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1-123 metaiodobenzylguanidine (MIBG) is a new radiopharmaceutical with properties that allow the characterization of the sympathetic innervation of several organ systems. In this study, we used MIBG with tomographic imaging to evaluate noninvasively the differences in myocardial sympathetic innervation in 14 healthy volunteers and 16 patients with severe dilated cardiomyopathy (CM). Initial (15-minute) images demonstrated no significant differences in MIBG concentration in the hearts of patients with CM and of healthy volunteers. However, the myocardial retention of MIBG was significantly reduced in the patients with CM. Expressed as the percent washout from 15 to 85 minutes, the patients with CM had a 28 ± 12% washout rate compared with 6 8% in the controls (p

This report describes the features of developing atherosclerosis in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of human familial hypercholesterolemia. Observations were made in 18 homozygous WHHL rabbits, aged 4 days to 15 months, fed standard rabbit chow; seven control New Zealand white rabbits fed a similar diet, and four New Zealand white rabbits fed rabbit chow containing 2% cholesterol and 10% corn oil for 2 weeks. The WHHL rabbits showed evidence of progressive disease of the aorta with accumulation of strongly birefringent llpid in intimal lesions, Including fatty streaks, raised foam cell lesions, and plaques (atheromas), as well as in the media. As seen by electron microscopy, the cellular population of the intimal lesions consisted predominantly of smooth muscle cells with lipid deposits and lipidladen foam cells. Llpid deposits occurred as cytoplasmic neutral lipid droplets and as multilamellar bodies. In addition to advanced atherosclerosis of the aorta, a 15-monthold WHHL rabbit also had focal coronary atherosclerosis and subcutaneous xanthomas. The New Zealand white rabbits fed a high cholesterol and fat diet for 2 weeks showed early intimal lipid accumulation in the aorta and prominent lipid accumulation in hepatocytes and macrophages of the liver and spleen. New Zealand white rabbits fed the standard rabbit chow had no abnormal lipid deposits. In contrast to the cholesterol-fed rabbits, WHHL rabbits had only mild lipid accumulation in other tissues. Thus, many similarities exist between atherosclerotic disease in the WHHL rabbit and in man. This study shows that the WHHL rabbit is a good model of familial hypercholesterolemia. (Arteriosclerosis 3:87-101, January/February 1983) F amilial hypercholesterolemia is a genetic disorder characterized by deficient cell surface receptors for low density lipoprotein (LDL), by hypercholesterolemia with high plasma levels of LDL, and by accelerated atherosclerosis and cutaneous xanthomatosis. 1 " 3 Recently, Watanabe and associates"-6 described a strain of rabbit that exhibits hypercholesterolemia, elevated plasma LDL levels, severe atherosclerosis, and cutaneous xanthomas. The ab- 7 It has been shown that homozygous WHHL rabbits lack LDL receptors on membranes from cultured fibroblasts, liver, and the adrenal gland.7 " 9 A lack of high affinity uptake and degradation of LDL have been demonstrated in studies of homozygous WHHL rabbits in vivo 10 and in isolated hepatocytes from these animals. 11The purpose of this study was to obtain a detailed characterization of the gross distribution and light and electron microscopic features of developing atherosclerosis in young WHHL rabbits. The preliminary results of this study have been previously reported.

IntroductionSmooth muscle cell contraction is an essential function of arteries and relies on the integrity of the actin-myosin apparatus. The tissue-specific α2-smooth muscle actin, encoded by ACTA2, is predominantly expressed in vascular smooth muscle cells. ACTA2 mutations predispose to development of aortic aneurysms and early onset coronary and cerebrovascular disease. Based on arteriographic findings, a distinct cerebrovascular disease has been proposed for ACTA2 heterozygous patients carrying the R179H mutation. Results We present the first integrated analysis of a severely compromised patient with the R179H mutation and define the arterial pathology of ACTA2-related cerebrovascular disease. Histologically, striking morphological abnormalities were present in cerebral arteries of all sizes. Massive intimal smooth muscle cell proliferation, fragmentation of the elastic laminae and medial fibromuscular proliferation characterized large arteries whereas prominent vessel wall thickening, fibrosis and smooth muscle cell proliferation were unique changes in small arteries. The medial fibrosis and smooth muscle cell proliferation explain the characteristic radiologic appearance of “straight arteries” and suggest impaired function of mutant smooth muscle cells. Actin three-dimensional molecular modeling revealed critical positioning of R179 at the interface between the two strands of filamentous actin and destabilization of inter-strand bundling by the R179H mutation, explaining the severe associated phenotype. ConclusionsIn conclusion, these characteristic clinical and pathologic findings confirm ACTA2-related cerebrovascular disease as a new cerebrovascular disorder for which new therapeutic strategies need to be designed.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0262-7) contains supplementary material, which is available to authorized users.

A B ST RA CT Human aortic smooth muscle cells accumulate only small amounts of cholesteryl esters in tissue culture, even when incubated for prolonged periods with high levels of plasma low density lipoprotein (LDL). This failure to overaccumulate LDL-cholesteryl esters is due to an LDL-mediated feedback suppression of the activity of the cell surface LDL receptor, a regulatory action that limits the rate at which the cells take up LDL. This regulatory system can be bypassed by incubating smooth muscle cells with LDL that has been given a strong positive charge by covalent linkage with N,N-dimethyl-1,3-propanediamine (DMPA-LDL). The unregulated uptake of DMPA-LDL produces a massive deposition of cholesteryl esters in the form of inclusions within the cell. These inclusions take up The above control mechanism can be overcome and an tinregtulated uiptake of LDL can be achieved in fibroblasts by inctubating the cells with LDL that has been rendered polycationic by the covalent attachment of N,N-dimethyl-1,3-propanediamine (DMPA) residtues to the lipoprotein (13). This positivelycharged DMPA-LDL binds to nonspecific negativelycharged sites on the cell sturface from which it is taken up by the fibroblasts through a process that does not involve the physiologic LDL receptor (13).2In the current sttudies, we have uitilized the information learned from the metabolism of DMPA-LDL in (14). Segments of N4. C.'s thoracic aorta were remoived during aortic valve replacement in October 1976. With the inf'ormed consent of NI. C.'s parents, these segments were used for tissue culture. The smooth muiscle cells were cultutred by the method of Ross (15) and uised between the 4th and 10th passage. By phase contrast microscopy the cells were observed to grow in multiple overlapping layers, and by electron microscopy they showed myofilaments and dense bodies that are characteristic of aortic smooth mtuscle cells in cuiltture (15).Stock ctultuires were maintained in a hutmidified inctubator (5% C02) at 37°C in 250-ml flasks containing 10 ml of growth medium consisting of Eagle's minimtum essential medium (Grand Island Biological Co., Grand Island, N.Y., catalogue no. F-11) supplemented with penicillin (100 U/ml); streptomycin (100 ,tg/ml); 20 mM Tricine-chloride, pH 7. Polarizing light microscopy. Monolayers were grown on glass coverslips that were subsequently mounted on glass slides. To enhance birefringence, the slides were first warmed to 40-45°C for 10 min, which cauised the initial birefringence to disappear, after which they were cooled to 10°C for 10 min, and examined immediately thereafter (4,22). The cells were photographed under polarizing optics with a Zeiss Photomicroscope III (Carl Zeiss, Inc. New York).

This study investigates the hypothesis that inflammatory cytokines, interleukin (IL)-1alpha IL-1beta, and tumor necrosis factor (TNF), influence cardiac function by affecting calcium homeostasis and that this effect is mediated by the beta-adrenergic-adenylate cyclase system. After 4 days in culture, neonatal rat ventricular myocytes were treated with cytokines (10 ng/ml) for short (2 h) or longer (18 h) times. Myocyte calcium, contractility, and adenylate cyclase were measured under each condition. Anticipated stepwise increases in adenylate cyclase and intracellular calcium were found in controls (non-cytokine-treated) with 10(-7) M isoproterenol, 10(-7) M isoproterenol + 0.1 mM guanosine triphosphate, and 10(-9) M forskolin. Cells in the presence of cytokine for 2 h show increased basal calcium levels but no changes in adenylate cyclase activities, and isoproterenol fails to elevate adenylate cyclase levels or affect contractile shortening. After long-term treatment with IL-1beta or TNF, but not IL-1alpha, the significantly elevated levels of basal systolic calcium remain, and isoproterenol increases adenylate cyclase activity, unlike after short exposure. Forskolin maximally activates adenylate cyclase following both short- and long-term incubation, but the stepwise increase in activity is blunted following prolonged exposure. Thus short-term cytokine treatment blocks the adrenergic receptor-mediated increases in adenosine 3',5'-cyclic monophosphate, dissociating adenylate cyclase activation from cytokine-mediated increases in cell calcium, whereas longer treatment apparently produces direct affects on adenylate cyclase. Time-dependent differences in contractile response were found with IL-1alpha at 2 h and TNF at 18 h, implying that myofibrillar responsiveness to increased cytoplasmic calcium is dependent on both cytokine species and exposure time.

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A B S T R A C T In 17 dogs with acute myocardial infarcts produced by ligation of the proximal left anterior descending coronary artery, a comparative study was made of myocardial scintigrams obtained with technetium-99m stannous pyrophosphate ("mTc-PYP) and thallium-201 ('Tl), tissue levels of 'Tc-PYP and 'Tl uptake, histopathologic alterations, and regional myocardial perfusion measured with radioactive microspheres. 9 of the 10 hearts examined histologically had transmural infarcts with outer peripheral, inner peripheral, and central zones characterized by distinctive histopathologic features. A progressive reduction in myocardial blood flow was demonstrated between normal myocardium and the centers of the infarcts, and correlated well with progressive reduction in 'Tl uptake in the same regions. Marked mTc-PYP concentration occurred in areas with partial to homogeneous myocardial necrosis and residual perfusion located in the outer peripheral regions of the infarcts. The latter areas also were characterized by the presence of muscle cell calcification. The patterns of distribution of "'Tc-PYP and m'°Tl explained the filling defects on 'Tl myocardial scintigrams and the doughnut patterns on 99mTc-PYP myocardial scintigrams in dogs with transmural infarcts. One dog with a subendocardial infarct had a small homogeneous area of activity on the "Tc-PYP myocardial scintigram, and showed marked uptake of 'mTc-PYP in subendocardial areas of extensive necrosis and calcification still receiving some coronary perfusion.Dr.