitors. Reduction of collateral conductance is most likely due to inhibition of perivascular leukocyte infiltration and subsequent lower vascular smooth muscle cell proliferation. This is the first report showing a negative influence of TNF-alpha inhibitors on collateral artery growth.

Hydroxymethyglutaryl coenzyme A reductase inhibition (statin) therapy has been shown to reduce cardiac hypertrophy in vitro and in vivo. We assessed the influence of short-term statin therapy on left ventricular (LV) remodeling after acute myocardial in-farction. Thirty-five patients with first anterior acute myocardial infarction, who underwent primary coronary angioplasty within 12 hours of onset, were divided into 2 groups. Ten patients taking statin served as the statin group, and 25 patients not taking statin served as the control group. Two-dimensional echocardiography was recorded after angioplasty (baseline) and at 4 weeks. LV ejection fraction (LVEF) at baseline was not significantly different between the 2 groups. However, the statin group had a higher LVEF at 4 weeks than the control group (58.2 +/- 5.0 versus 49.0 +/- 12.7%; P < 0.05). Moreover, the increase in LV end-diastolic volume (LVEDV) at 4 weeks was lower in the statin group than in the control group (12.1 +/- 29.6 versus 39.9 +/- 35.7 mL; P < 0.05). Multiple regression analysis demonstrated that administration of statin was an independent factor for the increase in LVEDV (P < 0.05). These findings indicate that short-term statin therapy can prevent postinfarct LV remodeling and improve LV function.

The incidence of congestive heart failure (CHF) is increasing in Westernized countries, and patients with CHF experience poor quality of life (functional impairment, high hospitalization rate and high mortality). Malnutrition occurring during the course of CHF is referred to as cardiac cachexia and is associated with higher mortality independent of the severity of CHF. Cardiac cachexia involving a loss of more than 10% of lean body mass can clinically be defined as a bodyweight loss of 7.5% of previous dry bodyweight in a period longer than 6 months. The energy requirements of patients with CHF, whether cachectic or not, are not noticeably modified since the increase in resting energy expenditure is compensated by a decrease in physical activity energy expenditure. Malnutrition in CHF has been ascribed to neurohormonal alterations, i.e. anabolic/catabolic imbalance and increased cytokine release. Anorexia may occur, particularly during acute decompensation of CHF. Function is impaired in CHF, because of exertional dyspnea and changes in skeletal muscle. Decreased exercise endurance seems to be related to decreased mitochondrial oxidative capacities and atrophy of type 1 fibers, which are attributed to alteration in muscle perfusion and are partially reversible by training. Malnutrition could also impair muscle function, because of decreased muscle mass and strength associated with decreased glycolytic capacities and atrophy of type 2a and 2b fibres. With respect to the putative mechanisms of cardiac cachexia, anabolic therapy (hormones or nutrients) and anticytokine therapy have been proposed, but trials are scarce and often inconclusive. In surgical patients with CHF, perioperative (pre- and postoperative) nutritional support has been shown to be effective in reducing the mortality rate. Long term nutritional supplementation trials in patients with CHF and cachexia are thus required to establish recommendations for the nutritional management of patients with CHF.

We present a case of a patient who presented with a febrile illness without obvious source initially, who developed profound cardiac decompensation and left ventricular dysfunction. Viral titers obtained during the course of illness confirmed parvovirus infection. Intravenous aggressive immunoglobulins and medical therapy for heart failure resulted in stabilization and, ultimately, a complete recovery. Recent data from clinical trials are discussed regarding the utility of immunoglobulins in the treatment of myocarditis and heart failure.

The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-alpha) that was synthesized during ischemia and exogenous TNF-alpha on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart.

Tumor necrosis factor-alpha is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF-alpha-induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF-alpha-induced myocardial dysfunction is highly controversial.

Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF-alpha on the expression of eNOS mRNA and iNOS mRNA and on NO production.

After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 +/- 0.08 to 0.68 +/- 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF-alpha had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 +/- 0.04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels.

We believe this is the first study to directly show that TNF-alpha does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.

Chronic heart failure is associated with inflammation and neurohormonal imbalance. The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, exert anti-inflammatory and vascular protective effects. We hypothesized that short-term statin therapy may have beneficial effects in patients with nonischemic heart failure.

Sixty-three patients with symptomatic, nonischemic, dilated cardiomyopathy were randomly divided into 2 groups. One group received simvastatin (n=24), and the other group received placebo (n=27). The initial dose of simvastatin was 5 mg/d, which was increased to 10 mg/d after 4 weeks. After 14 weeks, patients receiving simvastatin exhibited a modest reduction in serum cholesterol level compared with patients receiving placebo (130+/-13 versus 148+/-18, P<0.05). Patients treated with simvastatin had a lower New York Heart Association functional class compared with patients receiving placebo (2.04+/-0.06 versus 2.32+/-0.05, P<0.01). This corresponded to improved left ventricular ejection fraction in the simvastatin group (34+/-3 to 41+/-4%, P<0.05) but not in the placebo group. Furthermore, plasma concentrations of tumor necrosis factor-alpha, interleukin-6, and brain natriuretic peptide were significantly lower in the simvastatin group compared with the placebo group.

Short-term statin therapy improves cardiac function, neurohormonal imbalance, and symptoms associated with idiopathic dilated cardiomyopathy. These findings suggest that statins may have therapeutic benefits in patients with heart failure irrespective of serum cholesterol levels or atherosclerotic heart disease.

Patients with heart failure have increased circulating levels of tumor necrosis factor (TNF) and TNF receptors. It is not known whether TNF, which is known to blunt beta-adrenergic responsiveness in experimental models, contributes to the loss of heart rate variability in patients with heart failure. Therefore, we examined heart rate variability in relation to circulating levels of TNF, TNF receptors, and norepinephrine in patients with heart failure and in control subjects.

Heart rate variability was obtained from 24-h ambulatory ECG recordings in age-matched control subjects (n = 10) and patients with mild (n = 15) to moderate (n = 14) heart failure. Plasma levels of TNF and soluble type 1 and 2 TNF receptors were measured by enzyme-linked immunoassay; plasma norepinephrine levels were measured by high-performance liquid chromatography.

There was a significant inverse linear correlation between increased circulating levels of TNF, TNF receptors, and norepinephrine for time-domain and frequency-domain indexes of heart rate variability among patients with heart failure and control subjects. Multiple stepwise linear regression analysis showed that TNF was a stronger independent predictor of frequency-domain indexes of heart rate variability than norepinephrine.

TNF is an independent predictor of depressed heart rate variability in patients with heart failure. Insofar as TNF blunts beta-adrenergic signaling, this study suggests the possibility that overexpression of TNF and subsequent loss of beta-adrenergic responsiveness contributes to the decrease in heart rate variability observed in heart failure.

Several lines of evidence support a role of immune mechanisms in the pathogenesis of chronic heart failure (CHF). Proinflammatory cytokines (interleukin-1, -2, -6, and tumor necrosis factor) and chemokines are involved in cardiac depression and in the progression of heart failure. Other components believed to be relevant to the pathogenesis of CHF are adhesion molecules, autoantibodies, nitric oxide (NO), and endothelin-1. The origin of the immune activation in patients with CHF is still unknown, however two hypotheses have been proposed on the basis of experimental and clinical data. One suggests that the bowel wall edema leads to bacterial translocation with subsequent endotoxin release and immune activation. The second suggests that the heart in CHF is the main source of cytokines, as is shown by the fact that TNF alpha is produced by the failing myocardium but not by a normal one. No single source of cytokine production (gut or heart) seems sufficient to fully explain the multiple organ involvement and the systemic inflammation of CHF, which is probably related to systemic hypoxia, a potent stimulus for activation of the immune system and for cytokine production. The effort of define the immune system's role has opened new perspectives of therapeutic strategies, such as anti-cytokine drugs, to treat CHF.

This study, performed in a murine model of encephalomyocarditis virus myocarditis, used a new Millar 1.4F conductance-micromanometer system for the in vivo determination of the left ventricular (LV) pressure-volume relationship (PVR).

Viral myocarditis is an important cause of congestive heart failure and may lead to dilated cardiomyopathy. However, the hemodynamic changes associated with its acute phase have not been analyzed in detail.

Four-week-old DBA/2 mice were inoculated with EMCV (day 0). Serial hemodynamic measurements, compared with uninfected control mice were made on days 0, 1, 3, 4, 5, 7, 9, 12, and 14.

On day 1, the hearts of infected mice manifested enhanced contractile function, decreased LV compliance, and abnormal diastolic function with increased LV end-diastolic pressure (EDP). Mean stroke index, ejection fraction (EF), and cardiac index (CI) were significantly higher than in uninfected control mice (p < 0.05). Contractile function decreased from days 4 to 14. On day 7, when hemodynamic abnormalities consistent with heart failure culminated, end-diastolic volume (EDV), EDP, and EDPVR were significantly higher, and CI, EF, end-systolic pressure (ESP), and ESPVR significantly lower in the infected than in control mice. Heart rate remained comparable in both groups. Although heart failure receded between day 9 and day 14, ESPVR, ESP, and EF remained significantly depressed up to day 14, and EDV and EDP remained significantly higher.

These hemodynamic data provide new insights into the pathophysiology of acute viral myocarditis and may be useful in the development of therapeutic interventions.

Recent investigations have shown that, in addition to neurohormonal system overactivation, another class of biologically active molecules, termed cytokines, is also overexpressed in the setting of chronic heart failure and participates actively in the progression of the syndrome. In this article, we present recent experimental and clinical data describing the pathophysiological role of cytokines in left ventricular remodeling, endothelial dysfunction, and peripheral myopathy characterizing the progression of chronic heart failure, as well as novel therapeutic approaches aimed at attenuating the deleterious effects of cytokines on the cardiovascular system.

Recent evidence suggests the importance of noncardiac mechanisms in the genesis of the syndrome of cardiac cachexia. This raises the question of the relative role of the heart itself in this syndrome. This study sought to assess the cardiac dimensions, mass, and function and changes in these parameters over time in patients with chronic heart failure with and without cachexia.

Doppler echocardiography was performed in 28 patients with nonedematous weight loss (>7.5% over a period of >6 months) compared with 56 matched patients without weight loss in a ratio of 1:2 (age 71 +/- 13 vs 67 +/- 8 years, P =.07; New York Heart Association class 2.9 +/- 0.7 vs 2.6 +/- 0.6, P =.08). In 18 cachectic and 35 noncachectic patients with previous echocardiographic recordings, we analyzed the changes in left ventricular (LV) dimensions and mass over time.

Cardiac dimensions including LV diastolic (69 +/- 9 mm vs 67 +/- 13 mm) and systolic cavity diameter (58 +/- 11 mm vs 55 +/- 15 mm), LV mass (480 +/- 180 g vs 495 +/- 190 g), and LV systolic and diastolic function including fractional shortening (16% +/- 10% vs 18% +/- 10%), isovolumic relaxation time (29 +/- 22 ms vs 36 +/- 27 ms), and E/A ratio (2.7 +/- 1.6 vs 3.3 +/- 2.9) did not differ between cachectic and noncachectic patients (all P >.1). By analyzing changes in LV mass over time, we found an increase (>20%) in 2 (11%) cachectic and 14 (40%) noncachectic patients and a decrease in LV mass (>20%) in 9 (50%) cachectic and 8 (23%) noncachectic patients (chi2 test, P <.05).

Although no specific cardiac abnormality could be detected echocardiographically in cachectic patients compared with patients with noncachectic chronic heart failure in a cross-sectional study, over time a significant loss of LV mass (>20%) occurs more frequently in patients with cardiac cachexia.

Several immune system abnormalities have been noted in patients with chronic heart failure (CHF) including autoantibody production and abnormalities in tumor necrosis factor, interleukin 2, interleukin 6, natural killer cells, helper/inducer lymphocytes, lymphocyte reactivity, and subtherapeutic responses to the influenza vaccination. Patients with CHF have a higher risk of nosocomial infections, mainly pulmonary. Immune function abnormalities in patients with CHF raise concern over the ability of patients with symptomatic CHF to mount an effective and protective B-cell response.

B-cell function was assessed by measuring antibody production in response to pneumococcal vaccination. Antibody levels were increased markedly for all serotypes tested (P <or= .001), and all patients had an increase in the number of serotypes for which they had protective antibody levels from a mean of 7.9 to 10.5 of 12 serotypes tested (P <or= .001). These responses are consistent with normal responses to vaccination.

Despite evidence of multiple immune system abnormalities, patients with CHF seem to have an intact B-cell function and the etiology of CHF does not affect antibody response. The normal response to vaccination confirms the potential utility of the vaccination.

Recently, deletion of specific genes by so called knock-out techniques has become important for investigating the pathogenesis of various diseases. This form of genetic engineering is widely performed in murine models. There are, however, only a limited number of mouse models available in cardiovascular pathology. The objective of this study, therefore, was to develop a new model of overt congestive heart failure associated with myocardial hypertrophy in the mouse.

Female C57/BL6 mice weighing 19-20 g were anesthetized with ether. After abdominal incision, the aorta was temporarily clamped proximal to the renal arteries. The aorta was then punctured with a needle (outer diameter 0.6 mm) and the needle was further advanced into the adjacent vena cava. After withdrawal of the needle, the aortic puncture site was sealed with cyanoacrylate glue. The clamp was removed, and the patency of the shunt was visually verified as swelling and mixing of venous and arterial blood in the vena cava. Sham-operated mice served as controls.

Perioperative mortality of mice with aortocaval shunt was 42%. Four weeks after shunt induction, mice showed a significant cardiac hypertrophy with a relative heart weight of 7.5+/-0.2 mg/100 g body weight (vs. 5.1+/-0.7 mg/100 g in control mice, P<0.001). While no changes in blood pressure and heart rate occurred, left ventricular enddiastolic pressure was significantly increased in mice with shunt, and left ventricular contractility was impaired from 6331+/-412 to 4170+/-296 mmHg/s (P<0.05). Plasma concentrations of atrial natriuretic peptide (ANP) and its second messenger cGMP as humoral markers of heart failure as well as ventricular expression of ANP- and brain natriuretic peptide (BNP)-mRNA were significantly increased in mice with shunt compared to control mice.

The aortocaval shunt in the mouse constitutes a new model of overt congestive heart failure with impaired hemodynamic parameters and may be a useful tool to investigate the role of particular genes in the development of heart failure.

Recent studies have emphasized the importance of biologically active molecules, termed cytokines, in the development and progression of the syndrome of chronic heart failure. This article summarizes a glossary of major cytokines and other cytokine-related inflammatory factors implicated in the pathophysiology of chronic heart failure, describing the source of their synthesis and factors regulating their secretion and analyzing their biologic effects on the cardiovascular system.

Tumor necrosis factor (TNF) is a proinflammatory cytokine that can produce widespread deleterious effects when expressed in large amounts. It is produced in the heart by both cardiac myocytes and resident macrophages under conditions of cardiac stress, and is thought to be responsible for many of the untoward manifestations of cardiac disease. This article discusses the role of TNF in heart disease and some potential therapeutic modalities that can influence the cytokine activity. The results of controlled studies would suggest that TNF inhibition does not influence the clinical course of patients with heart failure.

Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy to modulate proinflammatory cytokine levels in patients with heart failure. Previous experimental studies suggested that vesnarinone has potent anticytokine properties in vitro. Therefore, we examined the effects of vesnarinone on circulating levels of cytokines and cytokine receptors in a large-scale, multicenter, clinical trial of patients with moderate-to-advanced heart failure: the Vesnarinone Trial (VEST).

Circulating levels of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type 1, soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked immunosorbent assay at baseline and at 24 weeks in patients who were receiving placebo (n = 352), 30 mg of vesnarinone (n = 367), and 60 mg of vesnarinone (n = 327).

Treatment with 30 mg and 60 mg of vesnarinone had no effect on circulating levels of cytokines or cytokine receptors in patients with advanced heart failure over a 24-week period.

In contrast to the potent anticytokine effects observed with vesnarinone in experimental studies in vitro, the results of this clinical study suggest that vesnarinone does not have any measurable anticytokine effects in vivo in patients with moderate-to-advanced heart failure.