Search

The poor patency rates for coronary artery bypass grafting (CABG) using autologous saphenous vein necessitate the need for continued research into the potential clinical utility of gene therapy. Bypass grafting is ideally suited for gene therapy, as graft can be genetically modified ex vivo prior to grafting in the coronary vasculature. Research to date has demonstrated effective blockade of late vein graft failure through overexpression of a variety of transgenes that modulate the proliferative, migratory and/or apoptotic indexes of cells in the graft wall. This has resulted in a substantial wealth of preclinical data that support advancement to clinical trials. Future translation into clinical trials will ensure that this exciting and highly relevant area of gene therapy is fully evaluated for potential routine clinical practice to improve patency rates of bypass graft procedures involving saphenous vein.

Coronary artery bypass grafting with cardiopulmonary bypass (CPB) is known to be associated with a systemic inflammatory response, which contributes to the development of postoperative complications including multiple organ dysfunction. Off-pump coronary surgery has been shown to attenuate the inflammatory injury compared to the conventional approach, thereby reducing the incidence of postoperative cardiopulmonary, renal, or neurological dysfunction. It is believed that off-pump experience may greatly impact on improving the outcome of coronary surgery in certain high-risk patients. Moreover, a better understanding of the underlying mechanism would also help to improve our current CPB management. Accumulating evidence to date indicates that a balance between pro- and antiinflammatory responses is crucial in limiting the extent of such systemic inflammatory injury following surgical myocardial revascularization.

Objectives: Hyperkalemia in cardioplegia impairs the endothelium-derived hyperpolarizing factor (EDHF)-mediated function. This study examined the effect of procaine in cardioplegia on the EDHF-mediated response in porcine coronary arteries., Methods: An isometric force study was performed in a myograph. Two rings taken from the same artery (diameter 200-450 microm) were incubated with Krebs solution (group I) or 20 mM K+ (group II) with/without procaine (1 mM) at 37 degrees C for 1 hour. The EDHF-mediated relaxation was induced by bradykinin (BK, -10 approximately -6.5 log M) after U46619 (-8 log M, in group I) or K+-precontraction (in group II) in the presence of indomethacin (7 microM), NG-nitro-L-arginine (300 microM), and hemoglobin (20 microM). The membrane potential of a single smooth muscle cell was measured by a microelectrode after superfusion with Krebs solution with/without procaine for 1 hour., Results: The EDHF-mediated relaxation was increased by the treatment with procaine with the EC50 shifted leftward (97.3 +/- 0.6% vs. 83.0 +/- 5.1% at -7 log M and 99.4 +/- 0.6% vs. 96.7 +/- 1.6% at -6.5 log M, p < 0.05; EC50: -8.57 +/- 0.24 vs. -7.92 +/- 0.23 log M, p < 0.05). Procaine decreased the BK-induced hyperpolarization from -72.3 +/- 0.7 mV to -68.8 +/- 0.8 mV (-6.5 log M, p < 0.01). The EDHF-mediated relaxation in arteries exposed to 20 mM K+ was not altered by procaine (49.9 +/- 7.4% vs. 55.8 +/- 7.6%, p > 0.05)., Conclusions: In the coronary arteries, procaine has a depolarizing effect but it enhances EDHF-mediated relaxation. Addition of procaine in cardioplegia did not change the EDHF-mediated endothelial function.

Superoxide (O2-) is a key risk factor for cardiovascular disease (CVD), including atherogenesis, reperfusion injury, angina, restenosis following balloon angioplasty, and vein graft failure. Axiomatically, O2- reacts with nitric oxide (NO) to form peroxynitrite (ONOO) resulting in a depletion of endogenous vascular NO, which is now firmly associated with CVD. Furthermore, risk factors for CVD, in particular diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are all associated with oxidative stress OS. Antioxidant therapies, including the gene transfer of antioxidant enzymes, are potentially valuable in the treatment of CVD.

Aims: The effects of a new potassium channel opener KRN4884 on human arteries have not been studied. This study was designed to investigate the effects of KRN4884 on the human internal mammary artery (IMA) in order to provide information on possible clinical applications of KRN4884 for preventing and relieving vasospasm of arterial grafts in coronary artery bypass grafting., Methods: IMA segments (n = 140) taken from patients undergoing coronary surgery were studied in the organ chamber. Concentration-relaxation curves for KRN4884 were established in the IMA precontracted with noradrenaline (NA), 5-hydroxytryptamine (5-HT), angiotensin II (ANG II), and endothelin-1 (ET-1). The effect of glibenclamide (GBC) on the KRN4884-induced relaxation was also examined in NA or 5-HT-precontracted IMA. Concentration-contraction curves for the four vasoconstrictors were constructed without/with pretreatment of KNR4884 (1 or 30 microM) for 15 min., Results: KRN4884 induced less relaxation (P < 0.05) in the precontraction induced by ET-1 (72.9 +/- 5.5%) than by ANG II (94.2 +/- 3.2%) or NA (93.7 +/- 4.1%) with lower EC50 (P < 0.05) for ANG II (-8.54 +/- 0.54 log M) than that for NA (-6.14 +/- 0.15 log M) or ET-1 (-6.69 +/- 0.34 log M). The relaxation in the IMA pretreated with GBC was less than that in control (P < 0.05). KRN4884-pretreatment significantly reduced the contraction (P < 0.05) induced by NA (151.3 +/- 18.4% vs 82.7 +/- 8. 7%), 5-HT (82.7 +/- 12.2% vs 30.1 +/- 7.3%), and ANG II (24.3 +/- 6. 3% vs 5.4 +/- 1.6%), but did not significantly reduce the contraction induced by ET-1 (P > 0.05)., Conclusion: KRN4884 has marked vasorelaxant effects on the human IMA contracted by a variety of vasoconstrictors and the effect is vasoconstrictor-selective.

Background: While the operative technique of left ventricular volume reduction (LVVR) is rapidly becoming standardized, the optimal perioperative management strategy is yet to be determined. We present our experience with the care of patients undergoing LVVR., Methods: LVVR was performed in 21 patients (mean age = 65.5 years) with congestive heart failure. Our management strategy was initially based on afterload reduction with sodium nitroprusside, but was later modified to include routine preoperative intra-aortic balloon support, normothermic cardiopulmonary bypass, antegrade intermittent warm blood cardioplegia, and postoperative support with phosphodiesterase-III inhibitors. Hemodynamic manipulations are aimed to attain systemic vascular resistance between 600 and 800 dyne/sec per cm(-5) and the lowest mean blood pressure that is able to maintain satisfactory systemic perfusion. Postoperatively, aggressive antifailure medical therapy with a high dose of angiotensin converting enzyme inhibitors, nitrates, and diuretics was initiated early and maintained indefinitely., Results: Using this approach, postoperative progress was characterized by hemodynamic stability. IABP support was used for 59.6+/-9 hours following surgery, and inotropic support for 103+/-12 hours. In our series there were four (19%) in-hospital deaths, two of which were related to heart failure., Conclusion: The described approach is associated with an acceptable early outcome. However, further advances in myocardial protection methods and pharmacological and mechanical support techniques are necessary for a wider adoption of this procedure.

1. Four types of prostanoid receptor are present on pulmonary arterial vessels of man. Thromboxane (TP) receptors mediate constriction and are blocked by antagonists such as BAY u-3405, GR 32,191 and EP 169. Prostaglandin (PG) EP3 receptors also mediate constriction, the agonist potency ranking being SC 46,275 > sulprostone > misoprostol > or = PGE2; this action needs to be borne in mind when PGE analogues are used therapeutically. 2. Prostaglandin E2 causes relaxation in a few pulmonary artery preparations: an EP2 receptor may be involved. Prostacyclin, acting through i.p. receptors, consistently produces relaxation and studies are in progress to determine the contribution made by K(+)-channel opening. Agonist potencies of stable prostacyclin analogues and non-prostanoid prostacyclin mimetics, such as BMY 45,778 and the novel diphenylindole CU 23, on human pulmonary artery and platelets are well correlated. Interestingly, the non-prostanoid mimetics show persistent relaxant effects in vitro, which may be related to their high lipophilicities. 3. Prostacyclin and iloprost are being used to treat severe pulmonary hypertension; further study of the pharmacodynamic and pharmacokinetic properties of other i.p. receptor agonists could produce improved therapy.