Links to abstracts and the journal's home page are provided.
| Stroke. 2006 |
Apr;37(4):1106-8. |
Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation. |
| Arterioscler Thromb Vasc Biol. 2006 |
Feb;26(2):235-6. |
Adiponectin: vascular protection from the fat? |
| Arterioscler Thromb Vasc Biol. 2006 |
Jan; 26(1):233. |
Aldosterone promotes thrombosis formation after arterial injury in mice. |
| J Thromb Haemost 2005 |
Oct;3(10):2149-53. |
Pioglitazone protects against thrombosis in a mouse model of obesity and insulin resistance. |
| Arterioscler Thromb Vasc Biol. 2005 |
Jun 9; [Epub ahead of print] |
Recombinant Leptin Promotes Atherosclerosis and Thrombosis in Apolipoprotein E-Deficient Mice. |
| Circulation. 2005 |
Apr 12; 111(14):1822-5. |
Homozygosity for factor V Leiden leads to enhanced thrombosis and atherosclerosis in mice. |
| Circulation. 2005 |
Feb 8; 111(5):629-32 |
Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency. |
| Ann Thorac Surg. 2004 |
Mar;77(3):1077-9 |
Ventricular tachycardia associated with transmyocardial migration of an epicardial pacing wire. |
| Journal of the American Society of Nephrology2003 |
Feb;14(2):298-302 |
Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. |
| Circulation2002 |
May; 105 (18): 2139-42 |
Lethal perinatal thrombosis in mice resulting from the interaction of tissue factor pathway inhibitor deficiency and factor V Leiden. |
| Jama2002 |
Apr; 287 (13): 1706 - 9 |
Effect of Leptin on Arterial Thrombosis Following Vascular Injury in Mice |
| American Journal of Managed Care2002 |
Apr; 8 (4): 384-8 |
Competitive bidding for interventional cardiology supplies: lessons learned during round 2. |
| Expert Reviews in Molecular Medicine2002 |
Mar 26 |
Recent advances in understanding endogenous fibrinolysis: implications for molecular-based treatment of vascular disorders. |
| J Clin Invest2002 |
Jan; 109 (2): 213 - 9. |
Heparin cofactor II inhibits arterial thrombosis after endothelial injury. |
| Obstet Gynecol2001 |
Nov; 98 (5 Pt 2): 899 - 902. |
Spontaneous coronary artery dissection in a pregnant woman. |
| J Am Soc Echocardiogr.2001 |
Oct; 14 (10): 1042 - 3. |
Eustachian valve endocarditis caused by Streptococcus viridans. |
| Circulation 2001 |
Jun26; 103 (25): 3044 - 6 |
Deficiency of Tissue Factor Pathway Inhibitor Promotes Atherosclerosis and Thrombosis in Mice. |
| Thromb Haemost.2001 |
Mar; 85 (3) : 441-4 |
Pulmonary fibrosis is increased in mice carrying the factor V Leiden mutation following bleomycin injury. |
| Arterioscler Thromb Vasc Biol. 2000 |
Jul; 20 (7) : 1831 - 4 |
Hyperlipidemia promotes thrombosis after injury to atherosclerotic vessels in apolipoprotein E-deficient mice. |
| Arterioscler Thromb Vasc Biol. 2000 |
Mar; 20 (3) : 846 - 52 |
Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. |
| Blood 2000 |
Dec 15; 96 (13) : 4222 - 6 |
Spontaneous thrombosis in mice carrying the factor V Leiden mutation. |
| Blood 2000 |
Dec 15; 96 (13) : 4212 - 5 |
Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. |
| Blood2000 |
Jan 15; 95 (2) : 577 - 80 |
Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. |
| Adv Exp Med Biol. 1997 |
425 : 131 - 41 |
Of mice and men. The function of plasminogen activator inhibitors (PAIs) in vivo. |
| Blood 1996 |
Jun 1; 87 (11) : 4718 - 22 |
Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse model of metastatic melanoma. |
| J Clin Invest. 1996 |
Jan 1; 97 (1) : 232 - 7 |
Bleomycin - induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. |
| J Clin Invest.1995 |
May; 95 (5) : 2416 - 20 |
Peptide - mediated inactivation of recombinant and platelet plasminogen activator inhibitor-1 in vitro. |
| Circulation 1994 |
Nov; 90 (5) : 2356 - 66 |
Relation of regional function, perfusion, and metabolism in patients with advanced coronary artery disease undergoin surgical revascularization. |
| Am Heart J. 1994 |
Apr; 127 (4 Pt 1) : 928 - 9 |
Management of myocardial stunning associated with electroconvulsive therapy guided by heperventilation echocardiography. |
| Circulation 1994 |
Apr; 89 (4) : 1523 - 9 |
Heparin neutralization by platelet -rich thrombi. Role of platelet factor 4. |
| Blood 1994 |
Jan 15; 83 (2) : 351 - 6 |
Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1 dependent and independent mechanisms. |
| J Am Coll Cardiol. 1992 |
Sep; 20 (3) : 559 - 65 |
Clinical outcome of patients with advanced coronary artery disease after viability studies with positron emission tomography. |
| Am J Med. 1992 |
Jun; 92 (6) : 701 - 2 |
Tracheal obstruction secondary to extravasation of intravenous fluids from a central catheter port. |
| J Am Coll Cardiol. 1989 |
Apr; 13 (5) :1176 - 83 |
Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic "stunned" myocardium. |
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Stroke. 2006 Apr;37(4):1106-8. Epub 2006 Mar 2.
Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation.
Shen Y, Bodary PF, Vargas FB, Homeister JW, Gordon D, Ostenso KA, Shayman JA, Eitzman DT.
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA.-0644, USA.
BACKGROUND: Factor V Leiden (FVL) is a common genetic risk factor for vascular thrombosis in humans. Fabry disease, an X-linked lysosomal storage disorder attributable to alpha-galactosidase A (GLA) deficiency, is associated with premature vascular events that may be thrombotic in nature. METHODS: To examine a potential interaction between FvL and Gla deficiency in vivo, we analyzed tissue fibrin deposition in mice carrying combined mutations in FvL and Gla. Gla deficiency markedly increased tissue fibrin deposition in mice carrying the FvL mutation (0.33+/-0.03%; n=7) compared with FvL mutation (0.14+/-0.02%; n=10; P<0.0005). CONCLUSIONS: These observations demonstrate a synergistic interaction between Gla deficiency and FvL toward tissue fibrin deposition in mice. Concomitant mutations in these genes may increase the penetrance of vascular thrombotic events in humans.
Arterioscler Thromb Vasc Biol. 2006 Feb;26(2):235-6. No abstract available.
Adiponectin: vascular protection from the fat?
Bodary PF, Eitzman DT.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0644, USA.
Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):233. No abstract available.
Aldosterone promotes thrombosis formation after arterial injury in mice.
Bodary PF, Sambaziotis C, Wickenheiser KJ, Rajagopalan S, Pitt B, Eitzman DT.
J Thromb Haemost. 2005 Oct;3(10):2149-53.
Pioglitazone protects against thrombosis in a mouse model of obesity and insulin resistance.
Bodary PF, Vargas FB, King SA, Jongeward KL, Wickenheiser KJ, Eitzman DT.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0644, USA.
BACKGROUND: As arterial thrombosis accounts for the vast majority of cardiovascular complications in obese, insulin resistant patients, we hypothesized that improving insulin sensitivity may be effective in reducing the thrombotic response following vascular injury. OBJECTIVES: We investigated the effect of the thiazolidinedione drug, pioglitazone, on the thrombotic response to injury in obese, insulin resistant mice. METHODS: Insulin-resistant, obesity-prone mice (KK strain) were treated with pioglitazone, placebo, or the sulfonylurea compound, glipizide, for 2.5 weeks and then subjected to photochemical injury of the carotid artery. RESULTS: KK mice have a significant increase in adiposity (7 weeks: 25.6%; 15 weeks: 34.4%; P < 0.0001) and thrombotic tendency (7 weeks: 21.2 +/- 1.9 min; 15 weeks: 13.7 +/- 1.7 min; P < 0.01) with age. Pioglitazone provided significant protection from thrombosis at both time points, prolonging the time to occlusive thrombosis by 40% and 68%, at 7 and 15 weeks of age, respectively (P < 0.05). Similarly, following a diet-challenge to promote diabetes, pioglitazone provided protection from occlusive thrombus formation (Placebo: 11.3 +/- 1.0 min; Pioglitazone: 22.3 +/- 3.9 min; P < 0.05). However, despite a salient effect of glipizide on the hyperglycemia of the mice, there was no effect on the time to occlusive thrombus formation (13.2 +/- 0.9 min, n = 4) compared with placebo-treated mice. The pioglitazone protection was paralleled by significantly lower soluble P-selectin and platelet P-selectin expression providing evidence of an antiplatelet effect. CONCLUSIONS: We conclude that pioglitazone treatment provides protection against arterial thrombosis in an obese, insulin resistant, prothrombotic mouse model.
Arterioscler Thromb Vasc Biol. 2005 Jun 9; [Epub ahead of print]
Recombinant Leptin Promotes Atherosclerosis and Thrombosis in Apolipoprotein E-Deficient Mice.
Bodary PF, Gu S, Shen Y, Hasty AH, Buckler JM, Eitzman DT.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor; and the Department of Molecular Physiology and Biophysics and Medicine, Vanderbilt University, Nashville, Tenn.
OBJECTIVE: The direct role of leptin in vascular disease remains controversial. The objective of this study was to examine the effects of leptin treatment on atherosclerosis and thrombosis in atherosclerotic-prone mice. METHODS AND RESULTS: Sixteen-week-old, male apolipoprotein E-deficient mice were treated with injections of recombinant leptin (125 microg per day IP; n=10) or vehicle (n=10) for 4 weeks. Leptin treatment resulted in reduced epididymal fat (352+/-30.7 versus 621+/-61.5 mg; P=0.005) and fasting insulin (0.57+/-0.25 versus 1.7+/-0.22 ng/mL; P=0.014). Despite these metabolic benefits, leptin treatment resulted in an increase in atherosclerosis (8.0+/-0.95% versus 5.4+/-0.59% lesion surface coverage; P<0.05). Leptin treatment also resulted in a shortened time to occlusive thrombosis after vascular injury (21+/-2.1 versus 34.6+/-5.4 minutes; P=0.045). CONCLUSIONS: These studies indicate that exogenous leptin promotes atherosclerosis and thrombosis and support the concept that elevations of leptin may increase the risk for cardiovascular disease.
Circulation. 2005 Apr 12;111(14):1822-5
Homozygosity for Factor V Leiden Leads to Enhanced Thrombosis and Atherosclerosis in Mice.
Daniel T. Eitzman, MD; Randal J. Westrick, BSc; Yuechun Shen, MD; Peter F. Bodary, PhD; Shufang Gu, PhD; Sara L. Manning, BSc; Sarah L. Dobies, BSc; David Ginsburg, MD
Background— Activated protein C resistance due to factor V Leiden (FVL) is a common genetic risk factor for venous thrombosis in humans. Although the impact of FVL on the development of venous thrombosis is well established, its effect on arterial thrombosis and atherosclerosis is controversial.
Methods and Results— To determine the effect of the FVL mutation on arterial thrombosis in the mouse, wild-type (Fv+/+), heterozygous FVL (FvQ/+), and homozygous FVL (FvQ/Q) mice underwent photochemical carotid arterial injury to induce occlusive thrombosis. FvQ/Q mice formed occlusive thromboses 27±3 minutes (n=7) after the onset of injury, which was significantly shorter than that observed for Fv+/+ mice (56±7 minutes, n=9, P<0.01), whereas FvQ/+ mice (41±7 minutes, n=5) were intermediate (P=0.5, compared with Fv+/+). To determine the source of FVL relevant to the enhanced vascular thrombosis, bone marrow transplantation experiments were performed between Fv+/+ and FvQ/Q mice. FvQ/Q mice transplanted with Fv+/+ bone marrow formed occlusive thromboses at 35±5 minutes (n=7, P<0.05 compared with Fv+/+ mice), whereas Fv+/+ mice transplanted with FvQ/Q bone marrow occluded at 59±7 minutes (n=6, P<0.001 compared with FvQ/Q mice). To assess the effect of the FVL mutation on the development of atherosclerosis, FvQ/Q mice were crossed with the atherosclerosis-prone apolipoprotein E (ApoE)–deficient strain (ApoE–/–) to generate FvQ/Q,ApoE–/– mice. By 52 weeks of age, FvQ/Q,ApoE–/– mice (n=8) had developed more aortic atherosclerosis (40±6% lesion area) compared with Fv+/+,ApoE–/– mice (15±3% lesion area; n=12, P<0.02).
Conclusions— In conclusion, homozygosity for the FVL mutation in mice leads to enhanced arterial thrombosis and atherosclerosis. The source of the FVL leading to accelerated thrombosis appears to be circulating, non–platelet-derived plasma FVL.
Circulation. 2005 Feb 8;111(5):629-32
Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency.
Bodary PF, Shen Y, Vargas FB, Bi X, Ostenso KA, Gu S, Shayman JA, Eitzman DT.
BACKGROUND: Alpha-galactosidase A (Gla) deficiency leads to widespread tissue accumulation of neutral glycosphingolipids and is associated with premature vascular complications such as myocardial infarction and stroke. Glycosphingolipids have been shown to accumulate in human atherosclerotic lesions, although their role in atherogenesis is unclear. METHODS AND RESULTS: To determine whether Gla affects the progression of atherosclerosis, mice were generated with combined deficiencies of apolipoprotein E and Gla. At 45 weeks of age, Gla-deficient mice had developed more atherosclerosis than mice with normal Gla expression (25.1+/-14.0 versus 12.3+/-9.3 mm2 of total lesion area, P<0.02). This increase in atherosclerosis was associated with the presence of increased Gb3, enhanced inducible nitric oxide synthase expression, and increased nitrotyrosine staining. CONCLUSIONS: These findings suggest that deficiency of Gla leads to increased inducible nitric oxide synthase expression and accelerated atherosclerosis.
Ann Thorac Surg. 2004 Mar;77(3):1077-9.
Ventricular tachycardia associated with transmyocardial migration of an epicardial pacing wire.
Meier DJ, Tamirisa KP, Eitzman DT.
A 66-year-old man who had undergone a three-vessel coronary artery bypass grafting (CABG) procedure 3 years previously presented with ventricular tachycardia (VT) and cardiac arrest. Echocardiography demonstrated a wire coursing through the right ventricle into the pulmonary artery. The wire was removed with a snare and confirmed to be an epicardial temporary pacing wire placed during the CABG operation. We suspect that the epicardial pacing wire eroded through the right atrium and migrated into the right ventricle, contributing to the VT. Complications due to temporary epicardial pacing wires placed during CABG are discussed.
J Am Soc Nephrol 2003 Feb;14(2):298-302
Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis.
Eitzman DT, Bodary PF, Shen Y, Khairallah CG, Wild SR, Abe A, Shaffer-Hartman J, Shayman JA.
ABSTRACT. Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-galactosidase A (GLA) activity that results in the widespread accumulation of neutral glycosphingolipids. Renal failure, neuropathy, premature myocardial infarction, and stroke occur in patients with this condition primarily due to deposition of glycosphingolipids in vascular endothelial cells. The clinical consequences of Fabry disease suggest that vascular thrombosis may play a prominent role in the pathogenesis of this disease; however, the vasculopathy associated with Fabry disease has not been extensively studied. To determine if mice genetically deficient in Gla are susceptible to vascular thrombosis, a photochemical carotid injury model was used to induce occlusive thrombosis. In this model, Gla-/0 mice displayed a progressive age-dependent shortening of the time to occlusive thrombosis after vascular injury that correlated with progressive accumulation of globotriasylceramide (Gb3) in the arterial wall. Bone marrow transplantation from Gla-/0 to Gla+/0 mice and from Gla+/0 to Gla-/0 mice did not change the thrombotic phenotype of the host. These studies reveal a potent vascular prothrombotic phenotype in Gla-deficient mice and suggest that antithrombotic therapies as well as therapies designed to reduce the vascular accumulation of Gb3 may have beneficial effects on thrombotic complications in patients with Fabry disease. E-mail: deitzman@umich.edu
Circulation 2002 May 7; 105 (18): 2139 - 42
Lethal perinatal thrombosis in mice resulting from the interaction of tissue factor pathway inhibitor deficiency and factor V Leiden.
Eitzman DT, Westrick RJ, Bi X, Manning SL, Wilkinson JE, Broze GJ, Ginsburg D.
BACKGROUND: Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor (TFPI) has also been proposed as a risk factor for venous thrombosis and has been shown to enhance the prothrombotic effect of FVL in vitro. METHODS AND RESULTS: To examine the potential in vivo interaction between Tfpi and FvL, we analyzed crosses between mice carrying FvL and a deficiency of TFPI. The Fv(Q/Q),Tfpi(+/-) genotype was nearly completely fatal in the early perinatal period. Increased fibrin deposition was observed in multiple organs from the Fv(Q/Q),Tfpi(+/-) fetuses, suggesting disseminated thrombosis. CONCLUSIONS: These observations demonstrate the prothrombotic effect of modest variations in the level of TFPI expression and suggest that TFPI could be an important genetic modifier for the thrombosis associated with FVL in humans.
JAMA 2002 Apr 3; 287 (13): 1706-9
Effect of Leptin on Arterial Thrombosis Following Vascular Injury in Mice
Peter F. Bodary, PhD; Randal J. Westrick, BS; Kevin J. Wickenheiser; Yuechen Shen, MD; Daniel T. Eitzman, MD.
Context Complications of atherosclerosis are the leading cause of morbidity and mortality in industrialized societies. Obesity has emerged as an independent risk factor for complications of atherosclerotic vascular disease. Leptin, a hormone produced by the adipocyte, increases with obesity and appears to modulate energy balance and food intake. In addition, other actions of leptin have been proposed, including an in vitro effect on platelet aggregation. Thus, the elevated plasma leptin levels in obese individuals may promote vascular thrombosis.
Objective To test the hypothesis that leptin contributes to in vivo thrombosis via the leptin receptor.
Design and Materials A vascular thrombosis model was used to test male 10- to 12-week-old mice completely deficient in leptin or the leptin receptor and mice with platelet leptin-receptor deficiency.
Main Outcome Measure Time to formation of an occlusive thrombosis of the common carotid artery following experimentally induced endothelial injury.
Results Following onset of vascular injury, wild-type mice (n = 8) formed occlusive thrombosis in a mean (SD) of 42.2 (4.6) minutes, whereas leptin-deficient (n =5) and leptin receptor deficient mice (n = 7) formed occlusive thrombosis in 75.2 (10.1) and 68.6 (10.3) minutes, respectively (P<.05 compared with wild-type mice). When recombinant murine leptin was administered to leptin-deficient mice (n = 4), the time to occlusion was reduced to 41.8 (6.6) minutes (P<.04 vs vehicle control). Following bone marrow transplantation from leptin receptor deficient (donor) mice to wild-type (recipient) mice, the time to occlusion was prolonged from 22.3 (2.8) minutes in wild-type mice receiving wild-type marrow (n = 3) to 56.8 (5.0) minutes in wild-type mice receiving leptin receptor deficient bone marrow (n = 5) (P<.003).
Conclusions These studies demonstrate that leptin contributes to arterial thrombosis following vascular injury in vivo and that these prothrombotic effects appear to be mediated through the platelet leptin receptor.
American Journal of Managed Care 2002 April; 8 (4): 384-8
Competitive bidding for interventional cardiology supplies: lessons learned during round 2.
Eagle KA, Knight BP, Moscucci M, Strickberger SA, Duvernoy CS, Pelosi F, Werns SW,Eitzman DT, Morady F, Bates ER.
OBJECTIVE: To assess the magnitude of savings and develop concepts for "best strategies" in reducing costs in the purchasing of high-technology, high-cost materials used in coronary interventions and electrophysiologic treatments. STUDY DESIGN: Observational experience in competitive bidding for defibrillators, pacemakers, coronary stents, and coronary balloon catheters at a large, midwestern, publicly owned, academic cardiovascular center. METHODS: Iterative negotiation following a broad request for proposal sent to a diverse group of vending organizations in high-technology areas of cardiology. Product costs and volume usage were assessed before and after the process to estimate annualized cost reduction achieved. RESULTS: Using a combination of identification of preferred vendors; consignment of supplies; and collaborative consensus among physicians, administration, materials management, purchasing, and vendors, an annualized savings of more than $1.3 million was achieved. CONCLUSIONS: Aggressive, collaborative, fair, and competitive bidding for high-cost products used for coronary interventions and electrophysiologic treatments leads to substantial cost savings and can promote provider-industry partnerships that further enhance product use, provision, and tracking.
Expert Reviews in Molecular Medicine 2002 March 26; http://www.expertreviews.org/02004362h.htm
Recent advances in understanding endogenous fibrinolysis: implications for molecular-based treatment of vascular disorders.
Peter F. Bodary, Kevin J. Wickenheiser and Daniel T. Eitzman
The fate of a forming thrombus is determined through the delicate balance between the coagulation cascade, favouring clot formation, and the fibrinolytic system, favouring clot lysis. These processes occur simultaneously, and enjancement of fibrinolysis has been shown to reduce occlusive thrombus formation in animal models. This review examines the roles of the major fibrinolytic factors involved in clot lysis. The regulation of plasmin activity by plasminogen activators, alpha-2-antiplasmin, plasminogen activator inhibitor 1, and thrombin-activatable fibrinolysis inhibitor, and their effects on thrombus formation in vivo are discussed. Since alterations in fibrinolytic capacity appear to affect thrombus formation in animal models, there is considerable interest in the pharmacological manipulation of fibrinolysis.
J Clin Invest 2002 Jan; 109 (2): 213 - 9
Heparin cofactor II inhibits arterial thrombosis after endothelial injury.
He L, Vicente CP, Westrick RJ, Eitzman DT, Tollefsen DM.
Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin rapidly in the presence of dermatan sulfate, heparan sulfate, or heparin. HCII has been proposed to regulate coagulation or to participate in processes such as inflammation, atherosclerosis, and wound repair. To investigate the physiologic function of HCII, about 2 kb of the mouse HCII gene, encoding the N-terminal half of the protein, was deleted by homologous recombination in embryonic stem cells. Crosses of F1 HCII(+/-) animals produced HCII(-/-) offspring at the expected mendelian frequency. Biochemical assays confirmed the absence of dermatan sulfate-dependent thrombin inhibition in the plasma of HCII(-/-) animals. Crosses of HCII(-/-) animals produced litters similar in size to those obtained from heterozygous matings. At 1 year of age, HCII-deficient animals were grossly indistinguishable from their wild-type littermates in weight and survival, and they did not appear to have spontaneous thrombosis or other morphologic abnormalities. In comparison with wild-type animals, however, they demonstrated a significantly shorter time to thrombotic occlusion of the carotid artery after photochemically induced endothelial cell injury. This abnormality was corrected by infusion of purified HCII but not ovalbumin. These observations suggest that HCII might inhibit thrombosis in the arterial circulation.
Obstet Gynecol 2001 Nov; 98 (5 pt 2): 899 - 902
Spontaneous coronary artery dissection in a pregnant woman.
McKechnie RS, Patel D, Eitzman DT, Rajagopalan S, Murthy TH.
BACKGROUND: Spontaneous coronary dissection is a rare condition occurring more often in women, with a higher frequency during the peripartum period. No specific etiology has been defined to describe this uncommon, yet often fatal phenomenon. CASE: A young woman presented at 36 weeks of a noncomplicated pregnancy with recent onset of diaphoresis, dyspnea, and tingling substernal chest discomfort. Upon evaluation, she developed cardiovascular collapse and ventricular fibrillation requiring aggressive resuscitative measures, eventually leading to extracorporeal membrane oxygenation. Right coronary artery dissection was ultimately diagnosed and treated with intracoronary angioplasty and stent placement. CONCLUSION: Spontaneous coronary dissection must be considered when evaluating a patient with a similar clinical presentation, given its overall mortality of more than 50% at presentation, particularly in the peripartum period.
J Am Soc Echocardiogr. 2001 Oct; 14 (10): 1042 - 3
Eustachian valve endocarditis caused by Streptococcus viridans.
Schmidt MA, Nigbor D, Eitzman DT.
A 76-year-old man was admitted for ethanol detoxification. He was found to be in atrial fibrillation with a rapid ventricular response that was refractory to electrical and chemical cardioversion attempts. The patient subsequently developed respiratory distress. A transesophageal echocardiogram revealed a vegetation attached to the eustachian valve and blood cultures grew Streptococcus viridans. After treatment with appropriate antibiotics, the patient converted to sinus rhythm with sotalol hydrochloride, and the eustachian valve vegetation resolved. This is the first reported case of eustachian valve endocarditis caused by S viridans.
Circulation 2001 Jun 26;103(25):3044-3046
Deficiency of Tissue Factor Pathway Inhibitor Promotes Atherosclerosis and Thrombosis in Mice.
Westrick RJ, Bodary PF, Xu Z, Shen YC, Broze GJ, Eitzman DT.
BACKGROUND:Tissue factor initiates blood coagulation after atherosclerotic plaque disruption.
Tissue factor pathway inhibitor (TFPI) inhibits tissue factor activity and may reduce thrombus
formation in this setting. We evaluated the effect of heterozygous TFPI deficiency on the
development of atherosclerosis and thrombosis in atherosclerosis-prone mice. Methods and
Results-Mice with a combined heterozygous TFPI deficiency and homozygous apolipoprotein E
deficiency (TFPI(+/-)/apoE(-/-)) were generated by crossbreeding, and they were analyzed for
atherosclerosis throughout the vascular tree. Compared with mice with a normal TFPI genotype
(TFPI(+/+)/apoE(-/-)), mice with a TFPI deficiency exhibited a greater atherosclerotic burden
involving the carotid and common iliac arteries. Staining for active tissue factor within the plaque
revealed more activity in TFPI(+/-)/apoE(-/-) mice compared with TFPI(+/+)/apoE(-/-) mice.
Consistent with increased plaque tissue factor activity, the time to occlusive thrombosis after
photochemical carotid plaque injury was significantly decreased in TFPI(+/-)/apoE(-/-) mice.
CONCLUSIONS:These observations indicate that TFPI protects from atherosclerosis and is an
important regulator of the thrombosis that occurs in the setting of atherosclerosis.
Thrombosis Haemostasis 2001 Mar;85(3):441-4
Pulmonary fibrosis is increased in mice carrying the factor V Leiden
mutation following bleomycin injury.
Xu Z, Westrick RJ, Shen YC, Eitzman DT.
Increased fibrin deposition following inflammatory lung injury has been proposed to facilitate the
development of pulmonary fibrosis. Therefore, factors predisposing to thrombosis may affect the
fibrotic response to injury. Activated protein C (aPC) resistance due to the factor V Leiden
mutation (FvL) is a common genetic risk factor for vascular thrombosis. To examine the
relationship between aPC resistance and the development of pulmonary fibrosis, lung inflammation
was induced by bleomycin in mice carrying the FvL mutation. Three weeks following the instillation
of 0.0375 U of bleomycin, the lungs of mice homozygous and heterozygous for FvL contained
significantly more hydroxyproline (35 +/- 4 and 36 +/- 7 ug hydroxyproline/mg total protein,
respectively) than wild-type mice (26 +/- 6 ug/mg protein, p <0.01 for both comparisons). These
data demonstrate a strong relationship between aPC resistance and the pulmonary fibrosis that
occurs following inflammatory lung injury.
Arteriosclerosis Thrombosis Vascular Biology 2000 Jul;20(7):1831-4
Hyperlipidemia promotes thrombosis after injury to atherosclerotic vessels
in apolipoprotein E-deficient mice.
Eitzman DT, Westrick RJ, Xu Z, Tyson J, Ginsburg D.
The increased risk of hyperlipidemia on the development of complications of atherosclerosis is well
established. Cholesterol-lowering therapies lead to a decrease in the incidence of vascular
thrombotic events that is out of proportion to the reduction in plaque size. This suggests that the
occurrence of acute thrombosis overlying a disrupted plaque is influenced by changes in lipid levels.
The influence of acute hyperlipidemia on the development of thrombosis overlying an
atherosclerotic plaque in vivo has not been extensively studied. We used a murine model of
vascular injury induced by a photochemical reaction to elicit thrombus formation overlying an
atherosclerotic plaque. Fifteen apolipoprotein E-deficient mice were maintained on normal chow
until the age of 30 weeks. Five days before the induction of thrombosis, 6 mice were started on a
high fat diet, and 9 mice were continued on normal chow. Mice then underwent photochemical
injury to the common carotid artery immediately proximal to the carotid bifurcation, where an
atherosclerotic plaque is consistently present. Mice maintained on normal chow developed occlusive
thrombi, determined by cessation of blood flow, 44+/-5 minutes (mean+/-SEM) after photochemical
injury, whereas mice fed a high fat chow developed occlusive thrombosis at 27+/-3 minutes
(P<0.02). Histological analysis confirmed the presence of acute thrombus formation overlying an
atherosclerotic plaque. These studies demonstrate a useful model for assessing the determinants of
thrombosis in the setting of atherosclerosis and show that acute elevations in plasma cholesterol
facilitate thrombus formation at sites of atherosclerosis after vascular injury.
Arteriosclerosis Thrombosis Vascular Biology 2000 Mar;20(3):846-52
Atherosclerosis progression in LDL receptor-deficient and apolipoprotein
E-deficient mice is independent of genetic alterations in plasminogen
activator inhibitor-1.
Sjoland H, Eitzman DT, Gordon D, Westrick R, Nabel EG, Ginsburg D.
Impaired fibrinolysis has been linked to atherosclerosis in a number of experimental and clinical
studies. Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of plasminogen
activation and has been proposed to promote atherosclerosis by facilitating fibrin deposition within
developing lesions. We examined the contribution of PAI-1 to disease progression in 2 established
mouse models of atherosclerosis. Mice lacking apolipoprotein E (apoE-/-) and mice lacking the low
density lipoprotein receptor (LDLR-/-) were crossbred with transgenic mice overexpressing PAI-1
(resulting in PAI-1 Tg(+)/apoE-/- and PAI-1 Tg(+)/LDLR-/-, respectively) or were crossbred with
mice completely deficient in PAI-1 gene expression (resulting in PAI-1-/-/apoE-/- and
PAI-1-/-/LDLR-/-, respectively). All animals were placed on a western diet (21% fat and 0.15%
cholesterol) at 4 weeks of age and analyzed for the extent of atherosclerosis after an additional 6,
15, or 30 weeks. Intimal and medial areas were determined by computer-assisted morphometric
analysis of standardized microscopic sections from the base of the aorta. Atherosclerotic lesions
were also characterized by histochemical analyses with the use of markers for smooth muscle cells,
macrophages, and fibrin deposition. Typical atherosclerotic lesions were observed in all
experimental animals, with greater severity at the later time points and generally more extensive
lesions in apoE-/- than in comparable LDLR-/- mice. No significant differences in lesion size or
histological appearance were observed among PAI-1-/-, PAI-1 Tg(+), or PAI-1 wild-type mice at
any of the time points on either the apoE-/- or LDLR-/- genetic background. We conclude that
genetic modification of PAI-1 expression does not significantly alter the progression of
atherosclerosis in either of these well-established mouse models. These results suggest that
fibrinolytic balance (as well as the potential contribution of PAI-1 to the regulation of cell migration)
plays only a limited role in the pathogenesis of the simple atherosclerotic lesions observed in the
mouse.
Blood 2000 Dec 15;96(13):4222-6
Spontaneous thrombosis in mice carrying the factor V Leiden mutation.
Cui J, Eitzman DT, Westrick RJ, Christie PD, Xu ZJ, Yang AY, Purkayastha AA, Yang
TL, Metz AL, Gallagher KP, Tyson JA, Rosenberg RD, Ginsburg D.
A polymorphism in coagulation factor V, factor V Leiden (FVL), is the major known genetic risk
factor for thrombosis in humans. Approximately 10% of mutation carriers experience clinically
significant thrombosis in their lifetime. In a small subset of patients, thrombosis is associated with
coinheritance of other prothrombotic gene mutations. However, the potential contribution of
additional genetic risk factors in the majority of patients remains unknown. To gain insight into the
molecular basis for the variable expressivity of FVL, mice were generated carrying the homologous
mutation (R504Q [single-letter amino acid codes]) inserted into the endogenous murine Fv gene.
Adult heterozygous (FvQ/+) and homozygous (FvQ/Q) mice are viable and fertile and exhibit
normal survival. Compared with wild-type mice, adult FvQ/Q mice demonstrate a marked increase
in spontaneous tissue fibrin deposition. No differences in fetal development or survival are observed
among FvQ/Q, FvQ/+ or control littermates on the C57BL/6J genetic background. In contrast, on a
mixed 129Sv-C57BL/6J genetic background, FvQ/Q mice develop disseminated intravascular
thrombosis in the perinatal period, resulting in significant mortality shortly after birth. These results
may explain the high degree of conservation of the R504/R506 activated protein C cleavage site
within FV among mammalian species and suggest an important contribution of other genetic factors
to the thrombosis associated with FVL in humans.
Blood 2000 Dec 15;96(13):4212-5
Plasminogen activator inhibitor-1 deficiency protects against
atherosclerosis progression in the mouse carotid artery.
Eitzman DT, Westrick RJ, Xu Z, Tyson J, Ginsburg D.
Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1
(PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic
vascular disease and are associated with premature myocardial infarction. The role of the
endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic
plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary
physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive
thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein
E-deficient (apoE(-/-)) mice. However, anatomic analysis revealed a striking difference in the
extent of atherosclerosis at the carotid artery bifurcation between apoE(-/-) mice and mice doubly
deficient for apoE and PAI-1 (PAI-1(-/-)/apoE(-/-)). Consistent with a previous report,
PAI-1(+/+)/apoE(-/-)and PAI-1(-/-)/apoE(-/-) mice developed similar atherosclerosis in the aortic
arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred
by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites
of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this
hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid
bifurcation compared to the aortic arch. These observations identify significant differences in the
pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously
unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of
turbulent flow.
Blood 2000 Jan 15;95(2):577-80
Plasminogen activator inhibitor-1 and vitronectin promote vascular
thrombosis in mice.
Eitzman DT, Westrick RJ, Nabel EG, Ginsburg D.
Occlusive thrombosis depends on the net balance between platelets, coagulation, and fibrinolytic
factors. Epidemiologic information suggests that plasminogen activator inhibitor-1 (PAI-1), a central
regulator of the fibrinolytic system, plays an important role in determining the overall risk for
clinically significant vascular thrombosis. Vitronectin (VN), an abundant plasma and matrix
glycoprotein, binds PAI-1 and stabilizes its active conformation. This study assessed the role of
PAI-1 and VN expression in the formation of occlusive vascular thrombosis following arterial or
venous injury. The common carotid arteries of 17 wild-type (WT) mice and 8 mice deficient in
PAI-1 were injured photochemically while blood flow was continuously monitored. WT mice
developed occlusive thrombi at 52.0 +/- 3.8 minutes (mean +/- SEM) following injury; mice
deficient in PAI-1 developed occlusive thrombosis at 127 +/- 15 minutes (P <.0001). Mice deficient
in VN (n = 12) developed vascular occlusion 77 +/- 11 minutes after injury, intermediate between
the values observed for WT mice (P <.03) and mice deficient in PAI-1 (P <.01). PAI-1 and VN
also affected the time to occlusion after injury to the jugular vein. Three WT mice developed
occlusive venous thrombosis an average of 39.7 +/- 1 minutes following the onset of injury, whereas
the jugular veins of 4 mice deficient in PAI-1 and 4 deficient in VN occluded 56.7 +/- 5 and 58.7
+/- 2 minutes, respectively, following injury (P <.04 and P <.01 compared to WT mice). These
results suggest that endogenous fibrinolysis and its regulation by PAI-1 and VN have important
roles in the development of occlusive vascular thrombosis after vascular injury.
Advances in Experimental Medical Biology 1997;425:131-41
Of mice and men. The function of plasminogen activator inhibitors (PAIs)
in vivo.
Eitzman DT, Ginsburg D.
Publication Types:
Review
Review, tutorial
Blood 1996 Jun 1;87(11):4718-22
Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse
model of metastatic melanoma.
Eitzman DT, Krauss JC, Shen T, Cui J, Ginsburg.
Tumor cell invasion and metastasis is a complex, multistep process that is postulated to require
degradation of extracellular matrix at several steps. Urokinase-type plasminogen activator (uPA) is
expressed on the cell surface of B16 murine melanoma cells and is thought to contribute to the
pericellular proteolysis necessary for tumor cell migration. In vitro modification of B16 melanoma
cell surface uPA activity has been shown to alter the invasive and metastatic potential of these
murine melanoma cells in vivo. Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of both
uPA and tissue-type plasminogen activator (tPA) is the major physiologic regulator of plasminogen
activator activity. To test the role of host PAI-1 in the invasive and metastatic capacity of B16
melanoma cells we analyzed local tumor growth and pulmonary metastasis in transgenic mice
engineered to overexpress murine PAI-1 in multiple tissues including lung, and in mice completely
deficient in PAI-1. No significant difference in the number of pulmonary metastases was observed
after intravenous inoculation of tumor cells into PAI-1-overexpressing and PAI-1-deficient mice
when compared with wild-type controls. Similarly, in a spontaneous metastasis model,
PAI-1-overexpressing and PAI-1-deficient mice demonstrated no difference in primary tumor size
or overall survival. These data demonstrate that wide variations of host PAI-1 expression, from
complete absence to marked overexpression, does not significantly influence the metastatic
potential of B16 melanoma cells in a murine model.
Journal of Clinical Investigation 1996 Jan 1;97(1):232-7
Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack
or overexpress the murine plasminogen activator inhibitor-1 gene.
Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, Simon RH.
Impaired fibrinolytic activity within the lung is a common manifestation of acute and chronic
inflammatory lung diseases. Because the fibrinolytic system is active during repair processes that
restore injured tissues to normal, reduced fibrinolytic activity may contribute to the subsequent
development of pulmonary fibrosis. To examine the relationship between the fibrinolytic system and
pulmonary fibrosis, lung inflammation was induced by bleomycin in transgenic mice that either
overexpressed or were completely deficient in murine plasminogen activator inhibitor-1 (PAI-1). 2
wk after 0.075 U of bleomycin, the lungs of transgenic mice overexpressing PAI-1 contained
significantly more hydroxyproline (118 +/- 8 micrograms) than littermate controls (70.5 +/- 8
micrograms, P < 0.005). 3 wk after administration of a higher dose of bleomycin (0.15 U), the lung
hydroxyproline content of mice completely deficient in PAI-1 (49 +/- 8 micrograms) was not
significantly different (P = 0.63) than that of control animals receiving saline (37 +/- 1 micrograms),
while hydroxyproline content was significantly increased in heterozygote (77 +/- 12 micrograms, P
= 0.06) and wild-type (124 +/- 19 micrograms, P < 0.001) littermates. These data demonstrate a
direct correlation between the genetically determined level of PAI-1 expression and the extent of
collagen accumulation that follows inflammatory lung injury. These results strongly support the
hypothesis that alterations in fibrinolytic activity influence the extent of pulmonary fibrosis that
occurs after inflammatory injury.
Journal of Clinical Investigation 1995 May;95(5):2416-20
Peptide-mediated inactivation of recombinant and platelet plasminogen
activator inhibitor-1 in vitro.
Eitzman DT, Fay WP, Lawrence DA, Francis-Chmura AM, Shore JD, Olson ST, Ginsburg
Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator
(t-PA) and urokinase plasminogen activator, is an important regulator of the blood fibrinolytic
system. Elevated plasma levels of PAI-1 are associated with thrombosis, and high levels of PAI-1
within platelet-rich clots contribute to their resistance to lysis by t-PA. Consequently, strategies
aimed at inhibition of PAI-1 may prove clinically useful. This study was designed to test the
hypothesis that a 14-amino acid peptide, corresponding to the PAI-1 reactive center loop (residues
333-346), can rapidly inhibit PAI-1 function. PAI-1 (0.7 microM) was incubated with peptide (55
microM) at 37 degrees C. At timed intervals, residual PAI-1 activity was determined by addition of
reaction mixture samples to t-PA and chromogenic substrate. The T1/2 of PAI-1 activity in the
presence of peptide was 4 +/- 3 min compared to a control T1/2 of 98 +/- 18 min. The peptide also
inhibited complex formation between PAI-1 and t-PA as demonstrated by SDS-PAGE analysis.
However, the capacity of the peptide to inhibit PAI-1 bound to vitronectin, a plasma protein that
stabilizes PAI-1 activity, was markedly attenuated. Finally, the peptide significantly enhanced in
vitro lysis of platelet-rich clots and platelet-poor clots containing recombinant PAI-1. These results
indicate that a 14-amino acid peptide can rapidly inactivate PAI-1 and accelerate fibrinolysis in
vitro. These studies also demonstrate that PAI-1 function can be directly attenuated in a physiologic
setting and suggest a novel approach for augmenting fibrinolysis in vivo.
Circulation 1994 Nov;90(5):2356-66
Relation of regional function, perfusion, and metabolism in patients with
advanced coronary artery disease undergoing surgical revascularization.
vom Dahl J, Eitzman DT, al-Aouar ZR, Kanter HL, Hicks RJ, Deeb GM, Kirsh MM,
Schwaiger M.
BACKGROUND--Imaging of myocardial glucose metabolism using [18F]fluorodeoxyglucose
(FDG) with positron emission tomography (PET) has been proposed for identification of tissue
viability in patients with advanced coronary artery disease. This study was designed to evaluate the
predictive value of flow and metabolic imaging for functional recovery after revascularization in
myocardial segments of varying degrees of dysfunction. METHODS AND
RESULTS--Thirty-seven patients (mean age, 59 +/- 11 years) with coronary artery disease and
impaired left ventricular function (ejection fraction, 34 +/- 10%) were studied with PET using FDG
and [13N]ammonia before surgical coronary revascularization (3 +/- 1 grafts per patient). Tissue
was scintigraphically characterized as normal, nonviable (concordant reduction of perfusion and
FDG uptake), viable without discordance of perfusion and metabolism (mildly reduced perfusion
and metabolism), or ischemically compromised (mismatch of reduced perfusion and maintained
FDG uptake). Functional outcome was assessed by serial radionuclide ventriculography before and
at 13 +/- 13 weeks (median interval of 8 weeks) after coronary revascularization. Preoperatively
impaired regional wall motion improved significantly in ischemically compromised (mismatch)
revascularized segments but not in nonviable myocardium or in viable myocardium without
discordance of perfusion and metabolism. The negative predictive value of PET for functional
recovery was 86%, whereas the positive predictive value in revascularized regions ranged from
48% to 86% depending on severity of baseline wall motion abnormalities. CONCLUSIONS--PET
identifies metabolically active tissue, which benefits from revascularization. Although the negative
predictive value of PET for recovery was high, functional improvement of viable but ischemically
compromised tissue was less frequent than previously reported. The predictive value of PET was
highest in left ventricular segments with severe dysfunction and a mismatch or reduced perfusion
but preserved metabolism. Integration of PET, angiographic, and functional data is necessary for
the optimal selection of patients with advanced coronary artery disease and impaired left ventricular
function for revascularization.
American Heart Journal 1994 Apr;127(4 Pt 1):928-9
Management of myocardial stunning associated with electroconvulsive
therapy guided by hyperventilation echocardiography.
Eitzman DT, Bach DS, Rubenfire M.
No Abstract Available
Circulation1994 Apr;89(4):1523-9
Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4.
Eitzman DT, Chi L, Saggin L, Schwartz RS, Lucchesi BR, Fay WP.
BACKGROUND: Platelets contain several factors that inhibit heparin. This study was designed to
assess the heparin-neutralizing activity present in acute, platelet-rich arterial thrombi formed at sites
of arterial injury in animals. METHODS AND RESULTS: Platelet-rich thrombi (n = 3) were
induced in pig coronary arteries by balloon catheter-mediated arterial injury. Soluble extracts were
prepared from each thrombus and assayed for the capacity to inhibit heparin in an in vitro clotting
assay (activated partial thromboplastin time). Mean heparin-neutralizing activity was 28 U of
heparin neutralized per milliliter of thrombus, indicating that 1 vol of coronary thrombus completely
inhibited the heparin present in 140 vols of therapeutically anticoagulated (0.2 U heparin/mL)
plasma. In contrast, thrombus extracts had no effect on the anticoagulant activity of hirudin, a
direct-acting thrombin inhibitor. The heparin-neutralizing activity present in coronary thrombi bound
to heparin-agarose and was eluted from it by 1.4 mol/L NaCl, suggesting that platelet factor 4
mediated the antiheparin effect of thrombi. Consistent with this hypothesis, a murine monoclonal
antibody to rabbit platelet factor 4 nearly completely inhibited the heparin-neutralizing activity
present in rabbit thrombi (n = 3) generated by carotid artery injury. CONCLUSIONS: Extracts
prepared from platelet-rich arterial thrombi significantly inhibit the in vitro anticoagulant potency of
heparin but not of hirudin. This antiheparin effect appears to be mediated by platelet factor 4. These
results are consistent with the hypothesis that localized inhibition of heparin at sites of platelet
activation may reduce its antithrombotic efficacy. In addition, they suggest an additional mechanism
for the apparent superiority of hirudin over heparin as a thrombin inhibitor at sites of arterial injury.
Blood 1994 Jan 15;83(2):351-6
Platelets inhibit fibrinolysis in vitro by both plasminogen activator
inhibitor-1-dependent and -independent mechanisms.
Fay WP, Eitzman DT, Shapiro AD, Madison EL, Ginsburg D.
Platelet-rich thrombi are resistant to lysis by tissue-type plasminogen activator (t-PA). Although
platelet alpha-granules contain plasminogen activator inhibitor-1 (PAI-1), a fast-acting inhibitor of
t-PA, the contribution of PAI-1 to the antifibrinolytic effect of platelets has remained a subject of
controversy. We recently reported a patient with a homozygous mutation within the PAI-1 gene
that results in complete loss of PAI-1 expression. Platelets from this individual constitute a unique
reagent with which to probe the role of platelet PAI-1 in the regulation of fibrinolysis. The effects
of PAI-1-deficient platelets were compared with those of normal platelets in an in vitro clot lysis
assay. Although the incorporation of PAI-1-deficient platelets into clots resulted in a moderate
inhibition of t-PA-mediated fibrinolysis, normal platelets markedly inhibited clot lysis under the same
conditions. However, no difference between PAI-1-deficient platelets and platelets with normal
PAI-1 content was observed when streptokinase or a PAI-1-resistant t-PA mutant were used to
initiate fibrinolysis. In addition, PAI-1-resistant t-PA was significantly more efficient in lysing clots
containing normal platelets than wild-type t-PA. We conclude that platelets inhibit t-PA-mediated
fibrinolysis by both PAI-1-dependent and PAI-1-independent mechanisms. These results have
important implications for the role of PAI-1 in the resistance of platelet-rich thrombi to lysis in vivo.
Journal of the American College of Cardiology 1992 Sep;20(3):559-65
Clinical outcome of patients with advanced coronary artery disease after
viability studies with positron emission tomography.
Eitzman D, al-Aouar Z, Kanter HL, vom Dahl J, Kirsh M, Deeb GM, Schwaiger M.
OBJECTIVE. The aim of this study was to determine the prognostic significance of
perfusion-metabolism imaging in patients undergoing positron emission tomography for myocardial
viability assessment. BACKGROUND. Positron emission tomography using nitrogen-13 ammonia
and 18fluorodeoxyglucose to assess myocardial blood flow and metabolism has been shown to
predict improvement in wall motion after coronary artery revascularization. The prognostic
implications of metabolic imaging in patients with advanced coronary artery disease have not been
investigated. METHODS. Eighty-two patients with advanced coronary artery disease and impaired
left ventricular function underwent positron emission tomographic imaging between August 1988
and March 1990 to assess myocardial viability before coronary artery revascularization. RESULTS.
Forty patients underwent successful revascularization. Patients who exhibited evidence of
metabolically compromised myocardium by positron emission tomography (decreased blood flow
with preserved metabolism) who did not undergo subsequent revascularization were more likely to
experience a myocardial infarction, death, cardiac arrest or late revascularization due to
development of new symptoms than were the other patient groups (p less than 0.01). Concordantly
decreased flow and metabolism in segments of previous infarction did not affect outcome in
patients with or without subsequent revascularization. Those with a compromised myocardium who
did undergo revascularization were more likely to experience an improvement in functional class
than were patients with preoperative positron emission tomographic findings of concordant
decrease in flow and metabolism. CONCLUSIONS. Positron emission tomographic myocardial
viability imaging appears to identify patients at increased risk of having an adverse cardiac event or
death. Patients with impaired left ventricular function and positron emission tomographic evidence
for jeopardized myocardium appear to have the most benefit from a revascularization procedure.
American Journal of Medicine 1992 Jun;92(6):701-2
Tracheal obstruction secondary to extravasation of intravenous fluids from
a central catheter port.
Pacelli CM, Eitzman DT.
Publication Types:
Letter
No Abstract Available
Journal of the American College of Cardiology 1989 Apr;13(5):1176-83
Nifedipine administered after reperfusion ablates systolic contractile
dysfunction of postischemic "stunned" myocardium.
Przyklenk K, Ghafari GB, Eitzman DT, Kloner RA.
Recent evidence suggests that postischemic contractile dysfunction of viable myocardium salvaged
by reperfusion ("stunned myocardium") may be a consequence of abnormal calcium flux within the
previously ischemic cells. Calcium channel blocking agents have been shown to enhance contractile
function of stunned postischemic tissue, but it is not certain whether these improvements in function
are due to the profound hemodynamic and vasodilator effects of these agents or to a direct effect
on calcium flux within the stunned myocytes. Therefore, the effects of 1) high doses of nifedipine,
given intravenously at 30 min after reperfusion, and 2) minute doses of nifedipine, infused directly
into the coronary circulation at 30 min after reflow, were assessed and compared in anesthetized
open chest dogs subjected to 15 min of transient coronary artery occlusion. As anticipated,
intravenous nifedipine significantly reduced arterial pressure and increased regional myocardial
blood flow. In addition, intravenous nifedipine restored systolic contractile function of the stunned,
previously ischemic tissue to essentially normal preocclusion values: segment shortening averaged
102 +/- 8% versus 26 +/- 11% of baseline at 2 h after treatment in treated versus control dogs,
respectively (p less than 0.003). Low dose intracoronary infusion of nifedipine did not alter
hemodynamic variables or myocardial blood flow, but did improve segment shortening (90 +/- 9%
versus 37 +/- 10% of preocclusion values at 1 h after treatment versus 25 min after reperfusion
[that is, pretreatment], respectively; p less than 0.03). These data indicate that the calcium channel
blocking agent nifedipine, given 30 min after reperfusion, enhances systolic contractile function of
postischemic stunned myocardium.