No abstract

The CARDia (Coronary Artery Revascularization in Diabetes) trial is the first randomized trial of coronary revascularization in diabetic patients, but the 1-year results did not show that PCI is noninferior to CABG. However, the CARDia trial did show that multivessel PCI is feasible in patients with diabetes, but longer-term follow-up and data from other trials will be needed to provide a more precise comparison of the efficacy of these 2 revascularization strategies. (The Coronary Artery Revascularisation in Diabetes trial; ISRCTN19872154).

Background-Autologous saphenous vein coronary artery bypass graft surgery is complicated by late graft failure due to neointima formation and subsequent atherosclerosis. Growth factors and metalloproteinases (MMPs) act in concert to promote neointima formation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), an extracellular matrix-associated MMP inhibitor, uniquely promotes apoptosis of isolated vascular smooth muscle cells. Here, we overexpressed TIMP-3 at the luminal surface of human saphenous veins before organ culture and in pig saphenous veins before interposition grafting into carotid arteries in vivo to assess neointima formation. Methods and Results-In both models, high TIMP-3 immunoreactivity occurred in the luminal and upper medial extracellular matrix after adenovirus delivery. MMP activity measured by in situ zymography was reduced throughout the veins, confirming a bystander effect. By use of 3 independent techniques, apoptosis levels in the neointima and medial layer were significantly elevated by TIMP-3 overexpression. Neointima formation was reduced by 84% in 14-day human organ cultures and by 58% in 28-day pig vein grafts (both PϽ0.05). In contrast, TIMP-2 overexpression had no effect on neointima formation in vivo. Conclusions-Our results highlight the potential therapeutic benefit for TIMP-3 overexpression to reduce neointima formation associated with late vein graft failure. (Circulation. 2000;101:296-304.)

CPB inclusive of cardioplegic arrest is the main independent predictor of postoperative AF in patients undergoing coronary revascularization.

The transition metals nickel (Ni), chromium (Cr) and cobalt (Co) are common causes of allergic contact dermatitis (ACD). Given the high frequency with which these allergens can be associated with hand eczema in those responsible for domestic work, it has been suggested that contamination of household consumer products with these metals may be of relevance to the causation/chronicity of hand dermatitis. Dose-response studies using 48 h occlusive patch test conditions in sensitized individuals show that !90% of sensitized patients fail to react below 1 p.p.m., even on irritated skin. Assessment under more realistic exposure conditions has shown that in the presence of irritants and/ or following repeated exposures, such individuals rarely react to levels below 10 p.p.m. On the basis of this information, it was recommended a decade ago that household (and other consumer) products should not contain more than 5 p.p.m. of each of Ni, Cr or Co and that, for an even greater degree of protection, the ultimate target level should be 1 p.p.m. The data generated since the original recommendations were made serve to reinforce the validity of these recommendations. Indeed, it is our view that typically the level of each of these transition metals should not normally exceed 1 p.p.m. Then, where consumer products meet this guideline fully, modern quantitative risk assessment shows clearly that elicitation of ACD is highly improbable, and the chance of the induction of sensitization is even lower. Some 10 years ago, the possibility that traces of the allergenic transition metals, nickel (Ni), chromium (Cr) and cobalt (Co), present as contaminants in household products might give rise to allergic contact dermatitis (ACD) was raised (1, 2) and then extensively reviewed (3). At that time, it was concluded that the risk of the induction of sensitization was negligible and the risk of elicitation in presensitized individuals was acceptably low, as long as the level of contamination was kept to very low levels: 'It is recommended that, for consumer products, current good practice which ensures Ni, Co and Cr contamination is less than 5 p.p.m. of each metal is an acceptable standard. To minimize the risk for very sensitive individuals (4), and when and where standardized analytical techniques permit, it is recommended that the ultimate target should be not more than 1 p.p.m. of each metal in consumer products.'Since that publication, several new pieces of information have become available. Firstly, an interlaboratory study in Italy of housewives' eczema showed no relationship of this disease to transition metal allergy (5, 6). In addition, new dose-response data which aid our understanding of elicitation thresholds in sensitized individuals have been published and have further information on the levels of product contamination with additional commentary on the possibility that trace levels of Ni, Cr and Co might play a role in ACD (and in particular in the chronicity of some hand eczemas) has been presented. Finally, now there are sop...

Bypass of stenotic coronary arteries with autologous saphenous vein is an established treatment for ischemic heart disease. However, its long-term clinical success is limited. Late vein graft failure is the result of medial and intimal thickening consequent upon medial vascular smooth muscle cell migration, proliferation and extracellular matrix deposition, followed later by superimposed atherosclerosis. These changes directly compromise graft blood flow and provoke thrombosis. Vein graft wall thickening may represent an adaptation imposed by arterial hemodynamic factors, and these factors have been shown to promote vascular smooth muscle cell migration and proliferation through activation of key mediators including platelet-derived growth factor (PDGF). Many pharmacological interventions aimed at preventing these long-term changes have proven unsuccessful in clinical evaluation. We recently demonstrated in a pig saphenous vein graft model that application of an external polyester stent to the outside of carotid interposition vein grafts reduced intimal hyperplasia and total wall thickness 1 month after implantation. However, it is not known whether the benefits of the stent are maintained in the longer term or what mechanisms underlie its effect. The present study therefore compared morphological changes and PDGF expression in stented grafts and contralateral unstented grafts in the same pigs, 6 months after graft implantation. Reduced medial thickening, neointima formation, and cell proliferation were sustained in externally stented grafts, and these effects were associated with a significant reduction in PDGF expression.

Neointimal formation involving smooth muscle cell (SMC) migration and proliferation is a common feature of atherosclerosis, restenosis after angioplasty, and vein graft intimal thickening. Extracellular matrix remodeling by metalloproteinase (MMP) enzymes is an essential component of neointimal formation and therefore MMPs are a potential target for localized gene therapy. To evaluate this concept using human tissue, we used the highly reproducible organ culture model of neointimal formation in human saphenous vein to investigate the effect of adenovirus-mediated gene transfer of tissue inhibitor of metalloproteinase 1 (TIMP-1) and the bacterial LacZ gene (RAd35) as a control. Incubating veins with 100 microl of RAd35 (1.2 x 10(10) pfu/ml) led to expression of LacZ in 39 +/- 7% of surface cells but had no effect on SMC proliferation, migration, or neointimal formation. Similar infection with RAdTIMP-1 increased explanation of TIMP-1 in surface cells and significantly inhibited neointimal formation and SMC migration after 14 days by 54% and 78%, respectively (n = 6, p < 0.05 Student's paired t test). No effect on SMC proliferation or deleterious effect on cell viability was observed. A specific MMP inhibitory effect was detected using in situ zymography. These data confirm the importance of MMPs in neointimal formation and highlight the potential for application of TIMP gene therapy.

Objective  To investigate further the mechanisms of action of sildenafil, a highly selective and potent inhibitor of type 5 cGMP phosphodiesterase (PDE5) that has proved effective in the treatment of erectile dysfunction, by assessing its effect on the in vitro formation of cGMP and cAMP in the corpus cavernosum of the rabbit. Materials and methods  Male New Zealand White rabbits (2.5 kg) were killed and their penises rapidly excised, cut into segments and pooled. Penile segments were then incubated with various concentrations of sildenafil or papaverine. The formation of cGMP was stimulated with increasing concentrations of sodium nitroprusside (SNP) and the cGMP and cAMP concentrations measured by radioimmunoassay. Responses were compared to those obtained with papaverine, which is used therapeutically as an erectogen. Results  In the presence or absence of SNP, sildenafil increased cGMP concentrations in rabbit penile tissue with increasing dose; the increase was greatest (about 28‐fold) when cGMP was stimulated with SNP (up to 10 μmol/L). At all stimulatory concentrations of SNP, the effective concentrations for 50% stimulation (EC50 ) of sildenafil were 430–520 nmol/L. Concentrations of cAMP were unaltered by sildenafil. Papaverine enhanced cGMP formation in response to SNP, but at much higher concentrations than did sildenafil (≥10 μmol/L). Conclusions  Sildenafil specifically increases cGMP levels in rabbit corpora cavernosa; the increase is greater in the presence of SNP indicating that, in vivo, sildenafil may enhance erection by the augmentation of nitric oxide‐mediated relaxation pathways. The erectogenic effect of sildenafil is mediated by a specific enhancement of cGMP accumulation in the corpus cavernosum, consistent with the known activity of sildenafil as a potent and highly selective inhibitor of cGMP‐specific PDE.