Role In Congestive Heart Failure Research Articles

Prognostic value of red blood cell distribution width combined with chloride in predicting short- and long-term mortality in critically ill patients with congestive heart failure: Findings from the MIMIC-IV database

BackgroundHypochloremia and red blood cell distribution width (RDW) play important roles in congestive heart failure (CHF) pathophysiology, and they were associated with the prognosis of CHF. However, the prognostic value of chloride combined with RDW in patients with CHF remains unknown. MethodsWe retrospectively analyzed critically ill patients with CHF. The database was derived from the Medical Information Mart for Intensive Care IV v2.0 (MIMIC-IV-v2.0) database. ResultsIn the final analysis, 5376 critically ill patients with CHF were included, and 2428 patients (45.2 %) experienced 5-year mortality. The restricted cubic spline model revealed a positive correlation between RDW and 5-year mortality, whereas chloride showed a U-shaped correlation with 5-year mortality. The median values of RDW and chloride were used to classify patients into four groups: high chloride/low RDW, low chloride/low RDW, high chloride/high RDW, and low chloride/high RDW. We observed the prognostic value of RDW combined with chloride in the Cox proportional hazard model, in predicting 5-year mortality, in-hospital mortality and 1-year mortality. Furthermore, we discovered that patients with chronic kidney disease (CKD) had a higher 5-year mortality risk than patients without CKD. ConclusionWe found the translational potential role of chloride combined with RDW in prioritizing patients at high risk for short- and long-term mortality in a cohort of critically ill patients with CHF. Prospective multicenter investigations are warranted to validate our results.

Identification, localization and expression of NHE isoforms in the alveolar epithelial cells.

Na+/H+ exchangers (NHEs), encoded by Solute Carrier 9A (SLC9A) genes in human, are ubiquitous integral membrane ion transporters that mediate the electroneutral exchange of H+ with Na+ or K+. NHEs, found in the kidney and intestine, play a major role in the process of fluid reabsorption together via Na+,K+-ATPase pump and Na+ channels. Nevertheless, the expression pattern of NHE in the lung and its role in alveolar fluid homeostasis has not been addressed. Therefore, we aimed to examine the expression of NHE specific isoforms in alveolar epithelial cells (AECs), and assess their role in congestive heart failure (CHF). Three NHE isoforms were identified in AEC and A549 cell line, at the level of protein and mRNA; NHE1, NHE2 and mainly NHE8, the latter was shown to be localized in the apical membrane of AEC. Treating A549 cells with angiotensin (Ang) II for 3, 5 and 24 hours displayed a significant reduction in NHE8 protein abundance. Moreover, the abundance of NHE8 protein was downregulated in A549 cells that were treated overnight with Ang II. NHE8 abundance in whole lung lysate was increased in rats with 1-week CHF compared to sham operated rats. However, lower abundance of NHE8 was observed in 4-week CHF group. In conclusion, we herein show for the first time, the expression of a novel NHE isoform in AEC, namely NHE8. Notably, Ang II decreased NHE8 protein levels. Moreover, NHE8 was distinctly affected in CHF rats, probably depending on the severity of the heart failure.

Platelet proteome changes in dogs with congestive heart failure

BackgroundPlatelets play a central role in the development of cardiovascular diseases and changes in their proteins are involved in the pathophysiology of heart diseases in humans. There is lack of knowledge about the possible role of platelets in congestive heart failure (CHF) in dogs. Thus, this study aimed to investigate the changes in global platelet proteomes in dogs with CHF, to clarify the possible role of platelets in the physiopathology of this disease. Healthy-dogs (n = 10) and dogs with acute CHF due to myxomatous mitral valve disease (MMVD, n = 10) were used. Acute CHF was defined based on the clinical (increased respiratory rate or difficulty breathing) and radiographic findings of pulmonary edema. Dogs Blood samples were collected into tubes with acid-citrate-dextrose, and platelet-pellets were obtained by centrifuge and washing steps. Platelet-proteomes were identified using LC-MS based label-free differential proteome expression analysis method and matched according to protein database for Canis lupus familiaris.ResultsTotally 104 different proteins were identified in the platelets of the dogs being 4 out of them were significantly up-regulated and 6 down-regulated in acute CHF dogs. Guanine-nucleotide-binding protein, apolipoproteins (A-II and C-III) and clusterin levels increased, but CXC-motif-chemokine-10, cytochrome-C-oxidase-subunit-2, cathepsin-D, serine/threonine-protein-phosphatase-PP1-gamma-catalytic-subunit, creatine-kinase-B-type and myotrophin levels decreased in acute CHF dogs. These proteins are associated with several molecular functions, biological processes, signaling systems and immune-inflammatory responses.ConclusionThis study describes by first time the changes in the protein composition in platelets of dogs with acute CHF due to MMVD. Our findings provide a resource for increase the knowledge about the proteome of canine platelets and their roles in CHF caused by MMVD and could be a tool for further investigations about the prevention and treatment of this disease.

Effect of Salt Intake on the Serum Cardiotrophin-1 Levels in Chinese Adults

Background: Dietary sodium affects fluctuations in blood pressure (BP) and vascular function. Cardiotrophin-1 (CT-1), a stress-induced cytokine that belongs to the interleukin 6 family, is released by cells in response to potentially harmful stresses and plays a pivotal role in congestive heart failure, hypertension and arterial stiffness. In this study, we performed a randomized trial to confirm the effects of altered salt intake on the serum CT-1 levels in humans. Methods: Forty-four subjects (18–65 years of age) were selected from a rural community in northern China. All subjects initially maintained a baseline period for 3 days, transitioned to a low-salt (LS) diet for 7 days (3.0 g/day of NaCl) and then a high-salt (HS) diet for an additional 7 days (18.0 g/day of NaCl). Results: For the whole group, the serum CT-1 concentrations were significantly increased in the HS period compared to those of the LS period (293.50 ± 137.70 vs. 360.40 ± 162.83 pg/mL, p = 0.040). The serum CT-1 concentrations significantly decreased from the baseline period to the LS diet (419.91 ± 123.50 to 256.49 ± 109.75 pg/mL, p < 0.01) and significantly increased from the LS to HS diet (256.49 ± 109.75 to 414.39 ± 191.21 pg/mL, p < 0.01). These changes were observed in salt-sensitive (SS) individuals but not in salt-resistant (SR) individuals. In addition, a significant positive relationship was observed between the changes in the CT-1 concentrations and systolic BP as well as the changes in the mean arterial pressure from the LS period to the HS period (r = 0.376, p = 0.012; r = 0.311, p = 0.040). The serum CT-1 concentrations were positively correlated with the 24-h urinary sodium-to-potassium (Na/K) excretion ratios during both of the LS and HS diet intervention periods in SS subjects (r = 0.621, p < 0.01), but this correlation was not evident in SR subjects (r = 0.208, p = 0.107). Conclusions: Our study indicates that variations in dietary salt intake affect the serum CT-1 levels in Chinese adults.

Can activity monitors predict outcomes in patients with heart failure? A systematic review.

Actigraphy is increasingly incorporated into clinical practice to monitor intervention effectiveness and patient health in congestive heart failure (CHF). We explored the prognostic impact of actigraphy-quantified physical activity (AQPA) on CHF outcomes. PubMed and Medline databases were systematically searched for cross-sectional studies, cohort studies or randomised controlled trials from January 2007 to December 2017. We included studies that used validated actigraphs to predict outcomes in adult HF patients. Study selection and data extraction were performed by two independent reviewers. A total of 17 studies (15 cohort, 1 cross-sectional, 1 randomised controlled trial) were included, reporting on 2,759 CHF patients (22-89 years, 27.7% female). Overall, AQPA showed a strong inverse relationship with mortality and predictive utility when combined with established risk scores, and prognostic roles in morbidity, predicting cognitive function, New York Heart Association functional class and intercurrent events (e.g. hospitalisation), but weak relationships with health-related quality of life scores. Studies lacked consensus regarding device choice, time points and thresholds of PA measurement, which rendered quantitative comparisons between studies difficult. AQPA has a strong prognostic role in CHF. Multiple sampling time points would allow calculation of AQPA changes for incorporation into risk models. Consensus is needed regarding device choice and AQPA thresholds, while data management strategies are required to fully utilise generated data. Big data and machine learning strategies will potentially yield better predictive value of AQPA in CHF patients.

Inflammatory Biomarkers in Refractory Congestive Heart Failure Patients Treated with Peritoneal Dialysis.

Proinflammatory cytokines play a pathogenic role in congestive heart failure. In this study, the effect of peritoneal dialysis treatment on inflammatory cytokines levels in refractory congestive heart failure patients was investigated. During the treatment, the patients reached a well-tolerated edema-free state and demonstrated significant improvement in NYHA functional class. Brain natriuretic peptide decreased significantly after 3 months of treatment and remained stable at 6 months. C-reactive protein, a plasma marker of inflammation, decreased significantly following the treatment. Circulating inflammatory cytokines TNF-α and IL-6 decreased significantly after 3 months of peritoneal dialysis treatment and remained low at 6 months. The reduction in circulating inflammatory cytokines levels may be partly responsible for the efficacy of peritoneal dialysis for refractory congestive heart failure.

The methionine 196 arginine polymorphism of the TNF receptor 2 gene (TNFRSF1B) is not associated with worse outcomes in heart failure

Tumor necrosis factor α (TNFα) may contribute to the pathologic process of congestive heart failure (CHF). TNFα signaling occurs through two receptors; TNFR1 (TNFRSF1A) and TNFRII (TNFRSF1B). In humans a single nucleotide polymorphism (rs1061622 in TNFRSF1B exon 6; T587G) encodes two different amino acids (M196R) in the transmembrane region. The 587G allele is associated with greater severity and/or prevalence of some inflammatory diseases, but its role in CHF in unknown. This study sought to test the hypothesis that the 587G allele is associated with a worse outcome or more severe phenotype in CHF. Peripheral blood DNA was isolated and genotyped from 379 heart failure patients enrolled in a genetic outcome study (GRACE); (44.7% ischemic, 70.4% male, 8.5% black race, age 55.6±11.7yr (SD), LVEF 24.5±8.3%, NYHA 2.53±0.64). Genotyping was performed by PCR-RFLP. Cardiac function was assessed from medical records at study entry. The distribution of genotypes in this population was 54% T/T, 38.4% G/T and 7.7% G/G. Mean LV ejection fraction (T/T 24.4±8.2, T/G 25.0±8.4, G/G 23.3±8.6, n=352, p=ns) and LV end-diastolic dimensions (T/T 6.57±0.93, T/G 6.53±1.0, G/G 6.57±0.78, n=211, p=ns) were comparable in all groups. Transplant-free survival (median 23months (range 1–62months) did not vary by genotype (p=0.95). A lack of effect (p=0.74) on transplant-free survival was also observed in a subset of patients with ischemic heart failure (n=169). The TNFRSF1B 587G allele is not associated with the severity of heart failure phenotype or clinical outcomes in patients with chronic CHF.

Iron Repletion in Heart Failure Patients

See related article, pp 497–504 There is increasing interest in the role of iron deficiency in causing or worsening congestive heart failure (CHF). A potential role for iron deficiency in playing a causal role in CHF is suggested by the fact that iron deficiency is common in CHF with or without anemia. In a recent study of 546 patients with stable systolic heart failure, if iron deficiency was defined as ferritin <100 μg/L, or as ferritin 100 to 300 μg/L and percent transferrin saturation of <20%, it was found in 37% of CHF patients; 32% did not have anemia, and 57% did have anemia (anemia defined as a hemoglobin [Hb] level of <12 g/dL in women and <13 g/dL in men).1 Iron deficiency was more prevalent in women, in those with more advanced CHF as measured by New York Heart Association class, those with higher N-terminal pro β-type natriuretic peptide levels (a sign of more severe CHF), and those with higher C-reactive protein levels (a sign of increased inflammation). After a mean duration of 731 days, in multivariable models, iron deficiency, but not anemia, was related to increased risk of death or heart transplantation, the adjusted hazard ratio being 1.58 ( P <0.01). In a study of anemic CHF patients, approximately half had serum iron levels below normal, and the great majority also had elevated soluble transferrin receptor (a dependable measure of iron deficiency).2 In another study of anemia in severe CHF, markedly reduced iron stores in the bone marrow were found in 73% of the cases.2,3 Thus, absolute iron deficiency (defined as a serum ferritin <100 μg/L and % transferrin saturation <20%) or functional iron deficiency (defined as a serum ferritin ≥100 μg/L and percentage transferrin …

The Future of Cardiovascular Imaging in the Diagnosis and Management of Heart Failure, Part 1

Radiographic, ultrasound, nuclear, and magnetic resonance methods have become indispensable in the management of heart failure (HF). Imaging is widely used in decision making in HF, not only in relation to left ventricular (LV) systolic and diastolic function but also in the selection of medical, device, and surgical therapy in HF and valvular heart disease. Future developments in the care of advanced heart disease, including stem cell therapy, device therapy to control remodeling, and percutaneous valve interventions, as well as the need to identify subclinical heart disease, are likely to expand this use. Moreover, the epidemic of diabesity (diabetes and obesity) will augment the existing epidemic of HF just when it appeared to have peaked.1 Large numbers of patients will need information from imaging to guide clinical decision making (Table 1). The sources of this information will need to be expeditious, inexpensive, and preferably objective and quantitative.2 View this table: Table 1. Established HF: What the Clinician Needs Although some of the measurements in HF patients are structural (LV mass and geometry), the main components of an imaging assessment in HF will continue to be primarily functional (LV ejection fraction, size, filling pressures, filling characteristics, and right ventricular [RV] function). A number of new technologies will enhance the future accuracy and reliability of these measures. ### LV Volumes and Ejection Fraction Routine techniques (contrast ventriculography, 2D echocardiography) provide real-time imaging in standard imaging planes. The only traditional method that has escaped this limitation has been radionuclide ventriculography, in which the ejection fraction is calculated from scintigraphic counts, but this introduces the separate potential problems of attenuation and overlying chambers. #### Limitations of 2D Imaging Two-dimensional imaging approaches require expert acquisition and observers and have limited reliability in obtaining appropriate cut planes in sequential studies. The limitation of requiring imaging planes in the correct axis is particularly an issue for 2D echocardiography, which …

Soluble CD40L, platelet surface CD40L and total platelet CD40L in congestive heart failure: relationship to platelet volume, mass and granularity

Many complications associated with congestive heart failure (CHF) have a thrombosis-related aetiology, which may involve platelets. The immune modulator pair CD40-CD40L has been proposed to be an important link between inflammation and thrombosis and may be important in the pathophysiology of CHF. To study soluble CD40L (sCD40L), platelet surface CD40L (%GCD40L) and total platelet CD40L (pCD40L) levels in CHF patients, their relationships to other platelet indices (platelet volume, mass and component) and to assess their prognostic value. We measured sCD40L (by ELISA); pCD40L (by a platelet lysate assay); platelet surface CD40L (%GCD40L) expression by flow cytometry; mean platelet volume (MPV), mean platelet mass (MPM) and mean platelet component (MPC); in 108 patients with stable CHF. Levels were compared with 37 'healthy controls' and 63 'disease controls'. After a median follow-up period of 490 days, clinical endpoints were determined. pCD40L was significantly higher in CHF than disease controls, but not sCD40L or %GCD40L levels. CHF patients and disease controls had higher MPV (one-way anova, P < 0.0001), whilst MPC was significantly lower in CHF patients (P < 0.0001), compared to healthy controls. All indices related to CD40L (i.e. sCD40L, pCD40L and %GCD40L) were neither related to disease severity or left ventricular ejection function, nor to clinical endpoints at follow-ups. Patients with stable CHF patients did not exhibit enhanced levels of CD40L and the latter did not predict clinical events at follow-up. The lack of difference in CD40L levels between CHF and disease controls suggests that CD40L may not have a major role in CHF per se, but in the comorbidities associated with CHF.

Cardiac l‐arginine transport: the CAT is back

Cardiac <scp>l</scp>‐arginine transport: the CAT is back

Flexible Versus Nonflexible Mitral Valve Rings for Congestive Heart Failure

Surgical intervention is playing an increasingly important therapeutic role in congestive heart failure (CHF) patients with ischemia and dilated cardiomyopathy. Their mitral regurgitation (MR) is a result of left ventricular (LV) geometrical distortion. The optimal type of ring for CHF patients with geometric ventricular-based MR is unknown. This study reviewed the results of flexible versus nonflexible complete mitral valve rings in CHF patients with geometric mitral regurgitation. Using a prospectively maintained database, patients undergoing mitral valve reconstruction (MVR) with either a flexible or nonflexible complete ring were identified on the basis of preoperative ejection fraction (EF) < or = 30% and no primary mitral pathology. These 2 groups of CHF patients with severe geometric MR were then compared in terms of recurrent MR requiring reoperation. Between 1992 and 2004, 289 patients with EF < or = 30%, received an undersized complete mitral annuloplasty ring as their MVR procedure. Of these, 170 patients had a flexible complete ring. In follow-up, 16 "flexible" patients (9.4%) required a repeat procedure for significant recurrent geometric MR and CHF (10 replacements, 3 re-repairs, 3 transplants). The average time to reoperation was 2.4 years. In contrast, 119 patients with an EF < or = 30% received a MVR using an undersized nonflexible complete ring. Only 3 "non-flexible" patients required a repeat operation, MVR (1), and 2 patients required a transplant. The time to reoperation was 4.0 years. A significant difference in reoperation rates, for recurrent MR, between the 2 groups (P=0.012). There were no differences between groups, in terms of age, ring size used, preoperative EF, LV size, MR grade, or New York Heart Association class. Patients with CHF having a flexible ring have a higher likelihood of developing recurrent MR requiring reoperation. The use of a nonflexible ring appears to significantly reduce the need for repeat surgical procedures. Further refinement and development of nonflexible ring systems, aimed at LV restoration, deserve ongoing investigation.

Upregulation of A 2A adenosine receptor expression by TNF-α in PBMC of patients with CHF: a regulatory mechanism of inflammation

Background Tumor necrosis factor (TNF)-α plays a role in congestive heart failure (CHF). A 2A adenosine receptor (A 2AR) activation on immune cells putatively reduces the release of cytokines contributing to CHF progression. The study is aimed at determining the role of the A 2AR in the modulation of TNF-α production, and the ex vivo effect of TNF-α on A 2AR in peripheral blood mononuclear cells (PBMC) from CHF patients. Methods and results Plasma levels of TNF-α and TNF-α production from lipopolysaccharide (LPS)-stimulated PBMC were evaluated in 26 CHF patients in comparison to controls. The effects of the A 2AR agonist CGS-21680 and antagonist ZM-241385 on TNF-α production from PBMC were also evaluated. Finally, reverse transcriptase-polymerase chain reaction and Western blot analyses of A 2AR in PBMC were performed in TNF-α–treated and untreated cells. TNF-α production from LPS-stimulated PBMC was enhanced in CHF patients with respect to controls. CGS-21680 blunted TNF-α production in both groups; ZM-241385 reverted this effect. A 2AR expression in PBMC was higher in CHF patients than in controls. TNF-α addition produced an increase in A 2AR in PBMC from controls but not in PBMC from CHF patients. Conclusions PBMC from CHF patients show an upregulation of A 2AR-mediated inhibition of TNF-α, which may represents a mechanism of protection against inappropriate cytokine production.

Natriuretic Peptides

natriuretic effects. They were first identified in 1981 by the pivotal work of de Bold and colleagues. In the 25 years elapsed since the initial discovery, an impressive amount of research has been carried out to identify the structure of the active peptide and its receptors, to characterise the biological functions of these molecules and their involvement in the pathophysiology of diseases and, finally, to identify their direct contributory role in the pathogenesis of some cardiovascular disorders. NPs include different biologically active fragments: the atrial natriuretic peptide (ANP), the brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Extensive research has identified some interesting features of ANP and BNP. In particular, it has been demonstrated that the ANP plays a role in the regulation of salt and water balance, as well as that of blood pressure homeostasis. In addition, ANP is involved in the pathophysiology of hypertension and heart failure, and it exerts a cellular antiproliferative effect in the cardiovascular system. More recently, a direct contributory role of ANP in the development of hypertension and cerebrovascular disorders has been demonstrated. On the other hand, BNP has a key role in congestive heart failure, particularly because of its distinct enhancement in terms of myocardial expression and production. These observations have progressively led researchers to consider ANP as a potential determinant of cardiovascular diseases and qualified BNP as a sensitive and specific marker of cardiac dysfunction. In this article, the most recently pathophysiological properties of NPs are reviewed, with particular regard to the most intriguing new hypothesis on their pathological and clinical significance in different cardiovascular

Interaction between cardiac sympathetic drive and heart rate in heart failure: Modulation by adrenergic receptor genotype

In the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine. Heightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the alpha(2)-, beta(1)-, and beta(2)-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (alpha(2) and beta(2)) and post-synaptically (beta(1) and beta(2)), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals. We determined the beta(1)-, beta(2)-, and alpha(2C)-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method. We showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 beta(2)-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the beta(1)-adrenoceptor. The genotype of the alpha(2C)- and beta(2)-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves. For the first time, we show that beta(2)-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals.

Role of Diastole in Left Ventricular Function, II: Diagnosis and Treatment

Left ventricular diastolic dysfunction plays an important role in congestive heart failure. Although once thought to be lower, the mortality of diastolic heart failure may be as high as that of systolic heart failure. Diastolic heart failure is a clinical syndrome characterized by signs and symptoms of heart failure with preserved ejection fraction (0.50) and abnormal diastolic function. One of the earliest indications of diastolic heart failure is exercise intolerance followed by fatigue and, possibly, chest pain. Other clinical signs may include distended neck veins, atrial arrhythmias, and the presence of third and fourth heart sounds. Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, and electrocardiographic and chest radiographic findings. Therefore, objective diagnostic testing with cardiac catheterization, Doppler echocardiography, and possibly measurement of serum levels of B-type natriuretic peptide is often required. Three stages of diastolic dysfunction are recognized. Stage I is characterized by reduced left ventricular filling in early diastole with normal left ventricular and left atrial pressures and normal compliance. Stage II or pseudonormalization is characterized by a normal Doppler echocardiographic transmitral flow pattern because of an opposing increase in left atrial pressures. This normalization pattern is a concern because marked diastolic dysfunction can easily be missed. Stage III, the final, most severe stage, is characterized by severe restrictive diastolic filling with a marked decrease in left ventricular compliance. Pharmacological therapy is tailored to the cause and type of diastolic dysfunction.

Therapeutic potential of anticytokine therapy in congestive heart failure.

Accumulating evidence indicates that inflammatory cytokines play a pathogenic role in congestive heart failure (CHF) by influencing heart contractility, inducing hypertrophy, and promoting apoptosis or fibrosis, contributing to the continuous myocardial remodeling process. While several stimuli may be operating such as heat-shock protein, microbial antigen, bacterial lipopolysaccharide, shear and oxidative stress, hypoxia and oxidized low-density lipoprotein (LDL), it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in CHF regardless of the initial event. Traditional cardiovascular drugs seem to have little influence on the overall cytokine network, and immunomudulatory therapy has emerged as a possible new treatment modality in CHF. Several animal studies, and some clinical pilot studies, have suggested that down-regulation of inflammatory cytokines may improve cardiac performance. On the other hand, preliminary results from the placebo-controlled studies suggest no effect, or even adverse effect, of antitumor necrosis factor (TNF) therapy on mortality and hospitalization. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'. These studies just underscore the difficulties and the challenges in developing treatment modalities that can modulate the cytokine network in CHF patients resulting in anti-inflammatory and beneficial net effects. Further research in this area will have to more precisely identify the most important actors in the immunopathogenesis of CHF in order to develop more specific immunomodulating agents for this disorder. However, at present the beneficial role of anticytokine therapy in patients with CHF remains unproven.

Angiopoietin/tie-2 as mediators of angiogenesis: a role in congestive heart failure?

Angiogenic factors, in particular vascular endothelial growth factor (VEGF) and the angiopoietins, Ang-1 and -2, have recently generated significant interest, especially in oncology. The process of angiogenesis is also thought to occur in response to ischaemic conditions, which lie at the core of cardiovascular disease states such as coronary artery disease and congestive heart failure. However, current data do not conclusively show evidence of angiogenesis per se in these conditions, despite (for example) the presence of high levels of VEGF and Ang-2. High levels of these angiogenic factors in heart disease also have not translated into clinically significant new vessel formation, as in accelerated cancer growth or proliferative retinopathy. Indeed, we would hypothesize that these angiogenic markers--especially the angiopoietins--do not necessarily translate into new vessel formation in congestive heart failure (CHF), but may well reflect disturbances of endothelial integrity in CHF.

The myosin binding protein is a novel mineralocorticoid receptor binding partner

The mineralocorticoid receptor (MR) plays a role in congestive heart failure; however, the molecular mechanism(s) remains undefined. We hypothesized that interaction of the MR with a cardiac protein modulates the transcriptional activation function of the MR within the heart. We used the yeast two-hybrid technique to screen a human heart library and found an aldosterone-dependent interaction between the hMR and the cardiac myosin binding protein (cMBP-c). The EC 50 of the hMR–MBP-c interaction was ∼80 nM, and the cMBP-c did not interact with the glucocorticoid receptor (GR). The GST pull-down technique was used to confirm an interaction between the MR and the cMBP-c as well as the lack of interaction with the GR. Spironolactone partially blocked this interaction, further suggesting MR specificity. We also determined the cMBP-c binding site lies within the C-terminus of the MR. We propose that interaction of the MR with cMBP-c may play a role in cardiac remodeling.

Antiapoptotic Effect of Endothelin-1 in Rat Cardiomyocytes In Vitro

Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4',6'-diamidine-2'-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ETA receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-xL, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-xL, and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-xL expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ETA receptor and the subsequent c-Src/Bcl-xL-dependent pathway.