Cardiotrophin-1 Levels Research Articles

Cardiotrophin-1 is not associated with carotid or coronary disease and is inversely associated with obesity in patients undergoing coronary angiography

IntroductionCardiotrophin-1 (CT-1) is a member of the interleukin-6 superfamily with known hypertrophic and protective actions upon cardiac myocytes. Although its effects on myocardial tissue and its role in hypertensive heart disease are well documented, there are no studies on CT-1 blood levels in patients with coronary artery disease. In this study we aimed to verify the relationships of serum CT-1 with vascular disease and metabolic parameters in a population of patients undergoing coronary angiography due to clinical indications.Material and methodsSerum levels of CT-1 were investigated in a cohort of 81 consecutive patients (median age 68 years (95% CI: 64–71), 59 males) undergoing coronary angiography and carotid Doppler ultrasound. Exclusion criteria were: acute coronary syndrome, already-established ischemic cardiopathy, chronic inflammatory diseases and presence or past history of cancer.ResultsLevels of CT-1 were inversely correlated with body mass index (BMI) and waist circumference (WC) (ρ = –0.261, p = 0.02; ρ = –0.224, p = 0.05, respectively). Moreover, obese patients showed significantly lower CT-1 concentrations than non-obese ones (1.18 (0.64–1.64) ng/ml vs. 1.56 (1.37–2.04) ng/ml, p = 0.013), and serum CT-1 was significantly reduced in patients with elevated compared to those with normal WC (1.43 (0.94–1.60) ng/ml vs. 1.64 (1.39–2.49) ng/ml, p = 0.047). Concentrations of CT-1 did not correlate either with the other parameters of metabolic syndrome or with markers of cardiovascular disease (carotid intima-media thickness, presence of carotid or coronary artery plaques).ConclusionsOur results failed to demonstrate any association between CT-1 and carotid or coronary disease. The inverse association with BMI and WC fits with the latest experimental data on the role of CT-1 in dysmetabolic conditions and could help to further clarify the role of CT-1 in obesity and diabetes.

Protective Effect of Montelukast, a Cysteinyl Leukotriene Receptor-1 Antagonist, against Intestinal Ischemia-Reperfusion Injury in the Rat

Objective : Ischemia-reperfusion (I-R) injury of the intestine is a significant problem because the initial damage caused by ischemia is exacerbated by reperfusion. In this study, we examined the protective effect of montelukast against I-R-induced intestinal tissue damage.Materials and methods : Eight-week-old male Sprague-Dawley rats were randomly divided into three treatment groups: a sham-operated group, a group receiving I-R, and a group receiving I-R plus montelukast (I-R/M). Tissue samples were evaluated and scored histologically. The blood levels of malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), and cardiotrophin-1 (CT-1) were measured.Results : In the I-R group, the histological score and the levels of serum MDA and MPO were increased compared with those in the control group. In the I-R/M group, the histological score and serum MDA and MPO levels were significantly decreased compared with those in the I-R group. Additionally, compared with the IR group, the I-R/M group had increased serum GSH and CT-1 levels and a decreased intestinal injury score. Ileal sections from the I-R/M group showed minimal alterations, characterized by moderate lifting of the epithelial layer from the lamina propria, and few apoptotic enterocytes were observed compare with the number in the I-R group.Conclusion : The findings of the present study demonstrated that montelukast can protect I-R-induced intestinal damage in rats.

Cardiotrophin-1 induces sarcoplasmic reticulum Ca2+ leak and arrhythmogenesis in adult rat ventricular myocytes

Plasma levels of cardiotrophin-1 (CT-1) are elevated in several cardiovascular diseases and are correlated with the severity of the pathology. However, the mechanisms by which this inflammatory cytokine participates in the pathology of the heart are not completely understood. It is well established that alterations in intracellular calcium ([Ca(2+)](i)) handling are involved in cardiac dysfunction during heart failure, but it is unknown whether CT-1 modulates [Ca(2+)](i) handling in adult cardiomyocytes. Here we have analyzed for the first time the effects of CT-1 on [Ca(2+)](i) homeostasis in adult rat cardiomyocytes. L-type calcium current (I(CaL)) was recorded using patch-clamp techniques, and [Ca(2+)](i) transients and Ca(2+) sparks were viewed by confocal microscopy. Treatment of cardiomyocytes with 1 nM CT-1 for 20-60 min induced a significant increase in I(CaL) density, [Ca(2+)](i) transients, and cell shortening compared with control cells. Our study reveals that CT-1 increases I(CaL) by a protein kinase A-dependent mechanism, and Ca(2+) sparks by a Ca(2+)/calmodulin kinase II-dependent and protein kinase A-independent mechanism. Cardiomyocytes treated with CT-1 exhibited a higher occurrence of arrhythmogenic behaviour, manifested as spontaneous Ca(2+) waves and aftercontractions. Our findings provide evidence that cardiomyocytes treated with CT-1 present high spontaneous Ca(2+) release during diastole, a mechanism linked to arrhythmogenicity in the pathologic heart.

Relationship between biomarkers and subsequent clinical and angiographic restenosis after paclitaxel-eluting stents for treatment of STEMI: a HORIZONS-AMI substudy

Drug-eluting stents (DES) reduce the incidence of in-stent restenosis (ISR) after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Whether the use of biomarkers might be of utility to identify patients who remain at risk for DES ISR after primary PCI has never been examined. A total of 26 biomarkers were measured at enrollment and 30 days and analyzed at a central core laboratory in 501 STEMI patients from the HORIZONS-AMI trial. All patients underwent primary PCI with the TAXUS paclitaxel-eluting stent (PES), were scheduled for routine angiographic follow-up at 13 months, and were followed for 3 years. Mean in-stent late-loss was 0.28 ± 0.57 mm, and target lesion revascularization (TLR) at 3 years occurred in 9.1 % of patients. Low levels of interleukin-6 (IL-6) and placental growth factor (PLGF) at admission were associated with both higher in-stent late loss and ischemia-driven TLR. Additionally, low admission levels of cardiotrophin-1 (CT-1) were associated with higher rates of ischemia-driven TLR. At 30-day follow-up lower values of IL-1ra (IL-1ra), matrix metalloproteinase 9 (MMP9), and myeloperoxidase (MPO), and a decline relative to admission in IL-1ra, monocyte chemotactic protein-1 (MCP-1), and MMP9 were associated with higher in-stent late loss. Low values of IL-6 at 30 days were also associated with ischemia-driven TLR. After multivariate adjustment, only MPO at 30 days and a decline of MCP-1 between admission and 30 days were associated with in-stent late loss, and only CT-1 was associated with TLR. MPO at 30 days and a decline of MCP-1 between admission and 30 days were independently associated with in-stent late loss, and CT-1 was associated with TLR. Additional studies to confirm and validate the utility of these biomarkers are warranted.

Effect of cardiac resynchronization therapy on cardiotrophin-1 circulating levels in patients with heart failure

Cardiotrophin-1 (CT-1) is a member of the interleukin (IL-6) family of cytokines. Plasma CT-1 levels correlate with the left ventricle mass index in patients with dilatated cardiomyopathy and congestive heart failure (CHF). The aim of this paper was to evaluate CT-1 plasma levels, before and after cardiac resynchronization therapy CRT, and to characterizeits prognostic role in patients with CHF. Fifty-two consecutive patients (M/F = 39/13; 56 ± 11 years old) underwent clinical and echocardiographic evaluation, and blood sample collection at baseline. The same evaluation was repeated 6.4 ± 0.79 months after CRT. Patients with a decreased LV end-systolic volume by at least 15% (reverse remodeling) were considered echo responders to CRT. Twenty-nine patients (56%) were responders to CRT. After CRT, only 15 patients (29%) showed increased CT-1 after CRT. They were all non responders to CRT. A multivariate, logistic model showed CT-1 as an independent predictor of CRT echo response (p = 0.005; OR 0.97). During follow-up (18 ± 7 months), 21 cardiac events in 18 patients occurred. A Cox multivariable model showed plasma BNP pre-CRT (p = 0.02; CI 1.2-5.6; OR 3.1) and CT1 post-CRT (p = 0.01; CI 1.4-4.3; OR 2.7) as independent predictors of cardiac events. Analysis of CT-1 plasma levels deserves future consideration for larger, longitudinal studies in patients with CHF.

HIF-1-mediated up-regulation of cardiotrophin-1 is involved in the survival response of cardiomyocytes to hypoxia

Cardiotrophin-1 (CT-1) is a cytokine of the interleukin-6 superfamily which is up-regulated in cardiac diseases, in part via hypoxia-dependent mechanisms. However, no evidence for a direct regulation of CT-1 gene (CTF1) promoter by hypoxia inducible factor-1 (HIF-1) has been provided. Hypoxia increased CT-1 mRNA levels in the murine adult cardiomyocyte cell line HL-1 in a time-dependent manner. Interestingly, in a murine model (C57BL/6), we show that systemic hypoxia also significantly up-regulated CT-1 in myocardial tissue. The effect of hypoxia on CT-1 expression was mediated through a transcriptional mechanism, since hypoxia increased luciferase activity of constructs containing CTF1 promoter sequences. The increase in CT-1 levels was significantly reduced by drugs that prevent calcium mobilization, such as lercanidipine, or that inhibit the activation of the PI3K/Akt pathway (wortmannin) or mammalian target of rapamycin (rapamycin). The CT-1 elevation was similarly induced by HIF-1α over-expression in co-transfection experiments and prevented by HIF-1α silencing. The direct interaction of HIF-1α with the CTF1 promoter was confirmed through site-directed mutagenesis of hypoxia response elements, electrophoreric mobility shift, and ChIP assays. Hypoxia induced HL-1 apoptosis (measured as annexin-V binding or caspase 3/7 activity) which was increased when CT-1 was silenced in knocked-down cells by lentiviral vectors. Hypoxia increased CT-1 levels in cardiac cells (in vitro and in vivo) through a direct regulation of CTF1 promoter by HIF-1α. This CT-1 activation by hypoxia may protect cells from apoptosis, thus supporting a protective role for CT-1 as a survival factor for cardiomyocytes.

The human heart releases cardiotrophin-1after coronary artery bypass grafting with cardiopulmonary bypass

Objectives. Cardiotrophin-1 (CT-1) is closely linked to many cardiovascular diseases, such as myocardial infarction and heart failure, and exhibits cardioprotective effect in ischemia-reperfusion injury. The present study was designed to investigate the course of CT-1 in patients undergoing on-pump coronary artery bypass grafting (CABG), and to evaluate the relationship between plasma CT-1 levels and postoperative cardiac function. Methods. Twenty-four patients undergoing elective CABG were studied. Radial artery blood samples were collected before cardiopulmonary bypass (CPB), 5 min and 20 min after reperfusion, and 1 h, 6 h, 12 h and 24 h after CPB. Coronary sinus blood samples were collected before CPB, 5 min and 20 min after reperfusion. Plasma CT-1 levels were measured using the ELISA method. Hemodynamic data were collected. Results. Peripheral CT-1 levels did not change significantly postoperatively. Trans-myocardial CT-1 levels increased significantly 5 min and 20 minutes after reperfusion as compared to baseline. A weak positive correlation (r = 0.408, p = 0.048) was found between trans-myocardial CT-1 levels at 20 min after reperfusion and CI at 12 h after CPB. Conclusions. The heart secretes CT-1 after ischemic injury. The precise effect of CT-1 in CABG needs further investigation.

Clinical research on correlation between CT-1 and cardiac function in patients with diabetic cardiopathy

Objective To study the eorrelation between the plasma cardiotrophin-1(CT-1)level and cardiac function of patients with diabetic cardiopathy.Methods Using the Biotin-StreptAvidin-enzyme-linked immunosorbent assay(BSA-ELISA),the level of plasma CT-1 jn 35 normal controls,40 patients with type 2 diabetes and 60 patients with diabetic cardiopathy was measured.The relation to heart function was observed.Results The difference of plasma CT-1 level in the three groups was significant(all P＜0.05).The level of plasma CT-1 in diabetic cardiopathy group was apparently higher than that of type 2 diabetes group and normal controls(all P＜0.01);The level in type 2 diabetes group was significantly higher than that of normal controls(P＜0.01).The level of plasma CT-1 elevated with the worsening of heart failure(NYHA classification).The level of plasma CT-1 was correlated with EF(r=0.669,P＜0.01);LAD(r=0.528,P＜0.01);PVE(r=0.502,P＜0.01);CK-MB(r=0.312,P＜0.01);TG(r=0.187,P＜0.05);DBP(r=0.158,P＜0.05)o Stepwise regression analysis revealed that EF and LAD were the most significant agents affecting the plasma CT-1.Conclusion The plasma CT-1 level could reflect the state of cardiac function of diabetic cardiopathy patient,it could help to diagnose diabetic cardiopathy earlier. Key words: Diabetic; Cardiopathy; Cardiotrophin-1; Cardiac function

Cardiotrophin-1 plasma levels are associated with the severity of hypertrophy in hypertrophic cardiomyopathy

AimsCardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM).Methods and resultsThe study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spirito's LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P < 0.001) plasma CT-1 levels. Significant correlations were found between CT-1 and maximal LV wall thickness (r = 0.284, P = 0.001) and the Spirito's LVH score (r = 0.287, P = 0.006) in HCM patients. In addition, the levels of CT-1 were higher (P = 0.02) in patients with severe LVH (maximal LV wall thickness ≥30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness <30 mm).ConclusionsThese findings show that plasma CT-1 is associated with the severity of LVH in patients with HCM. Further studies are required to ascertain whether CT-1 is a diagnostic biomarker of this cardiomyopathy.

Protective effect of the 1742(C/G) polymorphism of human cardiotrophin-1 against left ventricular hypertrophy in essential hypertension

Experimental and clinical evidence supports a role of cardiotrophin-1 (CT-1) in the development of hypertensive left ventricular hypertrophy (LVH). The goal of this study was to investigate the relationship between human CT-1 genetic background and LVH in essential hypertension. A total of 900 individuals were genotyped for the 1742(C/G) polymorphism of the human CT-1 gene. Serum CT-1 levels were assessed by ELISA in 681 individuals. Left ventricular parameters were determined by two-dimensional echocardiography in 297 individuals. The prevalence of the GG genotype of the 1742(C/G) polymorphism was reduced in essential hypertension (8.4% in normotensive individuals, 4.9% in hypertensive patients, P = 0.046 versus CC/CG individuals) and in LVH (11.5% in nonhypertrophic normotensive individuals, 12.2% in nonhypertrophic hypertensive patients, 2.6% in hypertensive patients with LVH, P = 0.008 versus CC/CG individuals). Apart from this, GG individuals presented lower serum concentration of CT-1 (GG, 147.1 ± 10.5 fmol/ml; CC/CG, 187.1 ± 4.8 fmol/ml; P = 0.036) and left ventricular mass index (GG, 91 ± 6 g/m; CC/CG, 119 ± 3 g/m; P = 0.002). Multivariate analyses showed that the 1742(C/G) polymorphism was a significant determinant of both left ventricular mass index and serum CT-1, after adjusting for confounding factors. Finally, in-vitro studies supported the functionality of the 1742(C/G) polymorphism. Our results indicate that the 1742(C/G) polymorphism of the human CT-1 gene is associated with LVH in hypertension and that the GG genotype may have a protective role. It is suggested that CT-1 is one of the mediators of this association.

Cardiotrophin-1 in Patients with Acute Myocardial Infarction

Problem statement: Myocardial infarction is the combined result of environmental and personal factors. Prothrombotic factors might play an important role in this phenomenon. Inflammation plays a pivotal role in atherosclerosis and coronary heart disease. Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, was identified as a growth factor for cardiac myocytes that induces cardiomyocyte hypertrophy and stimulates cardiac fibroblasts, protects myocytes from cell death. This study was designed to investigate whether plasma concentration of Cardiotrophin-1 (CT-1), in patients who had the first acute myocardial infarction and to analyze their relationship with traditional cardiovascular risk factors. Approach: This study was carried out on 45 patients with Acute Myocardial Infarction (AMI) in their first 24 h of admission as case group and 36 healthy matched individuals were studied as the control. Plasma level of cardiotrophin-1 was determined by enzyme-linked immunosorbent assay and the results were compared. Results: Plasma CT-1 levels in the patients with AMI on admission 615.279±5.109 pmol L-1 were significantly higher than those in the control group 534.767±6.750 pmol L-1 (p = 0.001). Plasma CT-1 level was not correlated with diabetes mellitus, hyperlipidemia, sex, age and smoking. Conclusion: Our findings suggested that high plasma CT-1 level in patients with AMI is indicative of hypercoagulable state that is not related to the traditional cardiovascular risk factors.

CARDIOTROPHÝN 1 LEVELS IN NONDIPPER HYPERTENSIVE PATIENTS: PP.12.464

Background: Cardiotrophin 1 (CT-1) is an interleukin cytokine with known hypertrophic and proctective actions upon cardiac myocytes. We know that CT-1 increases in hypertension. In nondipper hypertension there is a high risk for cardiovascular mortality as compared dipper hypertension. There is no study about CT-1 levels in nondipper hypertension. In our study we investigated CT-1 levels in nondipper hypertension. Material Method: Patients having ischemic heart disease, valvular heart diseases, heart failure, and having any other systemic or metabolic diseases were excluded. Patients haven't took any hypertension drugs when hypertension was diagnosed. Dipper and nondipper hypertensive patients were determined by 24 hour ambulatory blood pressure meassurement (Tracker NIBP2, Reynolds Medical Ltd. Hertford England). Twenty six nondipper patients (15 women, mean age: 60,0 ± 13,6 years) and 21 dipper (11 women, mean age: 54,3 ± 12,4 years) were included to the study. CT-1 were determined by ELISA method (Human Cardiotrophin 1 USCN Inc. Wuhan China). SPSS 10.0 packed programme T-Test was used for stastical analyses. Results: There were no differences in dipper and non-dipper patients regarding to age, sex, height and weight. We didn't find any difference CT1 levels in nondipper hypertension group and dipper hypertension group (9,92 ± 2,08; 9,75 ± 1,64 pg/ml, respectively). Conclusion: In this study we found that CT1 levels was similar in nondipper hypertension group and dipper hypertension group. Although cardiovascular diseases in nondipper hypertensive patients are higher than dipper hypertensive patients, CT-1 levels found similar in both group.

PROTECTIVE EFFECT IN HYPERTENSIVE HEART DISEASE OF THE 1742GG GENOTYPE OF THE HUMAN CARDIOTROPHIN-1 GENE: 6D.03

Introduction: Both clinical and experimental evidence indicates that cardiotrophin-1 (CT-1) is a cytokine that is critically involved in the development of left ventricular hypertrophy (LVH). We have investigated the effect of the 1742(C/G) polymorphism of human CT-1 gene (CTF1) on CT-1 levels and LVH in human essential hypertension. Materials and Methods: We genotyped 514 normotensive subjects and 386 hypertensive patients for 1742(C/G) polymorphism. Serum levels of CT-1 were assessed in 681subjects by ELISA. LVH was assessed in 297 subjects by bidimensional echocardiography. Results: The prevalence of the GG genotype was significantly reduced in the hypertensive group (8.4% in normotensive subjects, 4.9% in hypertensive patients, P = 0.046) and further reduced in patients with LVH (11.5% in normotensive subjects without LVH, 12.2% in hypertensives patients without LVH, 2.6% in hypertensive patients with LVH, P = 0.008). In addition, subjects of GG genotype presented lower serum levels of CT-1 (GG: 147.1 ± 10.5 fmol/mL, CC/CG: 187.1 ± 4.8 fmol/mL, P = 0.036) and lower left ventricular mass index (LVMI) (GG: 91 ± 6 g/m2, CC/CG: 119 ± 3 g/m2, P = 0.002) than CC/CG genotype subjects. Multivariate analyses showed that the 1742(C/G) polymorphism was a significant determinant of CT-1 levels and also of LVMI, after adjusting for confounding factors such as age, sex, systolic blood pressure and antihypertensive treatment. Conclusions: Our data indicate that the 1742(C/G) polymorphism of human CT-1 is a novel genetic marker in LVH, as it is associated with the LVMI in essential hypertension. The GG genotype may be protective against LVH and the levels of CT-1 may be one of the mechanisms underlying the effect of the polymorphism.

ACTIVATION OF PHAGOCYTIC NADPH OXIDASE IN HYPERTENSIVE HEART DISEASE: A ROLE FOR CARDIOTROPHIN-1?: PP.22.399

Objective: Oxidative stress and inflammation are interconnected mechanisms which are potentially involved in the pathogenesis of heart disease. We examined whether phagocytic NADPH oxidase activation is related to hypertensive heart disease (HHD). Besides, we analyzed whether NADPH oxidase activation is mediated by cardiotrophin-1 (CT-1), a cytokine that has been recently involved in the development of hypertensive left ventricular hypertrophy (LVH). Design and Method: Normotensive individuals, hypertensives without cardiac abnormalities and hypertensives with LVH were studied. LVH was determined by two-dimensional echocardiography. NADPH oxidase-mediated superoxide production was measured in peripheral blood mononuclear cells by luminescence. Serum CT-1 was measured by ELISA in samples from the antecubital vein. Results: Phagocytic NADPH oxidase activity and serum CT-1 levels were increased in hypertensives with LVH compared with normotensives and hypertensives without LVH. Phagocytic NADPH oxidase was positively correlated with serum CT-1 levels in all individuals, this association being independent of age and sex. In vitro experiments demonstrated that CT-1 stimulated NADPH oxidase activity in phagocytic cells. Conclusions: This study shows that phagocytic NADPH oxidase overactivity is associated with HHD. In addition, our data support a relevant role of CT1 as an additional player that promotes the activation of NADPH oxidase in phagocytic cells.

Exogenous expression of HIF-1α promotes cardiac differentiation of embryonic stem cells

Hypoxia plays an important role in the proliferation, differentiation and maintenance of the cardiovascular system during development. While low oxygen tension appears to direct the cultured embryonic stem cells (ESCs) to differentiate into cardiomyocytes, the underlying molecular mechanism remains unclear. At a molecular level, hypoxia inducible factor-1 (HIF-1) plays an important role in handling the hypoxia signal. In the present study, we demonstrated that expression of exogenous HIF-1α cDNA into murine ESCs significantly promoted cardiogenesis as indicated by a higher percentage of beating embryoid body and troponin-T positive cell counts as well as increased expression of early and late cardiac markers, such as GATA-binding protein 4 and 6, NK2 transcription factor related locus 5, α-myosin heavy chain, β-myosin heavy chain and myosin light chain 2 ventricular transcripts. In addition, the transduced cells exhibited increased mRNA levels of cardiotrophin-1 and vascular endothelial growth factor, along with phosphorylation of eNOS [p-eNOS (ser1171)]. Application of NOS inhibitors, diphenyleneiodonium chloride (DPI), Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) or Nω-Nitro-l-arginine (l-NNA) abolished the HIF-1α stimulated cardiac differentiation. With the clues of upregulated mRNA expression of calcium handling proteins, ryanodine receptor 2, sodium calcium exchanger and sarcoplasmic/endoplasmic reticulum calcium ATPase, in the transduced HIF-1α ESCs, further study indicated that the maximum upstroke and decay velocity was significantly increased in both non-caffeine and caffeine-induced calcium transient in ESCs-derived cardiomyocytes. This suggests a well developed function of the sarcoplasmic reticulum in ESC-derived cardiomyocytes. Electrophysiological study also indicated that a portion of the HIF-1α-transduced cells exhibited prominent phase-4 depolarization. These findings suggest that keen activation of the HIF-1 pathway enhances differentiation and maturation of cardiomyocytes derived from ESCs.

Cardiotrophin-1 and TNF-α circulating levels at rest and during cardiopulmonary exercise test in athletes and healthy individuals

There is a growing body of evidence that physical training exerts its potential benefits on the individual health status by modulating the immune system and the whole body metabolism. A better knowledge of the physiologic immune response to exercise may help to understand the benefits of physical exercise in healthy individuals and elite athletes. This study aims to analyse cardiotrophin-1 (CT-1) and Tumor Necrosis Factor-alpha (TNF-alpha) plasma levels at rest and during exercise in elite athletes and healthy controls. We studied 20 triathletes (TA) and 20 matched controls (CG). Chambers dimensions, left ventricular mass and left ventricular mass index were analysed by echocardiography. VO2 peak and VE/VCO2 were calculated by metabolic stress test. Blood samples were collected before the exercise session, at the exercise peak, and after the end of exercise. ELISA assays were used to measure CT-1 and TNF-alpha plasma levels. Among TA and CG, no significant differences were found for CT-1 (0.25+/-0.14 vs 0.20+/-0.14 fm/l; p=0.29) and TNF-alpha (10.8+/-2.7 vs 9.7+/-4.0 pm/l; p=0.29) basal levels. In the TA, plasma levels of CT-1 were significantly different at rest and during exercise (basal 0.25+/-0.13 pm/l; peak 1.07+/-1.5 pm/l; post-exercise 0.67+/-0.77 pm/l; p=0.04). Conversely, no significant differences were found between basal, peak and post-exercise plasma values of TNF-alpha (basal 10.8+/-2.7 pm/l; peak 11.7+/-2.1 pm/l; post-exercise 11.4+/-2.5 pm/l; p=0.78) in TA. This study gives novel insights on the behavior of inflammatory cytokines during physical exercise in athletes and healthy individuals.

Cardiotrophin-1: Another “player” in Cardiac Calcium Handling

Cardiotrophin-1 (CT-1) is a cytokine member of the interleukin-6 superfamily produced by cardiomyocytes and fibroblasts in the heart, in situations of haemodynamic overload, or in the presence of humoral factors as aldosterone. CT-1 is able to induce hypertrophic growth and dysfunction of cardiomyocytes in vitro. Moreover, plasma levels of CT-1 are elevated in patients with cardiac hypertrophy and heart failure (HF) and correlated with the severity of the disease. On the other hand, it is well established that alterations in calcium handling are involved in cardiac dysfunction during HF. However, it is yet unknown whether CT-1 modulates Ca2+handling in cardiomyocytes. Here we analyzed CT-1 effects on [Ca2+]i handling in rat single cardiomyocytes. The L-type calcium current (ICaL) was registered using whole-cell patch-clamp technique. Intracellular calcium [Ca2+]i transients and Ca2+ sparks were viewed by confocal miscroscopy in cardiomyocytes loaded with the fluorescence Ca2+ indicator Fluo-3 AM. Treatment of cardiomyocytes with 1 nM CT-1 for 30 min induced a significant increase in ICaL density compared to control cells (at −10 mV: −16.0 ± 0.9 vs. 11.9± 0.7 pA/pF; P< 0.01). The activity of ryanodine receptors (RyRs), estimated by Ca2+ spark frequency, was significantly increased in cardiomyocytes treated with CT-1 (Ca2+ sparks·s−1·100 μm−1: 2.3 ± 0.3 vs. 4.3 ± 0.5; P< 0.01). Moreover, we observed that the increase in the total Ca2+ spark frequency produced by CT-1 could be attributable to the increased propensity of some clusters of RyR to release Ca2+repetitively. Thus, we conclude that CT-1 is able to alter Ca2+ handling in isolated cardiomyocytes, enhancing the Ca2+ influx through L-type Ca2+ channel and the Ca2+release from sarcoplasmic reticulum through RyRs.

Response to Cardiotrophin-1 in Adolescents: Impact of Obesity and Blood Pressure

We read with interest the letter from Jung et al1 providing data on the potential impact of overweight/obesity and blood pressure on cardiotrophin-1 (CT-1) levels in adolescents. We saw that they found no differences in plasma CT-1 levels between overweight/obese and normal-weight adolescents and neither overweight/obesity indices nor HBA1c and adiponectin correlated with plasma levels of CT-1. In our study, the high plasma CT-1 in morbidly obese patients might possibly be attributable both to the degree of …

Association of Increased Plasma Cardiotrophin-1 With Left Ventricular Mass Indexes in Normotensive Morbid Obesity

To the Editor: We read with great interest the article by Lopez et al,1 who hypothesize that cardiotrophin-1 (CT-1), a cytokine that induces cardiomyocyte growth, may be abnormally upregulated in hypertensive patients with inappropriate left ventricular mass (LVM), suggesting that an excess of CT-1 may contribute to inappropriate left ventricular growth. This possibility is supported by the finding of a correlation between CT-1 levels and the observed LVM/predicted LVM ratio, independent from concentric left ventricular hypertrophy (LVH). de Simone et al2 suggested that, other than hemodynamic load, the process that yields to inappropriate LVH can also depend on the protracted activity over time of cytokines, among other nonhemodynamic factors. The observation by Lopez et al1 that CT-1 levels were high in treated patients in whom inappropriate LVM persisted …

Perioperative plasma brain natriuretic peptide and cardiotrophin-1 in off-pump coronary artery bypass

Objective. It has been suggested that brain natriuretic peptide (BNP) and cardiotrophin-1 (CT-1) are associated with myocardial dysfunction. The present prospective study was designed to investigate perioperative changes of plasma levels of BNP and CT-1 in off-pump coronary artery bypass (OPCAB). Method. Forty-nine patients undergoing elective OPCAB were divided into three groups. Group I: no previous myocardial infarction; Group II: previous myocardial infarction more than 12 weeks; Group III: recent myocardial infarction within 4–8 weeks. Perioperative BNP and CT-1 levels were measured, and hematochemical parameters were also collected. Results. Higher preoperative BNP and CT-1 levels were found in group III as compared to those in group I. BNP levels increased after operation, and reached peak value at 3–7 days after the operation. However, the postoperative changes of BNP levels were not different among groups in any time points. CT-1 levels did not change significantly after the operation as compared to baseline. Conclusion. Higher BNP and CT-1 levels were associated with recent myocardial infarction. BNP elevated after OPCAB, but CT-1 showed no significant postoperative changes. Postoperative changes of BNP and CT-1 do not associated with cardiac function in OPCAB.