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Exercise training reduces serum capacity to induce endothelial cell death in patients with chronic heart failure
Abstract and Figures
Physical training improves endothelial function and exercise capacity in patients with heart failure (HF). Serum from patients with cardiovascular diseases increases apoptosis of human endothelial cells suggesting the importance of humoral factors in the progression of the disease. We evaluated whether exercise training influences the apoptotic capacity of serum from patients with chronic HF (CHF).
The study included 39 patients with HF (NYHA II) and 10 age-matched healthy controls. Patients were allocated to either a structured programme of exercise training (24 patients) or standard care (15 patients). Human umbilical vein endothelial cells (HUVECs) were incubated with a medium containing 20% serum obtained before and after either a 3-week exercise training programme or standard care. At baseline, serum from patients with CHF induced a higher degree of lactate dehydrogenase (LDH) release and apoptosis in HUVECs compared with healthy controls (43 ± 1.5 vs. 16 ± 1.1%, P< 0.001 and 67 ± 5.4 vs. 23 ± 5.8%, P< 0.001, respectively). Exercise training significantly increased performance in the 6 min walking test (+34.7%) and reduced the ability of serum to induce LDH release and apoptosis of HUVECs. The reduction of apoptosis after exercise training correlated with the improvement in functional capacity. The expression of the apoptosis markers Bax and Caspase-3 was significantly reduced in HUVECs exposed to serum collected after exercise training. Circulating tumour necrosis factor-alpha, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were significantly reduced by exercise training and the MMP-9/TIMP-1 ratio increased.
A short term in-hospital structured cardiovascular training programme reduces the ability of serum-derived factors to induce endothelial cell death in patients with CHF.
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... In this study, we demonstrated that SPPB may have additional value in oncology and particularly in older patients with hematological malignancies. The notion that improvements in physical function may co-exist with reductions in serum LDH levels has also been demonstrated in patients with chronic heart failure [41]. Specifically, patients who underwent 3 weeks of aerobic training but not controls experienced a 34.7% improvement in the 6 minute-walk test [41]. ...
... The notion that improvements in physical function may co-exist with reductions in serum LDH levels has also been demonstrated in patients with chronic heart failure [41]. Specifically, patients who underwent 3 weeks of aerobic training but not controls experienced a 34.7% improvement in the 6 minute-walk test [41]. Additionally, serum from intervention but not control participants at the end of the study led to a significant reduction of LDH release from endothelial cells compared to baseline serum, indicating reduced cell apoptosis and improved endothelial health [41]. ...
... Specifically, patients who underwent 3 weeks of aerobic training but not controls experienced a 34.7% improvement in the 6 minute-walk test [41]. Additionally, serum from intervention but not control participants at the end of the study led to a significant reduction of LDH release from endothelial cells compared to baseline serum, indicating reduced cell apoptosis and improved endothelial health [41]. LDH levels increase in response to injury, hemolysis, myocardial infarction, and hypoxia [42]. ...
Background
Lactate dehydrogenase (LDH) reflects tumor burden and is a prognosticator of all-cause mortality in patients with cancer. Objective measures of physical function are associated with clinically relevant outcomes in older adults with cancer. However, whether physical function is associated with LDH in geriatric oncology is unknown. The objective of this study was to assess the relationship between objective measures of physical function and serum LDH in older adults with cancer prior to treatment.
Methods
Data from older adults with cancer prior to treatment were retrieved from an institutional database and medical records within a tertiary cancer centre. Physical function measures involved muscle strength and physical performance. Muscle strength and physical performance were assessed through grip strength and the Short Physical Performance Battery (SPPB), respectively. LDH was log transformed using the natural logarithm. Multivariable logistic regression was used to examine the relationship between objective measures of physical function and LDH prior to treatment in all participants. Stratified analyses were performed for participants with solid and hematological cancers.
Results
A total of 257 participants (mean age: 80.2y) were included in the analysis. Most participants were females (50.6%) and were diagnosed with locally advanced (26.8%), gastrointestinal disease (35.0%). The multivariable analysis indicated that SPPB was inversely associated with LDH in all participants (B = -0.019, 95%CI = -0.036 to -0.002, p = 0.028). Notably, the inverse relationship between SPPB and LDH persisted only in patients with hematological malignancies in the multivariable model of the stratified analysis (B = -0.049, 95%CI = -0.087 to -0.011, p = 0.013). Neither grip strength alone nor the combination of low grip strength and/or SPPB were associated with LDH. Compared to participants with metastatic disease, those with localized or locally advanced disease had lower serum LDH.
Conclusion
Physical performance is inversely associated with serum LDH in older adults with hematological cancers prior to treatment.
... An augmentation in TIMP-1 expression preceded the increased expression of TIMP-2 (24). Furthermore, Mammi et al observed that in patients with heart failure, serum levels of TIMP-1 can be decreased by physical exercise (25). Notably, Ramirez Correa et al (26) used local TIMP-1 gene transfer and achieved a significant reduction of restenosis in human coronary smooth muscle cells. ...
... The results of the present study indicated that EDPs may increase the production of TIMPs. The results of these two studies (24,25) and the present study can make one raise a question about an influence of EDPs on coronary arteries, whether EDPs may be deleterious or beneficial in certain circumstances. TIMP-2 also exhibits angioinhibitory properties, which comprise several mechanisms, including MMP inhibition or direct EC binding (27). ...
... A number of studies have calculated and analyzed various TIMP/MMP ratios (21,25). However, the present study was the first to calculate the ratios for three TIMP indicators: TIMP-1/TIMP-2, TIMP-1/TIMP-3 and TIMP-2/TIMP-3. ...
Tissue inhibitors of metalloproteinases (TIMPs) control the activity of metalloproteinases. Elastin‑derived peptides (EDPs) are generated as a result of the degradation of elastin fibers. The EDPs bind to the elastin receptor and exert numerous biological effects. The aim of the present study was to compare the production of TIMP‑1, TIMP‑2 and TIMP‑3 and their ratios in human endothelial cells (ECs) derived from three clinically important vascular localizations (coronary arteries, aorta and iliac artery), and evaluate the influence of a well‑known EDP, κ‑elastin. The highest concentration of TIMP‑1 was identified in the aortic ECs, while the lowest concentration was observed in the ECs derived from the coro‑ nary artery. The opposite pattern was observed for TIMP‑2 production. When the TIMP‑3 concentration was analyzed in the three EC lines, no statistically significant differ‑ ences were observed. Application of κ‑elastin was found to decrease the TIMP‑1 concentration in the aortic ECs, while an increase in the TIMP‑1 concentration was observed in the ECs derived from the iliac artery. The most significant decrease in TIMP‑2 concentration following κ‑elastin admin‑ istration was observed in the ECs obtained from the coronary arteries. Furthermore, the highest concentration of κ‑elastin resulted in an increase in TIMP‑3 production in the ECs derived from the coronary arteries. The following ratios of the TIMP concentrations were calculated: TIMP‑1/TIMP‑2, TIMP‑1/TIMP‑3 and TIMP‑2/TIMP‑3. Each ratio presented different values for the ECs obtained from the various local‑ izations. In the majority of cases, the addition of κ‑elastin did not significantly change these proportions. Therefore, these indicators may be characteristic features that can be used to describe ECs in various clinically important vascular localizations.
... In this context, a set of substantial evidence reveals that aerobic training is powerful enough to bolster the function of the endothelial system in HF patients [141,142]. To deliver endothelium benefits to patients with HF, aerobic training increases basal endothelial NO production [143], improves circulating endothelial progenitor cells (EPCs) [144], and promotes plasma total antioxidant capacity [145], whereas dampens levels of circulating pro-inflammatory TNF-α [146], and, most intriguingly, limits the capacity of serum-contained agents taken from individuals living with HF to instigate ex vivo endothelial cell apoptosis [146]. ...
... In this context, a set of substantial evidence reveals that aerobic training is powerful enough to bolster the function of the endothelial system in HF patients [141,142]. To deliver endothelium benefits to patients with HF, aerobic training increases basal endothelial NO production [143], improves circulating endothelial progenitor cells (EPCs) [144], and promotes plasma total antioxidant capacity [145], whereas dampens levels of circulating pro-inflammatory TNF-α [146], and, most intriguingly, limits the capacity of serum-contained agents taken from individuals living with HF to instigate ex vivo endothelial cell apoptosis [146]. ...
By definition, heart failure (HF) is a human pathological condition affecting the structure and function of all organs in the body, and the brain is not an exception to that. Failure of the heart to pump enough blood centrally and peripherally is at the foundation of HF patients' inability to attend even the most ordinary daily activities and progressive deterioration of their cognitive capacity. What is more, between heart and brain exists a bidirectional relationship that goes well beyond hemodynamics and concerns bioelectric and endocrine signaling. This increasingly consolidated evidence makes the scenario even more complex. Studies have mainly chased how HF impairs cognition without focusing much on preventive measures, notably cardio-cerebral health proxies. Here, we aim to provide a brief account of known and hypothetical factors that may explain how exercise can help obviate cognitive dysfunction associated with HF in its different forms. As we shall see, there is a stringent need for a deeper grasp of such mechanisms. Indeed, gaining this new knowledge will automatically shed new light on the inner workings of HF itself, thus resulting in more effective prevention and treatment of this escalating syndrome.
... The serum cTnT level is raised in patients with HF and correlates negatively with cardiac function . Serums from patients with chronic cardiac failure have been shown to induce a higher level of LDH and apoptosis (Mammi et al., 2011). In the context of ISO induced HF, Sigmar1 knockout aggravated ISO-induced ventricular remodeling and further reduced cardiac function when compared with WT-ISO mice. ...
Introduction
Heart failure (HF) is usually the end stage of the continuum of various cardiovascular diseases. However, the mechanism underlying the progression and development of HF remains poorly understood. The sigma-1 receptor (Sigmar1) is a non-opioid transmembrane receptor implicated in many diseases, including HF. However, the role of Sigmar1 in HF has not been fully elucidated.
Methods
In this study, we used isoproterenol (ISO) to induce HF in wild-type (WT) and Sigmar1 knockout (Sigmar1 −/− ) mice. Multi-omic analysis, including microbiomics, metabolomics and transcriptomics, was employed to comprehensively evaluate the role of Sigmar1 in HF.
Results
Compared with the WT-ISO group, Sigmar1 −/− aggravated ISO-induced HF, including left ventricular systolic dysfunction and ventricular remodeling. Moreover, Sigmar1 −/− exacerbated ISO-induced gut microbiota dysbiosis, which was demonstrated by the lower abundance of probiotics g_Akkermansia and g_norank_f_Muribaculaceae, and higher abundance of pathogenic g_norank_f_Oscillospiraceae and Allobaculum. Furthermore, differential metabolites among WT-Control, WT-ISO and Sigmar −/− -ISO groups were mainly enriched in bile secretion, tryptophan metabolism and phenylalanine metabolism, which presented a close association with microbial dysbiosis. Corresponding with the exacerbation of the microbiome, the inflammation-related NOD-like receptor signaling pathway, NF-kappa B signaling pathway and TNF signaling pathway were activated in the heart tissues.
Conclusion
Taken together, this study provides evidence that a Sigmar1 knockout disturbs the gut microbiota and remodels the serum metabolome, which may exacerbate HF by stimulating heart inflammation.
... LDH is released from dying cells and can be used to assess cellular death. 21 As shown in Figure 5, the combination of 10 μM menthol and 10 μM allethrin could reduce LDH release and alleviate cell injury compared with the GD group, indicating that menthol−allethrin had convincing cardioprotective properties. ...
... Since reactive oxygen species and ammonia are main causes of muscle fatigue, our data and these previous reports indicate the beneficial effect of KME on the accumulation of muscle fatigue. In the previous reports, long-term exercise training (3-4 weeks) was reported to decrease the plasma levels of LDH in heart failure patients (Mammi et al. 2011) and healthy humans (Messonnier et al. 2005). However, under our experimental condition, the plasma LDH levels of exercise-trained mice were greater than those of sedentary control mice after high-intensity exercise (Figure 2). ...
Many investigators have screened drugs and foods for the enhancement of endurance capacity and antifatigue. Mistletoe, a semiparasitic plant on various deciduous trees, has many known biological activities, including anticancer, anti-diabetes, antioxidant, and anti-cardiovascular disease effects. In a previous study, Korean mistletoe extract (KME) was reported to increase endurance capacity in mice. However, whether the administration of KME further enhances exercise performance, when combined with exercise training, was not investigated. In this study, we demonstrate that the administration of KME decreases the level of plasma lactate dehydrogenase, parameter of tissue damage and muscle fatigue when combined with exercise training. Exercise training increases the muscular glycogen and plasma free fatty acid (FFA) level, and KME administration in sedentary mouse group increases the plasma FFA level, indicating that KME administration alters the energy resources in muscle. In addition, KME administration enhances the exercise performance in sedentary mouse group, but did not further enhance exercise performance when combined with exercise training, suggesting that KME could be an excellent mimetic of exercise.
... 4. Antiapoptotic effects, such as decreased mitochondrial apoptotic signaling and endothelial cell apoptotic capacity. [109][110][111][112] ...
The importance of regular physical activity in essential hypertension has been extensively investigated over the last decades
and has emerged as a major modifiable factor contributing to optimal blood pressure control. Aerobic exercise exerts its beneficial
effects on the cardiovascular system by promoting traditional cardiovascular risk factor regulation, as well as by favorably
regulating sympathetic nervous system (SNS) activity, molecular effects, cardiac, and vascular function. Benefits of resistance
exercise need further validation. On the other hand, acute exercise is now an established trigger of acute cardiac events.
A number of possible pathophysiological links have been proposed, including SNS, vascular function, coagulation, fibrinolysis,
and platelet function. In order to fully interpret this knowledge into clinical practice, we need to better understand the
role of exercise intensity and duration in this pathophysiological cascade and in special populations. Further studies in
hypertensive patients are also warranted in order to clarify the possibly favorable effect of antihypertensive treatment on
exercise-induced effects.
Mechanisms underlying the protective effects of both habitual endurance exercise and the female sex on vascular function are incompletely understood. Blood-borne circulating factors, such as circulating microRNAs (ci-miRs), may partially explain these effects. Blood samples were obtained from young, healthy men and women who either habitually performed endurance exercise (trained) or were relatively inactive (sedentary). Women were tested during the early follicular phase of the menstrual cycle or placebo pill of oral contraceptive to control for estrogen. Cultured human umbilical vein endothelial cells (HUVEC) were exposed to participants' serum in migration, proliferation, and reactive oxygen species (ROS) assays. RT-qPCR was used to quantify an initial array of 84 CVD-related ci-miRs, followed by validation of 10 ci-miRs. All participants were devoid of traditional CVD risk factors, and circulating estradiol concentration was not different between groups. Serum of trained women induced greater HUVEC migration compared with serum of sedentary women. HUVEC ROS production was greater in response to serum of sedentary men compared to trained men and sedentary women. There were sex-effects on the levels of 9 ci-miRs, with greater levels in men, while ci-miRs-140-5p and 145-5p were also higher in sedentary compared to trained men and/or women. In a sex-specific manner, habitual endurance exercise was associated with beneficial effects of serum on HUVECs. Thus, alterations in circulating factors may contribute to the protective effects of habitual endurance exercise on vascular health. Additionally, sex had a greater impact than habitual activity level on the levels of vascular-related ci-miRs.
Following acute exercise, normotensive and hypertensive subjects both undergo changes in hemostatic and fibrinolytic properties, but the hypertensive patient’s response to exercise is exaggerated and prolonged, exposing them to increased cardiovascular risk during or immediately after unusual and strenuous exercise. Thrombotic complications are triggered by the activation of the autonomic sympathetic nervous system in a pathological milieu characterized by platelet α2-adrenergic receptors with increased responsiveness to circulating catecholamine, altered platelet profile and function, abnormal hemostatic parameters, impaired fibrinolytic potential, and endothelial dysfunction. The recovery period is particularly dangerous for triggering adverse cardiovascular events because the balance between the thrombotic and fibrinolytic systems is temporarily shifted toward increased pro-coagulative activity. This review highlights the analogies, similarities, and differences between normotensive and hypertensive subjects regarding the acute exercise-induced changes to the hemostatic and fibrinolytic properties, showing what differentiates essential hypertension from physiological status.
Abbreviations : HT, hypertensive; METs, metabolic equivalents; min, minutes; MPA, monocyte-platelet aggregates; NT, normotensive; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen activator; VO2 max, maximal oxygen consumption.
مقدمه: هدف از اجرای این پژوهش، بررسی تأثیر مکملدهی زعفران بر متالوپروتئینهای ماتریکس 9 (Matrix metallopeptidase 9 یا MMP9) و کسر جهشی به دنبال تمرین شدت بالا در بیماران پیوند عروق کرونری بود.
روشها: پژوهش حاضر از نظر روششناسی به روش نيمهتجربي و از نوع کاربردي بود. تعداد 30 نفر از بیمارانی که حدود یک ماه از عمل جراحی آنها گذشته بود، انتخاب و به طور تصادفی در گروهها قرار گرفتند. گروه تناوبی شدید در هر جلسه دو زمان 10 دقیقهای (15 ثانیه فعالیت با 100 درصد برونده اوج توان و 15 ثانیه استراحت غیر فعال و 4 دقیقه استراحت بین دو نوبت 10 دقیقهای) به فعالیت پرداختند. گروه مکمل در کنار تمرین روزانه، 300 میلیگرم مکمل زعفران را بعد از وعدهی ناهار مصرف نمودند. قبل و پس از اجرای شیوهنامه، نشانگرهای آنژیوژنز مورد اندازهگیری قرار گرفتند. از آزمون ANOVA و آزمون تعقیبی Bonferroni به ترتیب برای تعیین اختلاف و تشخیص محل تفاوت استفاده شد. تمام تحلیلهای آماری در سطح 050/0 > P انجام شد.
یافتهها: اجرای تمرینات تناوبی باعث عدم افزایش معنیداری در مقدار عامل MMP9، افزایش معنیداری در کسر جهشی در بین گروههای تمرین و تمرین با مکمل نسبت به گروه شاهد شد (050/0 > P).
نتیجهگیری: تمرین تناوبی باعث عدم افزایش معنیدار عامل MMP9 و افزایش کسر جهشی تمرینی ایمن و مؤثر در بهبود عوامل آنژیوژنز و میزان تخلیهی خون در بیماران پس از عمل پیوند عروق کرونری میشود.
Cardiac patients after an acute event and/or with chronic heart disease deserve special attention to restore their quality of life and to maintain or improve functional capacity. They require counselling to avoid recurrence through a combination of adherence to a medication plan and adoption of a healthy lifestyle. These secondary prevention targets are included in the overall goal of cardiac rehabilitation (CR). Cardiac rehabilitation can be viewed as the clinical application of preventive care by means of a professional multi-disciplinary integrated approach for comprehensive risk reduction and global long-term care of cardiac patients. The CR approach is delivered in tandem with a flexible follow-up strategy and easy access to a specialized team. To promote implementation of cardiac prevention and rehabilitation, the CR Section of the EACPR (European Association of Cardiovascular Prevention and Rehabilitation) has recently completed a Position Paper, entitled 'Secondary prevention through cardiac rehabilitation: A condition-oriented approach'. Components of multidisciplinary CR for seven clinical presentations have been addressed. Components include patient assessment, physical activity counselling, exercise training, diet/nutritional counselling, weight control management, lipid management, blood pressure monitoring, smoking cessation, and psychosocial management. Cardiac rehabilitation services are by definition multi-factorial and comprehensive, with physical activity counselling and exercise training as central components in all rehabilitation and preventive interventions. Many of the risk factor improvements occurring in CR can be mediated through exercise training programmes. This call-for-action paper presents the key components of a CR programme: physical activity counselling and exercise training. It summarizes current evidence-based best practice for the wide range of patient presentations of interest to the general cardiology community.
To study the role of extracellular proteolysis and antiproteolysis during adaptive arteriogenesis (collateral vessel growth) we took 58 collaterals at various developmental stages from 14 dogs with chronic occlusion of the left circumflex coronary artery (LCx) by ameroid constrictor. Immunofluorence and quantitative immunofluorescence with antibodies against α-smooth muscle actin, desmin, matrix metalloproteinases 2 (MMP-2), MMP-9. tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2). urokinase-type plasminogen activator (u-PA) and its inhibitor-1 (PAI-1) were studied with confocal microscopy. Additionally, SDS-PAGE zymography was employed, We found that in normal coronary arteries. MMP-2. MMP-9 and PAI-1 were present in all layers of the wall in small amounts. TIMP-1 was found only in smooth muscle cells. In contrast, in growing collaterals, MMP-2 and MMP-9 were 3.4-fold and 4.1-fold higher in the neointima than in the media respectively. TIMP-1 was 4.4-fold higher in the media over the growing neointima. Zymography showed MMP-2 and MMP-9 activated. PAI-1 was increased, especially in the growing neointima where it was 1.4-fold higher. In mature collaterals. MMP-2 and MMP-9 were downregulated in the neointima, 1.4-fold and 1.3-fold higher over the media. TIMP-1 was 1.4-fold increased in the neointima but PAI-1 was downregulated. Desmin and α-smooth muscle actin were significantly increased in the neointima compared to growing vessels. U-PA was moderately increased in growing vessels. TIMP-2 was not detectable in collaterals. We conclude that expression of MMP-2 and 9. TIMP-1 and PAI-1 showed a spatial and temporal pattern which is closely associated with the development of collateral vessels. The shift of the balance between proteolysis and antiproteolysis is regulated not only by MMPs and TIMP-1, but also by the PA-PAI system.
Objectives:
This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization.
Background:
Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is.
Methods:
Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group.
Results:
Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels.
Conclusions:
Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.
Objectives:
This study sought to determine the circulating levels of cytokines and their respective endogenous modulators in patients with congestive heart failure of variable severity.
Background:
Activation of immune elements localized in the heart or periphery, or both, may promote release of cytokines in patients with congestive heart failure. Although an increased circulating level of tumor necrosis factor-alpha (TNF-alpha) and its soluble receptor type II (sTNF-RII) is well documented, less is known about other cytokines (i.e., interleukin-1-beta [IL-1-beta], interleukin-6 [IL-6] and interleukin-2 [IL-2] and their soluble receptor/receptor antagonists).
Methods:
Circulating levels of TNF-alpha and sTNF-RII, IL-1-beta, IL-1 receptor antagonist (IL-1-Ra), IL-6, IL-6 soluble receptor (IL-6-sR), IL-2 and IL-2 soluble receptor-alpha were measured using enzyme-linked immunosorbent assay kits (Quantikine, R&D Systems) in 80 patients with congestive heart failure due to coronary artery disease or hypertension. The severity of their symptoms, which ranged from New York Heart Association functional class I to IV, was confirmed by measurement of peak oxygen consumption.
Results:
The percentage of patients with elevated levels of cytokines and their corresponding soluble receptor/receptor antagonists significantly increased with functional class. For TNF-alpha and IL-1-beta, the percentage of patients with elevated levels of soluble receptor/receptor antagonists was higher than that of patients with elevated levels of the cytokine itself. For IL-6, the percentage of patients with elevated levels of IL-6-sR tended to be lower than that of patients with elevated levels of IL-6. All but two patients had undetectable levels of IL-2, and all but seven had levels of IL-2-sR within a normal range.
Conclusions:
In patients with congestive heart failure, circulating levels of cytokines increased with the severity of symptoms. In these patients, circulating levels of sTNF-RII and IL-1-Ra are more sensitive markers of immune activation than are circulating levels of TNF-alpha and IL-1-beta, respectively. Levels of IL-2 and IL-2-sR are not elevated when congestive heart failure is due to coronary artery disease or hypertension.