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PubMed1997

Effect of cyclosporine during initiation of transplant arteriosclerosis. An ultrastructural study in the aorta-transplanted rabbit.

The immunosuppressant cyclosporine protects against the development of experimental transplant arteriosclerosis. To investigate the mechanism underlying this effect, aorta-allografted rabbits were randomly assigned to cyclosporine (n = 6) in the human therapeutic range or to its vehicle (n = 5). Perfusion fixation was performed 2 weeks after the transplantation, followed by light, scanning and transmission electron microscopy examination. Intimal proliferation was absent in native aortas, present in all grafts from vehicle-treated animals, and either absent or sparse in grafts from cyclosporine-treated rabbits. The endothelium of native aortas from both vehicle- and cyclosporine-treated rabbits was normal. Aortic allografts from cyclosporine-treated rabbits exhibited a normal endothelium with only a few adhering mononuclear cells, whereas aortic allografts from vehicle-treated rabbits exhibited an endothelial surface ranging from near-normal with only few adhering platelets and mononuclear cells, to an almost destroyed endothelium, lined with lymphocyte-like cells, monocytes/macrophages, platelets, erythrocytes and fibrin; in the subendothelial layer, mononuclear cells and smooth muscle cells were abundant. These results suggest that damage to the endothelial cells as well as invasion of lymphocytes, monocytes/macrophages and smooth muscle cells into the subendothelial space are important events during initiation of transplant arteriosclerosis, and that cyclosporine largely attenuates these early pathological changes.

Animals↗
PubMed2000

Platelet-derived microparticles in patients with arteriosclerosis obliterans: enhancement of high shear-induced microparticle generation by cytokines.

We evaluated the plasma concentrations of cytokines and platelet-derived microparticles in patients with arteriosclerosis obliterans and studied the effect of cytokines on platelet-derived microparticle generation under high shear stress. Interleukin-6 levels peaked at 48 hours after vascular surgery, while thrombopoietin started to increase at 24 to 48 hours postoperatively and peaked on the seventh day. Platelet activation markers were increased in the arteriosclerosis obliterans patients preoperatively. Levels of P-selectin and CD63 both increased further, peaking at 6 to 24 hours postoperatively. Platelet-derived microparticle levels were also increased preoperatively. At 6 hours postoperatively, the plasma level of platelet-derived microparticles was significantly increased. Plasma platelet-derived microparticle level was lower at 12 hours but only returned to the preoperative value at 7 days after grafting. There was a difference in the platelet-derived microparticle level at 7 days between patients with or without antiplatelet therapy (cilostazol). The effect of cytokines on platelet activation under high shear stress was also studied. Interleukin-6 and thrombopoietin enhanced both P-selectin expression and platelet-derived microparticle generation under high shear stress. These results suggest that platelet-derived microparticles are released by platelet activation after vascular grafting when certain cytokines increase under high shear stress and that antiplatelet therapy may reduce platelet-derived microparticle levels postoperatively.

Aged↗
PubMed1985

Experimental arteriosclerosis and the plasma kininogen and low molecular weight kininogen antigen concentration in rabbits.

A decrease in trypsin-releasable kinin and in low molecular weight kininogen antigen concentrations was observed in plasma of rabbits with cholesterol-induced arteriosclerosis. In rabbits receiving normal diet for 30 days after 30 days of cholesterol almost complete normalization of the morphological status was observed, which was accompanied by normalization of plasma kinin concentration and by higher than normal concentration of kininogen antigen measured. These changes were not observed in animals receiving normal diet for 30 days after 60 days of cholesterol administration. No data were obtained suggesting a massive kinin release during induction of arteriosclerosis by experimental hypercholesteremia. The possibility of intense kinin formation during a period of repair of the morphological changes was discussed.

Animals↗
PubMed1976

Arteriosclerosis, heredity, and some previous infections in the etiology of Parkinson's disease. A case-control study.

A case-control study was performed to investigate the significance of arteriosclerosis, heredity and some infections in the etiology of Parkinson's disease. The study group consisted of all traceable patients with Parkinson's disease living in a defined area, a total of 444 patients, and of control subjects for each patient, matched in sex and age, chosen from among the general population residing in the same area. No significant differences were found between the patients and the controls concerning the occurrence of cardiac insufficiency, coronary heart disease, or stroke. The Parkinsonian patients, however, had a significantly lower incidence of clinical arterial hypertension when compared with the controls. In addition, the patients more often had low systolic blood pressures and more rarely high pressures than the controls. Even the mean systolic blood pressure was significantly lower in the patients than in the controls. The low blood pressure seems to be an effect of Parkinson's disease itself with a minor contribution of levodopa therapy. The observations above are considered to indicate that arteriosclerosis and Parkinson's disease are probably only concurrent disorders and not in etiological relationship with each other. There was no statistically significant difference in the proportion of the patients and the controls with relatives with Parkinson's disease or essential tremor, which suggests that genetic factors do not have a significant role in Parkinson's disease and on the other hand that essential tremor and Parkinson's disease are two separate disease entities. No other encephalitis than a lethargic one was found to precede Parkinson's disease and the occurrence of meningitis was rare both among the patients and the controls. The history of Spanish influenza was found to be as frequent in the patients as in the controls, thus not supporting the idea that influenza has etiological importance in Parkinson's disease.

Aged↗
PubMed1988

Long-term results after arterial surgery for arteriosclerosis of the lower limbs in young adults.

Ninety-nine patients, with a mean age of 40 years, underwent surgery for arteriosclerosis of the lower limbs during 1975-81. The main indication for surgery was claudication and the median observation time 102 months (range 54-138 months). Twenty patients died during the follow-up period and fifteen of these could be related to arteriosclerotic disease. At follow-up, 43 patients had claudication, while 34 patients had developed other arteriosclerotic manifestations. Amputation was performed in 17 patients. At follow-up the number of patients at work remained almost unchanged, whereas the number of patients receiving disablement pension increased. This study shows that younger patients with arteriosclerosis of the lower limbs had a mortality of approximately 20%, during the period of observation of this study. However, many patients became asymptomatic after surgery suggesting that a conservative attitude to arterial surgery in these patients cannot be justified.

Adolescent↗
PubMed2000

Biomechanical-stress-induced signaling and gene expression in the development of arteriosclerosis.

The vascular wall is an integrated functional component of the circulatory system that is continually remodeling or develops arteriosclerosis in response to hemodynamic or biomechanical stress. How vascular cells sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and challenging question. Based on recent progress in this field, this article attempts to formulate a biomechanical-stress hypothesis-that physical force initiates signal pathways, especially mitogen-activated protein kinases (MAPKs), leading to vascular cell death and inflammatory response followed by smooth muscle cell proliferation. Thus, mechanical stress, akin to cytokines or growth factors, can effectively activate signal transduction pathways, resulting in morphological and functional changes in vascular cells, which contribute to the development of arteriosclerosis.

Animals↗
PubMed2000

Comparative effects of vitamin K2 and estradiol on experimental arteriosclerosis with diabetes mellitus.

In order to further investigate the radical scavenging and anti-arteriosclerotic activities of vitamin K2 and estradiol, the comparative effects of vitamin K2 and estradiol on aortic calcium (Ca) and inorganic phosphorus (P) levels in the aorta and the elastin fraction (fr.) were investigated in male rats after experimental arteriosclerosis with diabetes mellitus was induced by vitamin D2 and radical producing substance, streptozotocin (STZ). Pharmacological dose of vitamin K2 (100 mg/kg b.w.) and medical dose of estradiol (83 micrograms/kg b.w.) suppressed the increased serum glucose, and vitamin K2 and estradiol increased the decrease in serum insulin. Moreover, vitamin K2 and estradiol inhibited the increase of Ca and P in the aorta and the elastin fr. Vitamin K2 and estradiol decreased the increase in serum lipid peroxide (LPO). It is suggested that both the pharmacological dose of vitamin K2 and medical dose of estradiol suppressed the development of arteriosclerosis associated with diabetes mellitus, owing to radical scavenging activity of vitamin K2 and estradiol.

Animals↗
PubMed2002

Recipient cells form the intimal proliferative lesion in the rat aortic model of allograft arteriosclerosis.

Chronic rejection is the leading cause of late graft loss following solid organ transplantation and is characterized by a vasculopathy referred to as allograft arteriosclerosis. While the etiology of allograft arteriosclerosis remains unknown, it has been hypothesized that migration of donor medial smooth muscle cells into the intimal compartment is responsible for the formation of the occlusive lesion (neointima). In this study we have used aortic interposition grafts between fully histoincompatible rat strains (Brown Norway and Lewis) to investigate the origin of the neointimal cells. Three transplant paradigms were used: BN to Lew, Lew to BN and BN to Lew with immunosuppression. Neointimal cells were isolated from aortic transplant tissue through an EDTA wash/mechanical stripping technique. We have developed polymerase chain reaction primers to the MHC1 allele that are specific to each rat strains' DNA. Polymerase chain reaction analysis, using the strain-specific primers and purified neointimal cell DNA from transplanted aortic tissue from all three experimental groups, demonstrated that the neointimal cells are of recipient, and not donor origin.

Animals↗
PubMed2000

Interferon-gamma elicits arteriosclerosis in the absence of leukocytes.

Atherosclerosis and post-transplant graft arteriosclerosis are both characterized by expansion of the arterial intima as a result of the infiltration of mononuclear leukocytes, the proliferation of vascular smooth muscle cells (VSMCs) and the accumulation of extracellular matrix. They are also associated with the presence of the immunomodulatory cytokine interferon-gamma (IFN-gamma). Moreover, in mouse models of atheroma formation or allogeneic transplantation, the serological neutralization or genetic absence of IFN-gamma markedly reduces the extent of intimal expansion. However, other studies have found that exogenous IFN-gamma inhibits cultured VSMC proliferation and matrix synthesis, and reduces intimal expansion in response to mechanical injury. This discrepancy is generally explained by the idea that IFN-gamma either directly activates macrophages, or, by increasing antigen presentation, indirectly activates T cells within the lesions of atherosclerosis and graft arteriosclerosis. These activated leukocytes are thought to express the VSMC-activating cytokines and cell-surface molecules that cause the observed arteriosclerotic responses. Here we have inserted pig and human arteries into the aorta of immunodeficient mice, and we show that IFN-gamma can induce arteriosclerotic changes in the absence of detectable immunocytes by acting on VSMCs to potentiate growth-factor-induced mitogenesis.

Adult↗
PubMed1999

Role of inducible nitric oxide synthase in transplant arteriosclerosis.

1. Transplant arteriosclerosis is a major obstacle to long-term allograft survival. Nitric oxide (NO) has been implicated as a mediator in the development of this disease. 2. We and others have shown that inducible nitric oxide synthase (iNOS) is up-regulated in allografts with transplant arteriosclerosis. Despite the acute cytotoxic effects produced by high levels of NO, a chronic increase in NO availability is protective against neointimal hyperplasia, mainly by suppressing the inflammatory cell recruitment and neointimal smooth muscle cell accumulation. 3. Currently, we have the technology to directly transfer the iNOS gene to allografts. We have demonstrated that this exciting strategy is feasible and therapeutic and may improve the long-term survival and function of allografts. Future challenges include optimizing the methods and the vectors of gene delivery.

Animals↗
PubMed2003

Treatment of arteriosclerosis.

Summary. Arteriosclerotic disease develops over the course of several decades. Currently, a number of therapies are at hand to effectively stop this process and avoid complications of arteriosclerosis. Among the non-pharmacologic options, a balanced diet and physical activity predominate. A modern dietary plan offers a variety of tasty servings rich in fresh fruit and vegetables, cereals, fish, and poly-unsaturated fatty acids. The value of regular physical activity is demonstrated by the finding that an increase in exercise capacity ("cardiorespiratory fitness") by only one metabolic equivalent already reduces cardiovascular risk by 20-25 %. Regarding pharmacologic therapy, convincing data are available for cholesterol synthase inhibitors ("statins"), some substances which influence the renin-angiotensin system (such as ramipril), and platelet aggregation inhibitors. Statins produce a 20 to 30 % reduction of cardiac death, myocardial infarction, and stroke. In patients with increased cardiovascular risk, the beneficial action of statins is also evident in subjects with low baseline cholesterol values. Apart from the cholesterol-lowering effects, anti-inflammatory and other vasoprotective mechanisms are involved. The angiotensin-converting enzyme inhibitor ramipril has demonstrated that even independent of blood-pressure lowering, cardiovascular events (cardiac death, myocardial infarction, stroke) are substantially reduced in high-risk patients. The effect is in the same order as that of statins. In patients with left-ventricular hypertrophy, the angiotensin-receptor antagonist losartan produces a notable reduction in stroke, independent of its blood-pressure lowering action. Finally, the platelet aggregation inhibitors aspirin and clopidogrel have proven benefit in secondary prevention and, in the case of aspirin, also in primary prevention in cardiovascular high-risk patients. The anti-arteriosclerotic properties of other substances are actively investigated, including calcium channel blockers, betablockers, and novel drug classes. From the medical point of view, a broader use of the well-proven and effective therapies of arteriosclerosis and its complications is clearly warranted.

Arteriosclerosis↗
PubMed1996

Immunologic basis of transplant-associated arteriosclerosis.

Although immunosuppressive therapy minimizes the risk of graft failure due to acute rejection, transplant-associated arteriosclerosis of the coronary arteries remains a significant obstacle to the long-term survival of heart transplant recipients. The participation of specific inflammatory cell types in the genesis of this lesion was examined in a mouse model in which carotid arteries were transplanted across multiple histocompatibility barriers into seven mutant strains with immunologic defects. An acquired immune response--with the participation of CD4+ (helper) T cells, humoral antibody, and macrophages--was essential to the development of the concentric neointimal proliferation and luminal narrowing characteristic of transplant arteriosclerosis. CD8+ (cytotoxic) T cells and natural killer cells were not involved in the process. Arteries allografted into mice deficient in both T-cell receptors and humoral antibody showed almost no neointimal proliferation, whereas those grafted into mice deficient only in helper T cells, humoral antibody, or macrophages developed small neointimas. These small neointimas and the large neointimas of arteries grafted into control animals contained a similar number of inflammatory cells; however, smooth muscle cell number and collagen deposition were diminished in the small neointimas. Also, the degree of inflammatory reaction in the adventitia did not correlate with the size of the neointima. Thus, the reduction in neointimal size in arteries allografted into mice deficient in helper T cells, humoral antibody, or macrophages may be accounted for by a decrease in smooth muscle cell migration or proliferation.

Animals↗
PubMed2001

Effects of sarpogrelate hydrochloride on adenosine diphosphate- or collagen-induced platelet responses in arteriosclerosis obliterans.

To evaluate the effects of the 5-HT2 receptor antagonist sarpogrelate hydrochloride (sarpogrelate) on platelet responses in arteriosclerosis obliterans (ASO), we examined platelet aggregation and its relationships to platelet-derived growth factor (PDGF), soluble P-selectin (sP-selectin), and transforming growth factor-beta 1 (TGF-beta1). Circulating plasma levels of PDGF and sP-selectin in 13 patients with ASO after 1 week of medication with sarpogrelate were significantly lower than those before medication. In contrast, circulating plasma levels of TGF-beta1 after medication were significantly higher than those before medication. When platelet-rich plasma obtained from ASO patients after medication was stimulated with adenosine diphosphate (ADP) or collagen, platelet aggregation was suppressed compared with rates before medication. Significant decreases in levels of PDGF, sP-selectin and TGF-beta1 released from platelets in response to 5 micromol/l ADP and 1 microg/ml collagen after taking of sarpogrelate were found. There were close correlations between platelet aggregation and respective molecules released from platelets. In conclusion, since platelet activation is involved in pathogenesis of thrombotic disease, sarpogrelate may suppress the development of obstructive arteriosclerosis. PDGF and TGF-beta1, as well as sP-selectin, appear to be useful markers for clinical evaluation of anti-platelet drugs.

Adenosine Diphosphate↗
PubMed1997

Serum hepatocyte growth factor as a possible indicator of arteriosclerosis.

OBJECTIVE: To investigate the possible involvement of hepatocyte growth factor in arteriosclerotic lesions, by studying the relationship between serum concentrations of hepatocyte growth factor and grades of retinal arteriosclerosis. METHODS: We measured the blood pressure, body mass index, serum concentrations of total cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine, uric acid, total protein, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, gamma-glutamyltranspeptidase, alkaline phosphatase, and hepatocyte growth factor, erythrocyte counts, hemoglobin concentration, and hematocrit levels of 112 adults. Serum concentrations of hepatocyte growth factor were measured by a specific enzyme-linked immunosorbent assay. For each subject, photographs of both optic fundi were taken, and the grade of arteriosclerotic changes in the retinal arteries was evaluated according to Scheie's classification. RESULTS: Individuals with more advanced grades of arteriosclerotic changes had higher serum hepatocyte growth factor values (grade 0, 0.056 +/- 0.004 ng/ml, n = 86; grade 1, 0.132 +/- 0.026 ng/ml, n = 17, P < 0.01, versus grade 0; grade 2-3, 0.271 +/- 0.023 ng/ml, n = 9, P < 0.01, versus grades 0 and 1). The serum hepatocyte growth factor concentrations were also correlated significantly to the serum uric acid concentrations (r = 0.230, P = 0.015) and erythrocyte counts (r = 0.299, P = 0.001), but not to the systolic and diastolic blood pressures, and other physical and humoral parameters. CONCLUSIONS: Serum hepatocyte growth factor levels are thought to indicate the presence or development of arteriosclerotic lesions and may be a useful biochemical parameter for estimating the development of systemic arteriosclerosis irrespective of blood pressure levels.

Adult↗
PubMed1996

Ketanserin reduces graft arteriosclerosis after allogeneic aorta transplantation in rats.

The serotonin-2 receptor antagonist ketanserin has been suggested to diminish arteriosclerotic development by its effect on platelet function and on vascular smooth muscle cells. We investigated the ability of ketanserin in reducing immune-mediated arteriosclerosis using the BN-WAG and WAG-BN rat aortic transplantation models. Ketanserin (10 mg/kg/day) administered in drinking water significantly reduced posttransplant arteriosclerotic thickening of the intima in the BN-WAG rat model to 102 +/- 23 mu m as compared with 171 +/- 60 mu m in untreated BN-WAG allografts 8 weeks posttransplantation (p < 0.05). In the opposite WAG-BN combination, at 4 weeks posttransplantation, no significant reduction in intimal thickening was attained (112 +/- 42 vs. 152 +/- 49 mu m). Platelet aggregation to increasing amounts of collagen did not show a correlation between the effect of ketanserin on platelet function and reduction in intimal thickening. Ketanserin had no effect on systolic blood pressure or mononuclear cell infiltration. We conclude that ketanserin reduces graft arteriosclerosis by a mechanism other than by inhibition of platelet function, decrease in blood pressure, or immunosuppression. Because of this antiarteriosclerotic effect, ketanserin therapy might be beneficial to the long-term survival of vascular allografts.

Animals↗
PubMed1981

Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model.

Accelerated graft arteriosclerosis is a major cause of death in human heart transplantation. Despite many investigations, the pathogenesis of this disease remains undetermined and its control inadequate. In this study using a rat heart transplant model and cyclosporin A, a new immunosuppressant, acute rejection was prevented but arteriosclerotic-like vessel disease still developed consistently as early as 20 days postoperatively. The combination of cyclosporin A and dipyridamole prevented the development of this vessel disease in transplanted hearts at 20 and 50 days postoperatively. Sulfinpyrazone and cyclosporin A reduced but did not prevent the disease. These findings suggest that immunologically induced graft arteriosclerosis can be prevented in transplanted rat hearts by the combination of cyclosporin A and dipyridamole.

Animals↗
PubMed1993

Chronic rejection in the rat aortic allograft. V. Mechanism of the angiopeptin (BIM23014C) effect on the generation of allograft arteriosclerosis.

Synthetic cyclic octapeptide analogues of somatostatin, such as angiopeptin (BIM23014C; AP) inhibit myointimal proliferation in chronically rejecting rabbit and rat allografts and following angioplasty in rabbits. We have investigated the mechanism of angiopeptin inhibition of allograft arteriosclerosis. DA (RT1a) aortic allografts were transplanted to WF (RT1v) recipients, which either received 80 micrograms/kg/day of AP (Alzet mini-pumps, s.c., 0-180 days) or were left untreated. AP administration did not affect the intensity of adventitial inflammation, nor reduced the disappearance of smooth-muscle cell nuclei from the media (media necrosis); however, it reduced their appearance in the intima and intimal thickening. The effect disappeared, however, from the 3rd month onward. In vivo labeling with tritiated thymidine and autoradiograms demonstrated that AP reduced slightly the proliferation of the inflammatory cells in adventitia and of smooth-muscle cells in the media, and reduced strongly and significantly (P < 0.01) the proliferation of smooth-muscle cells in the intima. Analysis of the major chronic-rejection associated eicosanoids from the vascular wall showed that AP had no effect on the release of the pro-inflammatory thromboxane B2 from the allograft. As AP did not reduce the intensity of perivascular inflammation, reduced only slightly the proliferation of inflammatory cells, and did not affect the release of thromboxane B2 from the inflammatory macrophages, it is likely that the AP effect is not directed to the inflammatory cells. As previous in vitro studies have demonstrated that vascular smooth-muscle cells proliferate in response to several growth factors, and as somatostatin analogues are inhibitory to their action, our data suggest that the action of AP on allograft arteriosclerosis is due to a direct effect on smooth-muscle-cell proliferation.

Animals↗
PubMed2002

Correlation of chlamydia pneumoniae infection and severity of accelerated graft arteriosclerosis after cardiac transplantation.

BACKGROUND: Chlamydia pneumoniae has been associated with atherosclerosis, although its role in the process is not clearly defined. Heart transplant recipients are known to have high titers of antibodies to C. pneumoniae, and the organism has been recovered from the coronary arteries of both transplant recipients and donors. This study evaluated association between C. pneumoniae infection and accelerated graft arteriosclerosis (AGA), also known as cardiac allograft vasculopathy (CAV), after cardiac transplantation. METHODS: A case-control study was performed with 54 heart transplant recipients at the Johns Hopkins Hospital. Severe cases had >50% luminal narrowing on cardiac catheterization, mild cases <50% narrowing, and controls were free of arteriosclerotic disease. Blood specimens were examined for C. pneumoniae serology and DNA detection by polymerase chain reaction (PCR) assays. RESULTS: For every twofold increase in geometric mean C. pneumoniae immunoglobulin (Ig)G titer, the odds ratio for severe AGA versus controls was 3.13 (P=0.03) and for mild AGA versus control patients was 1.61 (P=0.45). On Kaplan-Meier survival analysis there was a nonsignificant trend toward faster development of CAV in patients with higher C. pneumoniae antibody titers. Overall, 29% of heart transplant patients evaluated had evidence of circulating C. pneumoniae DNA by PCR, without a statistical difference between groups. CONCLUSIONS: C. pneumoniae IgG titer correlates with severity of allograft arteriosclerosis after cardiac transplantation. Circulating C. pneumoniae DNA is detectable by PCR in up to 30% of cardiac transplant recipients, but this does not correlate with severity of allograft vasculopathy.

Adult↗