Biomedical subjects

W D Coats

Publications and source records attributed to W D Coats.

10 recordsLinked to original sources

PubMed1998

Arterial remodeling at the reference site after angioplasty in the atherosclerotic rabbit model.

Recent studies suggest that arterial remodeling plays an important role in restenosis and that remodeling at the reference site may also occur. To assess the chronic effect of the reference site remodeling on angioplasty results, we evaluated reference site remodeling in an experimental atherosclerotic restenosis model. Histological sections of iliac stenoses and their associated proximal reference segments from 50 atherosclerotic rabbits killed 4 weeks after angioplasty were analyzed. Lumen area (LA), external elastic lamina area (EEL), and intimal plus medial areas (I+M) were measured at the lesion (L) and reference (R) sites. Angiography was performed preangioplasty, immediately postangioplasty, and 4 weeks postangioplasty. Restenosis was defined as an angiographic loss/gain ratio of greater than 50% at follow-up angiography. Twenty-three lesions were restenotic (R+) and 32 were not (R-). There was no difference in reference site diameters (RD) between these two groups at the time of angioplasty. However, RDs were significantly smaller in the R+ group than in the R- group (1.24+/-0.18 versus 1.52+/-0.28 mm, n=55, P<.01) at 4-week follow-up. Morphometric analysis also showed a smaller LA(R) in the R+ group (0.85+/-0.27 versus 1.06+/-0.37 mm2, n=55, P<.02), whereas there was no difference in I+M(R) between the two groups. EEL(R) significantly correlated with EEL(L), LA(R), and I+M(R) in both groups combined (r=.53, n=55, P<.0001; r=.62, n = 55, P < .0001; and r = .86, n = 55, P < .0001, respectively). Remodeling can favorably and unfavorably affect both the lesion and the reference sites and appears to occur in parallel and proportionately at both sites. These data suggest that angiographic measurement of late percent stenosis using reference site diameters may lead to an underestimation of the percent luminal narrowing in restenotic lesions because unfavorable remodeling occurs in both the lesion and reference sites in restenotic vessels.

Angiography↗

PubMed1997

Collagen content is significantly lower in restenotic versus nonrestenotic vessels after balloon angioplasty in the atherosclerotic rabbit model.

BACKGROUND: It is recognized that restenosis is primarily due to alterations in geometric remodeling of the extracellular matrix rather than intimal hyperplasia. Prior studies have shown that angioplasty stimulates an increase in both synthesis and degradation of collagen in the atherosclerotic vessel. However, differences in collagen content and metabolism between restenotic and nonrestenotic vessels have not been examined. METHODS AND RESULTS: Four weeks after angioplasty in an atherosclerotic rabbit model, collagen content in restenotic and nonrestenotic vessels was measured both biochemically by hydroxyproline quantitation and histologically by a digital subtraction method with the use of circularly polarized images of picrosirius red-stained sections. Collagenase and gelatinase activity also were measured in the same restenotic and nonrestenotic vessels by use of a radiosubstrate assay. Collagen content was found to be significantly lower in restenotic vessels than in nonrestenotic vessels both biochemically (127.0 +/- 32.6 versus 212.6 +/- 84.3 micrograms/mg tissue; n = 11 vessels; P < .05) and histologically (67.3 +/- 7.9% versus 76.3 +/- 11.8% area fraction; n = 20 sections from 6 vessels; P = .05). There was a significant inverse correlation between biochemically determined collagen content and gelatinase activity (P = .02) and a significant correlation between histologically determined lumen are and percent collagen content (P = .0071). CONCLUSIONS: Collagen content is significantly decreased in restenotic versus nonrestenotic vessels after angioplasty in the atherosclerotic rabbit model. The increased collagen content in nonrestenotic vessels was associated with preserved lumen area and may play a role in geometric remodeling after angioplasty.

Angioplasty, Balloon↗

PubMed1997

Remodelling and restenosis: insights from animal studies.

Animal studies have been instrumental in elucidating the process of remodelling and its contribution to restenosis relative to neointimal formation following angioplasty. The majority of studies have utilized rabbit, porcine and nonhuman primate models of vascular injury. Despite the use of different experimental models, different forms of vascular injury, different methods of analysis and different definitions of arterial remodelling, all animal studies, with rare exceptions, have demonstrated the importance of remodelling in the maintenance of vascular patency in both atherogenesis and in restenosis following angioplasty. The finding that remodelling in the non-human primate is most comparable to that that occurs in man suggests that there may be a genetic predisposition to the balance of neointimal formation and arterial remodelling following vascular injury.

Adaptation, Physiological↗

PubMed1997

The role of the extracellular matrix in arterial remodelling.

The extracellular matrix is now recognized as a biologically active and dynamic composition of structural, adhesive, and counteradhesive fibrous proteins embedded in a hydrated ground substance of glycosaminoglycans and proteoglycans. The ability of resident cells to detect small differences in the specific combination, concentration and distribution of matrix components suggests that perturbation of the homeostatic matrix can lead to remodelling following angioplasty. Recent studies reviewed herein have focused on how alterations of the relative composition of matrix components ultimately leads to changes in cell growth, behaviour and differentiation, all of which can significantly contribute to remodelling of the vascular wall following injury. These cell-matrix interactions may provide novel therapeutic targets in the prevention of unfavourable remodelling that leads to restenosis.

Adaptation, Physiological↗

PubMed1996

Balloon angioplasty significantly increases collagen content but does not alter collagen subtype I/III ratios in the atherosclerotic rabbit iliac model.

Angioplasty has been reported to increase collagen content and to alter vascular collagen alpha 1(I), alpha 2(I), and alpha 1(III) mRNA levels. Collagen synthesis is tightly regulated by complex translational and post-translational mechanisms such that mRNA levels may not necessarily reflect biosynthesis. To test whether collagen subtype I and III protein levels are altered by angioplasty, we quantitatively analysed collagen I/III protein ratios at 4 weeks after balloon angioplasty. Twenty New Zealand White rabbits underwent iliac artery balloon de-endothelialization and then were placed on a 0.5% cholesterol/6% peanut oil diet for 7 weeks at which time angioplasty was performed on arteries with > or = 50% stenosis. Arteries with < 50% stenosis were not dilated and served as controls. Animals were killed 4 weeks later and hydroxyproline (OH-pro) content and subtype I/III ratios were analysed in 5-mm mid-iliac sections. OH-pro was measured by a colorimetric assay. Subtype ratios were determined by a highly quantitative two-dimensional cyanogen bromide peptide mapping method. The degree of stenosis was measured as the minimal vessel lumen diameter and calculated as a percentage stenosis compared to a proximal reference segment. Calculated collagen content (micrograms/mg tissue) was significantly higher 4 weeks following angioplasty compared to the non-dilated group (220.4 +/- 70.8 v 308.2 +/- 26.9, P = 0.04; n = 12), despite similar percentage stenosis in the primary and restenotic lesions. The ratio of collagen I/III subtype protein distribution was not significantly different in the non-dilated and angioplastied groups (4.88 +/- 1.00 v 4.70 +/- 0.82, respectively). These studies are the first to provide data on collagen I/III subtypes following angioplasty and suggest that collagen accumulation may be more important in restenosis than alteration of collagen protein subtypes.

Angioplasty, Balloon↗

PubMed1996

Tin ethyl etiopurpurin significantly inhibits vascular smooth muscle cell proliferation in vivo.

Smooth muscle cell proliferation is a major component of restenosis following angioplasty. Hematoporphyrin derivative and other photosensitive compounds inhibit proliferation by causing cellular necrosis upon light activation (photodynamic therapy). Other photosensitive compounds, such as benzoporphyrin derivative, have been suggested as having non-cytotoxic antiproliferative effects without photodynamic therapy, although other studies using benzoporphyrin derivative were negative. Inhibition of smooth muscle cell proliferation was examined in an in vivo rabbit model of vascular injury using a novel synthetic chlorin derivative, tin ethyl etiopurpurin, and benzoporphyrin derivative without photodynamic therapy. Tin ethyl etiopurpurin and benzoporphyrin derivative inhibited smooth muscle cell proliferation by 50-90% of control (p < or = 0.05) without toxic side effects. These results suggest that tin ethyl etiopurpurin and benzoporphyrin derivative without photodynamic therapy may provide a novel and potent antiproliferative therapy that might be useful in the treatment of restenosis.

Animals↗

PubMed1993

Cyclic AMP suppresses fibronectin expression in the rabbit aorta in vitro.

The effect of cAMP on the in vitro expression of rabbit aortic fibronectin was examined using a previously characterized organ culture system. Elevation of intracellular cAMP in incubated aortic rings by use of forskolin or dibutyryl cAMP (dbcAMP) inhibited the normally observed increase in fibronectin mRNA to levels below that found in unincubated tissue. The effect of dbcAMP on fibronectin mRNA was dose dependent and reversible. dbcAMP did not affect overall protein biosynthesis or the changes in collagen or elastin mRNAs that normally occurred during in vitro incubation, suggesting a selective regulatory effect on fibronectin. The inhibitory effect of dbcAMP on steady-state fibronectin mRNA levels was independent of the dibutyrate moiety, was not a result of cytotoxicity, did not require de novo protein synthesis, and did not appear to occur through a protein kinase A pathway. The data suggested that suppression of fibronectin mRNA levels potentially occurred via an indirect mechanism that may have involved a dbcAMP-induced reduction in intracellular calcium ([Ca2+]i) levels. The resultant decrease in [Ca2+]i may have affected fibronectin expression via a reduction in protein kinase C activity but did not depend on a calmodulin or calmodulin kinase I or II mechanism.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Coronary sinus occlusion: effect on ischemic left ventricular dysfunction and reactive hyperemia.

Pressure-controlled intermittent coronary sinus occlusion (PICSO) has been shown to reduce experimental infarct size. To examine the role of PICSO in limiting the consequences of brief ischemia on left ventricular function, we studied the effect of PICSO in nine open-chest anesthetized dogs. PICSO was performed using a pump-inflated, balloon-tipped catheter in the coronary sinus until coronary sinus occlusion pressure reached a plateau (10 +/- 3 seconds). The balloon was then rapidly deflated (2 seconds) and the cycle was repeated. Regional left ventricular function in the ischemic zone was assessed by sonomicrometry. Coronary blood flow was measured with a flow probe around the left anterior descending artery (LAD) proximal to an occluding suture. Measurements were obtained at baseline, during a 3-minute LAD occlusion, and for 10 minutes of reperfusion. In an additional five dogs, this sequence was repeated during an infusion of adenosine at a dose that abolished reactive hyperemia following LAD occlusion. The addition of PICSO beginning 15 minutes prior to ischemia and continuing throughout LAD occlusion and reperfusion did not prevent, reduce, or shorten ischemic left ventricular dysfunction. PICSO uniformly blunted reactive hyperemia during reperfusion. However, PICSO also reduced coronary blood flow during maximal vasodilatation achieved by adenosine infusion prior to LAD occlusion. Therefore, it is likely that PICSO decreases reactive hyperemia due to mechanical factors arising from venous engorgement rather than by reducing the ischemic stimulus causing vasodilation.

Animals↗

PubMed1990

Functional reconstitution of fMet-Leu-Phe receptor in Xenopus laevis oocytes.

fMet-Leu-Phe (fMLP) receptors were functionally reconstituted into Xenopus laevis oocytes by microinjection with RNA isolated from promyelocytic leukemia cells (HL-60) differentiated with 750 microM N6, O2-dibutyryl cyclic adenosine 3',5'-monophosphate. fMLP-induced Ca2+ mobilization was monitored by measurement of photon emission elicited by aequorin coinjected with RNA into albino X. laevis oocytes. Maximal expression of the fMLP receptor was achieved 48 h after microinjection of RNA. Dose-response experiments revealed a K0.5 of 9.5 nM fMLP which is in good agreement with the dissociation constants of the fMLP receptor complex in human neutrophils. Furthermore, the fMLP-induced Ca2+ mobilization in Xenopus oocytes was blocked by the fMLP receptor inhibitor t-butoxycarbonyl-Met-Leu-Phe. Size fractionation of the RNA and microinjection of the individual fractions indicated that messenger RNA for the fMLP receptor is between 1.5 and 2.0 kilobases. Reconstitution of the fMLP receptor into Xenopus oocytes can be employed to isolate the cDNA encoding the fMLP receptor as well as to study the regulation of the fMLP receptor in a functional system.

Animals↗

PubMed1985

Coronary sinus occlusion pressure and its relation to intracardiac pressure.

The hemodynamic components of coronary sinus (CS) occlusion pressure in humans have not been well described. If no other outflow for venous blood were present, then after acute occlusion of the coronary sinus the pressure would increase and equal aortic pressure. However, if thebesian vein drainage between the left ventricle and the coronary veins has an important role in humans, then CS occlusion pressure might reflect left ventricular (LV) pressure through transmitted LV pressure or intramyocardial pressure. To study this relation, 27 patients who underwent routine diagnostic cardiac catheterization were evaluated. Occlusion was accomplished by sudden inflation of a No. 7Fr balloon-tipped catheter placed into the CS. LV end-diastolic pressure and end-diastolic CS occlusion pressure were simultaneously recorded at rest. LV end-diastolic pressure (16.7 +/- 5.6 mm Hg) was not significantly different from end-diastolic CS occlusion pressure (15.9 +/- 5.4 mm Hg). LV end-diastolic and end-diastolic CS occlusion pressures were positively correlated (p less than 0.001) over the entire range of pressures (9 to 27 mm Hg). In contrast, systolic CS occlusion pressure was significantly lower than LV systolic pressure and unrelated to right-sided heart pressures. It is concluded that in humans, end-diastolic CS occlusion pressure closely parallels LV end-diastolic pressure, and measurement of CS occlusion pressure to assess LV end-diastolic pressure may have clinical use. These findings also suggest the existence of hemodynamically important thebesian vessel connections that may have implications for retroperfusion or pressure-controlled intermittent CS occlusion in humans.

Blood Pressure↗