Infections in Peripheral Arterial Disease

Peripheral vascular disease (PVD), also known as peripheral artery disease (PAD) or peripheral artery occlusive disease (PAOD), includes all diseases caused by the obstruction of large arteries in the arms and legs. PVD can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or thrombus formation. It causes either acute or chronic ischemia (lack of blood supply), typically of the legs.

Chlamydia pneumoniae DNA in the arterial wall of patients with peripheral vascular disease. J Gutierrez, J Linares-Palomino, C Lopez-Espada, M Rodriguez, E Ros, G Piedrola, MC del Maroto. Infection 2001 Aug;29(4):196-200. 71 PAOD patients vs. 50 varicose controls, p< 0.0001.

Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study. AM O'Hare, AB Newman, R Katz, LF Fried, CO Stehman-Breen, SL Seliger, DS Siscovick, MG Shlipak. Arch Intern Med 2005 Dec 12-26;165(22):2666-2670. "The association of cystatin C, a novel marker of renal function, with risk for developing complications related to peripheral arterial disease (PAD) has not been examined. METHODS: We evaluated the hypothesis that a high cystatin C concentration is independently associated with future PAD events among 4025 participants in the Cardiovascular Health Study who underwent serum cystatin C measurement at the 1992-1993 visit and who did not have PAD at baseline. The association of cystatin C quintiles with time to first lower-extremity PAD procedure (bypass surgery, angioplasty, or amputation) was evaluated using multivariable proportional hazards models. Secondary analyses were conducted using quintiles of serum creatinine level and estimated glomerular filtration rate (eGFR). RESULTS: The annualized risk of undergoing a procedure for PAD was 0.43% per year among participants in the highest cystatin C quintile (>1.27 mg/L) compared with 0.21% per year or less in all other quintiles. After multivariable adjustment for known risk factors for PAD, elevated cystatin C levels remained associated with the outcome (hazard ratio, 2.5 for highest vs lowest quintile of cystatin C, 95% confidence interval, 1.2-5.1). The highest quintiles of serum creatinine level and eGFR were not associated with future PAD events in either unadjusted or adjusted analyses. CONCLUSION: Elevated concentrations of cystatin C were independently predictive of incident PAD events among community-dwelling elderly patients."

[Role of chronic infection and heat shock proteins in peripheral arterial disease]. M Rabczyński, R Adamiec. Przegl Lek 2007;64(6):419-422. 31 patients with peripheral arterial disease or with diabetic macroangiopathy, 11 healthy volunteers. "Statistic analysis showed anti-C. pneumoniae IgG (p< 0.025) and anti-CMV IgG (p<0.0157) antibodies were significantly more frequent in both study groups in comparison with healthy controls. Antibodie levels were also found significantly higher than in controls. Mean concentration of anti-C. pneumoniae IgG in the study group was 69.67574 vs. 18.59722 [AU/ml] in the control group (p<0.01). Analogical anti CMV IgG levels in the study group were 337.6516 vs 121.3778 [AU/ml] in controls (p<0.025). Similar changes in antibody concentration were noticed for the C. pneumoniae IgA index. 0.835258 vs. 0.176333 (p< 0.005). Antibodies against HSP 60/65 were present in significantly higher titre (p<0.005). No significant differences in antibody levels were detected beteween groups I and II. The positive correlation between anti-C. pneumoniae Ig A (r=0.3910; p<0.03) and anti HSP 60/65 antibodies titre, as well as anti-C. pneumoniae Ig G (r= 0.7151; p<0.00009) and anti HSP 60/65 speaks for the heat shock protein involvement in atherosclerotic plaque development."

[Clinical Summary] Symptomatic peripheral arterial disease in women: nontraditional biomarkers of elevated risk. AD Pradhan, S Shrivastava, NR Cook, N Rifai, MA Creager, PM Ridker. Circulation 2008 Feb 12;117(6):823-831. 12.3-year prospective study of 27,935 US female health professionals > or = 45 years of age without diagnosed vascular disease at baseline. sICAM-1 (adjusted HR, 4.0; 95% confidence interval, 1.9 to 8.6). "Findings pertaining to novel biomarkers provide clinical confirmation of a prominent role of endothelial activation and leukocyte recruitment in lower-extremity arterial disease."

Periodontitis may increase the risk of peripheral arterial disease. YW Chen, M Umeda, T Nagasawa, Y Takeuchi, Y Huang, Y Inoue, T Iwai, Y Izumi, I Ishikawa. Eur J Vasc Endovasc Surg 2008 Feb;35(2):153-158. 25 patients with aorto-iliac and/or femoro-popliteal occlusive disease and 32 generally healthy controls. PCR was used to identify Porphyromonas gingivalis, Treponema denticola, Actinobacillus actinomycetemcomitans, Prevotella intermedia, Cytomegalovirus (CMV), Chlamydia pneumoniae, and Helicobacter pylori in tissue specimens, and serum IgG titres against the four bacteria were measured. "Periodontopathic bacteria were detected in 13/25 (52%) atherosclerotic specimens. CMV or C. pneumoniae was detected in 1/25 (4%) specimens; H. pylori was not detected from any of these specimens. Fontaine grade III or IV patients showed higher detection frequency of P. gingivalis than Fontaine grade II patients (57.1% vs 22.2%, P=0.09). After adjusting for age, gender, diabetes and smoking, periodontitis increased 5-fold the risk of having PAD (OR 5.45).... This association could result from the increased concentration of serum inflammatory cytokines in those with periodontitis."

Markers of Chlamydia pneumoniae and human cytomegalovirus infection in patients with chronic peripheral vascular disease and their relation to inflammation, endothelial dysfunction and changes in lipid metabolism. PJ Kraml, K Roubalová, M Bulvas, Z Sommerová, J PotoCková, V Mandys, M Andel. Folia Microbiol (Praha) 2008;53(6):551-557. "CPN genome was detected in 9 (47.4 %) patients by at least one PCR method. Serological markers of acute CPN infection were found in 5 (26.3 %) subjects; each of them showed also positivity in at least one of the PCR methods... Patients with laboratory markers of acute CPN infection exhibited more pronounced alterations in lipid metabolism and endothelial dysfunction."

Cystatin C--a marker of peripheral atherosclerotic disease? J Arpegård, J Ostergren, U de Faire, LO Hansson, P Svensson. Atherosclerosis 2008 Aug;199(2):397-401. "Blood samples were analysed for serum Cystatin C, IL6, CRP and creatinine in 103 males with peripheral arterial disease (PAD) and 96 controls matched for age and sex. "Cystatin C-concentration was higher in PAD-patients compared to controls; 1.09+/-0.40 vs. 0.95+/-0.17 mg/L (p<0.01). There was no difference in CCr; 81+/-27 vs. 82+/-22 mL/min or eGFR; 76+/-21 vs. 79+/-14 mL/min. Cystatin C correlated to CCr, logIL-6 and logCRP in both patients (r=-0.60, p<0.001), (r=0.35, p<0.001) and (r=0.30, p<0.01) and controls (-0.44, p<0.001), (0.38, p<0.001) and (r=0.32, p<0.01), respectively. In an analysis of covariance, corrected for difference in eGFR, Cystatin C remained higher in PAD-patients compared to controls; 1.09 (C.I. 1.04-1.14) vs. 0.96 (C.I. 0.90-1.01). CONCLUSION: Cystatin C-concentration, corrected for differences in eGFR, IL-6 and CRP values, is higher in PAD-patients compared to controls. Our finding suggests that Cystatin C may be an independent marker of atherosclerotic disease apart from its relation to kidney function."

A biomarker panel for peripheral arterial disease. ET Fung, AM Wilson, F Zhang, N Harris, KA Edwards, JW Olin, JP Cooke. Vasc Med 2008 Aug;13(3):217-24. 197 individuals with both coronary artery disease and peripheral arterial disease; 81 with CAD only; and 262 with no hemodynamically significant disease. "Among the plasma markers tested, beta 2 microglobulin (beta2M) and cystatin C had the highest correlation with ABI [ankle-brachial index], and higher than any of the conventional risk factors of age, smoking status, and diabetes status. A biomarker panel score derived from beta2M, cystatin C, hsCRP, and glucose had an increased association with PAD status (OR = 12.4, 95% confidence interval (CI) 6.6-23.5 for highest vs lowest quartile), which was still significant after adjusting for known risk factors (OR = 7.3, 95% CI 3.6-14.9 for highest vs lowest quartile)."

The human protease inhibitor cystatin C is an activating cofactor for the streptococcal cysteine protease IdeS. B Vincents, R Vindebro, M Abrahamson, U von Pawel-Rammingen. Chem Biol 2008 Sep 22;15(9):960-968. "Human cystatin C is considered the physiologically most important inhibitor of endogenous papain-like cysteine proteases. We present here an unexpected function of cystatin C. Instead of acting as an inhibitor, cystatin C acts as a facultative, endogenous cofactor for the papain-like IgG-cleaving enzyme IdeS of the human pathogen Streptococcus pyogenes. IdeS activity is not dependent on cystatin C, but is significantly enhanced in the presence of cystatin C. We report a protease inhibitor that accelerates the activity of its putative target protease and a unique example of how a host protease inhibitor is "hijacked" by a bacterial protease to increase its activity. This finding has important implications for the view on protease-inhibitor interactions, and is relevant to consider in the therapeutic use of protease inhibitors."

[Comment re Vincents] Friend or foe? Turning a host defense protein into a pathogen's accomplice. A Shen, M Bogyo. Chem Biol 2008 Sep 22;15(9):879-880. "Cystatins are cysteine protease inhibitors that are at the front-line of defense against pathogens that secrete proteases as virulence factors. In this issue, Vincents et al. (2008) reveal how the bacterial protease IdeS from Streptococcus pyogenes hijacks normal cystatin C function to convert it into a cofactor that enhances proteolytic destruction of host-defense antibodies."

Kidney function estimated from serum creatinine and cystatin C and peripheral arterial disease in NHANES 1999-2002. E Selvin, A Köttgen, J Coresh. Eur Heart J 2009 Aug;30(15):1918-1925. 3089 subjects. "Glomerular filtration rate estimated using cystatin C was more strongly associated with PAD compared with eGFR using serum creatinine before and after multivariable adjustment. Further, after adjustment for cystatin C, kidney function based on serum creatinine was no longer significantly associated with PAD. However, cystatin C remained significantly associated with PAD even after adjustment for GFR estimated by serum creatinine. Compared with optimal kidney function (eGFR(serum creatinine) >or=60, eGFR(cystatin C) >90), the odds ratio for PAD was 3.11 (95% confidence interval 1.26-7.64) for preclinical CKD (eGFR(serum creatinine) >or=60, eGFR(cystatin C) <76.7) and 5.07 (3.01-8.52) for 'confirmed' CKD (eGFR(serum creatinine) <60, eGFR(cystatin C) <60)."

White blood cell count predicts all-cause mortality in patients with suspected peripheral arterial disease. FA Arain, M Khaleghi, KR Bailey, BD Lahr, TW Rooke, IJ Kullo. Am J Med 2009 Sep;122(9):874.e1-7. 56 deaths / 242 patients. "Patients in the top tertile of WBC count and CRP level had a relative risk of mortality of 3.37 (confidence interval [CI], 1.56-7.27) and 2.12 (CI, 0.97-4.62), respectively. However, only the WBC count contributed incrementally to prediction of mortality. Inferences were similar when analyses were limited to patients with peripheral arterial disease (ABI<0.9, n = 114)."

Infections in Buerger's Disease

Buerger's disease (thromboangiitis obliterans) "is different from Peripheral Arterial Disease or PAD, because it is not caused by atherosclerosis (plaque) buildup that causes a narrowing of the artery. Instead, TAO is caused by inflammation of the artery wall, along with the development of clots in the small and medium sized arteries of the arms or legs causing the arteries to become blocked. Without blood flow below the inflamed artery or clots, the fingers, toes, and skin tissue do not receive adequate blood. This usually leads to enormous pain at rest or with exercise, plus sores may develop and may be slow to heal." (Buerger’s Disease : What is it? Vascular Disease Foundation, accessed 3/9/09.)

Oral bacteria in the occluded arteries of patients with Buerger disease. T Iwai, Y Inoue, M Umeda, Y Huang, N Kurihara, M Koike, I Ishikawa. J Vasc Surg 2005 Jul;42(1):107-115. "Fouteen male patients with a smoking history who had developed characteristics of Buerger disease before the age of 50 years were included in this study. Occluded arteries, including superficial femoral (n = 4), popliteal (n = 2), anterior tibial (n = 4), and posterior tibial (n = 4) arteries, were removed and studied. A periodontist performed a periodontal examination on each patient and collected dental plaque and saliva samples from them at the same time. The polymerase chain reaction method was applied to detect whether seven species of periodontal bacteria--Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, Campylobacter rectus, Actinobacillus actinomycetemcomitans, Prevotella intermedia , and Prevotella nigrescens--were present in the occluded arteries and oral samples. In addition, arterial specimens from seven control patients were examined by polymerase chain reaction analysis. RESULTS: DNA of oral bacteria was detected in 13 of 14 arterial samples and all oral samples of patients with Buerger disease. Treponema denticola was found in 12 arterial and all oral samples. Campylobacter rectus, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis, and Prevotella nigrescens were found in 14% to 43% of the arterial samples and 71% to 100% of the oral samples. A pathologic examination revealed that arterial specimens showed the characteristics of an intermediate-chronic-stage or chronic-stage lesion of Buerger disease. All 14 patients with Buerger disease had moderate to severe periodontitis. None of the control arterial samples was positive for periodontal bacteria. CONCLUSIONS: This is the first study to identify oral microorganisms in the lesions of Buerger disease. Our findings suggest a possible etiologic link between Buerger disease and chronic infections such as oral bacterial infections."

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cast 01-20-11