CLINICAL STUDIES
Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure
Lars Gullestad, MD, PhD*,
P.ål Aukrust, MD, PhD*,
Thor Ueland, SIBa,
Terje Espevik, PhD ,
Gail Yee, SIB ,
Randall Vagelos, MD,
Stig S. Frøland, MD, PhD* and
Michael Fowler, MD, FACC
a Department of Cardiology, Medical Department B, Rikshospitalet University Hospital, Oslo, Norway
* Section of Clinical Immunology and Infectious Diseases and Research Institute for Internal Medicine, Medical Department A, Rikshospitalet University Hospital, Oslo, Norway
Institute of Cancer Research and Molecular Biology, the Norwegian University of Science and Technology, Trondheim, Norway
Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, California, USA
Manuscript received November 6, 1998;
revised manuscript received March 2, 1999,
accepted September 7, 1999.
Reprint requests and correspondence: Dr. Lars Gullestad, Medical Department B, Rikshospitalet, 0027 Oslo, Norway
lagulles{at}online.no
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Abstract
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OBJECTIVES
We examined the effect of long-term treatment with two doses of the angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological variables in patients with chronic congestive heart failure (CHF).
BACKGROUND
Immunological mediators are increasingly recognized to play a pathogenic role in the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological variables has not previously been investigated.
METHODS
Seventy-five patients (mean age 52 ± 11 years) with CHF were randomized between low- (5 mg daily) and high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of immunological parameters (i.e., proinflammatory cytokines, chemokines and adhesion molecules) were measured at baseline, at 10 weeks and at the end of the study (34 weeks).
RESULTS
All immunological parameters, except soluble interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low-dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the high-dose (p < 0.001), resulting in a significant difference in change during treatment between the two dosage groups (p < 0.001). This decrease in IL-6 bioactivity was significantly associated with decreased interventricular septum thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other variables changed during treatment.
CONCLUSIONS
In patients with severe CHF, high-dose enalapril therapy is associated with a significant decrease in IL-6 activity. However, despite treatment with a high-dose ACE inhibitor, a persistent immune activation exists in these patients which may be of importance for the progression of CHF.
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Abbreviations and Acronyms
| | ACE | = angiotensin converting enzyme | | CHF | = congestive heart failure | | CONSENSUS | = Cooperative North Scandinavian Enalapril Survival Study | | EIA | = enzyme immunoassays | | IL | = interleukin | | IVS | = interventricular septum thickness | | MCP-1 | = monocyte chemoattractant peptide-1 | | s | = soluble | | sIL-6R | = soluble interleukin-6 receptor | | TNF alpha | = Tumor necrosis factor alpha |
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Immune mediated mechanisms have recently been recognized to play an important role in the pathophysiology of a number of cardiac disorders. Enhanced immune activation has not only been found in acute disorders such as myocarditis (1) but also in chronic conditions such as congestive heart failure (CHF), reflected in increased circulating levels of various proinflammatory cytokines (i.e., tumor necrosis factor [TNF alpha], interleukin [IL]-1 and IL-6) (2–5). We have recently also demonstrated elevated circulating levels of C-C chemokines (C-C subfamily of chemokine superfamily) and various soluble adhesion molecules in chronic CHF (6,7), further indicating that immune activation is a distinct feature of this disorder.
The precise pathophysiological importance of these immunological variables is at present unclear. However, TNF alpha appears to mediate negative inotropic effects on the myocardium by various mechanisms (8–10). Furthermore, IL-6 and related cytokines have been implicated in the development of ventricular hypertrophy through enhanced stimulation of their common gp130 receptor subunit expressed on cardiac myocytes (11). Less is known about the pathophysiological role of chemokines in CHF, but we have recently demonstrated that the C-C chemokine monocyte chemoattractant peptide-1 (MCP-1) may have a direct role in the induction of oxidative stress in this disorder (6). Moreover, the levels of circulating adhesion molecules appear to reflect the expression and shedding of adhesion molecules on the surface of various cells (12), and these molecules may be of importance for the inflammatory response in the vessel wall and the myocardium (12). Thus, it is tempting to hypothesize that modulation of immunological variables could be of importance for disease progression, possibly being a therapeutic goal in the treatment of CHF.
So far there are few reports on the effects of various cardiovascular treatment regimens on cytokine levels in CHF. In vitro studies have demonstrated that the positive inotropic agents ouabain and vesnarinone can modulate the production of proinflammatory cytokines in mononuclear cells from patients with heart failure (13,14), and the calcium antagonist amlodipine appears to decrease plasma levels of immunoreactive IL-6 in patients with CHF (15). However, for the angiotensin converting enzyme (ACE) inhibitors there are no reports on how they influence cytokine levels in vivo.
The ACE inhibitors have become a cornerstone in the treatment of CHF with favorable effects on mortality and morbidity (16), but the precise mode of action is not known. In this study we examined the effect of two doses of the ACE inhibitor enalapril on various immunological variables in 75 patients with CHF for a period of 34 weeks. Angiotensin converting enzyme inhibition has also been found to reverse ventricular hypertrophy (17), and it was of particular interest to see if enalapril could modulate IL-6 activity, as this cytokine appears to be involved in the development of cardiac hypertrophy (11).
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Methods
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Patients and controls.
The study population which previously has been reported (18) consisted of 75 patients (61 men and 14 women; mean age 52 ± 11 years) with chronic symptomatic heart failure for more than three months in New York Heart Association functional class II–IV and with left ventricular ejection fraction <40% (Table 1). Their clinical and hemodynamical situations were stable with no evidence of myocardial infarction in the last three months and no change in medication in the last month. Before the study all the patients were treated with low-dose ACE inhibitors. Other standard medical treatment consisted of diuretics (100%) and digoxin (79%). Patients with significant concomitant disease such as acute and chronic infections, pulmonary disease, malignancy or collagen vascular disease were not included.
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Table 1 Clinical Characteristics of the CHF Patients Participating in the Low-Dose (5 mg/day) Versus High-Dose (40 mg/day) Enalapril Study
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Control subjects were 21 gender- and age-matched healthy blood donors (16 men and 5 women; 25 to 69 years, mean 52 years) without any history of cardiac disease.
Study design.
The study design has previously been described (18). Briefly, 86 patients entered into open labelled treatment with a low-dose of enalapril, 2.5 mg b.i.d for two weeks. During this time period, 11 withdrew (four because of adverse clinical experience; two had intolerance to enalapril, two unable to comply with study drug, two had other reasons and one patient died). The study group therefore consisted of 75 patients who were randomized between low- (5 mg daily) and high doses (40 mg daily) of enalapril in a double blind fashion. The dose was gradually increased during 8 weeks and the patients were followed for an additional 26 weeks.
Blood sampling protocol.
Blood was collected from an antecubital vein at baseline after 10 weeks and at termination of the study (34 weeks) into pyrogen-free vacuum blood collection tubes (Becton Dickinson, San Jose, California) without any additives (serum) or with EDTA as anticoagulant (plasma). Tubes were immediately immersed in melting ice and centrifuged within 15 min at 1,000 g and 4°C for 15 min (plasma) or allowed to clot for 1 h before centrifugation at 1,000 g in 10 min (serum). Both serum and plasma were stored at –80°C in multiple aliquots until analysis. Samples were thawed only once.
Enzyme immunoassays (EIAs).
TNF alpha (detection limit 3.0 pg/ml) levels in plasma were measured by EIAs (Medgenix, Fleurus, Belgium) as previously described (19) using microtiter wells coated with several monoclonal antibodies against distinct epitopes of the TNF alpha molecule. Plasma levels of IL-1 receptor antagonist (IL-1Ra, detection limit 22.0 pg/ml), IL-6 (detection limit 0.70 pg/ml), soluble (s) IL-6 receptor (sIL-6R (detection limit 3.5 pg/ml), MCP-1 (detection limit 8 pg/ml), sP-selectin (detection limit 0.5 ng/ml) and soluble vascular adhesion molecule-1 (VCAM-1, detection limit 2 ng/ml) were measured by EIAs according to the manufacturer’s instruction (R&D Systems, Minneapolis, Minnesota). Plasma levels of IL-1beta (detection limit 0.1 pg/ml) were determined by a high sensitivity EIA as recommended by the manufacturer (R&D Systems). Plasma levels of soluble TNF receptors (sTNFRs), p55 and p75, were analyzed by EIAs (detection limit between 150–300 pg/ml) as described by Liabakk et al. (20). The intra- and interassay coefficients of variation were less than 10% for all EIAs.
IL-6 bioassay.
Serum levels of IL-6 bioactivity were determined by the IL-6 dependent mouse hybridoma cell line B13.29 assay (21) at baseline and at the end of the study in all but 11 patients. The sensitivity of the assay was 4 pg/ml.
Measurements of neopterin.
Plasma levels of neopterin were determined by radioimmunoassay (IMMU test Neopterin, Henning Berlin GMBH, Berlin, Germany).
Echocardiography.
Studies were performed by an experienced sonographer and were interpreted by a single cardiologist. Echocardiography was performed with the use of a Hewlett-Packard (Hewlett-Packard Co., Medical Products Group) ULS machine, 2.5 or 3.5 mHz, combined imaging and Doppler transducer. Each patient was studied in the left lateral decubitus position after 15 min of recumbency.
Statistical analyses.
The SPSS (SPSS Inc., Chicago, Illinois) statistical package was used for statistical analysis. Differences between groups were compared with Mann-Whitney U Rank-Sum test for unpaired data. In the paired situation, multiple analysis of variance (MANOVA) were performed priori and, if significant, Wilcoxon’s Rank-Sum test for paired data was performed a posteriori. Relations between variables were tested using Spearman’s Rank-Correlation test. Data are given as medians and 25th to 75th percentiles if not otherwise stated. P values are two-sided and considered significant when <0.05. Particular attention should, however, be directed toward small p values, i.e., those below 0.01, because a considerable number of p values have been calculated.
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Results
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The clinical characteristics of the two treatment groups are given in Table 1. The two groups were similar with respect to key demographic and clinical signs of CHF. Twenty-five patients (14 in the low-dose and 11 in the high-dose group) withdrew during treatment (9 due to adverse clinical experience, 6 were transplanted, 5 died, 2 due to protocol violation and 3 for other reasons).
Circulating levels of proinflammatory cytokines and their endogenous modulators during therapy.
At baseline plasma levels of IL-1beta, IL-6 and TNF alpha as well as IL-1Ra and both types of sTNFRs (p55 and p75), but not sIL-6R, were markedly elevated among CHF patients compared with healthy control subjects (Table 2).
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Table 2 Plasma Levels of Immunological Variables at Baseline, at 10 Weeks and at End of Study (34 weeks) After Treatment With Low (LD, 5 mg/day) or High (HD, 40 mg/day) Dose of Enalapril
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While IL-6 and sIL-6R remained unchanged during treatment with low-dose enalapril, high-dose therapy caused a significant decrease in IL-6 and an increase in sIL-6R levels (Table 2). However, the difference in changes during treatment between the two regimens was not statistically significant (p = 0.3).
In contrast to the fall in IL-6 and rise in sIL-6R, plasma levels of TNF alpha and IL-1beta as well as sTNFRs and IL-1Ra did not change during enalapril therapy in either dosage groups.
Chemokines, soluble adhesion molecules and neopterin.
Plasma levels of MCP-1, a member of the C-C chemokine family, the soluble adhesion molecules sVCAM-1 and sP-selectin and levels of neopterin, known to be a nonspecific marker of monocyte/macrophage activity (22), were all significantly increased at baseline compared with healthy controls but remained unchanged during therapy irrespective of the enalapril dosage (Table 2).
IL-6 bioactivity.
Our findings suggest that the persistent immune activation in CHF patients is not modulated by enalapril treatment in either dosage group, except for a decrease in IL-6 and a rise in sIL-6R levels during high-dose therapy. In contrast to other soluble cytokine receptors, sIL-6R has an agonistic effect on IL-6 activity (23,24). To investigate the biological significance of decreased IL-6 and increased sIL-6R levels during enalapril therapy, we therefore measured IL-6 bioactivity before and at the end of enalapril treatment. As can be seen in Figure 1, IL-6 bioactivity significantly decreased from 7.5 (5.4 to 10) pg/ml to 4.4 (4.3 to 6.2) pg/ml (p < 0.001) during high-dose therapy while no change was observed during low-dose treatment (4.8 [4.3 to 7.5] pg/ml to 4.6 [4.3 to 7.3] pg/ml). Furthermore, there was a significant difference in changes observed during treatment between the two enalapril dosage groups (Fig. 1, p < 0.001). In fact, during high-dose enalapril, 28 patients had a decrease in IL-6 bioactivity while only three and one had no change or an increase in IL-6 bioactivity, respectively. Thus, during high-dose enalapril therapy in CHF patients, there is a significant decrease in IL-6 levels as measured by both immuno- and bioassays, and as for IL-6 bioactivity, the response to enalapril was significantly different between the two dosage groups.
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Figure 1 Plasma levels of IL-6 bioactivity in CHF patients during therapy with low dose (5 mg/daily) and high dose (40 mg/daily) of enalapril at baseline and at end of study. The upper panel (A) shows the absolute concentrations of IL-6 bioactivity during therapy. ***p < 0.001 versus baseline. The lower panel (B) shows the changes in IL-6 bioactivity during therapy (concentration at the end of study—baseline levels). #p < 0.001 versus low-dose group. Data in box plots are given as medians, 25th–75th percentiles and ranges.
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There was a tendency for a positive correlation between changes in IL-6 bioactivity and immunoreactive IL-6 (r = 0.32, p = 0.66) but not between IL-6 bioactivity and sIL-6R (r = –0.08, ns). At baseline there was a slight but significant difference in IL-6 bioactivity between high- and low-dose enalapril with the highest levels in the high dose group (Fig. 1). However, in this latter group both patients with high and low baseline levels demonstrated a significant decrease in IL-6 bioactivity (data not shown).
Association between IL-6 levels and reduction in left ventricular hypertrophy.
Interleukin-6 has been suggested to play a role in the development of cardiac hypertrophy (11). We therefore next looked at the association between changes in IL-6 levels and indexes of left ventricular wall thickness as assessed by echocardiography (18). While posterior wall thickness remained unchanged, interventricular septum thickness (IVS) decreased significantly from 1.01 to 0.91 cm (p < 0.05) during high-dose treatment while no change was observed during the low dose (Table 3). In the high-dose enalapril group there was a significant positive correlation between changes in IL-6 bioactivity and IVS (r = 0.56, p = 0.013, Fig. 2), while no such relationship was found during low-dose treatment (r = –0.23, p = 0.31).
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Table 3 Echocardiographic Characteristics of the CHF Patients Participating in the Low-Dose (5 mg/day) Versus High-Dose (40 mg/day) Enalapril Study
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Figure 2 Correlation between change in levels of IL-6 bioactivity and change in interventricular septum thickness (IVS) measured by echocardiography during treatment with high-dose enalapril.
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Discussion
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In this study we demonstrate for the first time that ACE inhibitor therapy decreased IL-6 activity in circulation in CHF patients as measured by both immuno- and bioassay. The decrease in IL-6 activity was only observed with a high dose of ACE inhibition and as for IL-6 bioactivity the response to enalapril was significantly different between the two dosage groups, supporting previous studies suggesting that high-dose ACE inhibition is superior to low dose with regard to clinical effects (25). Furthermore, although there was a decrease in circulating IL-6 levels, even high-dose long-term treatment with enalapril did not normalize IL-6 levels and, more importantly, such therapy appears not to decrease the levels of other immunological parameters reflecting persistent immune activation in CHF.
Effect of cardiovascular therapy on cytokine levels.
There has recently been a growing interest in the contribution of cytokine activation in the pathophysiology of chronic CHF with its possible effect on myocardial contractility and remodeling (26), and the concept of immunomodulatory therapy has emerged as an option (27). There are, however, few data on how traditional medications used in this condition influence relevant cytokine levels in humans. A recent study with the dihydropyridine calcium channel blocker, amlodipine, demonstrated an improvement in exercise time which was associated with a reduction in serum neopterin levels (28) and a reduction in levels of immunoreactive IL-6 has been suggested to be of importance for the beneficial effect of this agent on mortality in patients with idiopathic dilated cardiomyopathy (15). As for the ACE inhibitors, no data have so far been available.
Effect of enalapril on the persistent immune activation in CHF.
Except for a favorable effect on the IL-6 system, all of the other immunological parameters measured were markedly elevated in CHF patients and remained unchanged during treatment with either dose of enalapril. Our results therefore confirm the findings from several cross-sectional observations demonstrating elevated circulating levels of various proinflammatory cytokines in CHF (2–5). However, there are very few longitudinal studies of cytokine levels in CHF, and this study demonstrated that the elevation of several immunological parameters in CHF patients persists during longitudinal testing and during optimal cardiovascular therapy including high-dose ACE inhibitors. The pathophysiological importance of this finding remains to be determined, but several of the immunological parameters studied may impair cardiac function, e.g., TNF alpha, IL-1 and MCP-1 (6,8,9,29–31). One might speculate that this persistent immune activity contributes to the high mortality and the continuous left ventricular remodeling in this patient group despite intensive treatment with ACE inhibitors in addition to optimal standard CHF medication (32).
Effect of enalapril therapy on IL-6.
In contrast to the persistent elevation of the other immunological variables, we found a significant reduction in circulating IL-6 levels during high-dose ACE inhibitor therapy as evaluated by both immuno- and bioassay. The human IL-6 gene is transcriptionally inducible in several different cell types in response to various inflammatory cytokines such as IL-1 and TNF alpha (23,24). However, in this study there was no reduction in levels of either of these cytokines, possibly suggesting a selective decrease in IL-6 activity during enalapril therapy in CHF. Interestingly, it has recently been shown that ACE inhibition as well as angiotensin II receptor type I antagonist may decrease the activation of NFkappaB at least partly involving redox-sensitive signaling events (33,34), and such a mechanism may also possibly be involved in the IL-6 inhibitory effect of enalapril. However, we found no effect of ACE inhibition on other cytokines known to be influenced by NFKappaB activation (e.g. MCP-1 and TNF alpha), and the mechanism for the selective decrease in IL-6 levels during ACE inhibitor treatment remains unclear.
Reduction in ventricular hypertrophy during enalapril therapy—a consequence of decreased IL-6 levels?.
Whatever the reason, this reduction in IL-6 activity may be of clinical importance. Angiotensin converting enzyme inhibitor therapy is known to reduce ventricular hypertrophy, but the mechanisms for this effect have not been clarified. Several studies in animal models demonstrate that IL-6 and related cytokines (e.g., leukemia inhibitory factor and cardiotrophin-1), through stimulation of their common receptor subunit gp130 in cardiomyocytes, are potent inducers of cardiac hypertrophy (11,35). It may well be that the reducing effect of ACE inhibition on cardiac hypertrophy at least partly is mediated by reduction of IL-6 levels. In this study the fall in levels of IL-6 bioactivity and the reduction of IVS was positively correlated, further supporting such a notion. Interestingly, ACE inhibition was recently found to inhibit the stimulatory effect of IL-6 (36), possibly by interfering with the JAK/STAT pathway (11,37). Thus, it is possible that an important "antihypertrophic" mechanism of ACE inhibitors on human myocardium may be a reduction in IL-6 levels possibly combined with an impairment of the IL-6 signal transduction.
Study limitations.
A limitation of this study is that all patients were treated with low-dose ACE inhibitors at the time of baseline blood sampling, and we do not know the effect of enalapril on "ACE inhibitor naive" patients. Preliminary results from the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) I trial demonstrated that enalapril did not modify plasma levels of TNF alpha, neopterin or prostaglandin E2 after six weeks in severe CHF (38). Thus, in the CONSENSUS trial, the effect of enalapril on hormonal levels seems to be dissociated from its effect on cytokines (16), which was also the case in this study (18). Whether this is also the case in milder form of CHF remains to be determined.
Another major limitation of this study was the lack of any placebo group. Although only IL-6 levels were found to decline during high-dose therapy, we cannot exclude that ACE inhibition may have some effects on levels of other cytokines measured. It is possible that the "natural history" of cytokine levels in CHF patients without ACE inhibition is a gradual increase as is the case for neurohormones (39). However, a major point in this study was that whatever the degree of immune activation that might exist without ACE inhibition, a high degree of immune activation persisted even during long-term high-dose ACE inhibition.
Another important question is whether the fall in IL-6 activity represents a true biological effect or simply reflects a statistically significant finding by chance. We believe that our observations represent a biological effect of enalapril therapy. First of all, the fall in immunoreactive IL-6 was not the only effect of high-dose enalapril, but was associated with an increase in sIL-6R and a decrease in IL-6 bioactivity. Moreover the changes were already observed after 10 weeks of therapy.
Conclusions.
This study supports the notion that high- dose ACE inhibitor therapy is superior to a low-dose therapy in the management of CHF patients. During high-dose enalapril there was a marked decrease in IL-6 activity in the circulation, and this decrease in IL-6 levels might be of importance for the reduction of ventricular hypertrophy seen during such therapy. However, despite "optimal" treatment of CHF, including a high dose of ACE inhibitor, a high degree of immune activation seems to persist. More specific immunomodulating treatment modalities therapy may be warranted in management of CHF patients.
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Acknowledgments
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We thank Bodil Lunden for excellent technical assistance.
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Footnotes
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This study was supported by Medinova Foundation, Rikshospitalet and by Merck Sharp and Dohme AS.
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E. M. Mortensen, M. J. Pugh, L. A. Copeland, M. I. Restrepo, J. E. Cornell, A. Anzueto, and J. A. Pugh
Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia
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Cardiac Function, Inflammatory Mediators and Mortality in Critical Limb Ischemia
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J. E Morley, D. R Thomas, and M.-M. G Wilson
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D. S Roffman
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N. Sattar, A. McConnachie, D. O'Reilly, M. N. Upton, I. A. Greer, G. D. Smith, and G. Watt
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S. Adamopoulos, J. T. Parissis, I. Paraskevaidis, D. Karatzas, E. Livanis, M. Georgiadis, G. Karavolias, D. Mitropoulos, D. Degiannis, and D. Th. Kremastinos
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M. Jessup and S. Brozena
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N. Sattar, C. G Perry, and J. R Petrie
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The British Journal of Diabetes & Vascular Disease,
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S. E. Lipshultz, S. R. Lipsitz, S. E. Sallan, V. C. Simbre II, S. L. Shaikh, S. M. Mone, R. D. Gelber, and S. D. Colan
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D. L. Mann
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B. J. Holycross and M. J. Radin
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T. S. Han, N. Sattar, K. Williams, C. Gonzalez-Villalpando, M. E.J. Lean, and S. M. Haffner
Prospective Study of C-Reactive Protein in Relation to the Development of Diabetes and Metabolic Syndrome in the Mexico City Diabetes Study
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C. Kluft, R. Kleemann, and M.P.M. de Maat
How best to counteract the enemies? By controlling inflammation in the coronary circulation
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J. B. Young
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Abstract
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