European Journal of Vascular & Endovascular Surgery
Volume 34, Issue 1 , Pages 18-22, July 2007

C-Reactive Protein (CRP) as a Marker in Peripheral Vascular Disease

  • A. Abdellaoui
    • ,
  • H. Al-Khaffaf

      Affiliations

    • Corresponding Author InformationCorresponding author. Mr. Haytham Al-khaffaf, East Lancashire Hospitals NHS Trust, General/Vascular Surgery, Burnley General Hospital, Casterton Avenue, Burnley, Lancashire BB10 2PQ, UK.

East Lancashire Hospitals NHS Trust, General/Vascular Surgery, Burnley General Hospital, Casterton Avenue, Burnley, Lancashire BB10 2PQ, United Kingdom

Accepted 25 October 2006. published online 14 February 2007.

Article Outline

Objective

To review the role of CRP as a marker for the prediction of development of Peripheral Vascular Disease (PVD) and as a prognostic indicator.

Methods

Search of the Cochrane Vascular Group Control Trials Register, Medline and Embase for all published studies on the role of CRP as a marker in peripheral vascular disease was undertaken.13 prospective studies were found.

Results

12 of the 13 prospective studies showed a strong association between CRP and PVD. Three population studies involving 16561 people, over a period of 6.5 to 12 years, revealed that high CRP levels approximately tripled the risk of developing PVD, independently of all other risk factors. Three case-control studies found that hsCRP was much higher in patients with PVD. Four other studies, which covered 2337 people, demonstrated that CRP levels were associated inversely with lower ankle brachial pressure index. One study conducted on 384 people failed to show a link between hsCRP and progression of ABPI. Two further small studies showed that raised pre and post intervention hsCRP were associated with restenosis after angioplasty.

Conclusions

CRP appears to be a strong predictor and marker of severity of PVD and also may predict the risk of restenosis after angioplasty.

Keywords: Peripheral vascular disease, C- reactive protein, Intermittent claudication

 

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Introduction 

High sensitivity C-reactive protein 

CRP is a pentameric protein,1 which was discovered 70 years ago.2 Historically, CRP has been used in the diagnosis and monitoring of active inflammation and infection. In response to tissue damage or infection, hepatocytes are stimulated by cytokines, especially IL6, IL1 and TNFα, to synthesise CRP. CRP binds to polysacharides of many bacteria in the presence of calcium. This results in the activation of classic complement pathway and can promote phagocytosis and opsonisation.3, 4, 5

In mild inflammation and viral infection, CRP increases to 10–50mg/l. However, in active inflammation and bacterial infection, CRP concentration is between 50 and 200mg/l. High concentrations are seen in severe infections.

Traditional CRP immunoassays are unable to accurately measure CRP concentrations smaller than 5mg/l. However, high sensitivity CRP techniques, using monoclonal and polyclonal antibodies (ELISA), can measure concentrations of high sensitivity CRP as small as 0.15mg/l.

There is currently ongoing debate as to the base line hsCRP measurement in a person, due to the daily variability in influencing factors, such as obesity6 infections, HRT and smoking.7 HsCRP should only be performed on patients in a metabolically stable condition, without any obvious inflammatory or infectious condition. CDC (Centres for Disease Control and Prevention) and The American Heart Association recommend taking two measurements at an interval of at least 2 weeks separation, especially when the CRP concentration is greater than 10mg/l. They have identified 3 risk groups of people: (1) a low risk group with CRP concentrations less than 1mg/l; (2) a moderate risk group with CRP between 1 and 3mg/l; (3) a high risk group when CRP is higher than 3mg/l.8

More recently, chronic inflammation has been identified as a component in the development and progression of atherosclerosis and CRP has been found to be a marker of cardiovascular risk.9, 10, 11, 12 Recent studies showed that high concentrations within a normal range (<5mg/l) can predict future cardiovascular events.13, 14, 15, 16, 17

CRP specificity and sensitivity in peripheral vascular disease 

Traditional CRP tests designed to monitor acute and chronic inflammation had poor sensitivity in the lower ranges and higher sensitivity CRP (hsCRP) tests have been developed. This has resulted in the recommendation of cut-off levels of hsCRP <1, 1 to 3 and >3mg/l, equating to low, moderate and high risk for future cardiovascular events. If the CRP levels are >10mg/l, it is recommended that repeat measurements are taken after two weeks, to rule out any co-existing infection and accurately measure the hsCRP base line.

There is continuing debate about the specificity of CRP in predicting Peripheral Vascular Disease, as atherosclerosis is a generalised disease and patients with PVD might have sub clinical ischaemic heart disease. The Physicians' Health Study showed a strong link between hsCRP and PVD, independently of all other risk factors, including heart disease.17

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Materials and Methods 

We searched the Cochrane Vascular Group Control Trials Register (2004), Medline (Jan 66–Oct 05) and Embase for all published prospective cohort studies and prospective case control studies on the role of CRP as a marker in PVD, using the keywords: Peripheral Arterial Disease; Peripheral Vascular Disease; PAD; PVD; CRP; C-reactive protein.

The studies had to include patients with PAD that had been diagnosed using ABPI or angiography and had undergone measurement of hsCRP. All cases were considered and there was no restriction on specific population groups or settings. Outcome measures were the levels of hsCRP correlated to the development or severity of PVD.

Abstracts returned from the search were manually checked for relevance, according to the above criteria. Review articles identified in this process were surveyed for additional and earlier citations. From the abstracts, 31 relevant studies were found, for which full articles were obtained. 15 articles were excluded, since their main subject was not PVD. From the 16 remaining studies, 3 duplicate publications were identified and excluded.Data were manually extracted from the 13 included studies, including the number of patients, number of males, number of females, type of study, length of study, end point, results and recommendations.

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Results 

CRP and the risk of developing peripheral vascular disease 

We found 3 studies that investigated the risk of developing PVD in a healthy population. All studies found a strong link between hsCRP and future development of PVD. These studies assessed 16561 individuals over periods ranging between 6.5 and 12 years. The risk of developing Peripheral Vascular Disease ranged between an odds ratio (OR) of 1.9 and a relative risk (RR) of 2.8.

Ridker et al. compared 11 inflammatory markers in 14916 initially healthy US male physicians over a 9 year period (Table 1). 140 of the participants developed PVD. This group was matched to a control group following age and risk factors. HsCRP was the strongest non lipid predictor of PVD (RR for the highest vs lowest quartile, 2.8; 95% CI: 1.3 to 5.9). The median CRP levels were significantly higher at base line among the participants who developed PVD (1.34 vs 0.99mg/l; P=0.04). This study showed nearly a three fold increased risk of developing PVD in asymptomatic subjects.17, 18

Table 1. Summary of the prospective studies that have investigated the role of CRP in PVD
StudyCountryType of studyNo. of patientsLength of the studyEnd pointStatistical results 95% CIP
CRP and the Risk of Developing PVD
Ridke et al. (2001) Physicians health studyUSAProspective Case Control141969 yearsPVDRR 2.8 (1.3–5.9)<0.001
Tzoulaki et al. (2005) Edinburgh Artery StudyUKCohort159212 yearsPVDCRPmg/l 2.7 symptomatic patients 1.7 normal patients0.02
Van Der Meer et al. (2002)NetherlandsCohort7736.5 yearsPVDOR1.9 (1–3.7)0.002

CRP in Patients with PVD
Bloemenkamp et al. (2002)NetherlandsCase Control687–PVDOR 3.9 (1.8–5.8)–
Vu et al. (2005)USACross-sectional1600–PVDOR 4.8 (1.42–16.11)0.01
Cassar et al.UKCase Control202–PVD–0.001

CRP and ABPI
Hozawa et al. (2004)JapanCross-sectional946–PVD (ABPI)OR 5.79 (2.99–11.2)0.01
Vainas et al. (2005)NetherlandsCohort38712 monthsPVD (ABPI)+other cardio-vascular eventsx2 for trend0.02
McDermott et al. (2003)USAObservational601–PVD (ABPI)Log CRP<0.001
Musicant et al. (2006)USACohort Study3841–99 months (mean 38)PVD (ABPI)Log CRP 0.85–
Aboyans et al.USALongitudinal Cohort4034.6±2.5 YearsPVD (ABPI)OR 1.37 (0.99–1.9)0.05

CRP and Outcome of Angioplasty
Schillinger et al. (2002)AustriaProspective Cohort1726 monthsRestenosis after above knee angioplastyOR 2.2 (1.1,4.2)<0.001
Schillinger et al. (2003)AustriaProspective Cohort896 monthsRestenosis after below knee angioplastyOR 3.7 (1.0–13.5)0.03

CI: Confidence Interval, OR: Odds Ratio, RR: Relative Risk, PVD: Peripheral Vascular Disease.

In the Edinburgh Artery Study a population of 1592 people were followed over a 12 year period. HsCRP was measured at base line, 5 years and 12 years, and were correlated to the patients' symptoms and ABPI. This study identified HsCRP as a useful predictor of PVD and its progression. The mean hsCRP was 2.7mg/l in symptomatic patients compared to 1.7 in the control group (p=0.02).19

Van der Meer et al. measured hsCRP levels in a random sample of 773 participants (age≥55). Sub-clinical atherosclerosis was measured at various sites in the arterial tree on 2 different occasions, with a mean time between assessment of 6.5 years. In iliac and lower extremity atherosclerosis, risk of PVD increased across quartiles of CRP with iliac OR, 2.2; 95% CI: 1.3 to 3.8 and lower extremity OR, 1.9; 95% CI: 0.9 to 4.1. This study concluded that CRP predicts the progression of PVD.20

The different designs and reporting of these studies precluded calculation of a pooled risk estimate in a formal meta-analysis.

CRP in patients with peripheral vascular disease 

We found 3 studies that evaluated hsCRP levels in patients already affected by Peripheral Vascular Disease. All studies found that HsCRP was much higher in patients with PVD compared to a control group.

Bluemenkamp et al. compared 212 young women (age 48±8.1 years) with PVD to a control group of 475 healthy women. The study concluded that elevated hsCRP levels were associated with an increased likelihood of PVD (OR=3.9; 95% CI: 1.8 to 8.5 for women in the third quartile; OR=3.1; 95% CI: 1.4 to 6.8 for women in the fourth quartile).21 Cassar et al. showed that HsCRP levels were significantly higher in patients with PVD, with an average CRP of 3.4mg/l range 0.15–24 (p<0.001).22 In a third study, Vu et al. concluded that patients with metabolic syndrome and hsCRP higher than 3mg/l have an increased risk of PVD. This risk was much greater in diabetic patients, OR of 4.79 (95% CI 1.42–16.11, p=0.01) compared to OR 8.57 (95% CI 2.16–34.02, p=0.001) respectively.23

CRP and ABPI 

We found 5 Studies that looked into the relationship of hsCRP and PVD; four of them concluded that ABPI was significantly inversely associated with hsCRP.

McDermott et al. investigated the relationship between different inflammatory markers and ABPI in patients with and without PVD, 370 men and women with PVD (ABPI<0.90) and 231 without PVD. ABPI was significantly inversely associated with hsCRP.24 This study also concluded that higher CRP levels were associated with a poorer 6 minute walk performance.25

Vainas et al. studied 387 PVD patients, at baseline and 12 months, looking for progression of the disease and future events. They concluded that hsCRP was related to the severity of PVD (p<0.01) and development of future cardiovascular events including death (p=0.04).26

In the Tsurugaya Project Hozawa et al. looked at the relationship between hsCRP and ABPI in 946 elderly Japanese (>70 year old). They found that higher CRP levels were independently associated with a lower ABPI, OR 5.79(95% CI: 2.99–11.2).27 Aboyans et al. showed a borderline association between hsCRP and the progression of ABPI for large vessel disease (P=0.05).28

In contrast, another study found no significant association between hsCRP and progression of ABPI in a study conducted on 384 subjects, results attributed to small sample size and limited follow up.29

CRP and outcome of angioplasty 

Schillinger et al. looked at the risk of restenosis following above and below knee angioplasty in two different prospective studies. They concluded that raised pre and post-angioplasty hsCRP levels were independently associated with restenosis at 6 months.30, 31

The first prospective cohort study was conducted on 89 patients with PVD, who underwent a successful below knee angioplasty, and restenosis occurred in 36 patients.30 Patients with pre-intervention CRP levels of 2.3–9.2mg/l had a 3.7 fold increased risk of restenosis (OR=3.7; 95% CI: 1.0 to 13.5; P=0.05). If CRP>9.2mg/l there is a 4.7 fold increased risk of restenosis (OR=4.7; 95% CI: 1.2 to 18.5; P=0.03). Post intervention CRP greater than 24.2mg/l was associated with a 10.7 fold adjusted risk of restenosis (OR=10.7; 95% CI: 2.4 to 47.6; P=0.02). In the second study, 172 patients underwent a successful above knee angioplasty.31 Restenosis was found in 56 patients (33%) within 6 months. CRP values at baseline (OR, 2.3; 95% CI:1.1, 4.2) and 48 hours after angioplasty (OR, 2.3; 95% CI:1.6, 3.1) were independently associated with restenosis at 6 months.

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Conclusion 

Cholesterol concentrations remain used widely to determine the risk of developing ischemic heart disease, although it is well known that approximately 50% of patients with myocardial infarction have normal cholesterol levels. HsCRP has shown promising results in predicting the developments and severity of coronary heart disease, and more recently, Peripheral Vascular Disease. PVD should be investigated in a similar manner to coronary heart disease, with patients divided into low (CRP<1mg/l), moderate (CRP between 1 and 3mg/l) and high risk (CRP>3mg/l) groups.

There are likely to be several limitations to the studies that we identified. For instance, positive case control studies are more likely to be reported than negative ones. In some studies blood samples were taken only once, therefore the individual variation could not have been taken into account. However, we found sufficient evidence to conclude that CRP can be used to predict the development of PVD and assess its severity. It also shows promise in the prediction of the outcome of angioplasty, but larger studies are needed to confirm this.

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References 

  1. Khreiss T, József L, Potempa LA, Filep JG. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation. 2004;109:2016–2022
  2. Yeh Edware TH. CRP as a mediator of disease. Circulation. 2004;109(Suppl I):II-1–II-14
  3. Tracy RP, Kuller LH, Psaty BM, Cushman M, Meilahn EN, Smith N. C-reactive protein and incidence of cardiovascular disease in older women: the rural health promotion project and the cardiovascular health study. Circulation. 1996;93:622
  4. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, et al. The prognostic value of C-reactive protein and serum amyloid. A protein in severe unstable angina. N Engl J Med. 1994;331:417–424
  5. Ledue TB, Rifai N. Preanalytic and analytic sources of variations in C-reactive protein measurement: implications for cardiovascular disease risk assessment. Clin Chem. 2003;49:1258–1271
  6. Ford ES, Giles WH, Mokdad AH, Myers GL. Distribution and correlates of C-reactive protein concentrations among adult US women. Clin Chem. 2004;50(3):574–581
  7. Roivainen M, Viik-Kajander M, Palosuo T, Toivanen P, Leinonen M, Saikku P, et al. Infections, inflammation, and the risk of coronary heart disease. Circulation. 2000;101:252–257
  8. Pearson TA, Mensah GA, Alexander WR, Anderson JL, Cannon RO, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511
  9. Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem. 2001;47:403–411
  10. Morrow DA, Ridker PM. High sensitivity C-reactive protein (hs-CRP): a novel risk marker in cardiovascular disease. Prev Cardiol. 1999;1:13–1641
  11. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321:199–204
  12. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843
  13. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979
  14. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–242
  15. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke. 2001;32:2575–2579
  16. Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation. 2002;105:2595–2599
  17. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285:2481–2485
  18. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425–428
  19. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GDO, Fowkes FGR. C-reactive protein, Interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh artery study. Circulation. 2005;112:976–983
  20. Van Der Meer IM, De Maat MP, Hak AE, Kiliaan AJ, Del Sol AI, Van Der Kuip DA, et al. C-reactive protein predicts progression of Atherosclerosis measured at various sites in the arterial tree: the Rotterdam study. Stroke. 2002;33:2750–2755
  21. Bloemenkamp DG, Van Den Bosch MA, Mali WP, Tanis BC, Rosendaal FR, Kemmeren JM, et al. Novel risk factors for peripheral arterial disease in young women. Am J Med. 2002;113(6):462–467
  22. Cassar K, Ford I, Greaves M, Bachoo P, Brittenden J. Randomized clinical trial of the antiplatelet effects of aspirin-clopidogrel combination versus aspirin alone after lower limb angioplasty. Br J Surg. 2005 Feb;92(2):159–165
  23. Vu JD, Vu JB, Pio JR, Malik S, Franklin SS, Chen RS, et al. Impact of C-reactive protein on the likelihood of peripheral arterial disease in United States adults with the metabolic syndrome, Diabetes Mellitus, and pre-existing cardiovascular disease. Am J Cardiol. 2005;96(5):655–658
  24. McDermott MM, Green D, Greenland P, Liu K, Criqui MH, Chan C, et al. Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index. Am J Cardiol. 2003;92:194–199
  25. McDermott MM, Greenland P, Guralnik JM, Ferrucci L, Green D, Liu K, et al. Inflammatory markers, D-dimer, pro-thrombotic factors, and physical activity levels in patients with peripheral arterial disease. Vasc Med. 2004;9(2):107–115
  26. Vainas T, Stassen F, de Graaf R, Twiss E, Herngreen S, Welten R, et al. C-reactive protein in peripheral arterial disease: relation to severity of the disease and to future cardiovascular events. J Vasc Surg. 2005;42(2):243–251
  27. Hozawa A, Ohmori K, Kuriyama S, Shimazu T, Niu K, Watando A, et al. C-reactive protein and peripheral artery disease among Japanese elderly: the Tsurugaya Project. Hypertens Res. 2004;27(12):955–961
  28. Aboyans V, Criqui MH, Denenberg JO, Knoke JD, Ridker PM, Fronek A. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation. 2006 Jun 6;113(22):2623–2629
  29. Musicant SE, Taylor LM, Peters D, Schuff RA, Urankar R, Landry GJ, et al. Prospective evaluation of the relationship between C-reactive protein, D-dimer and progression of peripheral arterial disease. J Vasc Surg. 2006 Apr;43(4):772–780(discussion 780)
  30. Schillinger M, Exner M, Mlekusch W, Haumer M, Rumpold H, Ahmadi R, et al. Endovascular revascularization below the knee: 6-month results and predictive value of C-reactive protein level. Radiology. 2003;227:419–425
  31. Schillinger M, Exner M, Mlekusch W, Rumpold H, Ahmadi R, Sabeti S, et al. Vascular inflammation and percutaneous transluminal angioplasty of the femoropopliteal artery: association with Restenosis. Radiology. 2002;225:21–26

PII: S1078-5884(07)00029-9

doi:10.1016/j.ejvs.2006.10.040

European Journal of Vascular & Endovascular Surgery
Volume 34, Issue 1 , Pages 18-22, July 2007

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