© 2003 European Society of Cardiology
The prognostic value of circulating soluble cell adhesion molecules in patients with chronic congestive heart failure
a Division of Cardiology, Cheng-Hsin General Hospital 45, Cheng-Hsin Street, Pei-Tou, Taipei, Taiwan, ROC
b Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
c Faculty of Medicine, National Yang-Ming University, School of Medicine Taipei, Taiwan, ROC
d Division of Cardiology, Taipei Veterans General Hospital Taipei, Taiwan, ROC
e Department of Internal Medicine, Cheng-Hsin General Hospital 45, Cheng-Hsin Street, Pei-Tou, Taipei, Taiwan, ROC
* Corresponding author. Tel./fax: +886-2-28261242 E-mail address: yin.wh{at}msa.hinet.net
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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Background: Circulating soluble (s) cell adhesion molecules (CAMs) are elevated in patients with congestive heart failure (CHF) and may play an important role in the pathogenesis of CHF by mediating the cell–cell interactions of the immune response. However, clinical data about the prognostic value of sCAMs are sparse. The purpose of this study is to determine whether various sCAMs can provide prognostic information in patients with CHF.
Methods: We measured circulating levels of three sCAMs (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and sP-selectin) in 74 patients with symptomatic chronic CHF and left ventricular ejection fraction (LVEF) <50%. We compared these levels with those of a group of 19 age-matched control subjects. Major adverse cardiac events (death, heart transplantation or hospitalization with worsening CHF) during a median follow-up period of 240 days were determined.
Results: The concentrations of the three sCAMs in the 74 patients with CHF were significantly associated with one another. Their levels were higher than those of the control subjects and increased with the severity of CHF. Significantly higher sCAM levels were noted in those patients who had major adverse cardiac events during the follow-up period. There were significant negative correlations between LVEF and sCAMs. However, only high levels of sP-selectin were found to be an independent significant predictor of CHF by Cox proportional hazards analysis.
Conclusions: These findings indicate that the levels of these three sCAMs increase with the severity of CHF and are related to clinical outcomes. Among them, high levels of sP-selectin can provide prognostic information independently in patients with CHF.
Key Words: Cell adhesion molecules • Congestive heart failure • Major adverse cardiac event • Left ventricular ejection fraction
Received May 24, 2002; Revised October 3, 2002; Accepted November 20, 2002
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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Recent studies suggest a role for immunologic and inflammatory processes in the pathogenesis of congestive heart failure (CHF) [1–4]. Cytokines such as tumor necrosis factor-alpha (TNF-
) and interleukin-6 are significantly elevated, producing negative inotropic effects on the heart, and the levels of these cytokines may be negatively associated with prognosis [2–6]. The interaction between endothelial cells, leukocytes and platelets involves various cell adhesion molecules (CAMs), and the CAMs may play an important role in the biologic activity of cytokines by mediating the cell–cell interactions of the immune response [7–13]. Circulating soluble (s) isoforms of CAMs reflect enhanced expression and/or enhanced shedding of the CAMs, and are elevated in patients with CHF [7,8,14]. Until now, however, only the level of soluble intercellular adhesion molecule-1 (sICAM-1) has been reported to be related to adverse clinical outcomes in patients with CHF [7]. Because the expression of each CAM is regulated differently, different patterns among the different sCAMs on serial measurements after heart-failure treatment or heart transplantation have been found over time [7,8]. This study measures the circulating levels of sICAM-1, soluble vascular cell adhesion molecule-1 (sVCAM-1) and sP-selectin, and determines their relations to each other and to clinical outcomes in patients with chronic CHF.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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2.1. Patient population
Seventy-four patients (50 men and 24 women, aged 46–76 years (mean 61±15)) with chronic CHF were enrolled from inpatient cardiology services at Cheng-Hsin General Hospital. Patients were included if, at the time of enrolment, they had New York Heart Association (NYHA) class II to IV symptoms of heart failure and a left ventricular ejection fraction (LVEF) of <50% by left ventriculography with radionuclide or contrast medium. Patients were excluded if there was severe comorbidity, renal failure, myocardial infarction or unstable angina in the 6 weeks leading up to enrolment, or if there was infection or an inflammatory illness such as sepsis, malignancy, arthritis or connective tissue disease. A sample of 74 patients meeting these criteria was chosen. Among these, the cause of heart failure was ischemic heart disease in 23 patients, dilated cardiomyopathy in 21, and valvular heart disease in 30. Thirty-two patients were in NYHA class II and 42 were in class III or IV. All patients were clinically stable on blood sampling, while receiving continuous therapy for heart failure. Forty patients used digoxin and 55 used diuretics; 45 patients were also treated with angiotensin-converting enzyme inhibitors, 30 with beta-blockers, and 31 with vasodilators. Nineteen patients needed intravenous inotropic agents for stabilizing their decompensated CHF.
An age-matched group of 19 volunteers provided blood samples for use as a control. All of these subjects were free of heart disease and other major medical problems. This study was approved by the Human Investigation Committee of Cheng-Hsin General Hospital.
2.2. Blood sampling and baseline clinical evaluation
Baseline clinical evaluation was performed on the 74 patients with CHF. At the time of enrolment, 54 of the patients also underwent right heart catheterization for clinical (noninvestigational) evaluation of new-onset or worsened CHF symptoms. Venous blood was drawn during right heart catheterization (central vein) or collected into vacuum tubes at bedside (peripheral vein) after 30 min of bed rest, with the patients in a supine position. All samples were placed immediately on ice, centrifuged at 4 °C within 2 h, and then frozen to –20 °C and stored at that temperature until analysis. The time intervals between blood sampling and LVEF studies were all within 1 week.
2.3. Clinical follow-up
All patients were followed either in-hospital or through regular outpatient visits. Clinical information regarding major adverse cardiac events (cardiac death, requirement for heart transplantation or hospitalization with a primary diagnosis of worsening CHF) during a median follow-up period of 240 days was provided by the treating cardiologist without knowledge of the sCAM levels.
2.4. Measurement of circulating levels of sCAMs
Assays for all three sCAMs were done concurrently to minimize any effects of repeated freeze–thaw cycles. The levels of sICAM-1, sVCAM-1 and sP-selectin were measured by means of enzyme-linked immunosorbent assay by commercial kits (R&D Systems, Inc., Minneapolis, MN for sICAM-1 and sP-selectin, and Biosource International, Camarillo, CA for sVCAM-1). The intra-assay and inter-assay coefficients for each factor were approximately 5% and approximately 10%, respectively.
2.5. Hemodynamic measurements
Fifty-eight patients underwent cardiac catheterization or coronary arteriography for clinically indicated purposes. Informed consent was obtained from all patients according to a protocol approved by the committee on human investigation at our institution. Left-sided cardiac catheterization, including left ventriculography and coronary arteriography, was performed in 43 patients. Right-sided cardiac catheterization, both with and without endomyocardial biopsy, was performed in 22 and in 32 patients, respectively. Right heart pressure, such as pulmonary capillary wedge pressure, was measured with a 7Fr Swan-Ganz catheter, and cardiac output was measured by the thermodilution technique.
The LVEF was determined by left ventriculography with standard radionuclide or contrast medium.
2.6. Data analysis
All values, except for the levels of the sCAMs, are expressed as mean±S.D. Because the distribution of the biological markers in these patients did not follow a normal distribution, they were expressed by a median (25th–75th percentiles).
The patients with CHF were divided into two groups, based on their NYHA class: the mild CHF group (NYHA class II) and the severe CHF group (NYHA class III or IV). Univariate comparisons of clinical and hemodynamic characteristics between these two groups were made with the Wilcoxon rank-sum test for quantitative data and with the Fisher exact test for qualitative data. Comparisons between multiple groups were determined by means of a one-way analysis of variance test.
The CHF patients were also divided into those who had major adverse cardiac events during follow-up and those who were event-free. Levels of sCAMs were compared between these two groups by the Wilcoxon rank-sum test. Kaplan-Meier analyses of cumulative event-free rates in CHF patients, stratified into two groups on the basis of median levels of sCAMs, were compared. The differences between event-free curves were tested by a log rank test. Cox proportional hazards analysis was performed to determine the significance of LVEF, circulating levels of sVCAM-1, sICAM-1 and sP-selectin as independent predictors of CHF.
Linear regression analysis was used to determine the correlation between the various sCAM levels, the correlations between the sCAM levels and LVEF, and various hemodynamic parameters derived from cardiac catheterization.
A P value <0.05 was considered statistically significant.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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3.1. Patient characteristics and hemodynamic data
The baseline characteristics of the 74 patients with CHF are shown in Table 1.
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The study population was representative of a cross-section of general cardiovascular medicinal practice. No significant differences in age, sex or cause of CHF were detected between the two groups. There were more men than women in this sample, and patients were included with both ischemic as well as non-ischemic aetiology. The mean LVEF was significantly lower (P<0.0001) and the hemodynamic parameters were significantly worse in the severe CHF group than in the mild CHF group. Patients with severe CHF used more angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, vasodilator, beta-blocker therapy and intravenous inotropic agents. However, the event-free rate was significantly lower (P=0.03) in patients with severe CHF than in those with mild CHF.
3.2. Circulating levels of sCAMs and their interrelations with one another
The concentrations of all three sCAMs were significantly higher in the patients with CHF than in the 19 healthy controls, and the circulating levels of sICAM-1 and sP-selectin increased with the severity of CHF (Fig. 1). Not all of the 74 patients with CHF had elevated sCAM levels. The 32 patients in the mild CHF group had a median sVCAM-1 level similar to the control group, but this level was significantly elevated in patients with severe CHF.
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The correlation coefficients between circulating levels of sVCAM-1 and those of sICAM-1 and of sP-selectin were 0.46 (P<0.0001) and 0.29 (P=0.01), respectively. The correlation coefficient between circulating levels of sICAM-1 and of sP-selectin was 0.21 (P=0.06) (Fig. 2).
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3.3. Prognosis
The median follow-up period was 240 days (205–295 days, 25th–75th percentiles). There was a 27% (20 of 74) overall event rate in the CHF population. Six of the 74 patients died of cardiac causes (2 died of sudden death without premonition of the progression of symptoms, presumed to be due to arrhythmia, and 4 of intractable end-stage CHF) during the follow-up period. One patient underwent heart transplantation, and 14 patients were readmitted for worsening heart failure.
We divided the 74 patients with chronic CHF into two groups, based on those who had major adverse cardiac events during follow-up vs. those who were event-free. The exact sCAM levels of the patients of both groups are shown and compared in Fig. 3. The 20 patients who had adverse events had significantly higher sVCAM-1, sICAM-1 and sP-selectin levels (P=0.01, P=0.005 and P=0.002, respectively) than the 54 patients who were event-free. This is further illustrated by a Kaplan–Meier analysis of event-free survival of the two groups on the basis of median levels of sCAMs in Fig. 4. The median (25th–75th percentiles) sVCAM-1, sICAM-1 and sP-selectin levels in the 74 patients with CHF were 1088.8 (850.5–1739.4), 235.9 (184.4–297.8) and 57.8 (44–72.9), respectively. The differences between event-free curves were all significant (P=0.04, P=0.04 and P=0.01, respectively). However, among these three factors, only high circulating levels of sP-selectin were found to be an independent significant predictor according to the Cox proportional hazards analysis Table 2.
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3.4. Relation between concentrations of sCAMs and LVEF, and between sCAMs and various hemodynamic parameters
Significant negative correlations, with the correlation coefficients between LVEF and sVCAM-1, sICAM-1 and sP-selectin of –0.39 (P=0.0006), –0.32 (P=0.006) and –0.26 (P=0.003), respectively were noted (Fig. 5). However, there were no significant correlations between sCAMs and other hemodynamic parameters such as left ventricular filling pressure, systemic vascular resistance and so on (data not shown).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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4.1. Comparison with previous studies of circulating sCAMs in CHF
Cellular adhesion molecules play a pivotal role in the biological processes of cell–cell interactions. During the past decade, many adhesion molecules have been identified and structurally analysed. This has allowed an understanding of their role in the pathophysiology of many cardiac diseases, including atherosclerosis, cardiac transplant rejection and allograft vasculopathy, angiogenesis and others [15].
Soluble isoforms of CAMs have been identified, and increased levels of these sCAMs have also been reported in various cardiac diseases [8,16–18]. However, no study described the sCAM levels in patients with CHF until the 1990s, when expression of CAMs and elevation of circulating sCAMs in CHF patients were reported [7–9,14]. Tsutamoto et al. reported that the plasma level of sICAM-1 increased with the severity of CHF and was related to clinical outcomes [7]; until now, however, it has been the only study to examine the prognostic value of a sCAM.
To determine whether various sCAMs can provide prognostic information in patients with CHF, this study measures the levels of sVCAM-1, sICAM-1 and sP-selectin, and determines their relationship to clinical outcomes in patients with chronic CHF. Our data demonstrate that even though the expression of these adhesion molecules on the surface of endothelial cells is regulated differently [10,11,19], the circulating sCAMs increase with the severity of CHF, correlate negatively with LVEF, and supply important prognostic information. This implies that CAMs may play a role in the pathogenesis of CHF, instead of being merely a marker of inflammatory response.
However, we found only high circulating levels of sP-selectin to be an independent significant predictor of CHF, which is not consistent with the findings of Tsutamoto et al. [7]. The limited sample size in the current study, the differential expression of each CAM in response to stimuli, and different immunological actions of these three CAMs are all possible explanations for the inconsistency. For example, P-selectin is different from VCAM-1 and ICAM-1 with respect to the ligand to which it binds, the duration of its expression and the cell and tissue type in which it is expressed. Because sP-selectin may also derive from platelets, and after surface expression, P-selectin can be recycled for re-expression [10], whether its elevation indicates more extensive and chronic inflammatory activation involving the cell–cell interactions between leukocytes, endothelium and platelets, and thus may have a stronger predictive value remains to be determined.
4.2. Potential role of CAMs in the pathogenesis of CHF
As heart failure is a complex syndrome with many different underlying etiologies, and as a variety of organs other than the heart are involved, the mechanisms involved in the worsening of heart failure are manifold. In patients with chronic CHF, the sympathetic nervous and the renin–angiotensin–aldosterone systems are activated as compensatory mechanisms. Recent studies also suggest that CHF may, in part, be an inflammatory disease. Strong evidence has been presented that enhanced oxygen-free radical damage and marked cytokine activation both persist in patients with CHF [12,13,20,21]. Although the precise cellular sources of oxygen-free radicals and the mechanisms involved in initiating the oxidative stress that occurs in patients with CHF are still unknown, it is conceivable that oxygen-free radicals and the mechanisms involved in initiating the oxidative stress produced by the ischemic failing myocardium may contribute to myocardial cellular toxicity and damage, and to apoptosis [12,13,21]. These mechanisms form a network of interactions involving neurohormones, cytokines, inducible nitric oxide synthase, ischemia and free radical production and apoptosis, which lead to abnormalities in cardiac receptors, signalling processes, calcium homeostasis, contractile protein desensitization and endothelial dysfunction, as well as structural alterations such as necrosis, fibrosis, inappropriate hypertrophy and cardiac dilatation—a multitude of changes leading to progressive cardiac dysfunction, worsening heart failure and death [12,13,20,21].
Cell to cell interactions are dependent upon the expression of adhesion molecules, which have been implicated in a wide range of cardiovascular diseases. However, their significance in CHF is less well understood. In CHF, there is a phenotypic shift of intramyocardial endothelial cells [22], an upregulation of CAMs, and presence of macrophages expressing TNF- in failing myocardium [9]. Circulating sVCAM-1, sICAM-1 and sP-selectin levels have also been found to be elevated in patients with CHF compared with controls [7–9,14]. It is known that these CAMs are important in the biologic activity of leukocytes and cytokines because adhesion to the endothelium and migration into the tissue are needed for the biologic actions of cytokines [7,10–13,19,20]. For example, having adhered to the surface of the arterial endothelial cells by interacting with a receptor such as VCAM-1, the monocytes and lymphocytes penetrate the endothelial layer and take up residence in the intima. Once resident in the intima, the mononuclear phagocytes differentiate into macrophages, which may produce cytokines and growth factors [10–12,19]. A number of growth factors or cytokines elaborated by the infiltrating leukocytes and vascular wall cells can stimulate smooth muscle cell proliferation, express inducible nitric oxide synthase and production of large, potentially cytotoxic amounts of nitric oxide radicals, and produce extracellular matrix and interstitial forms of collagen. These may play a role in causing endothelial dysfunction, impairment of coronary vascular reserve and myocardial tissue perfusion, apoptosis of cardiac myocytes and endothelial cells, cytotoxicity and/or inhibition of myocyte contractility, and myocardial fibrosis [12,13,20,21]. It is believed that, as CHF progresses, the mixture of cytokines and other mediators become very complex and the interactions of mediators and cytokines may affect the overall outcome. The CAMs, by mediating cell–cell interactions and the biologic activity of cytokines, may thus participate in the development and progression of CHF [7–9,12,13,20,21].
Treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blocker and carvedilol can decrease the plasma levels of TNF- and sCAMs [23–25]. Anticytokine treatment such as anti-TNF- drugs can improve clinical outcomes [21], and targeted disruption of ICAM-1 and P-selectin genes improves cardiac function and survival in TNF- transgenic mice [26]. These factors may become potential targets for the treatment of CHF. However, future trials with refined hypotheses and approaches will be needed.
4.3. Potential mechanisms of CAM expression in CHF
Several possible mechanisms may be involved in the expression of CAMs.
First, in patients with CHF, increased oxidative stress may activate a key transcription factor, nuclear factor kappa B (NF
B) that, in turn, activates several genes associated with organ remodeling, primarily through immune and inflammatory mediators. Such genes include the inducible form of nitric oxide synthase, cytokines (such as TNF-), and adhesion molecules (such as ICAM-1) [12]. Second, as a proinflammatory cytokine, TNF- is also known to be a potent upregulator of adhesion molecules of various cells through activation of the transcription factor NFB [10,27–29]. Third, raised serum concentrations of other inflammatory mediators in patients with chronic CHF, such as the acute-phase reactant C-reactive protein, may also have a direct proinflammatory effect on endothelial cells and induce the expression of CAMs [30,31]. Fourth, there is evidence that angiotensin II can upregulate ICAM-1 and VCAM-1 expression by endothelial cells in vitro and in vivo sICAM-1 release [23,29]. Finally, although endothelial cells are an important cellular source of sCAMs, the raised levels of sCAMs in CHF patients may, at least in part, derive from other cellular sources such as platelets (sP-selectin), macrophages and dendritic cells (sVCAM-1).
4.4. Study limitations
The current study is limited by its modest sample size. The relationship of these serum markers to prognosis on the basis of only 6 deaths and 14 admissions with worsening heart failure is relatively weak. The conclusions of the study should be diluted to reflect the rather small number of patients studied and the rather few adverse events. Because of its observational design, the findings are hypothesis-generating rather than conclusive. Further and larger studies will be required to confirm and refine these findings and to address specific pathological mechanisms.
Although these significant cross-sectional associations suggest that our assay methods were reasonably robust, serial measurements would be needed to quantify and correct for possible underestimation or overestimation of associations due to fluctuations of sCAM values within individuals over time and for any protein degradation that may have occurred during sample storage.
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5. Conclusions |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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This study assessed the predictive ability of concentrations of three sCAMs (sVCAM-1, sICAM-1 and sP-selectin) for adverse cardiac events in patients with chronic CHF. Among them, high sP-selectin levels can provide prognostic information in patients with CHF independently according to Cox proportional hazards analysis. Our study adds further data to the available information on circulating values of sCAMs in patients with CHF, and it shows that these factors are generally modestly associated with one another. Furthermore, the elevation of sCAMs was negatively correlated with LVEF, supporting a role in this disorder for immune activation and interaction between endothelial cells, platelets and leukocytes. These data support the view that soluble forms of CAMs reflect inflammatory events and can serve as prognostic markers for chronic CHF. Even if these CAM and cytokine disturbances may not be the ultimate cause of heart failure, they may nevertheless represent a kind of ‘final common pathway’ independent of the etiology of cardiac disease.
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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