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European Journal of Heart Failure 2002 4(5):593-595; doi:10.1016/S1388-9842(02)00102-2
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© 2002 European Society of Cardiology

Increased levels of high sensitive C-reactive protein in patients with chronic rheumatic valve disease: evidence of ongoing inflammation

Zehra Gölbasia,*, Özgül Uçara, Telat Kelesa, Ahmet Sahinb, Kerim Çaglic, Ahmet Çamsaria, Erdem Dikera and Sinan Aydogdua

a Department of Cardiology, Ankara Numune Education and Research Hospital Yuva sok No 20/2, Küçükesat 06660, Ankara, Turkey
b Düzen Laboratory Groups Ankara, Turkey
c Yüksek Ihtisas Hospital, Department of Cardiovascular Surgery Ankara, Turkey

* Corresponding author. Tel.: +90-312-3103030/3635; fax: +90-312-3103460. E-mail address: zgolbasi{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
The precise pathogenetic mechanism(s) of rheumatic fever and rheumatic heart disease have never been defined. C-reactive protein (CRP) is increased in patients with acute rheumatic fever, but it is not known whether plasma levels increase in patients with chronic rheumatic valve disease. The aim of this study was to determine the role of inflammation detected by high sensitivity CRP (hs-CRP) levels in the progression of chronic rheumatic valve disease. A total of 113 patients with chronic rheumatic valve disease (81 women, 32 men; mean age 40±14 years, range 13–70), 51 patients with prosthetic valve(s) (31 women, 20 men; mean age 48±13 years, range 21–71) and 102 healthy subjects (68 women, 34 men, mean age 41±12 years, range 25–73), as a control group, were assessed. Patients with acute rheumatic fever, acute infection, inflammatory disease, malignancy, acute myocardial infarction and trauma were excluded. hs-CRP was determined using latex-enhanced immunonephelometric assays on a BN II analyzer (Behring). Transthoracic echocardiography was performed in all patients in order to evaluate valvular disease. Levels of hs-CRP were significantly higher in patients with chronic rheumatic heart disease than in patients with prosthetic valve(s) and healthy subjects (0.62±0.64 vs. 0.35±0.41 vs. 0.24±0.18 mg/l, P<0.01 and P<0.001 respectively). No correlation was observed between CRP and age, sex or functional capacity. We found that hs-CRP is increased in chronic rheumatic heart disease; this may indicate that inflammatory response still persists in the chronic phase.

Key Words: Rheumatic valve disease • Acute rheumatic fever • C-reactive protein

Received November 6, 2001; Revised February 6, 2002; Accepted April 22, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The precise pathogenetic mechanism(s) of rheumatic fever and rheumatic heart disease have never been defined. It has been hypothesized that on exposure to group A streptococci during infection, ‘antigenic mimicry’ leads to autoimmune-like reaction within the human host and results in valvulitis, ultimately leading to rheumatic valvular heart disease [1]. It has been considered that chronic rheumatic valve disease is usually the result of repeated episodes of carditis alternating with healing and is characterized by the deposition of fibrous tissue. The debate continues about whether the anatomical changes in chronic rheumatic valve disease result from a smoldering rheumatic process or whether, once the valve has been deformed by turbulent flow, this leads to progressive fibrosis, thickening and calcification of the valve apparatus [2]. C-reactive protein (CRP) is increased in patients with acute rheumatic fever, but it is not known whether plasma levels increase in patients with chronic rheumatic valve disease. The aim of this study was to determine the role of inflammation detected by hs-CRP levels in the progression of chronic rheumatic valve disease.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
A total of 131 patients with chronic rheumatic heart disease and 72 patients who had undergone valve replacement due to rheumatic etiology, all followed up on an out-patient basis, were included in the study. Patients with acute rheumatic fever, acute infection, inflammatory disease, malignancy, acute myocardial infarction and trauma were excluded. In addition, patients who had rheumatic valve involvement other than in the replaced valve(s), as detected on echocardiographic examination, were excluded from the study. After the initial evaluation, 113 patients with chronic rheumatic valve disease (81 women, 32 men; mean age 40±14 years, range 13–70), 51 patients with prosthetic valve(s) (31 women, 20 men; mean age 48±13 years, range 21–71) and 102 healthy subjects (68 women, 34 men; mean age 41±12 years, range 25–73), as a control group, were assessed. Of the patients with chronic rheumatic valve disease, 51 patients had mitral valve disease, 59 patients had combined mitral and aortic valve disease, and three patients had aortic valve disease; 49 patients were New York Heart Association (NYHA) functional class I, 49 were class II, and 15 were class III. Of the patients with prosthetic valve(s), 28 patients had mitral valve replacement, 12 patients had aortic valve replacement, and 11 patients had combined mitral and aortic valve replacement. Of these, 27 patients were NYHA class I, 23 patients were class II and one patient was class III. The mean time from valve replacement surgery to enrolment was 4.2±3 years in the prosthetic valve group. Levels of hs-CRP were determined using latex-enhanced immunonephelometric assay on a BNP analyzer (Behring) [3]. Transthoracic echocardiography was performed in all patients in order to evaluate valvular disease (GE Vingmed System FiVe, 2.5-MHz transducer).

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

2.1. Statistics
Data were analyzed with the SPSS for Windows statistical package and are presented as mean±S.D. Differences between mean values were analyzed by Student's unpaired t-test. Univariate comparisons between groups were made with non-parametric tests: Kruskal–Wallis tests for multigroup comparisons and Mann–Whitney tests for two-group comparisons. The {chi}2 test and Fischer's probability test were used to compare proportions. Differences were considered significant at P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The levels of hs-CRP were significantly higher in patients with chronic rheumatic heart disease than in patients with prosthetic valve(s) and healthy subjects (0.62±0.64 vs. 0.35±0.41 vs. 0.24±0.18 mg/dl, P<0.01 and P<0.001, respectively) (Fig. 1). Although in the prosthetic valve group the hs-CRP level was higher than in healthy subjects, the difference was not statistically significant. In addition, compared with patients with one valve lesion, patients with multivalvular disease had significantly higher plasma hs-CRP levels (1.24±0.60 vs. 0.49±0.54 mg/dl, P<0.05). No correlation was observed between hs-CRP levels and age, sex or functional capacity.


Figure 1
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  		Fig. 1 Individual values of levels of C-reactive protein (mg/dl) in patients and in healthy subjects.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this cross-sectional study of patients with rheumatic valve disease, hs-CRP was found to be significantly higher in the chronic phase. In addition, we observed that, in patients with prosthetic valve(s), hs-CRP levels were no longer high.

One current hypothesis, so-called ‘antigenic mimicry’, to explain the valvular damage in acute rheumatic fever, is based upon an antigenic similarity between human heart valves and group A streptococci [1,4]. It has been postulated that an abnormal antibody response leads to an ‘autoimmune’ process, which causes continuing or smoldering damage to the heart valves. This hypothesis is based upon an earlier study, in which the prolonged persistence of group A streptococcal carbohydrate antibody and the reduction of humoral antibody levels to the group A carbohydrate after surgical removal of the involved valve were shown [5]. The findings in our study indicating an increase in hs-CRP levels in patients with rheumatic heart disease in chronic phase, and hs-CRP levels after surgical removal of the involved valve(s) comparable with the healthy subjects, may support this hypothesis.

High levels of hs-CRP in patients with chronic rheumatic valve disease indicate the persistence of inflammation in the chronic phase. In a previous study, it was shown that myocarditis associated with acute rheumatic fever itself may remain ‘active’ months after the clinical disease has entered a quiescent period [6]. We might expect this to be a similar case with progressive valvular damage in rheumatic heart disease.

C-reactive protein is not only an indicator of the acute phase response to the primary underlying process, but can also exacerbate existing tissue damage itself. In chronic rheumatic valve disease, involvement is either univalvular or multivalvular. In our study, compared with the patients who had a single valve lesion, patients with multivalvular disease showed significantly higher plasma hs-CRP levels. This finding may have two meanings: one is that high CRP levels can cause multiple valve involvement, and the other is that the severity of the underlying process can cause an augmented CRP production. In our study, hs-CRP levels in patients with replaced valve(s) were significantly lower than those without valve replacement. This may be due to attenuation of the antigenic stimulus after the removal of the involved valve(s) carrying antigenic similarity. Pepys and Berger have suggested that it will only be possible to test CRP as a pathogenic factor in coronary artery disease when drugs are developed that can selectively inhibit CRP production or binding [7]. The same assumption may be valid regarding chronic rheumatic heart disease. If the presence of CRP could be demonstrated on surgically removed valve(s), this would denote the contribution of CRP to valvular damage.

The results of this study may have implications in the management of chronic rheumatic valve disease. Although corticosteroids and salicylates can provide symptomatic improvement in acute rheumatic fever, they do not alter the long-term outcome of rheumatic heart disease. Currently the treatment of chronic rheumatic heart disease mainly involves the prevention of acute attacks of rheumatic fever, and no specific treatment is defined to prevent the progression of valvular damage. The high level of CRP in the chronic phase brings the use of anti-inflammatory therapy, such as aspirin, into question. In addition, it has been suggested that statins may also inhibit the inflammatory or non-inflammatory process that induces the acute-phase response and can reduce CRP levels [8]. The biochemical mechanism of their anti-inflammatory effect is uncertain [9]. Chronic degenerative aortic valvular stenosis is another valvular disease that shows signs of local and systemic inflammation, and in a recent study CRP levels were found to be increased in this condition [10]. Furthermore, it was reported that statins could reduce the progression of aortic stenosis in patients with chronic degenerative aortic valvular stenosis and that their mechanism of action is believed to be anti-inflammatory [11]. It can be speculated that statins may be useful in the management of chronic rheumatic heart disease. However, randomized controlled trials are required to determine the value of anti-inflammatory therapy in the chronic phase.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Goldstein I., Halpern B., Robert L. Immunologic relationship between streptococcus A polysaccharide and the structural glycoprotein of heart valve. Nature (1967) 213:44–47.[CrossRef][Web of Science]
  2. Dalen JE, Alpert JS, editors. Valvular Heart Disease. 2nd ed. Boston: Little, Brown and Co, 1987, 600 pp.
  3. Rifai N., Tracy R.P., Ridker P.M. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin Chem (1999) 45:2136–2141.[Abstract/Free Full Text]
  4. Dudding B.A., Ayoub E.M. Persistence of streptococcal group A antibody in patients with rheumatic valvular disease. J Exp Med (1968) 128:1081–1087.[Abstract]
  5. Ayoub E.M., Taranta A., Bartley T.D. Effect of valvular surgery on antibody to the group A streptococcal carbohydrate. Circulation (1974) 50:144–150.[Abstract/Free Full Text]
  6. Narula J., Chopra P., Reddy K.S., et al. Endomyocardial biopsies in acute rheumatic fever. In: Proceedings of the Third World Congress on Pediatric Cardiology, Bangkok, Thailand, November (1989) Abstract no F226.
  7. Pepys M.B., Berger A. The renaissance of C-reactive protein. Br Med J (2001) 322(7277):4–5.[Free Full Text]
  8. Jialal I., Stein D., Balis D., Grundy S.M., Adams-Huet B., Devaraj S. Effects of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation (2001) 103:1933–1935.[Abstract/Free Full Text]
  9. Sparrow C.P., Burton C.A., Hernandez M., et al. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arter Throm Vasc Biol (2001) 21:115–121.
  10. Galante A., Pietroiusti A., Vellini M., et al. C-reactive protein is increased in patients with degenerative aortic valvular stenosis. J Am Coll Cardiol (2001) 38:1078–1082.[Abstract/Free Full Text]
  11. Novaro G.M., Tiong I.Y., Pearce G.L., et al. Effect of hydroxymethylglutaryl coenzyme A reductase inhibitors on the progression of calcific aortic stenosis. Circulation (2001) 104:2205–2209.[Abstract/Free Full Text]

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