Restenosis occurs in 35% of patients within months after balloon angioplasty, due to a fibroproliferative response to vascular injury. These studies describe a combined fibrosuppressive/antiproliferative strategy on smooth muscle cells cultured from human primary atherosclerotic and restenotic coronary arteries and from normal rat aortas. LMimosine suppressed the posttranslational hydroxylation of the precursors for collagen and for eukaryotic initiation factor-5A (eIF-5A) by directly inhibiting the specific protein hydroxylases involved, prolyl 4-hydroxylase (E.C. 1.14.11.2) and deoxyhypusyl hydroxylase (E.C. 1.14.99.29), respectively. Inhibition of deoxyhypusyl hydroxylation correlated with a dose-dependent inhibition of DNA synthesis. Inhibition of prolyl hydroxylation caused a dose-dependent reduction in the secretion of hydroxyproline-containing protein and decreased the formation of procollagen types I and III. The antifibroproliferative action could not be attributed to nonspecific or toxic effects of mimosine, appeared to be selective for the hydroxylation step in the biosynthesis of the procollagens and of eIF-5A, and was reversible upon removal of the compound. The strategy of targeting these two protein hydroxylases has important implications for the pathophysiology of restenosis and for the development of agents to control fibroproliferative diseases. (J. Clin. Invest. 1995. 95:446-455.)
Hematoporphyrin derivative, a photosensitive material used to identify and treat neoplastic tissue in humans, has been found to localize in atheromatous plaques in animals and has recently been found in postmortem human atherosclerotic plaques. It is not known whether human plaques take up hematoporphyrin derivative in vivo. In five patients undergoing surgical vascular procedures, specimens containing atheromatous plaques were removed and immediately incubated in autologous oxygenated blood at 37 degrees C with hematoporphyrin derivative at a clinically relevant concentration for 2 hours. On exposure to ultraviolet light, porphyrin fluorescence was noted throughout each plaque, whereas adjacent plaque-free tissue showed no fluorescence. To compare in vitro with in vivo hematoporphyrin derivative uptake by plaques, the fluorescence of three types of arterial lesions (induced by a high cholesterol diet, catheters or balloon injury) was studied in 16 New Zealand White rabbits. Each lesion fluoresced selectively with the same intensity whether hematoporphyrin derivative exposure was performed in vitro or in vivo. Fluorescence microscopy did not show a difference in the pattern of hematoporphyrin derivative fluorescence between in vitro and in vivo specimens. The results suggest that human atheromatous plaques should take up hematoporphyrin derivative in vivo and are, therefore, potentially suitable for photochemical treatment as a new therapeutic approach to atherosclerosis.
Little data exists regarding the relationship between the volume of radiographic contrast infused and the risk of contrast nephropathy for individual patients based on specific patient characteristics. Because the likelihood of renal failure is increased when there is preexisting azotemia or when larger volumes of contrast are used, it was hypothesized that the contrast volume:estimated creatinine clearance ratio would serve as a predictor of nephropathy following cardiac angiography. A retrospective analysis was performed of 152 high risk patients whose baseline serum creatinine concentration was >2.0 mg/dL or who received ± 300 ce of contrast. Nephropathy, defined as in increase in serum creatinine of > 1.0 mg/dL within 48 hours, occurred in 11 patients (7%). The contrast volume: creatinine clearance ratio was > 6.0 in 64% of patients who developed nephropathy and 31% of patients who did not (P < 0.05). The contrast volume:creatinine clearance ratio was then studied prospectively in 250 consecutive patients. The risk of nephropathy was 61% for patients with a ratio > 6.0, but only 1% otherwise (P < 0.01). This ratio can be used to calculate an upper limit for contrast volume and might reduce the chance of renal failure.
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