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European Journal of Heart Failure 2004 6(6):731-734; doi:10.1016/j.ejheart.2003.11.006
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© 2004 European Society of Cardiology

C-reactive protein predicts response to pentoxifylline in patients with idiopathic dilated cardiomyopathy

Karen Sliwaa,*, Angela Woodiwissb, Elena Libhabera, Fitzgerald Zhanjea, Carlos Libhabera, Riaz Motaraa and Rafique Essopa

a Department of Cardiology, Chris-Hani Baragwanath Hospital, University of the Witwatersrand P.O. Bertsham, 2013, Johannesburg, South Africa
b School of Physiology, University of the Witwatersrand Johannesburg, South Africa

* Corresponding author. Tel.: +27-11-933-8197; fax: +27-11-938-8945. E-mail address: hahnle{at}netactive.co.za

Received June 12, 2003; Revised September 30, 2003; Accepted November 19, 2003


   1. Background
Top
 1. Background
2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 
We have previously reported that the addition of pentoxifylline to standard heart failure therapy results in improvements in systolic function in patients with idiopathic dilated cardiomyopathy (IDC) [1–3]. However, these improvements, which are associated with a reduction in inflammatory cytokines [4–7] and Fas/Apo-1 [8] only occur in some patients.

C-reactive protein (CRP) is an inflammatory marker which is associated with adverse prognosis in patients with IDC [9,10]. It is therefore possible that elevations of CRP at baseline may predict the response of patients with IDC to the immuno-modulating agent pentoxifylline.


   2. Aims
Top
 1. Background
 2. Aims
3. Methods
 4. Results
 5. Conclusion
 References
 
Our primary objective was to evaluate whether the degree of elevation of CRP at baseline predicts left ventricular systolic function in patients with IDC treated with pentoxifylline. A secondary objective was to determine whether elevations of CRP are associated with changes in TNF-alpha and a plasma marker of apoptosis (Fas/Apo-1).


   3. Methods
Top
 1. Background
 2. Aims
 3. Methods
4. Results
 5. Conclusion
 References
 
3.1. Pooled analysis of two studies
In the present analysis we used the databases of two single-center, double-blind, randomized trials of pentoxifylline treatment in patients with idiopathic dilated cardiomyopathy in New York Heart Association Functional Class II–III heart failure.

In the first study (n=49) the patients received treatment with diuretics, digoxin and angiotensin-converting-enzyme inhibitors for at least 4 months prior to randomization [8]. In the second trial (n=39) carvedilol was added to baseline medication and given for 4 months prior to randomization [2]. In both studies the treatment arm received pentoxifylline 400 mg TID in addition to previous therapy.

The investigation conforms with the principles outlined in the Declaration of Helsinki.

Inclusion criteria for both trials were: (1) age≥18 and ≤70 years, (2) stable NYHA functional class II or III congestive heart failure of unknown etiology, (3) left ventricular ejection fraction <40% by radionuclide ventriculography after 4 months of standard therapy, (4) sinus rhythm, and (5) eligible patients in whom high quality echocardiographic images could be obtained.

Exclusion criteria were: (1) chronic obstructive pulmonary disease, (2) significant valvular heart disease, (3) history or evidence of ischaemic heart disease, (4) systolic blood pressure >160 mmHg and/or diastolic blood pressure >95 mmHg, (5) clinical conditions other than cardiomyopathy that could increase cytokine levels, (i.e. rheumatoid arthritis, sepsis), (6) pregnancy, (7) severe liver disease, defined as enzymes >2 times the upper limit of normal, and (8) any clinical condition that according to the investigators precluded inclusion in the study.

3.2. Hemodynamic assessments
Clinical examination, echocardiography and radionuclide ventriculography studies were performed prior to and 6 months after randomization. Details of the measurement of left ventricular function are described elsewhere [1,2].

Improvement in radionuclide ventriculography ejection fraction was predefined as an increase in more than 10 absolute units.

3.3. CRP measurements
For plasma CRP measurements blood was obtained prior to randomization and measured as a routine investigation with a commercially available enzyme-linked immunosorbent assay at the hospital laboratory (Roche Diagnostics). The assay used was of low sensitivity and uses 0.1–10 mg/l as a referent range for normal values.

3.4. TNF-alpha and Fas/Apo-1 measurements
For plasma cytokine and Fas/Apo-1 receptor measurements blood was obtained prior to and 6 months after randomization. Plasma was stored at –70 °C within 15 min of blood collection. Plasma concentrations of TNF-{alpha} were determined from undiluted samples using commercially available enzyme-linked immunoassays (Amersham, Maidstone). Fas/Apo-1 concentrations were measured from appropriately diluted samples using a commercially available non-isotopic quantitative immunoassay (Calbiochem). Measurements were made in triplicate and the mean of 3 values used for statistical analysis.

3.5. Analysis
Data management and statistical analysis were performed with SAS software, version 8.0 (SAS Institute INC.). Between group and within group differences in continuous measurements were tested with Wilcoxon two sample tests and Wilcoxon matched pairs test respectively as well as unpaired and paired t-test when variables showed normal distribution. Proportions were compared using Chi-Square test or Fisher exact test when required. Spearman correlation coefficients adjusted for intake of carvedilol were calculated and single and stepwise multiple linear regression analysis was used to analyze the relationship between change in ejection fraction and various variables including CRP, TNF-alpha and Fas/Apo-1. Significance was assumed at a two-tailed value of P<0.05.


   4. Results
Top
 1. Background
 2. Aims
 3. Methods
 4. Results
5. Conclusion
 References
 
4.1. Characteristics of groups at randomization
At randomization no differences in clinical characteristics were noted between the 45 patients in the treatment group and the 43 patients in the placebo group (Table 1a). Importantly, the doses of enalapril, digoxin, furosemide and carvedilol were similar between the groups (Table 1b). In addition, there were no differences in the characteristics of the patients receiving a beta-blocker (as part of their standard therapy) vs. those not receiving a beta-blocker (data not shown). Thirteen patients died (nine in the placebo group, P=0.058 between groups) and three patients were not available for follow-up.


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  		Table 1a Characteristics of the study population at randomization

 


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  		Table 1b Background medication at randomization

 
4.2. Association of CRP with changes in systolic function, Fas/Apo-1 and TNF-{alpha}
After 6 months the group of patients treated with pentoxifylline had a significant increase in ejection fraction and a significant decline in the plasma levels of TNF-alpha and Fas/Apo-1 (Table 2) whereas no significant changes occurred in the placebo group. Eighteen of the pentoxifylline treated patients improved their radionuclide ejection fraction by >10 absolute units, and were arbitrarily defined as improvers. These patients had significantly higher CRP levels at randomization (n=18, 13.4±4.4 mg/l) compared to the patients that did not improve their ejection fraction on therapy with pentoxifylline (n=24, 8.3±4.4 mg/l; P<0.0014). In the placebo group CRP levels did not differ between the improvers (n=6) and the non-improvers (10.3±4.2 vs. 9.5±5.2 respectively, P=0.52).


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  		Table 2 Clinical parameters, left ventricular function and plasma levels of cytokines in the patients who completed the 6-month follow-up

 
When splitting CRP levels in the pentoxifylline group along the median CRP=10.65 mg/l, above the median CRP levels 21 patients showed a mean change in EF of 15.0±12.9 (P=0.004) and below the median CRP levels 21 patients showed a mean change in EF of 3.4±9.5 (P=0.39). Instead in the placebo group (median CRP=10.00 mg/l), above the median CRP levels 12 patients showed a mean change in EF of –0.4±13.7 and below the median CRP levels 18 patients showed a mean change in EF of 0.9±6.9.

CRP at randomization was correlated with the change in ejection fraction after therapy with pentoxifylline (P<0.0006) (Table 3). In addition, CRP at randomization was correlated with the change in Fas/Apo-1 after 6 months of therapy with pentoxifylline (P<0.05, Table 3). However CRP was not correlated with changes in TNF-alpha (Table 3). No significant correlations were observed in the patients treated with placebo (Table 3).


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  		Table 3 Partial correlation coefficients (rs) between CRP and change in ({Delta}) MUGA EF, LVEDD, LVESD, TNF-alpha and FAS/Apo-1 after 6 months of treatment (adjusted for intake of carvedilol)

 
Stepwise multiple linear regression analysis in the pentoxifylline treated group (multiple r=0.55; P=0.0001) showed that CRP and Fas/Apo-1 at randomization were independent predictors of change in ejection fraction after 6 months of therapy with pentoxifylline (Table 4).


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  		Table 4 Multivariate analysis for changes in EF after 6 months of treatment

 

   5. Conclusion
Top
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
References
 
Like other treatment strategies for heart failure, improvements in systolic function with pentoxifylline occur only in a sub-fraction of the patients treated [1,2]. Hence it is important to identify those patients who stand to benefit the most from this therapy. Improvements in systolic function with pentoxifylline are accompanied by reductions in the inflammatory cytokine TNF-{alpha} and in the marker of apoptosis Fas/Apo-1 [1,2,8]. However as TNF-{alpha} is subject to circadian variation [11] and has a short half-life, it is unlikely to be reliable as a marker to predict improvements. In contrast the inflammatory marker CRP shows no circadian variation and is highly reproducible within individuals [12,13].

CRP is an acute-phase protein which recognizes a range of pathogenic targets including membranes of apoptotic and reactive cells [14]. In addition CRP is implicated in the synthesis of TNF-{alpha} [15,16]. Hence it is possible that CRP may predict those patients who are likely to respond to the immuno-modulating agent pentoxifylline. Indeed we found that those patients who responded to pentoxifylline had higher initial concentrations of CRP than those who did not. Furthermore, CRP was correlated with reductions in Fas/Apo-1 as well as with improvements in systolic function following pentoxifylline therapy.

As CRP measurements are relatively inexpensive and considered routine in comparison to TNF-{alpha} and Fas/Apo-1 measurements, CRP could provide us with a readily available tool to target pentoxifylline therapy in a subgroup of patients with IDC.


   References
Top
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 

  1. Sliwa K., Skudicky D., Candy G., Wisenbaugh T., Sareli P. Randomized investigation of effects of pentoxifylline on left ventricular performance in idiopathic dilated cardiomyopathy. Lancet (1998) 351:1091–1093.[CrossRef][Web of Science][Medline]
  2. Skudicky D., Bergemann A., Sliwa K., Candy G., Sareli P. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardiomyopathy treated with angiotensin-converting enzyme inhibitor and carvedilol. Results of a randomized study. Circulation (2001) 103:1083.[Abstract/Free Full Text]
  3. Sliwa K., Woodiwiss A., Candy G., Badenhorst D., Libhaber C., Norton G., et al. Pentoxifylline modifies cytokine profiles and improves left ventricular performance in patients with decompensated congestive heart failure. Am J Cardiol (2002) 90:118–122.
  4. Neuner P., Klosner G., Schauer E., Pourmojib M., Macheier W., Grunwald C., et al. Pentoxifylline in vivo down-regulates the release of IL-1β, IL-6, IL-8 and tumour necrosis factor-{alpha} by human peripheral blood mononuclear cells. Immunology (1994) 83:262–267.[Web of Science][Medline]
  5. Schadene L., Vandenbussche P., Crusiaux A., Schwarz T. Differential effects of pentoxifylline on the production of TNF-alpha and IL-6 monocytes and T cells. Immunology (1992) 75:30–40.
  6. Weinberg J.B., Mason S.N., Wortham T.S. Inhibition of TNF-alpha and interleukin-1 beta messenger RNA expression in HL-60 leukaemia cells by pentoxifylline and dexamethasone. Blood (1992) 79:3337–3343.[Abstract/Free Full Text]
  7. D'Hellencourt C.L., Diaw L., Cornillet P., Guenounou M. Differential regulation of TNF-alpha, IL-beta, IL-6, IL-8, TNF-beta, and IL-10 by pentoxifylline. Int Immunopharmacol (1996) 18:739–748.[CrossRef][Web of Science]
  8. Skudicky D., Sliwa K., Bergemann A., et al. Reduction in Fas/Apo-1 plasma levels correlates with improvement in left ventricular function in patients with idiopathic dilated cardiomyopathy treated with pentoxifylline: results of a randomized trial. Heart (2000) 84:438–441.[Free Full Text]
  9. Sato Y., Takatsu Y., Kataoka K., Yamada T., Taniguchi R., Sasayama S., et al. Serial circulating concentrations of C-reactive protein, interleukin-4, and IL-6 in patients with acute left heart decompensation. Clin Cardiol (1999) 22:811–813.[Web of Science][Medline]
  10. Kanebo K., Kanada T., Yamauchi Y., Hasegawa A., Iwasaki T., Arai M., et al. C-reactive protein in dilated cardiomyopathy. Cardiology (1999) 91:215–219.[CrossRef][Web of Science][Medline]
  11. Dibbs Z., Thornby J., White B.G., Mann D.L. Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials. Am J Cardiol (1999) 33:1935–1942.[CrossRef]
  12. Meier-Ewert H.K., Ridker P.M., Rifai N., Prince N., Dinges D.F., Mullington J.M. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects. Clin Chem (2001) 47:426–430.[Abstract/Free Full Text]
  13. Ockene I.S., Matthews C.E., Rifai N., Ridker P.M., Reed G., Stanek E. Variability and classification accuracy of serial high sensitivity C-reactive protein measurements in healthy adults. Clin Chem (2001) 47:444–450.[Abstract/Free Full Text]
  14. Volanakis J.E. Human C-reactive protein: expression, structure, and function. Immunolgy (2001) 38:189–197.
  15. Barna B.P., Thomassen M.J., Clements M., Rankin D., Ahmed M. Cytokine induction associated with human C-reactive protein. Fed Am Soc Exp Biol J (1989) 3:284–285.
  16. Vetter M.L., Gerwurz H., Hansen B., James K., Baum L.L. Effects of C-reactive protein on human lymphocyte responsiveness. J Immunol (1983) 130:2121–2126.[Abstract]

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