Allograft coronary artery disease (CAD) remains the leading cause of morbidity and mortality affecting the long-term survival of patients after cardiac transplantation. Because there is increasing evidence that imbalances in hemostatic and fibrinolytic pathways are associated with graft failure, we hypothesized that atherothrombotic risk factors may contribute to allograft CAD. This study sought to determine if plasma hemostatic and fibrinolytic parameters are associated with the severity of allograft CAO. The extent of allograft CAD was investigated by angiography and intravascular ultrasound (IVUS) in 16 cardiac transplant recipients. Intimal thickening was quantified using IVUS by measuring the intimal index (li = intimal area/[intimal area + luminal area]) in two to five segments of the left anterior descending (LAD) coronary artery. The maximal li per patient was calculated and index to the time post-transplant (Mxli/Yr). Plasma fibrinogen (FGN), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a) (Lp(a)), and net fibrinolytic activity of plasma were assayed 6−24 months after transplant as indicators of the fibrinolytic system and then correlated with the IVUS measurements. The FGN level correlated with the severity of initimal thickening, Mxli/Yr (r2 = 0.41, p = 0.008), and was inversely correlated with angiographic tertiary vessel filling (r2 = −0.25, p = 0.051). In patients with lower plasma fibrinolytic activity (lytic zone less than 100 mm2), Mxli/Yr was increased eightfold (0.218 ± 0.137 versus 0.025 ± 0.021, p = 0.001). t-PA (r2 = 0.0004, p = 0.94), PAI-1 (r2 = 0.008, p = 0.75) and Lp(a) levels (r2 = 0.11, p = 0.21) did not predict Mxli/Yr. Thus, we demonstrate that plasma FGN and net fibrinolytic activity correlate with the degree of intimal thickening measured by IVUS after cardiac transplantation. These data suggest that fibrin deposition may play a role in allograft CAD after cardiac transplantation.
BieberCPHumSASchwinnDA. Complications in long-term survival of cardiac transplantation. Transplant Proc1981; 8: 207–11.
2.
GaoSZSchrocderJSAldermanELHuntSASilvermanJFStinsonEB. Clinical and laboratory correlates of accelerated coronary artery disease in the cardiac transplant patient. Circulation1987; 76(suppl V): V-56–V-61.
3.
GaoSZAldermanELSchroederJSSilvermanJFHuntSA. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol1988; 12: 334–40.
4.
MillerL.Long-term complications of cardiac transplantation. Prog Cardiovasc Dis1991; 33: 229–82.
O'NeillBJPflugfelderPWSinghNR. Frequency of angiographic detection and quantitative assessment of coronary arterial disease one and three years after cardiac transplantation. Am J Cardiol1989; 63: 1221–26.
7.
St GoarFGPintoFJAldermanELIntracoronary ultrasound in cardiac transplant recipients: in vivo evidence of ‘angiographically silent’ intimal thickening. Circulation1992; 85: 491–97.
8.
AndersonTJMeredithITUehataAFunctional significance of intimal thickening as detected by intravascular ultrasound early and late after cardiac transplantation. Circulation1993; 88: 1093–100.
9.
MacDonaldKRectorTSBraunlinEAKuboSHOlivariMT. Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection. Am J Cardiol1989; 64: 359–62.
10.
BarbirMBannerNThompsonGRKhaghaniAMitchellAYacoubM.Relationship of immunosuppression and serum lipids to the development of coronary arterial disease in the transplanted heart. Int J Cardiol1991; 32: 51–56.
11.
PetrossianGANicholsABMarboeCCRelation between survival and development of coronary artery disease and anti-HLA antibodies after cardiac transplantation. Circulation1989; 80(suppl III): II-122–III-125.
12.
UretskyBFMuraliSReddyPSDevelopment of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporinc and prednisone. Circulation1987; 76: 827–34.
13.
SalomonRNHughesCWSchoenFJPayneCDPoberJSLibbyP.Human coronary transplantation-associated evidence for chronic immune reaction to activated graft endothelial cells. Am J Pathol1991; 138: 791–98.
14.
ArdehaliALaksHDrinkwaterDCZivEDrakeTA. Vascular cell adhesion molecule-l is induced on vascular endothelia and medial smooth muscle cells in experimental cardiac allograft vasculopathy. Circulation1995; 92: 450–56.
15.
MeadeTWMellowsSBrozovicMHaemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet1986; ii: 533–37.
16.
ThompsonSGKienastJPykeSDMHaverkateFvan de LooJCW.Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Engl J Med1995; 332: 635–41.
17.
WilhemsenLSvardsuddKKorsan-BengtsenKLarssonBWelinLTibblinG.Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med1984; 311: 501–505.
18.
HandaKKonoSSakuKPlasma fibrinogen levels as an independent indicator of severity of coronary atherosclerosis. Atherosclerosis1989; 77: 209–13.
LoweGODrummondMMLorimerARRelation between extent of coronary artery disease and blood viscosity. Br Med J1980; 280: 673–74.
21.
HamstenAWimamBde FaireUBlombackM.Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med1985; 313: 1557–63.
22.
RidkerPMVaughanDEStampferMKMansonJEHennekensCH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet1993; 341: 1165–68.
23.
SalomaaVStinsonVKarkJDFolsomARDavisCEWuKK. Association of fibrinolytic parameters with early atherosclerosis. Circulation1995; 91: 284–90.
24.
McLeanJWTomlinsonJEKuangWJcDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature1987; 330: 132–37.
25.
LoscalzoJ.Lipoprotein(a): a unique risk factor for atherothrombotic disease. Arteriosclerosis1990; 10: 672–79.
26.
BarbirMSudhirKHuntBLipoprotein(a) and accelerated coronary artery disease in cardiac transplant patients. Lancet1992; 340: 1500–502.
27.
LabarrereCAPittsDHalbrookHFaulkWP. Tissue plasminogen activator, plasminogen activator inhibitor −1, and fibrin as indexes of clinical course in cardiac allograft recipients. Circulation1994; 89: 1599–608.
28.
LabarrereCAPittsDNelsonDRFaulkWP. Vascular tissue plasminogen activator and the development of artery disease in heart-transplant recipients. N Engl J Med1995; 333: 1111–16.
29.
FitzgeraldPJSt GoarFGConollyAJIntravascular ultrasound imaging of coronary arteries: is three layers the norm?Circulation, 1992; 86: 154–58.
30.
ClausA.Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol1957; 17: 237–47.
SimonDIEzzrattyAMLoscalzoJ.The fibrin(ogen)olytic properties of cathepsin D. Biochemistry1994; 33: 6555–63.
33.
LendrumACFraserDSSliddersWHendersonR.Studies on the character and staining of fibrin. J Clin Path1962; 15: 401–13.
34.
RussellHKJ.A modification of Movat's pentachrome stain. Arch Pathol1972; 94: 187–91.
35.
SchmidtWHavemannK.Isolation of elastase-like and chymotrypsin-like neutral proteases from human granulocytes. Hoppe Seylers Z Physiol Chem1974; 355: 1077–82.
36.
PlowEFEdgingtonTS. An alternative pathway for fibrinolysis. I. the cleavage of fibrinogen by leukocyte proteases at physiologic pH. J Clin Invest1975; 56: 30–38.
37.
HuntBJSegalHYacoubM.Hemostatic changes in heart transplant recipients and their relationship to accelerated coronary sclerosis. Transplantation1993; 55: 309–15.
38.
de LorgeilMDureauGBoissonnatPIncreased platelet aggregation after heart transplantation: influence of aspirin. J Heart Lung Transplant1991; 10: 600–603.
39.
de LorgerilMBoissonnatPMamelleNPlatelet aggregation and HDL cholesterol are predictive of acute coronary events in heart transplant recipients. Circulation1994; 89; 2590–94.
40.
GreenFHumphriesS.Control of plasma fibrinogen levels. Baillières Clin Haematol1989; 2: 945–59.
41.
BalleisenLSchulteHAssmanGEppingPHvan de LooJ.Coagulation factors and the progress of coronary heart disease. Lancet1987; ii: 461.
42.
KannelWBWolfPCastelliWPD'AgostinoRB. Fibrinogen and risk of cardiovascular disease. JAMA1987; 258: 1183–86.
43.
YarnellJWBakerIASweetmanPMFibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. Circulation1991; 83: 836–44.
44.
CremerPNagelDBottcherBSeidelD.Fibrinogen: ein koronarer risikofaktor. Diagnose Labor1992; 42: 28–35.
45.
ErnstEReschKL. Fibrinogen as a cardiovascular risk factor: a metaanalysis and review of the literature. Ann Intern Med1993; 118: 956–63.
46.
MaedaSAbeASeishimaMMakinoKNomaAKawadeM.Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis1989; 78: 145–50.
47.
SuffrediniAFHarpelPCParrilloJE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med1989; 320: 1165–72.
48.
HustMWyllieJMoreR.Atherogenesis and plasma constituents: I. Demonstration of fibrin in the white plaque by fluorescent antibody technique. Am J Pathol1964; 44: 255–67.
49.
SmithEBKeeneGAGrantAStirkG.Fate of fibrinogen in human arterial intima. Arteriosclerosis1990; 10: 263–75.
50.
SimonDISchoenFJFlessGMLipoprotein(a) accumulates intracellularly in coronary atherectomy specimens obtained from primary and restenotic lesions after PTCA [abstract]. J Am Coll Cardiol1991; 17: 299A.
51.
SmithEBKeenGAGrantAStirkC.Fate of fibrinogen in human arterial intima. Arteriosclerosis1990; 10: 263–75.
52.
LanguinoLRPlesciaJDuperrayAFibrinogen mediates leukocyte adhesion to vascular endothelium through an [CAM-I-dependent pathway. Cell1993; 73: 1423–34.
53.
RossR.The pathogenesis of atherosclerosis: An update. N Engl J Med1986; 314: 488–500.
54.
KadishJLButterfieldCEFolkmanJ.The effects of fibrin on cultured vascular endothelial cells. Tissue Cell1979; 11: 99–108.
55.
IshidaTTanakaK.Effects of fibrin and fibrinogen degradation products on the growth of rabbit aortic smooth muscle cells in culture. Atherosclerosis1982; 44: 161–74.
56.
FreedmanJEFabianALoscalzoJ.Impaired EDRF production by endothelial cells exposed to fibrin monomer and FDP. Am J Physiol1995; 268: C520–26.
57.
WatanabeKIshidaTYashitomiFTanakaK.Fibrinogen degradation products influence PGI2 synthesis by cultured porcine aortic endothelial and smooth muscle cells. Atherosclerosis1984; 51: 151–61.
58.
MeadeTWVickersMVThompsonSGStirlingTHainesAPMillerGJ. The epidemiological characteristics of platelet aggregability. Br Med J1985; 290: 428–32.
59.
CerielloAPirisiMGiacomelloRFibrinogen plasma levels as a marker of thrombin activation: new insights on the role of fibrinogen as a cardiovascular risk factor. Thromb Haemost1994; 71: 593–95.
60.
van Pelt-VerkuilEvan de ReePEmeisJJ. Defibrinogenation by arvin reduces air-drying induced arteriosclerosis in rat carotid artery. Thromb Haemostasis1989; 61: 246–49.
61.
ClausellNJagdishBSilvanaMAbnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries. J Am Coll Cardiol1995; 26: 110–19.
