Cardiac Function,Inflammatory Mediators and Mortality in Critical Limb Ischemia

Abstract

Patients with critical limb ischemia (CLI) have a high frequency of concomitant coronary heart disease and congestive heart failure. The aim of the study was to evaluate cardiac function in relation to inflammatory markers and 1-year mortality rate among patients with CLI. The authors investigated 232 consecutive patients with CLI by means of electrocardiogram (ECG), and measurements of endothelin (ET)-1, tumor necrosis factor alpha (TNF)a, interleukin (IL)-6, neopterin, CD40 ligand, and 8-epi-prostaglandin (PG)F₂a in plasma. Echocardiography (echo) was performed in 88 (38%) patients. One-year mortality rate was assessed after prospective follow-up. One hundred and eighty-six (80%) patients had sinus rhythm (SR), 36 (16%) had atrial fibrillation or flutter (AF), and 10 (4%) pacemaker rhythm. Ischemic ECG changes occurred in 143 (62%) patients. Patients with AF showed higher IL-6 (p=0.0296) and neopterin (p=0.0494) concentrations. Patients with ischemic ECG changes showed higher ET-1 (p=0.0303), 8-epi-PGF₂a (p=0.0027), neopterin (p=0.0004) concentrations and 1-year mortality rate (p=0.0105). The difference in ET-1 remained in logistic regression (p=0.0152). Internal diameter of the left ventricle on echo correlated with IL-6 (r =0.345, p=0.0017), TNFa (r =0.240, p=0.0273), and neopterin (r =0.327, p=0.0028). Internal diameter of the left atrium correlated with TNFa (r =0.384, p=0.0092) and neopterin (r =0.526, p=0.0004), and ejection fraction (EF) correlated inversely with IL-6 (r =-0.380, p=0.0015) and neopterin (r =-0.346, p=0.0038). Patients with EF <40% showed higher (p=0.0462) 1-year mortality rate than patients with EF >40%. In conclusion, in critical limb ischemia, cardiac rhythm disturbances and ischemic ECG changes were related to inflammatory mediators and predicted 1-year mortality rate. The inflammatory mediators correlated with echocardiographic signs of congestive heart failure.

Get full access to this article

View all access options for this article.

References

Mautner GC , Mautner SL , Roberts WC : Amounts of coronary arterial narrowing by atherosclerotic plaque at necropsy in patients with lower extremity amputation. Am J Cardiol 70:1147-1151, 1992.

Aronow WS , Ahn C : Prevalence of coexistence of coronary artery disease, peripheral artery disease, and atherothrombotic brain infarction in men and women 62 years of age. Am J Cardiol 74:64-65, 1994.

Ness J , Aronow WS : Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc 47:1255-1256, 1999.

Aronow WS , Ahn C : Association of valvular aortic stenosis with symptomatic peripheral arterial disease in older persons. Am J Cardiol 88:1046-1047, 2001.

Hertzer NR : Fatal myocardial infarction following lower extremity revascularisation—273 patients followed 6–11 postoperative years. Ann Surg 193:492-498, 1981.

Fowkes FGR : Epidemiology of atherosclerotic arterial disease in the lower limbs. Eur J Vasc Surg 2:283-291, 1988.

Ross R : Atherosclerosis—an inflammatory disease. N Engl J Med 340:115-126, 1999.

Libby P , Ridker PM , Maseri A : Inflammation and atherosclerosis. Circulation 105:1135-1143, 2002.

Dormandy JA , Rutherford RB , TASC Working Group : TransAtlantic Inter-Society Consensus (TASC). Management of peripheral arterial disease (PAD). J Vasc Surg 31:S170-s170, 2000.

10.

Young JL , Libby P , Schönbeck U : Cytokines in the pathogenesis of atherosclerosis. Thromb Haemost 88:554-567, 2002.

11.

Tatzber F , Rabl H , Koriska K , et al: Elevated serum neopterin levels in atherosclerosis. Atherosclerosis 89:203-208, 1991.

12.

Kishimoto T : The biology of interleukin-6. Blood 74:1-10, 1989.

13.

Schönbeck U , Libby P : CD40 signaling and plaque instability. Circ Res 89:1092-1103, 2001.

14.

Schönbeck U , Gerdes N , Varo N , et al: Oxidized lowdensity lipoprotein augments and 3-hydroxy-methyl-glutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells. Circulation 106:2888-2893, 2002.

15.

Newby DE , Webb DJ : The endothelin system in cardiovascular disease. Br Med J 314:531-532, 1997.

16.

Ikeda U , Yamamoto K , Maeda Y , et al: Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells. Hypertension 29:65-69, 1997.

17.

Davì G , Ciabattoni G , Consoli A , et al: In vivo formation of 8-iso-prostaglandin F2a and platelet activation in diabetes mellitus; effects of improved metabolic control and vitamin E supplementation. Circulation 99:224-229, 1999.

18.

Morrow JD , Hill KE , Burk RF , et al: A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci USA 87:9383-9387, 1990.

19.

Patrono C , Fitzgerald GA : Isoprostanes: Potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 17:2309-2315, 1997.

20.

Burstein M , Scholnik HR , Morfin R : Rapid method for the isolation of proteins from human serum by precipitation with polyanions. J Lipid Res 11:583-595, 1970.

21.

Ubbink J , Vermaak W , Bissbort S : Rapid high-performance liquid chromatographic assay for total homo-cysteine levels in human serum. J Chromatogr 565:441-446, 1991.

22.

Blackburn H , Keys A , Simonsen E , et al: The electrocardiogram in population studies. A classification system. Circulation 21:1160-1175, 1960.

23.

MacFarlane PW : Minnesota coding and the prevalence of ECG abnormalities. Heart 84:582-584, 2000.

24.

De Bacquer D , de Backer G , Kornitzer M . Prevalences of ECG findings in large population-based samples of men and women. Heart 84:625-633, 2000.

25.

Gueret P , Meerbaum S , Zwehl W , et al: Two-dimensional echocardiographic assessment of left ventricular stroke volume: Experimental correlation with thermodilution and cineangiography in normal and ischemic states. Cathet Cardiovasc Diagn 7:247-258, 1981.

26.

Balmer H , Mahler F , Do DD , et al: Balloon angioplasty in chronic critical limb ischemia: Factors affecting clinical and angiographic outcome. J Endovasc Ther 9:403-410, 2002.

27.

Lassila R , Lepantalo M , Lindfors O : Peripheral arterial disease—natural outcome. Acta Med Scand 220:295-301, 1986.

28.

Zouridakis EG , Schwartzman R , Garcia-Moll X , et al: Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression. Eur Heart J 22:1578-1584, 2001.

29.

Cesari M , Penninx BWJH , Newman AB , et al: Inflammatory markers and cardiovascular disease (The Health, Aging and Body Composition [Health ABC] Study). Am J Cardiol 92:522-528, 2003.

30.

Roldán V , Marín F , Blann AD , et al: Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation. Eur Heart J 24:1373-1380, 2003.

31.

Siriwardena AK , Ruckley CV : Echocardiography in acute limb ischemia. J R Coll Surg Edinb 36:155-157, 1991.

32.

Wolf YG , Landersberg G , Mosseri M , et al: Preoperative dipyridamole-thallium scanning, selective coronary revascularization and long-time survival in patients with critical lower limb ischemia. J Cardiovasc Surg 42:89-95, 2001.

33.

Vonhof S , Brost B , Stille-Siegener M , et al: Monocyte activation in congestive heart failure due to coronary artery disease and idiopathic dilated cardiomyopathy. Int J Cardiol 63:237-244, 1998.

34.

Kosar F , Varol E , Ileri M , et al: Circulating cytokines and complements in chronic heart failure. Angiology 50:403-408, 1999.

35.

Gullestad L , Aukrust P , Ueland T , et al: Effects of high-versus low-dose angiotensin-converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol 34:2061-2067, 1999.

36.

Wiedermann CJ , Beimpold H , Herold M , et al: Increased levels of serum neopterin and decreased production of neutrophil superoxide anions in chronic heart failure with elevated levels of tumor necrosis factor-alpha. J Am Coll Cardiol 22:1897-1901, 1993.

37.

Caforio ALP , Goldman JH , Baig MK , et al: Elevated serum levels of soluble interleukin-2 receptor, neopterin and b-2-microglobulin in idiopathic dilated cardiomyopathy: Relation to disease severity and autoimmune pathogenesis. Eur J Heart Failure 3:155-163, 2001.

38.

Orús J , Roig E , Perez-Villa F , et al: Prognostic value of serum cytokines in patients with heart failure. J Heart Lung Transplant 19:419-425, 2000.

39.

Rudzite V , Skards JI , Fuchs D , et al: Serum kynure-nine and neopterin concentrations in patients with cardiomyopathy. Immunol Lett 32:125-129, 1992.

40.

Clerico A : Pathophysiological and clinical relevance of circulating levels of cardiac natriuretic hormones: Are they merely markers of cardiac disease? Clin Chem Lab Med 40:752-760, 2002.

41.

Stumpf C , Lehner C , Eskafi S , et al: Enhanced levels of CD154 (CD40 ligand) on platelets in patients with chronic heart failure. Eur J Heart Failure 5:629-637, 2003.