(Circulation. 1997;96:1398-1402.)
© 1997 American Heart Association, Inc.
Articles |
Simvastatin Reduces Graft Vessel Disease and Mortality After Heart Transplantation
A Four-Year Randomized Trial
From the Department of Cardiac Surgery (K.W.), Munich- Bogenhausen; Department of Cardiac Surgery (B.M., B.R.), University Hospital, Munich-Grosshadern; Institute of Clinical Chemistry (J.T., D.N., D.S.), Medical Statistics, University Hospital, Munich-Grosshadern; and Department of Medicine I (W. von S., G.S.), University Hospital, Munich-Grosshadern, Germany.
Correspondence to Dr K. Wenke, Department of Cardiac Surgery, Munich-Bogenhausen, D-81925 Munich, Germany.
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Abstract |
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Background Accelerated graft vessel disease (GVD) represents the most serious long-term complication of heart transplantation. A possible cause underlying this progressive coronary vascular disease is believed to be post-transplantation hypercholesterolemia.
Methods and Results In a 4-year prospective randomized study with heart transplant recipients, the efficacy of primary antihypercholesterolemic therapy with simvastatin was compared with that of general dietary therapy. The aim of the treatment was to maintain post-transplantation LDL-cholesterol levels at <120 mg/dL. Seventy-two heart transplant recipients receiving standard triple immunosuppression were randomly assigned to an active-treatment group (low-cholesterol diet and simvastatin, n=35) or a control group (general dietary measures, n=37). In the course of 4 years after transplantation, the simvastatin group had significantly lower LDL-cholesterol concentrations than the control group (mean±SD, 115±14 versus 156±17 mg/dL, P=.002), a significantly better long-term survival (88.6% versus 70.3%, P=.05), and a lower incidence of GVD in the coronary angiographic findings (16.6% versus 42.3%, P=.045). The incidence of graft rejections did not differ between the two groups, although there was a tendency toward a lower number of serious rejections in the simvastatin group (2.8% versus 13.5%, P=.1). Intracoronary ultrasound performed after 4 years in a subgroup of 27 patients (simvastatin, 10; control, 17) showed less intimal thickening in patients with LDL-cholesterol levels of <110 mg/dL (170±84 versus 370±171 µm, P=.04) and a lower intimal index (13.8±7.1% versus 27.9±12.1%, P=.04).
Conclusions In comparison with dietary measures alone, the combination of a low-cholesterol diet and simvastatin after heart transplantation led to a significant reduction in cholesterol levels, a significantly higher long-term survival rate, and a lower incidence of GVD.
Key Words: simvastatin • hypercholesterolemia • transplantation • graft vessel disease
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Introduction |
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Hypercholesterolemia—in particular, elevation of low-density lipoproteins (LDL) to >130 mg/dL—is observed in 60% to 80% of heart transplant recipients.1 2 A number of studies have shown a correlation between hypercholesterolemia and the development of GVD.3 4 However, other investigations have found no association between lipid levels and vessel disease in transplanted hearts.5 6 Therefore, the importance of cholesterol levels in the pathology of graft vessel disease remains to be determined. Accelerated GVD is the most important late complication of heart transplantation, with an incidence of 5% to 10% per year.7 The Scandinavian Simvastatin Survival Study (4S) showed that simvastatin, an HMG-CoA reductase inhibitor, significantly lowers cholesterol levels, extends overall survival, and reduces the number of serious cardiac events in nonimmunosuppressed coronary patients.8 Even regression of existing atherosclerotic vascular wall changes has been observed after antihyperlipidemic therapy with HMG-CoA reductase inhibi- tors.9 10 11 Moreover, in experiments in animals, simvastatin inhibited the proliferation of smooth muscle cells in cell cultures12 and reduced the incidence of GVD after heterotopic heart transplantation.13 Other in vitro studies have shown that the HMG-CoA reductase inhibitor lovastatin suppresses T lymphocytes (natural killer cells),14 which may influence the development of transplantation rejection and, thus, the incidence of GVD. Furthermore, in a 12-month prospective trial, the HMG-CoA reductase inhibitor pravastatin was found to lower cholesterol levels; reduce the incidence of cardiac rejection accompanied by hemodynamic compromise, thereby improving first-year survival; delay development of GVD in the first year after cardiac transplantation; and reduce the increase of mean intimal thickness in heart transplant recipients.15 Until now, because the concurrent use of the immunosuppressive agent cyclosporin A may lead to myolysis and rhabdomyolysis,16 17 HMG-CoA reductase inhibitors have been used only very reluctantly for the treatment of hypercholesterolemia in heart transplant patients.18 19 20 21
In the present prospective randomized study, we set out to investigate the effects of primary long-term antihypercholesterolemic therapy with diet and simvastatin in terms of cholesterol levels, survival rate, graft rejection rate, and incidence of GVD.
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Methods |
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Selection of Patients
After successful orthotopic heart transplantation, during the period of January 1, 1991, through December 31, 1991, 72 consecutive patients with or without hypercholesterolemia were randomly assigned to two different groups: 35 patients were treated with a low-cholesterol diet and simvastatin, and 37 patients were treated only by dietary measures. All patients received triple immunosuppression consisting of cyclosporin A (blood level >500 ng/mL), azathioprine (1 mg/kg body wt), and prednisolone (0.1 mg/kg body wt). Graft rejections were diagnosed by endomyocardial biopsy in response to clinical changes and classified according to the system of the ISLHT (mild, IA or IB; focal moderate, II; multifocal moderate, IIIA; diffuse borderline severe, IIIB).
Exclusion criteria were severe hepatic impairment (bilirubin >2 mg/dL) or renal impairment (creatinine >3 mg/dL), signs of existing myopathy, and known intolerance to HMG-CoA reductase inhibitors. The study design was accepted by the Ethics Committee of the Ludwig Maximilian University Munich.
Study Design
Patients in the active-treatment group received, in addition to
a low-cholesterol diet, 5 mg/d
simvastatin starting on the fourth postoperative day. The
target was an LDL-cholesterol level of 110 to 120
mg/dL. In the fourth posttransplantation week, the
simvastatin dose was increased to 10 mg/d, depending
on the LDL-cholesterol level. After 6 weeks, the dose was
again adjusted, if necessary, to a maximum of 20 mg/d
simvastatin. The patients in the control group were treated
by dietary measures alone. All patients received extensive dietary
counseling with their partners in accordance with the guidelines for
the American Heart Association stage II diet (total
cholesterol intake <200 mg/d). In the first year
after transplantation, laboratory tests were conducted regularly at
4-week intervals (creatinine kinase, complete blood counts,
fibrinogen, lipoprotein analysis, and drug assays
[simvastatin and cyclosporin A]). Clinical and
echocardiographic examinations, chest radiographs, and
endomyocardial biopsies were performed at the same
intervals. The endomyocardial biopsies were
analyzed by pathologists who had no information on the
allocation of the patients to the respective treatment groups.
From the second to the fourth year after transplantation, all the aforementioned tests were performed at 3-month intervals on an outpatient basis. The study was planned to run for 4 years.
The aim of the study was to determine the efficacy of simvastatin therapy in terms of cholesterol levels, incidence of GVD, overall survival rate, and occurrence of acute graft rejections.
Coronary Angiography and IVUS
Coronary angiography was performed in the first
posttransplantation month to establish the baseline coronary
status and repeated at yearly intervals. GVD was defined as any
angiographically demonstrated new stenosis of 
50% or new
distal obliterative changes. The angiographic findings were
analyzed by two independent cardiologists who had no knowledge
of the sequence of the angiographic examinations or the allocation of
the patients to the treatment groups.
In a subgroup of 27 patients (simvastatin, 10; control, 17), who had given their respective consent, IVUS imaging was performed in conjunction with coronary angiography in the fourth postoperative year to detect any angiographically invisible changes of the intima. Because this technique was not available at the start of the trial, no baseline data were collected immediately after transplantation. The left anterior descending coronary artery, which served as the target vessel, was examined using a 30-MHz, 2.9-F IVUS catheter (CVIS). The images were recorded using a manual pullback from the distal LAD to the main stem of the left coronary artery. The measured data were analyzed off-line by quantitative morphometry. For quantification, the three most severely affected sites were examined and averaged. The parameters determined were the mean intimal thickness and intimal index, defined as the ratio of the area of plaque to total vessel area.
Statistical Analysis
The data from the two groups were compared with the help of the
two-tailed t test and the 
2 test. The
log rank test was used to compare the Kaplan-Meier survival curves in
the two groups. In all the tests used, the significance level was
defined as P=.05.
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Results |
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Patient Characteristics
The two treatment groups did not differ significantly in terms of the preoperative baseline data (Table 1
),
nor were there any differences with regard to a possible requirement
for an immunosuppressive medication after transplantation. Blood
cyclosporin A levels in the two groups did not differ significantly
during the observation period. The average of simvastatin
dose in the treatment group was 10 mg/d (5 to 15 mg/d).
Infection complications (6 patients in the simvastatin
group versus 5 in the control group) and diagnosed cytomegalovirus
infections (4 versus 3) did not differ significantly in the two groups.
Hypertension requiring treatment occurred in 16 patients in the
simvastatin group compared with 14 patients in the control
group. All the affected patients were treated with ACE
inhibitors. The mean blood pressure values were
133±13/86±8 mm Hg in the simvastatin group
versus 135±14/85±11 mm Hg in the control group and did not
differ significantly. Laboratory tests (creatinine kinase,
complete blood counts, fibrinogen) did not reveal any significant
differences between the two groups throughout the 4-year observation
period.
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Cholesterol Level
Cholesterol and LDL levels were analyzed
repeatedly during the study (24 times per patient). The
pretransplantation cholesterol levels were comparable in
the two groups: 181±17 mg/dL in the simvastatin
group versus 175±19 mg/dL in the control group. In the course
of the study, the mean serum cholesterol level in the
simvastatin group was significantly lower than that in the
control group (198±18 versus 228±19 mg/dL, P=.03).
The LDL levels at the time of transplantation were likewise comparable
in the two groups: 105±15 mg/dL in the simvastatin
group versus 109±13 mg/dL in the control group. In the long
term, significantly lower LDL levels were found in the
simvastatin group than in the control group (115±14 versus
156±17 mg/dL, P=.002) (Fig 1). Elevated liver enzymes and renal
functional parameters were not observed. Myolysis was not
observed in any patient, and creatinine kinase remained
within the normal range in all the study participants.
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Survival Rate
After 4 years of observation, the survival rate was significantly
higher in the simvastatin group than in the control group.
After this period, 88.6% of the patients treated with
simvastatin were still alive compared with 70.3% of the
control patients (P=.05) (Fig 2). The causes of death in the
simvastatin group were severe graft rejection (n=1), severe
pulmonary infection (n=2), and GVD (n=1); in the control group,
the causes were severe graft rejection (n=5), severe pulmonary
infection (n=2), multiple-organ failure (n=1), prostate cancer (n=1),
and GVD (n=2).
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Coronary Angiography
Of the patients in the simvastatin group, 3% showed
coronary angiographic signs of GVD in the first
posttransplantation year, 9.1% in the second year, 12.9% in the third
year, and 16.6% after 4 years. The corresponding figures in the
control group were 10% after the first year, 17.2% after the second
year, 25.9% after the third year, and 42.3% after 4 years. The
differences between the two groups were significant over the 4-year
observation period (P=.045). The 3 patients who died from
GVD were included in the statistical analysis (Fig 3).
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Intracoronary Ultrasound
In the fourth postoperative year, 27 patients
(simvastatin, 10; control, 17) were examined using an
intracoronary ultrasound catheter in conjunction with
coronary angiography. Patients of the treatment group with an
LDL-cholesterol level of <110 mg/dL had
significantly less mean intimal thickness than those of the control
group, with an LDL-cholesterol level of >110 mg/dL
(170±84 versus 370±171 µm, P=.04) as well as a
significantly lower intimal index (13.8±7.1% versus 27.9±12.1%,
P=.04) (Fig 4).
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Graft Rejections
The mean incidence of mild (ISLHT Ia, Ib) and moderate (ISLHT II,
IIIa) graft rejections was not significantly different between the two
groups. However, the control patients showed a statistical tendency
toward a higher incidence of severe graft rejections (ISLHT IIIb)
accompanied by graft failure. In the simvastatin group,
only 1 patient died as the result of refractory graft rejection (2.8%)
compared with 5 patients in the control group (13.5%, P=.1)
(Table 2).
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Discussion |
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The results of the present long-term study show that simvastatin therapy, initiated early after heart transplantation, safely and effectively reduced total and LDL cholesterol, significantly improved the 4-year survival rate, and significantly reduced the incidence of GVD. These effects could, on the one hand, result directly from the cholesterol reduction; on the other hand, cholesterol-independent effects of simvastatin on the immune system, which are still not clearly understood, are also possible. HMG-CoA reductase inhibitors have been shown to regulate DNA in cycling cells,22 inhibit monocyte chemotaxis,23 regulate cytotoxicity of T lymphocytes,14 15 24 and inhibit antibody-dependent cellular cytotoxicity.25 All the aforementioned characteristics could account for the fact that fewer severe graft rejections occurred with simvastatin. Simvastatin-induced potentiation of the immunosuppressive action of cyclosporin A is also a possibility. The immunosuppressive effect of cyclosporin A is due to blockade of interleukin-2 synthesis in activated T lymphocytes. A similar effect of the HMG-CoA reductase inhibitor lovastatin has been demonstrated in cell cultures. Lovastatin inhibited antibody-dependent cytotoxicity of T lymphocytes, an effect that was neutralized by the addition of interleukin-2 to the cell culture.26 These observations could explain a potential synergistic immunosuppressive action of cyclosporin A and simvastatin. It should also be borne in mind that a large proportion of cyclosporin A is bound to LDL in plasma. Drug-induced reduction of LDL may therefore may lead to more free cyclosporin in the blood and, consequently, prevention of cardiac rejection.
Hypercholesterolemia is regarded as the chief risk factor for coronary heart disease.27 Consistent treatment of hyperlipidemia brings about a marked reduction in coronary heart disease mortality and the incidence of cardiac events, as demonstrated in the 4S8 and the Pravastatin Multinational Study.28 According to the results of our study, patients with low cholesterol levels had a significantly lower incidence of GVD over the course of 4 years. In this respect, early postoperative initiation of simvastatin therapy appears to be important because liquid cholesterol deposits occur in the vascular wall even in the early phase.29 GVD associated with heterotopic heart transplantation was also significantly reduced with simvastatin in an animal model.13 In in vitro studies, simvastatin inhibited the proliferation of smooth muscle cells,12 a process that is believed to play a key role in atherogenesis.30 This effect of simvastatin could explain why the IVUS-determined coronary intima is significantly less thick in patients with low cholesterol levels. In compliance with these findings, other workers15 observed a significantly reduced increase of the intimal thickness 1 year after cardiac transplantation in patients treated with pravastatin; they also reported on a significantly better first-year survival and reduced cardiac rejection accompanied by hemodynamic compromise in these patients. However, as of today, the described effects of antihypercholesterolemic therapy on the development of GVD had not been observed in long-term studies, which are required to investigate a slow process like the development of GVD.
The baseline data showed two statistically comparable groups. The incidence of GVD, cholesterol concentrations, and the survival rate represented objective end points permitting a valid statistical analysis.
In conclusion, in heart transplant recipients, simvastatin significantly reduces cholesterol and LDL-cholesterol levels, significantly improves the long-term survival rate, lowers the incidence of GVD, and reduces graft rejections with graft failure. It therefore appears reasonable to initiate routine antihyperlipidemic therapy with simvastatin or other HMG-CoA reductase inhibitors as early as possible after heart transplantation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We are indebted to Traute Meyer and Klaus Krischock for preparation of the manuscript.
Received February 28, 1997; revision received April 21, 1997; accepted April 26, 1997.
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References |
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K. Shimizu, M. Aikawa, K. Takayama, P. Libby, and R. N. Mitchell Direct Anti-Inflammatory Mechanisms Contribute to Attenuation of Experimental Allograft Arteriosclerosis by Statins Circulation, October 28, 2003; 108(17): 2113 - 2120. [Abstract] [Full Text] [PDF]
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F. Mulhaupt, C. M Matter, B. R Kwak, G. Pelli, N. R Veillard, F. Burger, P. Graber, T. F Luscher, and F. Mach Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells Cardiovasc Res, September 1, 2003; 59(3): 755 - 766. [Abstract] [Full Text] [PDF]
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 H. J. Eisen, E. M. Tuzcu, R. Dorent, J. Kobashigawa, D. Mancini, H. A. Valantine-von Kaeppler, R. C. Starling, K. Sorensen, M. Hummel, J. M. Lind, et al. Everolimus for the Prevention of Allograft Rejection and Vasculopathy in Cardiac-Transplant Recipients N. Engl. J. Med., August 28, 2003; 349(9): 847 - 858. [Abstract] [Full Text] [PDF]
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A. Hognestad, K. Endresen, R. Wergeland, O. Stokke, O. Geiran, T. Holm, S. Simonsen, J. K. Kjekshus, and A. K. Andreassen Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients J. Am. Coll. Cardiol., August 6, 2003; 42(3): 477 - 482. [Abstract] [Full Text] [PDF]
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D. Mancini, S. Pinney, D. Burkhoff, J. LaManca, S. Itescu, E. Burke, N. Edwards, M. Oz, and A. R. Marks Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy Circulation, July 8, 2003; 108(1): 48 - 53. [Abstract] [Full Text] [PDF]
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G. Vassalli, A. Gallino, M. Weis, W. von Scheidt, L. Kappenberger, L.K. von Segesser, J.-J. Goy, and on behalf of the Working Group Microcirculation of Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy Eur. Heart J., July 1, 2003; 24(13): 1180 - 1188. [Abstract] [Full Text] [PDF]
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 B. A. Johnson, A. T. Iacono, A. Zeevi, K. R. McCurry, and S. R. Duncan Statin Use Is Associated with Improved Function and Survival of Lung Allografts Am. J. Respir. Crit. Care Med., May 1, 2003; 167(9): 1271 - 1278. [Abstract] [Full Text] [PDF]
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 P. D. Thompson, P. Clarkson, and R. H. Karas Statin-Associated Myopathy JAMA, April 2, 2003; 289(13): 1681 - 1690. [Abstract] [Full Text] [PDF]
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P. Libby and D. X.-M. Zhao Allograft Arteriosclerosis and Immune-Driven Angiogenesis Circulation, March 11, 2003; 107(9): 1237 - 1239. [Full Text] [PDF]
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 C. M. Ballantyne, A. Corsini, M. H. Davidson, H. Holdaas, T. A. Jacobson, E. Leitersdorf, W. Marz, J. P. D. Reckless, and E. A. Stein Risk for Myopathy With Statin Therapy in High-Risk Patients Arch Intern Med, March 10, 2003; 163(5): 553 - 564. [Abstract] [Full Text] [PDF]
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P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
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K. Wenke, B. Meiser, J. Thiery, D. Nagel, W. von Scheidt, K. Krobot, G. Steinbeck, D. Seidel, and B. Reichart Simvastatin Initiated Early After Heart Transplantation: 8-Year Prospective Experience Circulation, January 7, 2003; 107(1): 93 - 97. [Abstract] [Full Text] [PDF]
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 B. T. Bethea, D. D. Yuh, J. V. Conte, and W. A. Baumgartner Heart Transplantation Card. Surg. Adult, January 1, 2003; 2(2003): 1427 - 1460. [Full Text]
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 J. C. Fang, S. Kinlay, D. Behrendt, H. Hikita, J. L. Witztum, A. P. Selwyn, and P. Ganz Circulating Autoantibodies to Oxidized LDL Correlate With Impaired Coronary Endothelial Function After Cardiac Transplantation Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2044 - 2048. [Abstract] [Full Text] [PDF]
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M. R. Mehra, P. A. Uber, K. Vivekananthan, S. Solis, R. L. Scott, M. H. Park, R. V. Milani, and C. J. Lavie Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival J. Am. Coll. Cardiol., November 6, 2002; 40(9): 1609 - 1614. [Abstract] [Full Text] [PDF]
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W. Palinski and C. Napoli Unraveling Pleiotropic Effects of Statins on Plaque Rupture Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1745 - 1750. [Full Text] [PDF]
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W. Palinski and S. Tsimikas Immunomodulatory Effects of Statins: Mechanisms and Potential Impact on Arteriosclerosis J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1673 - 1681. [Abstract] [Full Text] [PDF]
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M. Pascual, T. Theruvath, T. Kawai, N. Tolkoff-Rubin, and A. B. Cosimi Strategies to Improve Long-Term Outcomes after Renal Transplantation N. Engl. J. Med., February 21, 2002; 346(8): 580 - 590. [Full Text] [PDF]
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S. R. Kapadia, S. E. Nissen, K. M. Ziada, G. Rincon, T. D. Crowe, N. Boparai, J. B. Young, and E. M. Tuzcu Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study J. Am. Coll. Cardiol., July 1, 2001; 38(1): 206 - 213. [Abstract] [Full Text] [PDF]
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H. Valantine, P. Rickenbacker, M. Kemna, S. Hunt, Y.-D. I. Chen, G. Reaven, and E. B. Stinson Metabolic Abnormalities Characteristic of Dysmetabolic Syndrome Predict the Development of Transplant Coronary Artery Disease : A Prospective Study Circulation, May 1, 2001; 103(17): 2144 - 2152. [Abstract] [Full Text] [PDF]
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A. M Lefer, R. Scalia, and D. J Lefer Vascular effects of HMG CoA-reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease Cardiovasc Res, February 1, 2001; 49(2): 281 - 287. [Full Text] [PDF]
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W. Palinsk New Evidence for Beneficial Effects of Statins Unrelated to Lipid Lowering Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 3 - 5. [Full Text] [PDF]
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C. P. Sparrow, C. A. Burton, M. Hernandez, S. Mundt, H. Hassing, S. Patel, R. Rosa, A. Hermanowski-Vosatka, P.-R. Wang, D. Zhang, et al. Simvastatin Has Anti-Inflammatory and Antiatherosclerotic Activities Independent of Plasma Cholesterol Lowering Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 115 - 121. [Abstract] [Full Text] [PDF]
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 J. M. Aranda Jr. and J. Hill Cardiac Transplant Vasculopathy Chest, December 1, 2000; 118(6): 1792 - 1800. [Abstract] [Full Text] [PDF]
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 K Pethig, V Klauss, B Heublein, H Mudra, A Westphal, C Weber, K Theisen, and A Haverich Progression of cardiac allograft vascular disease as assessed by serial intravascular ultrasound: correlation to immunological and non-immunological risk factors Heart, November 1, 2000; 84(5): 494 - 498. [Abstract] [Full Text]
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M. R. Ward, G. Pasterkamp, A. C. Yeung, and C. Borst Arterial Remodeling : Mechanisms and Clinical Implications Circulation, September 5, 2000; 102(10): 1186 - 1191. [Full Text] [PDF]
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P. Holvoet, J. Van Cleemput, D. Collen, and J. Vanhaecke Oxidized Low Density Lipoprotein Is a Prognostic Marker of Transplant-Associated Coronary Artery Disease Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 698 - 702. [Abstract] [Full Text] [PDF]
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B. J. Ansell, K. E. Watson, and A. M. Fogelman An Evidence-Based Assessment of the NCEP Adult Treatment Panel II Guidelines JAMA, December 1, 1999; 282(21): 2051 - 2057. [Abstract] [Full Text] [PDF]
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B. Lindelow, C.-H. Bergh, C. Lamm, B. Andersson, and F. Waagstein Graft coronary artery disease is strongly related to the aetiology of heart failure and cellular rejections Eur. Heart J., September 2, 1999; 20(18): 1326 - 1334. [Abstract] [PDF]
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 U. Laufs, D. Marra, K. Node, and J. K. Liao 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27Kip1 J. Biol. Chem., July 30, 1999; 274(31): 21926 - 21931. [Abstract] [Full Text] [PDF]
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K. Pethig, B. Heublein, R. R. Meliss, and A. Haverich Volumetric remodeling of the proximal left coronary artery: Early versus late after heart transplantation J. Am. Coll. Cardiol., July 1, 1999; 34(1): 197 - 203. [Abstract] [Full Text] [PDF]
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 H. Holschermann, R. M. Bohle, H. Zeller, H. Schmidt, U. Stahl, L. Fink, H. Grimm, H. Tillmanns, and W. Haberbosch In Situ Detection of Tissue Factor within the Coronary Intima in Rat Cardiac Allograft Vasculopathy Am. J. Pathol., January 1, 1999; 154(1): 211 - 220. [Abstract] [Full Text] [PDF]
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S. P. Jain, S. R. Ramee, C. J. White, M. R. Mehra, H. O. Ventura, S. Zhang, J. S. Jenkins, and T. J. Collins Coronary stenting in cardiac allograft vasculopathy J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1636 - 1640. [Abstract] [Full Text] [PDF]
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D. H. Walter, J. Haendeler, J. Galle, A. M. Zeiher, and S. Dimmeler Cyclosporin A Inhibits Apoptosis of Human Endothelial Cells by Preventing Release of Cytochrome C From Mitochondria Circulation, September 22, 1998; 98(12): 1153 - 1157. [Abstract] [Full Text] [PDF]
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