Graft Atherosclerosis Research Articles

Seventeen-year experience with 1,083 heart transplants at a single institution

Background Heart transplantation is the most accepted treatment for end-stage heart disease. A review of 1,083 consecutive transplants (1984 to 2001) was undertaken. Methods Adult recipients were divided into quartiles. The last 540 transplants were combined. Three eras were created from these, 1984 to 1991, 1991 to 1995, and 1995 to 2001, with three age groups: 0 to 18 years, 19 to 61 years, and 62 to 74 years. All patients have at least 1 year of follow-up time. End points were survival, rejection, and graft coronary artery disease. Results There were 1,012 patients. Donor age, graft ischemic time, and the proportion of elderly recipients and nonstandard donor hearts have increased in the current era. Actuarial 60-month survivals of recipients after 1995 were 80.7% (0 to 18 years); 75.3% (19 to 61 years); and 76.2% (>62 years). The current era children and younger adult groups demonstrated improved results when compared with previous eras ( p = 0.003 and p = 0.05). Rejection episodes equal to or greater than ISHLT grade 3A per person per year improved to 0.15 in the current era ( p < 0.001). During the three eras, older recipients (>62 years) demonstrated fewer episodes of rejection when compared with other adults (0.13 versus 0.58, p = 0.03). Deaths attributed to graft coronary artery disease decreased from 11% to 5% from era 2 to era 3. Regression analysis revealed a mild effect of donor age on survival and graft coronary artery disease (hazard ratio = 1.02, p = 0.001; hazard ratio = 1.039, p < 0.001, respectively). Recipient predictors of graft coronary artery disease were diagnosis of ischemic cardiomyopathy (hazard ratio = 1.6, p = 0.014) and congenital heart disease (hazard ratio = 3.41, p = 0.02). Conclusions Improved survival in the current era may be attributed to better organ preservation, improved immunosuppression and control of infection, and less life-threatening graft coronary artery disease.

Pediatric heart transplantation.

Heart transplantation is now a treatment option with good outcome for infants and children with end-stage heart failure or complex, inoperable congenital cardiac defects. One-year and 5-year actuarial survival rates are high, approximately 75% and 65%, respectively, with overall patient survival half-life greater than 10 years. To date, survival has been improving as a result of reducing early mortality. Further reductions in late mortality, in part because of graft coronary artery disease and rejection, will allow achievement of the goal of decades-long survival. Quality of life in surviving children, as judged by activity, is usually "normal." Somatic growth is usually at the low normal range but linear growth can be reduced. Of infant recipients, 85% evaluated at 6 years of age or older were in an age-appropriate grade level. Long-term management of childhood heart recipients requires the collaboration of transplant physicians, given the increasing number of immunosuppressive agents and the balance between rejection and infection. Currently, recipients are maintained on immunosuppressive medications that target calcineurin (eg, cyclosporine, tacrolimus), lymphocyte proliferation (eg, azathioprine, mycophenolate mofetil [MMF], sirolimus) and, in some instances antiinflammatory corticosteroids. Emerging evidence now suggests a favorable immunologic opportunity for transplantation in childhood and, conversely, a higher mortality rate in children who have had prior cardiac surgery. Further studies are needed to define age-dependent factors that are likely to play a role in graft survival and possible graft-specific tolerance (eg, optimal conditions for tolerance induction and how immunosuppressive regimens should be changed with maturation of the immune system). As late outcomes continue to improve, the need for donor organs likely will increase, as transplantation affords a better quality and duration of life for children with complex congenital heart disease, otherwise facing a future of multiple palliative operations and chronic heart failure.

Accelerated atherosclerosis and calcification in vein grafts: a study in APOE*3 Leiden transgenic mice.

Vein grafts fail due to development of intimal hyperplasia and accelerated atherosclerosis. Many murine genetic models in which genes are overexpressed, deleted, or mutated have been introduced recently. Therefore, mouse models are very well suited to dissect the relative contribution of different genes in the development of accelerated atherosclerosis. In the present study, we evaluated whether accelerated atherosclerosis in human vein grafts could be mimicked in hypercholesterolemic APOE*3 Leiden transgenic mice. Venous bypass grafting was performed in the carotid artery in APOE*3 Leiden mice fed either a standard chow diet or a high cholesterol-rich diet for 4 weeks. At several time points (0 hour to 28 days), mice were euthanized and the morphology of the vein grafts was analyzed. In normocholesterolemic mice, vein graft thickening up to 10-fold original thickness, predominantly consisting of alpha-smooth muscle cell actin-positive cells, was observed after 28 days. In hypercholesterolemic mice, accelerated atherosclerosis with accumulation of lipid-loaded foam cells was observed within 7 days after surgery. This accelerated atherosclerosis progressed in time and resulted in significant increase in vein graft thickening up to 50 times original thickness with foam cell-rich lesions and calcification within 28 days after surgery. The atherosclerotic lesions observed in these murine grafts show high morphological resemblance with the atherosclerotic lesions observed in human vein grafts. This accelerated, diet-dependent induction of atherosclerotic-like lesions in murine vein grafts provides a valuable tool in evaluating the mechanisms of accelerated atherosclerosis and therapeutic interventions of vein graft disease.

Both Donor and Recipient Origins of Smooth Muscle Cells in Vein Graft Atherosclerotic Lesions

Smooth muscle cell (SMC) accumulation in the inner layer of the vessel wall is a key event in the pathogenesis of atherosclerosis in vein grafts, but the origin of the cells in these lesions has yet to be shown. Herein, we use animal models of vein grafts in transgenic mice to clearly identify the sources of SMCs in atherosclerosis. Vena cava segments were isografted to carotid arteries between four types of transgenic mice, including SM-LacZ expressing beta-galactosidase (beta-gal) in vascular SMCs, SM-LacZ/apoE(-/-), ROSA26 expressing beta-gal in all tissues, and wild-type mice. beta-gal-positive cells were observed in neointimal and atherosclerotic lesions of all vein segments grafted between LacZ transgenic and wild-type mice. Double staining for beta-gal and cell nuclei revealed that about 40% of SMCs originated from hosts and 60% from the donor vessel. This was confirmed by double labeling of the Y-chromosome and alpha-actin in the lesions of sex-mismatched vein grafts. The possibility that bone marrow cells were the source of SMCs in grafts was eliminated by the absence of beta-gal staining in atherosclerotic lesions of chimeric mice. Furthermore, vein SMCs of SM-LacZ mice did not express beta-gal in situ, but did so when these cells appeared in atherosclerotic lesions in vivo, suggesting that hemodynamic forces may be crucial for SMC differentiation. Thus, we provide the first evidence of SMC origins in the atherosclerotic lesions of vein grafts, which will be essential for providing insight into new types of therapy for the disease. The full text of this article is available at http://www.circresaha.org.

The use of 99mtechnetium-labeled MCP-1 to assess graft coronary artery disease in rat cardiac allografts

Background Monocyte chemoattractant protein-1 (MCP-1) is associated with the development of graft coronary artery disease (GCAD) following cardiac transplantation. This study assessed whether technetium 99m ( 99mTc)-labeled MCP-1 binds its receptors in chronic cardiac transplants and thereby provides a potential modality to assess GCAD. Methods Allogeneic (PVG→ACI, n = 9) and syngeneic (ACI→ACI, n = 9) rat heterotopic heart transplants were performed. Allograft recipients were treated with 7.5 mg/kg per day of Cyclosporin A for 10 days until tolerance was achieved. After 90 days, animals were injected intravenously with 99mTc–MCP-1 and killed after 1 hour. Radioactivity of heart tissues was measured and standardized to uptake in the overall blood pool. Two-dimensional 99mTc–MCP-1 uptake (autoradiographs) was imaged by exposing 50-μm sections on a phosphoimager overnight. ED-1 staining of monocyte/macrophages was performed on serial sections. Additional sections were stained with elastin von Gieson and hematoxylin. Hearts were scored for luminal narrowing and intima/media ratio (I/M) with computerized image analysis. Results Allografts exhibited significantly more luminal narrowing (22.5 ± 10.7% vs 2.6 ± 4.6, p = 0.0005) and higher I/M (0.173 ± 0.151 vs 0.015 ± 0.029, p = 0.0088) than isografts. The ratio of 99mTc–MCP-1 uptake in allografts (1.04 ± 0.4) was greater than that of isograft controls (0.72 ± 0.11, p = 0.03). Pixel counts of autoradiographs and ED-1–stained sections demonstrated a modest correlation between the two ( R 2 = 0.50). No significant differences were seen in acute rejection scores. Conclusion 99mTc–MCP-1 uptake was higher in allografts vs isografts and was consistent with a greater degree of GCAD. These data demonstrating increased radiopharmaceutical uptake in hearts with GCAD provide a foundation for the development of a potentially non-invasive imaging assay of this disease process in heart transplantation.

Understanding and treating vein graft atherosclerosis

Background: Vein grafts have been used as bypass conduits for coronary artery disease since the 1960s. This widely used treatment, however, is complicated by the development of changes in the vein graft, which resemble atherosclerosis and are often termed as such. They occur at about 10 years, which leads to the need for reoperation in some patients. The purpose of this review is to summarize the knowledge regarding the pathophysiology of vein graft “atherosclerosis,” as well as promising new treatments for this disease. Methods: The relevant literature relating to the epidemiology, histology, cell and molecular pathophysiology and treatment of vein graft atherosclerosis is reviewed. Results: The development of vein graft atherosclerosis differs from arterial atherosclerosis. Studies have examined the role of trauma, lipids, vasoactive mediators, smooth muscle cell mitogens, smooth muscle cells apoptosis, adhesion molecules and proteases. Therapies have been developed to prevent vein graft atherosclerosis based on these studies and have been tested using animal models and in patients. Discussion: Promising new therapies have been developed based on current knowledge and further applications of genomics will allow for the further identification of risk factors and mechanistic insights. The use of arterial grafts such as the internal mammary artery, which have higher patency rates at 10 years compared with vein grafts as well as approaches to revascularize infarcted myocardium may one day replace the use of vascular conduits.

Inhibition of accelerated atherosclerosis in vein grafts by placement of external stent in apoE*3-Leiden transgenic mice.

Vein grafts fail because of the development of intimal hyperplasia and accelerated atherosclerosis. Placement of an external stent around vein grafts resulted in an inhibition of intimal hyperplasia in several animal studies. Here, we assess the effects of external stenting on accelerated atherosclerosis in early vein grafts in carotid arteries in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice. Venous interposition grafting was performed in apolipoprotein E*3-Leiden mice fed standard chow or a highly cholesterol-rich diet for 4 weeks. After engraftment, external stents with different inner diameters (0.4 or 0.8 mm) were placed. In unstented vein grafts in hypercholesterolemic mice, thickening up to 50 times the original thickness, with foam cell-rich lesions, calcification, and necrosis, was observed within 28 days. The atherosclerotic lesions observed show high morphological resemblance to atherosclerotic lesions observed in human vein grafts. In stented vein grafts in hypercholesterolemic mice, no foam cell accumulation or accelerated atherosclerosis was observed. Compared with unstented vein grafts, stenting of vein grafts in a hypercholesterolemic environment resulted in a 94% reduction of vessel wall thickening. These effects were independent of stent size. Extravascular stent placement results in strong inhibition of accelerated vein graft atherosclerosis in hypercholesterolemic transgenic mice and thereby provides a perspective for therapeutic intervention in vein graft diseases.

Long-term follow-up after total lymphoid irradiation in pediatric heart transplant recipients

Background Total lymphoid irradiation (TLI) is used to treat recurrent allograft rejection. Short-term success and complication rates have been reported in pediatric and adult cardiac transplant populations. We report the long-term efficacy and safety of TLI in treating intractable rejection in pediatric patients. Methods Eight pediatric patients were treated with TLI (7 for recurrent rejection, 1 for risk of medication non-compliance). Therapy consisted of a mid-plane dose of 8 Gy administered with a 6-MeV linear accelerator using an anterior–posterior opposed technique. We reviewed outcomes for a total of 40 patient-years of follow-up. Results We encountered rejection (>Grade 2 by International Society for Heart and Lung Transplantation criteria) in 56.7% ± 34.7% of biopsies performed within 90 days before TLI. Rejection rates dropped to 3.1% ± 8.8% within the first 90 days ( p < 0.005) after therapy and remained low at 5.6% ± 1.3% ( p < 0.05) during the first year after completion of TLI. Median time from TLI to the first subsequent rejection episode was 305 days (range, 77–1,920 days). Long-term follow-up (>3 years) of 5 patients demonstrated a continuing low incidence of rejection. Non-Hodgkin’s lymphoma was diagnosed in 1 of 8 patients, graft coronary artery disease in 4 of 8 patients, and restrictive cardiomyopathy in 1 of 8 patients after TLI. Conclusions Total lymphoid irradiation is an effective treatment for recurrent rejection and has short- and long-term efficacy. Morbid events may include cancer, graft coronary artery disease, and restrictive cardiomyopathy.

Accelerated atherosclerosis in saphenous vein bypass grafts: A spectrum of diffuse plaque instability

Our understanding of plaque instability may be extended to vein graft atherosclerosis, which appears to represent the end of a continuum of plaque instability. Compared with plaque in native coronary arteries, vein graft atheroma is more diffuse and vulnerable to rupture, and the consequences of plaque rupture in vein grafts seem to be associated with almost certain thrombotic occlusion within 7 to 12 years after surgery. Copyright 2002, Elsevier Science (USA). All rights reserved.

Ex vivo blockade of endothelin-1 inhibits graft coronary artery disease in a rodent cardiac allograft model

Background: Graft coronary artery disease (GCAD) is characterized by vascular narrowing resulting from intimal hyperplasia. Endothelin (ET)-1, derived from the vascular endothelium and macrophages, stimulates vascular smooth muscle cells (SMCs), which leads to neointimal formation in donor graft coronary arteries. In this study, we hypothesized that antisense (AS) oligodeoxynucleotides (ODN) for preproendothelin-1 (ppET-1) delivered to rat cardiac allografts by means of hyperbaric pressure would reduce the incidence of GCAD. Methods: PVG donor hearts were infused with ppET-1 AS ODN (80 μmol/liter), sense ODN, scrambled ODN or saline alone and incubated in a pressure chamber at 75 psi or ambient pressure for 45 minutes. Cardiac allografts were heterotopically transplanted into ACI rats treated with cyclosporine (7.5 mg/kg, Days 0 to 9). Allografts were procured at post-operative days (POD) 7 or 90. Reverse transcription–polymerase chain reaction (RT-PCR) assay for ET-1 mRNA and ET01 immunohistochemistry (IHC) were performed at PODs 7 and 90. Elastic staining and IHC with anti-macrophage and α-SMC actin antibodies were performed to assess GCAD at POD 90. Results: Treatment with AS ODN and pressure significantly reduced ET-1 mRNA and protein expression. A significant reduction in GCAD was achieved with inhibition of ET-1 and was associated with attenuation of macrophages and SMCs in the neointima. Conclusions: Peri-operative ex vivo inhibition of ET-1 expression results in a reduction of GCAD. This highly targeted therapy may be a clinically viable strategy for the prevention of ET-1–induced GCAD following cardiac transplantation.

Intraoperative cell-cycle blockade therapy using E2F decoy for prevention of early atherosclerosis in coronary bypass vein grafts: a volumetric IVUS subanalysis from a prospective randomized double blind clinical trial

Intraoperative cell-cycle blockade therapy using E2F decoy for prevention of early atherosclerosis in coronary bypass vein grafts: a volumetric IVUS subanalysis from a prospective randomized double blind clinical trial

Adenoviral upregulation of BCL-2 decreases oxidative stress and graft coronary artery disease in rat heart transplants

Adenoviral upregulation of BCL-2 decreases oxidative stress and graft coronary artery disease in rat heart transplants

New mouse model of vein bypass graft atherosclerosis

Animal models of vein graft disease are used as preliminary tools to study and understand the pathogenesis of the disease in humans and improve its diagnosis, prevention and therapy. Several animal models that manifest lesions resembling neointimal hyperplasia of human vein grafts have been developed, but there are limitations in studying the mechanism of this disease in these models. We previously established a mouse model of vein bypass graft atherosclerosis that allows us to take advantage of transgenic and knockout techniques. Using this model, we studied the pathogenesis of vein graft atherosclerosis. The lesion in the grafts was characterised by mononuclear cell infiltration followed by smooth muscle cell (SMC) proliferation and matrix protein deposition, which is similar to the human lesion. Studies of the molecular mechanism of pathogenesis in this model revealed that physical force initiated signal pathways, particularly mitogen-activated protein kinases (MAPK), leading to vascular cell death and an inflammatory response, followed by SMC proliferation, which contributed to the development of arteriosclerosis. Suramin inhibited SMC migration and proliferation in vivo and in vitro by blocking platelet-derived growth factor (PDGF)-initiated PDGF receptor activation and MAPK-AP-1 signalling, and was also effective in inhibition of neointima hyperplasia in mouse vein bypass grafts. This new mouse model of vein bypass graft atherosclerosis affords us with a valuable new approach to attain further understanding of the mechanism of vein graft disease with the use of transgenic mice, and in evaluating the effects of drugs and gene therapy on vascular diseases.

Effect of a novel anti-oxidant and anti-inflammatory compound on rodent allograft arteriosclerosis

Background: The long term success of cardiac transplantation continues to be limited by the development of graft coronary artery disease. AGI-1096 is a newly developed antioxidant and anti-inflammatory compound that inhibits the inducible expression of VCAM-1 and MCP-1 in endothelial cells (IC50=11μM and 5μM, respectively) as well as smooth muscle cell proliferation (IC50 =5.5μM), giving it the potential to prevent chronic allograft arteriosclerosis. In this study, we evaluated the efficacy of this compound using a rodent aortic transplantation model.

Christiaan Neethling Barnard

With the sudden death of Christiaan Barnard⇓ in Cyprus on September 2, 2001, the world lost not only a pioneering cardiac surgeon but also a charismatic, if controversial, figure. On December 3, 1967, Chris Barnard led the surgical team that performed the first human-to-human heart transplant. The operation captured the public’s imagination as no procedure had before or since, and the personable Barnard rapidly became an international celebrity. Monarchs and heads of state honored him. According to French President Jacques Chirac, “Dr Barnard will remain the symbol of audacious modern medicine, able to surpass accepted ideas to bring solutions to victims of suffering and illness.” Born on November 8, 1922, in the small country town of Beaufort West in South Africa, Christiaan Neethling Barnard was one of 4 sons of a church pastor who ministered to the poor. After graduating from the local high school, Barnard entered the University of Cape Town Medical School. By his own admission, he was not an outstanding student academically, but he worked hard and graduated as a doctor in 1946. After spending a short period as a primary care physician and a resident in medicine, during which time he completed a dissertation on the treatment of tuberculous meningitis, Barnard began a busy surgical residency at Groote Schuur Hospital in Cape Town. In 1956, he received a scholarship to the University of Minnesota Medical School, where he soon was drawn to the emerging field of open heart surgery. During 2 highly productive and exciting years in the Department of Surgery under the direction of Richard Varco and C. Walton Lillehei, Barnard worked hard in both the clinic and the research laboratory. Some years later, Lillehei expressed his high regard for Barnard, particularly for his innovation, courage, “prodigious” memory, and “intensity and seriousness.” Lillehei noted …

Superiority of Bilateral Internal Thoracic Artery Grafting

A myriad of data have established the superiority of the left internal thoracic artery (LITA) graft to the left anterior descending (LAD) coronary artery.1,2 Late patency rates of LITA-LAD grafts far exceed those of saphenous vein grafts (SVG) to the LAD, and ITA grafts avoid the late complications of vein graft atherosclerosis.3 Once an ITA graft is patent, late failure is extremely rare. These advantages are reflected in improved clinical outcomes. When compared with patients receiving only SVGs, patients receiving LITA-to-LAD grafts and SVGs to other vessels experience an improved long-term survival rate, fewer reoperations, and fewer cardiac hospital admissions.1,2 See p 2164 If one ITA graft is good, might two be better? Even before the demonstration of the benefit of LITA-LAD grafts in the 1980s, a minority of coronary artery surgeons used bilateral ITA (BITA) grafts for selected patients based on the premise that more extensive ITA use might further improve outcomes. However, the incremental benefit of BITA grafts over the LITA-LAD plus SVG strategy has been difficult to document, despite its apparent logic. Why has the benefit of BITA grafting been difficult to show? Probably for multiple reasons. First, the LITA-LAD plus SVG strategy produces very good outcomes during the first postoperative decade. Therefore, to show improved outcomes, a large sample size is needed and those patients must be followed for relatively long postoperative intervals. BITA grafting has not been a common operation at most institutions, and the length of follow-up has often been short. Also, if it is the case that only some patient subgroups benefit from BITA grafting, the sample size needed to produce a statistically significant difference becomes greater. Second, no randomized data exist comparing BITA and single ITA (SITA) surgical strategies and, in nonrandomized comparisons, patient and surgeon-related factors introduce potentially …

Pediatric cardiac transplantation: Management issues

Pediatric heart transplantation is an effective therapeutic modality for children with end-stage heart disease. The overall survival of young heart recipients is very good: 89% to 92% one year survival. Survival data for the long term indicates that pediatric heart recipients have a very good chance of living for decades. Advances in immunosuppression have lent optimism for the future. There are now alternatives in induction, maintenance, and acute rejection therapy. Immunosuppressants are more specific in action and prevent and treat allograft rejection with less toxic side effects and decreased morbidity. Acute rejection and infection are early complications that reduce in incidence significantly after six months post-transplant. Graft coronary artery disease continues to be the most significant hurdle to long-term survival. Currently there is a plateau in the number of heart transplants performed annually. Lack of available pediatric donors plays a large role in the paucity of pediatric transplants. This review focuses on the key management issues involved in the care of the pediatric heart transplant recipient and incorporates the experiences and protocols of the Stanford University Pediatric Heart Transplant Program. Copyright © 2001 by W.B. Saunders Company

VCAM-1 expression precedes macrophage infiltration into subendothelium of vein grafts interposed into carotid arteries in hypercholesterolemic rabbits — a potential role in vein graft atherosclerosis

Intimal hyperplasia and atherosclerosis are major causes of late vein graft failure after coronary artery bypass surgery. Hypercholesterolemia appears to be a key risk factor for atherosclerosis in vein grafts as well as in native arteries. We used a rabbit model of interposition jugular vein graft to the carotid artery and compared intimal thickening, macrophage accumulation, and VCAM-1 expression between hypercholesterolemic (H group) and normocholesterolemic (N group) rabbits. Fifty-nine rabbits were divided into H and N groups. Intimal thickening in vein grafts was approximately three times more prominent in the H group than in the N group. Macrophage accumulation progressively increased with time in H group vein grafts, although it was negligible in the N group. In the H group, moreover, macrophages were initially more abundant in deep intima, and subsequently accumulated in subendothelium of the grafted vein. VCAM-1 expression in luminal endothelial cells of the grafted veins was time-dependently increased after the vein graft surgery in both the H and N groups, and was more prominent in the H group. Comparison of the time-courses between macrophage accumulation and VCAM-1 expression revealed that VCAM-1 expression in luminal endothelium preceded subendothelial accumulation of macrophages. VCAM-1 expression and macrophage accumulation may be key factors which regulate progression of vein graft atherosclerosis.

Matters of Sex

Despite the popular concept that heart disease preferentially affects the male population, in every year for the past 16 years, cardiovascular disease has killed more women than men.1 Unfortunately, a disparity still exists between men and women in the diagnosis and aggressive treatment of heart disease. The perception that women are relatively protected is reflected by the fact that women are much more fearful of dying from some form of cancer than from cardiovascular disease.1 Understanding any risk factors that predispose or protect the female population from cardiovascular and coronary disease is therefore a compelling goal for the research community. See p 1419 Left ventricular hypertrophy is a compensatory response of the heart to a variety of stresses, and it is a strong predictor of morbidity and mortality in individuals whether or not they have been diagnosed with cardiovascular disease. Sex differences in the development of this disease over time have been suggested by clinical studies dealing with patients who suffer from aortic stenosis or hypertension.2,3 For example, older female patients with aortic stenosis tend to have increased hypertrophy accompanied by greater concentric remodeling and preserved left ventricular function when compared with male patients. Premenopausal women, in fact, exhibit a thinner posterior wall, smaller left ventricular mass, and better load-dependent and load-independent cardiac function than age-matched men under conditions of mild essential hypertension.4 Population studies have shown an age-dependent increase in left ventricular mass in healthy normotensive women that is not seen in men, as determined by echocardiography.5 These and many other studies in both humans and animals suggest that estrogens can affect the remodeling of the heart. Estrogens are potent vasodilators; they act in this capacity by increasing nitric oxide production. However, recent findings indicate that estrogens have direct actions on the myocardium as …

A chymase gene variant is associated with atherosclerosis in venous coronary artery bypass grafts.

Angiotensin II is known to stimulate proliferation of fibroblasts and smooth muscle cells and enhance the atherosclerotic process in native coronary arteries. The impact of genetic polymorphisms of the renin-angiotensin-aldosterone system on coronary bypass graft degeneration is unknown. We examined polymorphisms of four genes (AGTR1, CYP11B2, ACE, CMA) in 101 patients who had follow-up coronary angiography due to symptoms 88 +/- 52 months after coronary artery bypass graft surgery. Bypass degeneration was determined with quantitative coronary angiography and an adjusted Gensini score. Homozygosity for the G allele of the CMA-1905 polymorphism was associated with a higher degree of bypass degeneration (Bypass Gensini score CMA AA 21.4 +/- 39; AG 24.2 +/- 39.8; GG 27.8 +/- 42.3; NS-time adjusted Gensini bypass scores CMA AA 0.25 +/- 0.68; AG 0.57 +/- 1.82; GG 3.25 +/- 13.2; P = 0.005). No association could be detected for the AGTR1, CYP11B2 or ACE polymorphism. The CMA allele G is a genetic risk factor for atherosclerosis in venous coronary artery bypass grafts. Its importance has to be shown in further studies. Other polymorphisms of the renin-angiotensin-aldosterone system do not seem to play a role in bypass degeneration.