Vascular, cardiac, and renal lesions attributed to primary systemic hypertension in western pygmy marmosets (Cebuella pygmaea).

In a retrospective study of a western pygmy marmoset (Cebuella pygmaea) colony, postmortem examination of 1/8 juvenile and 29/47 adult animals identified vascular, cardiac, and renal lesions consistent with systemic hypertension. This included frequent renal arteriolar hypertrophy, hyaline and proliferative arteriolosclerosis, fibrinoid necrosis of arterioles, glomerulosclerosis, and nephrosclerosis. Affected animals ranged from 0.6 to 12 years of age (mean 6 years) and had an observed male predominance. Genealogical relatedness was evident in several breeding pairs and spanned multiple generations. Concurrent cardiac and renal disease was commonly identified, although frequently subclinical, and both were important causes of morbidity and mortality in affected animals. Cardiomegaly and hypertrophy were typical features and were accompanied by left atrial thrombosis in 10 animals. Signs of heart failure included chronic pulmonary edema in 20 cases and body cavity effusions in 17. In the kidneys, 19 cases had glomerular disease and hypertensive vasculopathy, and 26 cases had nephrosclerosis or glomerulosclerosis. Common extrarenal secondary causes of hypertension were excluded by necropsy examination. The pathogenesis is suggested to involve primary hypertension leading to renal and cardiac disease. Elevated sympathetic activity might be an underlying factor in the frequent development of primary systemic hypertension in the pygmy marmoset, as for the owl monkey.

Hyaline Arteriolosclerosis in 30 Strains of Aged Inbred Mice.

During a screen for vascular phenotypes in aged laboratory mice, a unique discrete phenotype of hyaline arteriolosclerosis of the intertubular arteries and arterioles of the testes was identified in several inbred strains. Lesions were limited to the testes and did not occur as part of any renal, systemic, or pulmonary arteriopathy or vasculitis phenotype. There was no evidence of systemic or pulmonary hypertension, and lesions did not occur in ovaries of females. Frequency was highest in males of the SM/J (27/30, 90%) and WSB/EiJ (19/26, 73%) strains, aged 383 to 847 days. Lesions were sporadically present in males from several other inbred strains at a much lower (<20%) frequency. The risk of testicular hyaline arteriolosclerosis is at least partially underpinned by a genetic predisposition that is not associated with other vascular lesions (including vasculitis), separating out the etiology of this form and site of arteriolosclerosis from other related conditions that often co-occur in other strains of mice and in humans. Because of their genetic uniformity and controlled dietary and environmental conditions, mice are an excellent model to dissect the pathogenesis of human disease conditions. In this study, a discrete genetically driven phenotype of testicular hyaline arteriolosclerosis in aging mice was identified. These observations open the possibility of identifying the underlying genetic variant(s) associated with the predisposition and therefore allowing future interrogation of the pathogenesis of this condition.

Potential role of Anitschkow cells in cardiovascular disease in human and veterinary medicine: A review of the literature.

Anitschkow cells (AC) are a peculiar type of stromal cells observed in myocardium, cardiac valves and coronary vessels wall whose origin, characterization and role remain controversial. In human heart, they represent a histological hallmark of Aschoff nodules in rheumatic fever, but they have also been observed in other myocardial pathologies. Firstly, they have been considered a myocyte-derived cells, but light microscopy, immunohistochemical and ultrastructural studies pointed out that a macrophagic/histiocytic origin cannot be excluded. Many authors also reported extracardiac AC or an Anitschkow nuclear pattern, thus suggesting that these cells may represent a chromatin pattern rather than a specific cell type. In veterinary medicine, AC were described in myocarditis, myocardial necrosis, degenerative and inflammatory endocardial diseases of several species. Recently, AC have been observed in intramural coronary arteries of different animals (including cattle and fish) affected by arteriosclerotic processes. Stress related to the intensive livestock farming could represent a mechanotransduction promoting factor of arteriosclerotic changes allowing the development of Anitschkow chromatin pattern. Further studies both in human and veterinary medicine are needed to confirm the origin and role of these peculiar cells.

Arteriosclerosis in the ventral aorta and epicarditis in the bulbus arteriosus of Atlantic salmon (Salmo salar L).

Spontaneous mortality of seemingly healthy, farmed Atlantic salmon (Salmo salar L) is an increasing problem in Norwegian aquaculture. In this study, we present a morphological study of the previously undescribed syndrome of arteriosclerosis of the ventral aorta and epicarditis of the adjacent bulbus arteriosus found in farmed Atlantic salmon, with wild-captured fish as a control group. Both the ventral aorta and epicardium are vital for correct arterial compliance and vascular resistance in the respiratory capillaries of the gills. We discuss the possible implications of ventral aorta arteriosclerosis and epicarditis for blood vascular health and in particular for the increasing frequency of spontaneous gill bleeding in farmed salmon. As both these conditions primarily occur in farmed salmon, we suggest that they should be considered pathological.

Soft Tissue Mineralization in Captive 2-Toed Sloths.

Soft tissue mineralization was diagnosed in 19 captive 2-toed sloths (Choloepus didactylusandCholoepus hoffmanni) ranging from 2 months to 41 years of age. Gross mineralization was evident at necropsy in 6 of 19 sloths and was prominent in the aorta and arteries. Histologically, 11 sloths had arterial mineralization, including mural osseous and chondroid metaplasia and smooth muscle hyperplasia consistent with arteriosclerosis. Visceral mineralization most commonly involved the gastric mucosa (17 sloths), kidneys (17 sloths), and lungs (8 sloths). Eleven sloths ranging in age from 5 to 41 years old had moderate to severe renal disease, which may be an important underlying cause of soft tissue mineralization in adult sloths. However, 5 sloths (juveniles and adults) had severe soft tissue mineralization with histologically normal kidneys or only mild interstitial inflammation or fibrosis, suggesting other causes of calcium and phosphorus imbalance. Degenerative cardiac disease was a common finding in 10 sloths with vascular mineralization and varied from mild to severe with fibrosis and acute noninflammatory myocardial necrosis. Although the prevalence of cardiac disease in adult sloths has not been documented, disease may be exacerbated by hypertension from degenerative arteriosclerosis as noted in this study group. Although renal disease likely contributed substantially to mineralization of tissues in most sloths in this study, nutritional causes of soft tissue mineralization-such as imbalances in dietary vitamin D or calcium and phosphorus-may be an important contributing factor.

Caracterización del pollo como biomodelo experimental en arteriosclerosis: lesiones en troncos supra-aórticos / Use of the chicken as experimental biomodel in atherosclerosis: supra-aortic lesions

La enfermedad cardiovascular es hoy en día la primera causa de mortalidad en las sociedades desarrolladas. Dada la complejidad del desarrollo de la lesión aterosclerótica en el ser humano resulta interesante investigar en modelos animales en los que dicho proceso sea semejante a la enfermedad humana. El pollo, al igual que otras aves, es capaz de desarrollar arteriosclerosis aórtica y coronaria de forma natural o espontánea, e inducida por una dieta enriquecida en colesterol. Teniendo en cuenta que la mayoría de los trabajos publicados describen las lesiones en segmentos aórticos y la variedad de métodos de inducción de la arteriosclerosis, el objetivo de esta investigación es caracterizar de manera adecuada en el modelo aviar utilizado, las lesiones arterioscleróticas de troncos supra-aórticos en un grupo experimental con respecto a un grupo control. Se emplearon 20 pollos de la raza White Leghorn divididos en dos grupos (control y aterogénico) que recibían una dieta normal o hiperlipémica respectivamente durante un periodo de 6 meses. Se sacrificaron entonces los animales para llevar a cabo el estudio bioquímico del plasma (perfil lipídico), evaluación histológica de los troncos supra-aórticos y valoración semicuantitativa de las lesiones según la clasificación de Stary. Se observaron diferencias estadísticamente significativas entre ambos grupos para los diferentes parámetros bioquímicos estudiados y para la cuantificación del grado de lesión de Stary. En el grupo aterogénico se observó un endotelio conservado, con íntimas muy aumentadas de tamaño (10 veces el tamaño del grupo control) y muy desorganizadas. En conclusión, estos hallazgos confirman el uso del pollo como biomodelo experimental para el estudio de la arteriosclerosis en troncos supra-aórticos, y podrían ser empleados como referencia para futuros estudios intervencionistas(AU)

Cardiovascular diseases are considered first cause of human mortality in developed countries. Animal models allow adequate research of atherosclerosis, given the similarities with the human lesions. Chickens may develop spontaneous and also induced atherosclerosis by use of a cholesterol-enriched diet. Most published findings describe aortic lesions in a variety of induction methods. Therefore, the aim of this research is to characterize the used avian model, describing supra-aortic trunk lesions in atherosclerotic chickens and to compare it with control animals. Twenty White Leghorn chickens were used (10 controls fed with a normal diet and 10 atherogenic animals fed with a hyperlipidemic diet, for 6 months). After sacrifice, lipid biochemical parameters were analysed, as well as histologic evaluation of supra-aortic vessels and quantification of lesions following the Stary classification. Statistically significant differences for each parameter were observed between the control and experimental groups. Increased intima layer width with disorganization was observed in atherogenic animals. These findings confirm the use of the chicken as an adequate experimental animal for atherosclerosis, and could be used as a reference for future interventional studies(AU)

El conejo como modelo de experimentación. Inducción de lesión vascular: técnica e incidencias / The rabbit as an experimental model: technique for the induction of vascular lesions and incidents

Objetivo: Describir el proceso para conseguir la lesión aterogénica en el conejo, mostrar el daño vascular producido por 2 catéteres de balón de diferente calibre y el valor de la ecografía para su cuantificación. Material y métodos: Se emplearon 36 conejos. Se estudiaron los valores de triglicéridos y colesterol, y se realizó una ecografía de aorta e ilíacas. Se realizó una arteriografía y se indujo la lesión vascular denudando la arteria ilíaca izquierda con catéter de balón: grupo A, catéter-balón 2,5mm, y grupo B catéter-balón 3mm de diámetro. Tras 8 semanas con dieta hiperlipídica se realizaron nuevas mediciones bioquímicas y ecográficas. Resultados Colesterol antes de la dieta 37,96±19,3mg/dl, y tras la dieta 1.761±296,91mg/dl. Los hallazgos ecográficos mostraron un diámetro de la aorta de 4,1±0,7mm, de la arteria ilíaca derecha de 3±0,3mm, de la arteria ilíaca izquierda de 3±0,4mm. Tras el daño vascular y 8 semanas de dieta, en el grupo A la luz de la aorta era de 2,78±1,21mm, la arteria ilíaca derecha medía 2,18±0,81mm y la arteria ilíaca izquierda 1,16±0,63mm; en el grupo B la luz de la aorta fue de 3,07±1,06mm, la arteria ilíaca derecha 2,53 ± 0,9mm y la arteria ilíaca izquierda 1,39±1,1mm. Resultados: Murieron 4 conejos y de los 32 restantes hubo más morbimortalidad con el catéter de balón de 3 mm. Conclusión Tras la denudación con catéter de balón y dieta los conejos desarrollan estenosis de la arteria. El daño con catéter de 2,5 mm de diámetro disminuye las complicaciones (AU)

Objective: To describe the process for inducing atherogenic lesions in rabbits, to show the damage to vessels caused by two different caliber balloon catheters, and to show the usefulness of ultrasonography in the quantification of vascular damage. Material and methods: We used 36 rabbits. We studied the levels of triglycerides and cholesterol and examined the aorta and iliac arteries by ultrasonography. We performed arteriography and induced a vascular lesion by denuding the left iliac artery with a balloon catheter: group A 2.5mm diameter balloon catheter, group B 3mm diameter balloon catheter. After 8 weeks on a hyperlipidic diet, biochemical and ultrasonographic measurements were repeated. Results: Cholesterol before the diet: 37.96±19.3mg/dL and after the diet: 1761±296.91mg/dL. The baseline ultrasonographic measurements of vessel diameter were: aorta 4.1±0.7mm, right iliac artery 3±0.3mm, left iliac artery 3±0.4mm. After vascular damage and 8 weeks hyperlipidic diet, in group A the ultrasonographic measurements of vessel diameter were: aortic lumen 2.78±1.21mm, right iliac artery 2.18±0.81mm, and the left iliac artery 1.16±0.63mm; in group B, the aortic lumen measured 3.07±1.06mm, the right iliac artery 2.53±0.9mm, and the left iliac artery 1.39±1.1mm. Results: Four rabbits died; in the 32 remaining rabbits, morbidity was higher with a 3mm balloon catheter. Conclusion: After denudation with a balloon catheter and a hyperlipidic diet, the rabbits developed arterial stenosis. The damage with a 2.5mm diameter catheter reduces complications (AU)

Efecto vasodilatador in vitro de la cafeína en aorta de conejos ateroscleróticos / In-vitro vasodilator effect of caffeine in atherosclerotic aorta rabbits

Introducción. Se desconocen los efectos directos de la cafeína en arterias con disfunción endotelial y aterosclerosis. Objetivo. Evaluar los efectos vasoactivos in vitro de la cafeína en anillos de aorta de conejos ateroscleróticos. Metodología. La aterosclerosis fue inducida en conejos (n = 10) alimentados con dieta aterogénica (1% colesterol, durante 16 semanas) (grupo 1). El grupo control (n = 10) recibió una dieta estándar libre de colesterol (grupo 2). Al final de las 16 semanas, se sacrificó a los animales y se determinó el colesterol sérico. Los estudios de reactividad vascular y análisis morfométrico se llevaron a cabo en anillos de aorta torácica. Se estudió la reactividad vascular en respuesta a la acetilcolina, la nitroglicerina y la cafeína a 3 dosis correspondientes al contenido de esta sustancia de 1, 2 y 3 triples cafés expresso. Resultados. La relajación máxima a la acetilcolina en arterias de conejos sanos (22,5 ± 16,8%) fue mayor que en arterias de conejos ateroscleróticos (3,6 ± 3,7%; p = 0,006). Aunque el efecto vasodilatador de la cafeína fue dependiente de la concentración (p < 0,001), no se encontraron diferencias entre las arterias provenientes de conejos sanos (75,73 ± 11,20%) y las de conejos ateroscleróticos (68,19 ± 15,07%; p = 0,238). La nitroglicerina produjo una relajación menor que la cafeína, tanto en arterias de conejos sanos (32,78 ± 12,30%), como en las de conejos enfermos (73,48 ± 18,93%; p < 0,001). El EC50 (concentración del agente vasodilatador que causa un 50% de relajación) fue similar para los 2 vasodilatadores (p = 0,178). Las lesiones aórticas en el grupo 1 consistieron en placas tempranas. El recubrimiento endotelial (CD31) fue del 92,2 ± 5,6% y el 92 ± 4,8%, respectivamente (p = 0,927). Conclusiones. La cafeína ejerce un potente efecto vasodilatador arterial in vitro, independiente de la presencia o la ausencia de aterosclerosis (AU)

Introduction. The effects of caffeine on arteries with endothelial dysfunction and atherosclerosis are unknown. Objective. To evaluate the in-vitro vasoactive effects of caffeine on aortic rings from atherosclerotic rabbits. Methodology. Atherosclerosis was induced in rabbits (n = 10) fed an atherogenic diet (1% cholesterol) (group 1). The control group (n = 10) received a cholesterol-free diet (group 2). At 16 weeks we evaluated serum cholesterol, and all the animals were sacrificed. Thoracic aorta rings were obtained for vasoreactivity studies and morphometric analyses. Agonists were nitroglycerine, acetylcholine, and caffeine at 3 doses corresponding to one, 2 and 3 triple espressos. Results. Arterial relaxation with acetylcholine in arteries from healthy rabbits (22.5 ± 16.8%) was greater than in arteries from atherosclerotic rabbits (3.6 ± 3.7%; p = 0.006). Although the vasodilator effect of caffeine was dependent on the concentration (p < 0.001), no differences were found between arteries from healthy rabbits (75.73 ± 11.20%) and those from diseased rabbits (68.19 ± 15.07%; p = 0.238). Nitroglycerine generated less relaxation than caffeine, both in arteries from healthy rabbits (32.78 ± 12.30%) and from diseased rabbits (73.48 ± 18.93%; p < 0.001). The EC50 (half maximal effective concentration) was similar for both vasodilators (p = 0.178). The aortic lesions in group 1 consisted of early plaques. The endothelial covering (CD31) was 92.2 ± 5.6% and 92 ± 4.8% respectively (p = 0.927). Conclusions. Caffeine exerts a potent arterial vasodilator effect in-vitro regardless of the presence or absence of aterosclerosis (AU)

Efectos vasculares y moleculares de los andrógenos endógenos en un modelo experimental en conejos ateroscleróticos / Vascular and molecular effects of endogenous androgens in an atherosclerotic experimental rabbit model

Introducción. Existe controversia acerca de los efectos de los andrógenos sobre la aterosclerosis y sus manifestaciones clínicas. El objetivo de este trabajo fue comparar, en conejos ateroscleróticos castrados y no castrados, las características morfológicas, funcionales y la expresión de genes asociados con el metabolismo reverso del colesterol. Métodos. Cuarenta conejos machos NZ fueron distribuidos en 4 grupos: 1: no castrados, con dieta normal; 2: castrados, con dieta normal; 3: no castrados, con dieta aterogénica, y 4: castrados, con dieta aterogénica. En cada conejo se realizaron mediciones de colesterol total, testosterona libre, relajación vascular in vitro, análisis histomorfométricos de la aorta torácica, y la expresión de genes IL-1b, LRX-a y ABCA1. Resultados. La castración redujo los valores de testosterona total (2,1 ± 0,3 frente a 0,8 ± 0,4 ng/ml; p = 0,024). En animales con dieta normal (grupos 1 y 2), la castración incrementó la expresión de IL-1b (0,71 ± 0,07 frente a 0,77 ± 0,06; p < 0,001), redujo LXR-a (0,77 ± 0,008 frente a 0,41 ± 0,01; p < 0,001) y aumentó ABCA1 (0,2 ± 0,008 frente a 0,31 ± 0,08; p < 0,001). En animales con dieta aterogénica (grupos 3 y 4), la castración se asoció a mayor área de la placa (0,9 ± 1,3 frente a 2,6 ± 2,3 mm2; p = 0,026), índice área placa/área vaso (0,08 ± 0,1 frente a 0,25 ± 0,1; p < 0,001), índice área placa/área de la media (0,2 ± 0,2 frente a 0,4 ± 0,3; p = 0,003), mayor expresión de IL-1b (0,93 ± 0,05 frente a 1,1 ± 0,02; p < 0,001), reducción de LXR-a (1,45 ± 0,01 frente a 1,29 ± 0,01; p < 0,001) y reducción de ABCA1 (0,22 ± 0,1 frente a 0,20 ± 0,02; p < 0,001). Conclusiones. Este estudio demuestra que, en presencia de aterosclerosis inducida por hipercolesterolemia, la testosterona endógena podría tener un efecto atenuante o protector de la aterogénesis (AU)

Introduction. The effects of androgens on atherosclerosis and its clinical manifestations are controversial. The objective of this study was to compare the morphologic and functional characteristics and gene expression associated with reverse metabolism of cholesterol in castrated and non-castrated atherosclerotic rabbits. Methods. Forty male NZ rabbits were distributed in four groups: 1: non-castrated with a normal diet; 2: castrated with a normal diet; 3: non-castrated with an atherogenic diet, and 4: castrated with an atherogenic diet. Measurements of total cholesterol, free testosterone, in vitro vascular relaxation, histomorphometric analyses of the thoracic aorta and expression of the IL-1b, LRX-a and ABCA1 genes were carried out in each rabbit. Results. Castration decreased levels of total testosterone (2.1 ± 0.3 vs. 0.8 ± 0.4 ng/mL; P=.024). In animals with a normal diet (groups 1 and 2), castration increased expression of IL-1b (0.71 ± 0.07 vs. 0.77 ± 0.06; P<.001), decreased that of LXR-a (0.77 ± 0.008 vs. 0.41 ± 0.01; P<.001) and increased that of ABCA1 (0.2±0.008 vs. 0.31±0.08; P<.001). In animals with an atherogenic diet (groups 3 and 4), castration was associated with a larger plaque area (0.9 ± 1.3 vs. 2.6 ± 2.3 mm2; P=.026), plaque area/vessel area ratio (0.08 ± 0.1 vs. 0.25 ± 0.1; P<.001), plaque area/media area ratio (0.2 ± 0.2 vs. 0.4 ± 0.3; P=.003), greater expression of IL-1b (0.93 ± 0.05 vs. 1.1 ± 0.02; P<.001), reduction of LXR-a (1.45 ± 0.01 vs. 1.29 ± 0.01; P<.001), and reduction of ABCA1 (0.22 ± 0.1 vs. 0.20 ± 0.02; P<.001). Conclusions. This study shows that in the presence of atherosclerosis induced by hypercholesterolemia, endogenous testosterone could have an attenuating or protective effect on atherogenesis (AU)

Arteriosclerotic changes in the myocardium, lung, and kidney in dogs with chronic congestive heart failure and myxomatous mitral valve disease.

BACKGROUND: The occurrence of small vessel arteriosclerosis in the myocardium, kidney, and lung in dogs with naturally occurring myxomatous mitral valve disease has not been previously investigated systematically. METHODS: Twenty-one dogs with naturally occurring congestive heart failure and 21 age-matched, sex-matched, and weight-matched control dogs underwent extensive pathological and histopathological examination. Morphometry and scoring of tissue sections were used to measure arterial narrowing and fibrosis in the myocardium, kidney, and lung; and intimal thickness and plaque formation in the aorta and pulmonary artery. RESULTS: Dogs with congestive heart failure had significantly more arterial narrowing in the left ventricle (P < .003), lung (P < .0001), and kidney (P < .02); intimal-medial thickening in the pulmonary artery (P = .04); and fibrosis in the left ventricle (P < .0001) than control dogs. However, they did not have more plaque formation or intimal-medial thickening in the aorta than controls. There was significantly more arterial narrowing in papillary muscles than in all other locations in dogs with congestive heart failure (P < .002). In control dogs, arterial changes were less pronounced and did not differ in different locations. CONCLUSIONS: Dogs with naturally occurring myxomatous mitral valve disease have significantly more arterial changes in the myocardium, lung, and kidney, and significantly more fibrosis in the myocardium than control dogs. This could have important implications in the management of myxomatous mitral valve disease and raises interesting questions about the occurrence and importance of intramural small vessel disease in humans with primary mitral valve prolapse.

Experimentos con ratones susceptibles a arteriosclerosis. Ventajas, inconvenientes y aspectos que considerar / Experimentation with arteriosclerosis-susceptible mice. Advantages, disadvantages and aspects to be considered

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Dietary salt restriction accelerates atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Whether a general reduction in salt intake reduces or actually enhances cardiovascular mortality in man remains an issue of controversy. Low sodium diets may lead to adverse side effects by stimulating the renin-angiotensin and sympathetic nervous systems. The present study was designed to investigate the effects of low dietary salt on atherosclerotic lesion progression in apolipoprotein E deficient (apoE(-/-)) mice. METHODS AND RESULTS: We fed 7-week-old apoE(-/-) mice on low (0.036% NaCl; n=28) or regular (0.64% NaCl; n=26) salt diets for 16 weeks. At the age of 23 weeks, the cross-section surface area of atherosclerotic plaques was measured in aortic root and thoracic aorta. Serum total cholesterol, triglycerides, plasma angiotensin levels and urinary protein/creatinine concentrations were assessed. Exposure to low salt caused significant increases in atherosclerotic lesion surface area in thoracic aorta, but did not alter lesion area in aortic root. Low-salt mice also had higher serum total cholesterol and higher plasma angiotensin II (ANG-II) concentrations. Atherosclerotic lesion area was correlated with ANG-II levels in low-salt but not in regular-salt animals, and with total cholesterol concentration in all mice. Mean arterial pressure was comparable in both groups. CONCLUSIONS: Dietary salt restriction accelerated atherosclerotic lesion formation in apoE(-/-) mice through a mechanism that is probably related to ANG-II formation. Whether these findings are relevant to human cardiovascular disease remains to be evaluated.

Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. III. Acute and chronic effects of CAPs on heart rate, heart-rate fluctuation, and body temperature.

Normal mice (C57) and mice prone to develop atherosclerosis (ApoE-/-) were implanted with electrocardiograph (EKG), core body temperature, and motion transmitters were exposed daily for 6 h to Tuxedo, NY, concentrated ambient particles (CAPs) for 5 day/wk during the spring and summer of 2003. The series of 5-min EKG monitoring and body-temperature measurements were obtained for each animal in the CAPs and filtered air sham exposure groups. Our hypothesis was that chronic exposure could cause cumulative health effects. We used our recently developed nonparametric method to estimate the daily time periods that mean heart rates (HR), body temperature, and physical activity differed significantly between the CAPs and sham exposed group. CAPs exposure most affected heart rate between 1:30 a.m. and 4:30 a.m. With the response variables being the average heart rate, body temperature, and physical activity, we adopted a two-stage modeling approach to obtain the estimates of chronic and acute effects on the changes of these three response variables. In the first stage, a time-varying model estimated daily crude effects. In the second stage, the true means of the estimated crude effects were modeled with a polynominal function of time for chronic effects, a linear term of daily CAPs exposure concentrations for acute effects, and a random component for unknown noise. A Bayesian framework combined these two stages. There were significant decreasing patterns of HR, body temperature, and physical activity for the ApoE-/- mice over the 5 mo of CAPs exposure, with smaller and nonsignificant changes for the C57 mice. The chronic effect changes of the three response variables for ApoE-/- mice were maximal in the last few weeks. There was also a significant relationship between CAPs exposure concentration and short-term changes of heart rate in ApoE-/- mice during exposure. Response variables were also defined for examining fluctuations of 5-min heart rates within long (i.e., 3-6 h) and short time periods (i.e., approximately 15 min). The results for the ApoE-/- mice showed that heart-rate fluctuation within the longer periods increased to 1.35-fold by the end of exposure experiment, while the heart-rate fluctuation within 15 min decreased to 0.7-fold.

Effects of subchronic exposures to concentrated ambient particles in mice. IX. Integral assessment and human health implications of subchronic exposures of mice to CAPs.

In order to examine the biologic plausibility of adverse chronic cardiopulmonary effects in humans associated with ambient particulate matter (PM) exposure, we exposed groups of normal mice (C57) and knockout mice that develop atherosclerotic plaque (ApoE-/- and ApoE-/- LDLr-/-) for 6 h/day, 5 days/wk for 5 or 6 mo during the spring/summer of 2003 to either filtered air or 10-fold concentrated ambient particles (CAPs) in Tuxedo, NY (average PM2.5 concentration during exposure = 110 microg/m3). Some of the mice had implanted electrocardiographic monitors. We demonstrated that: (1) this complex interdisciplinary study was technically feasible in terms of daily exposure, collection of air quality monitoring data, the collection, analysis, and interpretation of continuous data on cardiac function, and the collection and analyses of tissues of the animals sacrificed at the end of the study; (2) the daily variations in CAPs were significantly associated, in ApoE-/- mice, with daily variations in cardiac functions; (3) there were significant differences between CAPs and sham-exposed ApoE-/- mice in terms of cardiac function after the end of exposure period, as well as small differences in atherosclerotic plaque density, coronary artery disease, and cell density in the substantia nigra in the brain in the ApoE-/- mice; (4) there are suggestive indications of gene expression changes for genes associated with the control of circadian rhythm in the ApoE-/- LDLr-/- double knockout (DK) mice. These various CAPs-related effects on cardiac function and the development of histological evidence of increased risk of clinically significant disease at the end of exposures in animal models of atherosclerosis provide biological plausibility for the premature mortality associated with PM2.5 exposure in human subjects and provide suggestive evidence for neurogenic disease as well.

Longitudinal left ventricular myocardial dysfunction assessed by 2D colour tissue Doppler imaging in a dog with systemic hypertension and severe arteriosclerosis.

A 12-year-old sexually intact male Vendee Griffon Basset was presented for acute pulmonary oedema. Severe systemic systolic arterial hypertension (SAH) was diagnosed (290 mmHg). Despite blood and abdominal ultrasound tests, the underlying cause of the systemic hypertension could not be determined, and primary SAH was therefore suspected. Conventional echocardiography showed eccentric left ventricular hypertrophy with normal fractional shortening. Despite this apparent normal systolic function, 2D colour tissue Doppler imaging (TDI) identified a marked longitudinal systolic left ventricular myocardial alteration, whereas radial function was still preserved. Three months later, the dog underwent euthanasia because of an acute episode of distal aortic thromboembolism. Necropsy revealed severe aortic and iliac arteriosclerosis. SAH related to arteriosclerosis is a common finding in humans, but has not been previously described in dogs. Moreover, its consequence on longitudinal myocardial function using TDI has never been documented before in this species.

Atheroma stabilizing effects of simvastatin due to depression of macrophages or lipid accumulation in the atheromatous plaques of coronary plaque-prone WHHL rabbits.

Clinical studies showed that both hydrophilic and lipophilic statins reduce coronary events although in vitro studies demonstrated that lipophilic statins inhibited proliferation of arterial smooth muscle cells. Therefore, we examined whether lipophilic simvastatin reduces smooth muscle cells in atheromatous plaque and how simvastatin affects stability of atheroma in vivo. Coronary atherosclerosis-prone WHHLCA rabbits aged 10 months were given simvastatin (15 mg/kg) orally for 52 weeks and examined the serum lipid levels, plasma drug concentration, and aortic and coronary atherosclerosis. Compared to the placebo group, the plasma cholesterol levels decreased by about 20%. In the simvastatin group, the lipid component (macrophages+extracellular lipids) was decreased in the coronary and aortic atheroma, despite no decrease in the fibromuscular components. Consequently, the frequency of vulnerable plaque decreased. In the coronary plaque of the simvastatin group, PCNA-positive cells (which appeared to be macrophages) of the plaques decreased but the TUNEL-positive cells did not show significant change. Finally, fully differentiated smooth muscle cells increased in the aortic lesions of the simvastatin group. In conclusion, our results suggest that simvastatin did not depress the fibromuscular components in atheromatous plaques and the plaque-stabilizing effects were due to the reduction of macrophages/lipid deposits.

A new HMG-CoA reductase inhibitor, pitavastatin remarkably retards the progression of high cholesterol induced atherosclerosis in rabbits.

BACKGROUND: The remarkable anti-atherosclerotic effects of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model. OBJECTIVE: We have investigated the effect of pitavastatin, a newly developed statin, on atherosclerosis in rabbits. METHODS AND RESULTS: Oophorectomized female NZW rabbits were fed 0.3% cholesterol chow for 12 weeks with or without pitavastatin (0.1mg/kg per day) (Gp.NK and HCD). The level of serum cholesterol was decreased in Gp.NK compared with Gp.HCD (772.8 +/- 70.2 versus 1056.9 +/- 108.3 mg/d), whereas no significant alterations were observed in triglyceride and HDL-cholesterol. NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-l-arginine acetate were all improved by pitavastatin treatment. Pitavastatin treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits. In the aorta, the expression of eNOS mRNA was significantly up regulated and O(2)(-) production was slightly reduced in Gp.NK animals. Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp.NK compared with those from Gp.HCD ( 15.1 +/- 5.3 versus 41.9 +/- 10.2%, 3.1 +/- 1.1versus 7.9 +/- 1.2% in Gp.NK and Gp.HCD aortic arch and thoracic aorta). Anti-macrophage staining area, the MMP1 or 2 and the nitrotyrosine positive area were decreased in Gp.NK. CONCLUSION: Pitavastatin retards the progression of atherosclerosis formation and it improves NO bioavailability by eNOS up-regulation and decrease of O(2)(-).

Vitamin E supplementation suppresses macrophage accumulation and endothelial cell expression of adhesion molecules in the aorta of hypercholesterolemic rabbits.

Suppression of cell adhesion molecule expression and macrophage accumulation by the endothelium is believed to play an important role in preventing the development of atherosclerosis. Earlier, we have shown that in vitro supplementation of human aortic endothelial cells with Vitamin E dose-dependently reduced expression of adhesion molecules and monocyte adhesion. Here, we report the in vivo down-regulation of endothelial cell adhesion molecules expression and macrophage accumulation in the aortas of hypercholesterolemic rabbits supplemented with Vitamin E. To this end, New Zealand White rabbits were fed a semi-purified diet containing 30 (control) or 1000 IU/kg Vitamin E. After 4 weeks, both groups' diets were switched to an atherogenic diet (0.3% cholesterol, 9% hydrogenated coconut oil, and 1% corn oil) containing the respective levels of Vitamin E and fed for 2, 4, and 6 weeks. Vitamin E supplemented rabbits had significantly higher levels of Vitamin E in their plasma and aortas. Frozen aorta sections were fixed and stained by an avidin-biotin complex method using Rb2/3 and Rb1/9 monoclonal antibodies against rabbit ICAM-1 and VCAM-1, respectively, and with RAM-11 for macrophage and von Willebrand factor for endothelial cells, followed by staining with secondary antibodies and counterstaining and evaluation under the microscope. At 6 weeks on atherogenic diet treatment, a trend (P = 0.08) toward a lower score of ICAM-1 expression by endothelial cells was observed in the aorta of Vitamin E treated rabbits compared to the control. However, a decrease in the score of VCAM-1 expression by endothelial cells in Vitamin E treated rabbits did not reach to a statistical significance. At 4 and 6 weeks on atherogenic diet, Vitamin E supplementation also significantly (P = 0.003) inhibited the accumulation of macrophages in the aorta. These results support the concept that down-regulation of adhesion molecule expression and suppression of monocyte/macrophage activation by Vitamin E in vivo is one of the potential mechanisms by which Vitamin E may suppress the development of aortic lesions in a rabbit model of atherosclerosis.