Splenic artery transposition for hepatic arterial reconstruction in a locally advanced pancreatic cancer: a case report and literature review.

OBJECTIVE: During pancreatic surgery for malignancies, hepatic revascularization is needed in case of en bloc resection with hepatic artery involvement. In these cases, the use of the splenic artery is described in the literature, including transposition and interposition techniques. PATIENTS AND METHODS: We report the case of pancreatic cancer resection with involvement of the right hepatic artery, anomalous arising from the superior mesenteric artery, and hepatic revascularization with splenic artery reconstruction. A literature review to analyze the use of splenic artery in hepatic revascularization during pancreatic cancer surgery was performed. RESULTS: A 61-year-old man with a 55-mm hypovascular tumor in the pancreatic head, in wide contact with the right hepatic artery, underwent total pancreatectomy and splenectomy. Right hepatic artery was resected, and the distal part of the splenic artery was transposed to the right hepatic artery with a termino-terminal anastomosis. Histopathological examination revealed R0 resection. CONCLUSIONS: Hepatic revascularization with splenic artery should be considered in patients suitable to extend resectability in pancreatic cancer surgery. A multidisciplinary approach and careful pre-operative planning are essential.

Management of mycotic aorto-iliac aneurysms: a 30-year monocentric experience.

OBJECTIVE: This study aims to analyze the early and late outcomes of our 30-year experience with mycotic aneurysms of the abdominal aorta and iliac arteries. PATIENTS AND METHODS: This retrospective cohort study compared the outcomes of all the patients with mycotic aneurysm, by analyzing prospectively collected data between September 1989 and October 2019 from the Unit of Vascular Surgery of Fondazione Policlinico Universitario Gemelli - IRCCS in Rome, Italy. RESULTS: Twenty-three patients with mycotic aneurysm were included. Twenty-two patients underwent surgery; one patient arrived at the emergency room with unstable clinical conditions and died before being treated. Fourteen cases (60.9%) were located at the infrarenal aorta, while three cases (13.0%) were pararenal aortic aneurysms. Six cases (26.1%) had an iliac arteries localization. Seventeen patients (77.3%) underwent open surgical repair aneurysmectomy with in situ reconstruction, while three cases (13.6%) underwent extra-anatomic revascularization. Three patients (13.6%) underwent the placement of an endoprosthesis, of whom two underwent hybrid procedures, and one EVAR. The latter underwent an early conversion to open repair due to a type I endoleak. The mean length of hospital stay was 35 ± 18.7 days. Five patients (22.7%) died in the immediate postoperative period. In the follow-up of 45.5 ± 41.3 months (range 2-156), we documented six deaths (35.3%), of whom two (11.8%) were aortic-related for a 34.8% overall aortic-related mortality. Eleven patients were alive, with an overall survival of 47.8%. CONCLUSIONS: Mycotic aneurysm is an extremely rare and varied pathology. Open surgical repair showed to be a safe approach because of a complete and aggressive debridement of local infected tissues, with an acceptable long-term mortality rate.

The potential role of quantitative digital subtraction angiography in evaluating type B chronic aortic dissection during TEVAR: preliminary results.

OBJECTIVE: To evaluate the role of quantitative digital subtraction angiography (Q-DSA) with parametric color coding (PCC) in assessing patients with type B chronic thoracic aortic dissection (TBCAD) during thoracic endovascular aortic repair (TEVAR) procedures. PATIENTS AND METHODS: A total of 11 patients electively treated in our Department for a TBCAD were retrospectively enrolled. All cases were treated with TEVAR for false lumen aneurysm of the thoracic descending aorta. For digital subtraction angiography (DSA) series post-processing, a newly implemented PCC algorithm was used to turn consecutive two-dimensional images into a single color-coded picture (syngo iFLOW, Siemens AG, Forchheim, Germany). In consensus reading, two clinicians experienced in vascular imaging evaluated the DSA series in blinded assessment and compared them to the color-coded images. PCC was assessed for its accuracy in identifying the true and false lumen as well as whether it could provide improved visualization in pre-deployment stent grafting and the final evaluation of treatment. RESULTS: PCC facilitated the visualization of the aortic dissection angioarchitecture in terms of contemporary true and false lumen vision in 81.8% of the cases. In 72.7% of the procedures, Q-DSA was estimated to improve aorta information assessment in terms of false lumen viewing, and it was possible to identify the proximal entry tear position in 45.4% of the cases. After stent graft deployment, in 72.7% of the cases (all 8 patients in which the aortic arch false lumen was visible in pre-treatment), Q-DSA confirmed the absence of early false lumen reperfusion. CONCLUSIONS: Our results indicate that Q-DSA could be useful in the intraprocedural evaluation of patients with aortic dissection during TEVAR procedures without additional x-ray costs and contrast exposure.

Analysis of Italian regulations on pathways of care for patients in a vegetative or minimally conscious state.

Different rehabilitation models for persons diagnosed with disorders of consciousness have been proposed in Europe during the last decade. In Italy, the Ministry of Health has defined a national healthcare model, although, to date, there is a lack of information on how this has been implemented at regional level. The INCARICO project collected information on different regional regulations, analysing ethical aspects and mapping care facilities (numbers of beds and medical units) in eleven regional territories. The researchers found a total of 106 laws; differences emerged both between regions and versus the national model, showing that patients with the same diagnosis may follow different pathways of care. An ongoing cultural shift from a treatment-oriented medical approach towards a care-oriented integrated biopsychosocial approach was found in all the welfare and healthcare systems analysed. Future studies are needed to explore the relationship between healthcare systems and the quality of services provided.

Effect of gestational hypercholesterolaemia on omental vasoreactivity, placental enzyme activity and transplacental passage of normal and oxidised fatty acids.

OBJECTIVE: Maternal hypercholesterolaemia during pregnancy increases lipid peroxidation in mothers and fetuses and programs increased susceptibility to atherosclerosis later in life. The objective of this study was to elucidate the role of the placenta in mediating oxidative stress from mother to offspring. DESIGN: Comparison between normo- and hypercholesterolaemic mothers (n = 36 each) and their children. SETTING: Obstetric wards, hospitals of the University of Naples and Regione Campania. POPULATION: Healthy primiparas delivering by caesarean section. METHODS: Biochemical measurements of oxidative stress and serum leptin in cord plasma and placenta, immunochemistry of placenta microvessels, and vasoreactivity studies were performed. MAIN OUTCOME MEASURES: Oxidative status (i.e. lipid composition and content of oxidised fatty acids, activity of pro- and antioxidant enzymes, immunohistochemical presence of oxidation-specific epitopes) in maternal and cord blood and in placental tissue, as well as vascular reactivity in omental arteries. RESULTS: Hypercholesterolaemia during pregnancy was associated with extensive changes in fatty acid composition of both maternal and cord blood lipids, sufficient to alter vasoreactivity of omental vessels. Results also indicated that the placenta is not only subject to substantial oxidative stress, but that it may further increase fetal oxidative stress through changes of pro- and antioxidant enzyme activities. CONCLUSIONS: The placenta plays an important role in both transmitting and enhancing pathogenic effects of gestational hypercholesterolaemia.

Cooperation between Myc and YY1 provides novel silencing transcriptional targets of alpha3beta1-integrin in tumour cells.

We show that human osteosarcoma cells (Saos-2) have downregulation of alpha3beta1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The alpha3 gene was silenced in Saos-2 cells causing a low expression of alpha3beta1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on alpha3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the alpha3 gene. This silencing mechanism involves the binding of Myc and YY1 to DNA and formation of complexes among Myc/Max, YY1, CREB-binding protein and deacetylation activity. The promoter containing deletions of E-boxes or YY1 cassettes failed to downregulate the transcription of a reporter gene as well as the inhibition of deacetylation activity. Overexpression of both Myc and YY1 was necessary to determine the alpha3-integrin promoter downregulation in normal osteoblasts. This downregulation of alpha3beta1-integrin can contribute to the acquisition of a more aggressive phenotype. YY1 regulated negatively the Myc activity through a direct interaction with the Myc/Max and deacetylase complexes. This represents a novel silencing mechanism with broad implications in the transcription machinery of tumours.

In vivo veritas: thrombosis mechanisms in animal models.

Experimental models have enhanced our understanding of atherothrombosis pathophysiology and have played a major role in the search for adequate therapeutic interventions. Various animal models have been developed to simulate thrombosis and to study in vivo parameters related to hemodynamics and rheology that lead to thrombogenesis. Although no model completely mimics the human condition, much can be learned from existing models about specific biologic processes in disease causation and therapeutic intervention. In general, large animals such as pigs and monkeys have been better suited to study atherosclerosis and arterial and venous thrombosis than smaller species such as rats, rabbits, and dogs. On the other hand, mouse models of arterial and venous thrombosis have attracted increasing interest over the past two decades, owing to direct availability of a growing number of genetically modified mice, improved technical feasibility, standardization of new models of local thrombosis, and low maintenance costs. To simulate rupture of an atherosclerotic plaque, models of arterial thrombosis often involve vascular injury, which can be achieved by several means. There is no animal model that is sufficiently tall, that can mimic the ability of humans to walk upright, and that possesses the calf muscle pump that plays an important role in human venous hemodynamics. A number of spontaneous or genetically engineered animals with overexpression or deletion of various elements in the coagulation, platelet, and fibrinolysis pathways are now available. These animal models can replicate important aspects of thrombosis in humans, and provide a valuable resource in the development of novel concepts of disease mechanisms in human patients.

New trends in anti-atherosclerotic agents.

New approaches to atherosclerosis-related diseases include novel uses of proven treatments and development of innovative agents. Several commonly used cardiovascular drugs such as dihydropyridine calcium antagonists, ACE inhibitors containing the sulphydryl group, or highly lipophilic beta-blockers have some anti-atherosclerotic activities. Moreover, new clinical trials suggesting that additional reduction of low-density lipoprotein cholesterol levels with statin therapy results in additional benefit in coronary heart disease prevention. Notably, new cholesterol transport or bile acid transport inhibitors have been found to produce significant reductions in intestinal cholesterol absorption and experimental atherosclerosis. Inhibitors of acyl coenzyme A:cholesterol acyltransferase, which can reduce cholesterol storage in macrophages and in arterial lesions, have also been developed. Finally, newer therapeutical strategies against atherogenesis may include the use of antioxidants and cholestyramine during pregnancy or the development of metalloproteinase inhibitors.

Sulfhydryl angiotensin-converting enzyme inhibition induces sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension.

BACKGROUND: Essential hypertension is associated with enhanced LDL oxidation and impaired endothelium-dependent vasodilation. The antioxidant status is linked to the nitric oxide (NO) pathway. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors inhibit oxidative stress and atherogenesis in experimental models; therefore we tested whether this beneficial antioxidant activity could be also clinically relevant in patients with essential hypertension. METHODS: Plasma LDL oxidizability was investigated initially in untreated normocholesterolemic patients with moderate essential hypertension without clinically evident target organ damage (n = 96) and in control normotensive subjects (n = 46). Patients were then randomly assigned into two age- and sex-matched groups to receive the new sulfhydryl ACE inhibitor zofenopril (15 to 30 mg/d; n = 48) or enalapril (20 mg/d, n = 48). LDL oxidizability was evaluated (generation of malondialdehyde, MDA) and systemic oxidative stress was evaluated by isoprostanes (8-isoPGF2alpha). Asymmetrical dimethyl-L-arginine (ADMA), a competitive inhibitor of endothelial NO synthase, and plasma nitrite and nitrates (NOx) were also measured. RESULTS: LDL from hypertensive subjects had enhanced susceptibility to oxidation in vitro compared with that in control subjects (P <.05). Similarly, isoprostanes were significantly increased (P <.01) in hypertensive subjects versus control subjects. After 12-week treatment, MDA levels were significantly reduced by zofenopril (P <.05) but not enalapril treatment (P = not significant). Isoprostanes were normalized after zofenopril treatment (P <.03), whereas enalapril was ineffective. After treatment with both ACE inhibitors, plasma NOx concentrations were significantly reduced (P <.05). Similarly, hypertension increased ADMA concentration compared with the normotensive state, whereas ACE inihibition elicited a significant decrease. However, the reduction of ADMA concentration was significantly higher in patients receiving sulfhydryl ACE inhibition (P <.05 vs enalapril). CONCLUSIONS: The sulfhydryl ACE inhibitor zofenopril reduces oxidative stress and improves the NO pathway in patients with essential hypertension. If confirmed in a large multicenter clinical trial, our data suggest a possible vasculoprotective effect of the compound in retarding vascular dysfunction and atherogenesis that often develops rapidly in hypertensive patients.

Evidence that protease activated receptor 2 expression is enhanced in human coronary atherosclerotic lesions.

AIM: To investigate protease activated receptor 2 (PAR-2) expression in human coronary atherosclerotic lesions because PAR-2 is involved in the modulation of inflammatory events and vascular function. METHODS: An immunohistochemical analysis was performed on serial arterial sections, using the following antibodies: MDA2, a murine monoclonal antibody against malondialdehyde lysine epitopes of oxidised low density lipoprotein (oxLDL); HAM-56, a monoclonal antibody against human macrophages/foam cells; B5, a rabbit polyclonal antibody against PAR-2; and SAM11, a mouse monoclonal antibody against human PAR-2. Sections containing at least one lesion showing substantial immunostaining were counted as positive, and results were expressed as per cent of all sections of the same artery. RESULTS: PAR-2 expression was enhanced in human coronary atherosclerotic lesions. This phenomenon correlated with an increase in oxLDL epitopes in the coronary artery. CONCLUSION: This study shows for the first time that PAR-2 expression is enhanced in human coronary atherosclerotic lesions, and suggests that PAR-2 dependent cellular trafficking may be one of the regulatory signalling responses to vascular injury. Further pharmacological studies will establish whether modulation (and in which direction) of PAR-2 represents a possible therapeutic target for controlling the vascular response to injury.

Review article: maintenance treatment of Crohn's disease.

The aetiology of Crohn's disease is unknown and therefore no curative treatments are available for the disease. The natural history of Crohn's disease is characterized by recurrent flare-ups of symptoms. Several drug treatments are effective in inducing clinical remission. However, no drug treatments are available in order to prevent clinical relapses, although several drug regimens may delay clinical flare-ups. Crohn's disease treatment for maintaining clinical remission needs to be tailored in relation to specific characteristics of each patient. The frequency of clinical relapse indeed shows marked variations in subgroups of patients, as the likelyhood of relapse is higher in patients in clinical remission for less than 6 months. Treatment strategies for maintaining remission may therefore differ among inactive patients. In chronically active, steroid-dependent or steroid-refractory Crohn's disease patients immunomodulatory drugs (azathioprine 2-2.5 mg/kg by mouth, 6-mercaptopurine 1-1.5 mg/kg by mouth, or methotrexate 15-25 mg/i.m./week) should be added to oral mesalazine (2.4 g/day), while in long-term inactive Crohn's disease patients mesalazine alone may be effective in delaying relapse. Recently, treatment with anti-tumour necrosis factor-alpha monoclonal antibodies (Infliximab or CDP571) has shown efficacy in delaying relapse in responsive patients. One other issue which needs to be considered before selecting drug treatments for maintaining remission in Crohn's disease, is that Crohn's disease activity is currently assessed on the basis of standard clinical scores which may not appropriately reflect the biological activity of the disease. Clinical remission as defined by standardized scores may include heterogeneous subgroups of patients showing different endoscopic and histological activity or persistence of activated immunocompetent cells within the gut. Several sub-clinical markers of relapse have indeed been reported in quiescent Crohn's disease, although their usefulness in clinical practice in currently uncertain.

Microarray analysis: a novel research tool for cardiovascular scientists and physicians.

The massive increase in information on the human DNA sequence and the development of new technologies will have a profound impact on the diagnosis and treatment of cardiovascular diseases. The microarray is a micro-hybridisation based assay. The filter, called microchip or chip, is a special kind of membrane in which are spotted several thousands of oligonucleotides of cDNA fragments coding for known genes or expressed sequence tags. The resulting hybridisation signal on the chip is analysed by a fluorescent scanner and processed with a software package utilising the information on the oligonucleotide or cDNA map of the chip to generate a list of relative gene expression. Microarray technology can be used for many different purposes, most prominently to measure differential gene expression, variations in gene sequence (by analysing the genome of mutant phenotypes), or more recently, the entire binding site for transcription factors. Measurements of gene expression have the advantage of providing all available sequence information for any given experimental design and data interpretation in pursuit of biological understanding. This research tool will contribute to radically changing our understanding of cardiovascular diseases.

Renal blood flow in hypercholesterolemic pigs is increased by chronic antioxidant treatment.

Oxygen radical species can influence vascular tone, and antioxidants may have hemodynamic and vascular effects. To date, the vascular effects of chronic intervention with a combination of antioxidant vitamins E and C on renal blood flow (RBF) in hypercholesterolemia (which increases oxidative stress) have not been fully defined. The aim of this intervention study was to explore the involvement of increased oxidative stress in pig RBF disturbance by using chronic dietary antioxidant vitamin intervention. Responses of RBF to the acetylcholine (Ach) were measured in vivo using electron beam computed tomography (EBCT). Acetylcholine significantly increased RBF in normal and hypercholesterolemic + vitamins (P < 0.05 for both), but not in hypercholesterolemic pigs (P=0.1). In normocholesterolemic + vitamins pigs, Ach infusion did not induce any further increase in RBF, but RBF was similar to that observed in normal and hypercholesterolemic + vitamins under the same conditions, and tended to be higher than in hypercholesterolemic pigs (P=0.06). Thus, antioxidants improve RBF in hypercholesterolemic pigs and this effect may help to prevent renal diseases and hypertension in animals.

Review article: monitoring the activity of Crohn's disease.

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-alpha and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.

Isolation of a SIR-like gene, SIR-T8, that is overexpressed in thyroid carcinoma cell lines and tissues.

We used subtractive library screening to identify the changes that occur in gene expression during thyroid cell neoplastic transformation. Complementary DNA from normal thyroid cells (HTC 2) was subtracted from a complementary DNA library constructed from a human thyroid papillary carcinoma cell line. The library was screened for genes upregulated in human thyroid papillary carcinoma cell line cells, and several cDNA clones were isolated. One of these clones has a sirtuin core and high homology with the human silent information regulator protein family. This clone, designated "SIR-T8", was overexpressed in human thyroid carcinoma cell lines and tissues, but not in adenomas. The human SIR-T8 protein has a molecular weight of 39 kDa and is primarily located in the cytoplasm under the nuclear membrane. The SIR-T8 gene is located on chromosome 17q25-1.

Chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma LDL to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein E knockout mice.

The effects of chronic treatment with the new sulfhydryl angiotensin-converting enzyme (ACE)-inhibitor, zofenopril, in comparison with the classical sulfhydryl ACE-inhibitor captopril or enalapril or placebo on the development of atherosclerosis were determined in apolipoprotein-E knockout (apoE(-/-)) mice. Groups of 2-month-old male mice received either placebo (N=10), 0.05 mg/kg/day of zofenopril (N=10), 1 mg/kg/day of zofenopril (N=10), 5 mg/kg/day of captopril (N=10) or 0.5 mg/kg/day of enalapril (N=8). After 29 weeks of treatment, computer-assisted imaging analysis revealed that zofenopril reduced the aortic cumulative lesion area by 78% at 0.05 mg/kg/day and by 89% at 1 mg/ml/day of zofenopril compared to that of the placebo (P<0.0001). Captopril reduced by 52% aortic lesions compared to placebo (P<0.01 vs. placebo; P<0.05 vs. zofenopril at both doses). Enalapril did not reduce aortic lesions. Furthermore, 0.05 mg/kg/day of zofenopril reduced susceptibility of plasma LDL to in vitro oxidation compared to captopril, enalapril or placebo, as shown by significant reduction of malondialdehyde content (P<0.001 vs. placebo or enalapril; P<0.05 vs. captopril), as well as by the prolongation of lag-time (P<0.01 vs. placebo or enalapril P<0.05 vs. captopril). More importantly, mice treated with 1 mg/ml/day of zofenopril had a significant decrease in the intimal immunohistochemical presence of oxidation-specific epitopes on oxLDL (NA59 monoclonal antibody, P<0.01), macrophages derived foam cells (F4/80 monoclonal antibody, P<0.05) and native LDL (NP monoclonal antibody, P<0.01) compared to placebo, captopril or enalapril. Thus, chronic treatment with the new sulfhydryl ACE-inhibitor zofenopril has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic apoE(-/-) mice. This protection was significantly higher than that reached with captopril and at lower doses of the drug. Treatment with 0.5 mg/kg/day of enalapril did not provide any protective effect.

Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis occurs later and is less extensive in intracranial arteries than in extracranial arteries. However, the mechanisms responsible are poorly understood. A previous study has suggested a better antioxidant protection of intracranial arteries. METHODS: To assess the influence of age on arterial activity of antioxidant enzymes and atherogenesis, we compared intracranial and extracranial arteries of humans of different ages who retrospectively lacked confounding classic risk factors (48 premature fetuses aged 6.4+/-0.8 months [mean+/-SD], 58 children aged 7.9+/-3.8 years, 42 adults aged 42.5+/-5.1 years, and 40 elderly subjects aged 71.8+/-3.4 years; all males). Lesions were quantified by computer-assisted imaging analysis of sections of the middle cerebral and basilar arteries, the left anterior descending coronary artery, the common carotid artery, and the abdominal aorta. Macrophages, apolipoprotein B, oxidized LDL, and matrix metalloproteinase-9 in lesions were determined by immunocytochemistry. The effect of aging on atherogenesis was then compared with that on the activity of 4 antioxidant enzymes in the arterial wall. RESULTS: Atherosclerosis was 6- to 19-fold greater (P<0.01) in extracranial arteries than in intracranial arteries, and it increased linearly with age. Intracranial arteries showed significantly greater antioxidant enzyme activities than did extracranial arteries. However, the antioxidant protection of intracranial arteries decreased significantly in older age, coinciding with a marked acceleration of atherogenesis. An increase in matrix metalloproteinase-9 protein expression and in gelatinolytic activity consistent with the degree of intracranial atherosclerosis was also observed. CONCLUSIONS: These results suggest that a greater activity of antioxidant enzymes in intracranial arteries may contribute to their greater resistance to atherogenesis and that with increasing age intracranial arteries respond with accelerated atherogenesis when their antioxidant protection decreases relatively more than that of extracranial arteries.

Maternal hypercholesterolemia and treatment during pregnancy influence the long-term progression of atherosclerosis in offspring of rabbits.

Maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in human fetuses and faster progression of atherosclerosis during childhood even under normocholesterolemic conditions. A causal role of maternal hypercholesterolemia in lesion formation during fetal development has previously been established in rabbits. The same experimental model is now used to establish that maternal hypercholesterolemia or ensuing pathogenic events in fetal arteries enhance atherogenesis later in life. Five groups of rabbit mothers were fed chow, cholesterol-enriched chow, or cholesterol-enriched chow plus 1000 IU vitamin E, 3% cholestyramine, or both during pregnancy. Offspring of all groups (n=136) were fed a mildly hypercholesterolemic diet for up to a year and had similar cholesterol levels. Aortic lesion sizes and lipid peroxidation products in plasma and lesions in offspring were determined at birth, 6 months, or 12 months. Lesion progression in offspring of hypercholesterolemic mothers was greater than in all other groups. At each time point, offspring of hypercholesterolemic mothers had 1.5- to 3-fold larger lesions than offspring of normocholesterolemic mothers (P<0.01), with the greatest absolute differences at 12 months. Maternal treatment reduced lesions by 19% to 53%, compared with offspring of untreated hypercholesterolemic mothers (P<0.01), with the greatest effect in the vitamin E groups. At 12 months, lesions in offspring of all vitamin E and cholestyramine-treated mothers were similar to those of normocholesterolemic mothers. Lipid peroxidation end-products in lesions and plasma showed analogous differences between groups as lesions (P<0.01). Thus, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering drugs or antioxidants reduce postnatal lipid peroxidation and atherosclerosis in their offspring.