Endothelial function and dysfunction in coronary artery bypass grafting

Sammanfattning: The integrity of the endothelium is of importance for short- and long-term results following coronary artery bypass grafting (CABG). In this thesis different factors of the endothelial role in the regulation of vascular tone in relation to various current aspects of CABG have been investigated. In study I, the time dependent effects of local ischaemia and reperfusion on the coronary vasoreactivity in the pig was evaluated. The model used was chosen because of its similarities to offpump CABG. It was shown that already short-term (10 min) interruption of the coronary blood flow caused marked effects on the endothelium-dependent vasodilator capacity. In study II, the cardiac outflow of vasoactive substances (Endothelin-1 (ET-1), Nitric oxide (NO) and prostacyclin (PGI2)), and the metabolic strain, in off-pump CABG was evaluated. An increased outflow of PG12 was observed, as well as a significant myocardial lactate release. In study III, the coronary vasoreactivity following on-pump CABG in patients with stable and unstable angina pectoris, and following off-pump CABG was studied. Endothelium-dependent vasodilator mechanisms were better preserved in off-pump CABG, while there was no difference in endothelium independent coronary vasodilatation in off- and on-pump CABG. In study IV, the tissue content of ET-1 in the internal mammary artery (IMA) and the radial artery (RA) was determined. Furthermore the in vitro functional effects of ET-1 on the IMA and the RA was investigated. The highest level of ETA was found in the distal RA, and followed in declining order by the proximal RA, the ascending aorta and the distal IMA. ETA acted as a potent vasoconstrictor of the IMA and the RA, through interaction with mainly ETA-receptors. ETA-blockers abolished this constriction. In study V, the influence of CABG on the plasma levels of ETA and Big ETA, as well as the pericardial levels of ETA and Big ET-1, in stable and unstable patients was determined. In addition, the tissue content of ETA and Big ETA in the IMA, and the in vitro functional effects of ETA and Big ETA on the IMA, in stable and unstable patients, were investigated. Unstable angina pectoris was associated with an increased ETA turnover, as indicated by higher Big ETA, but lower ETA circulating plasma levels. The pericardial levels of ETA was lower in the unstable patients. Revascularisation of the unstable patients caused a normalisation of Big ETA and ETA levels. ET-1 and Big ETA acted as potent vasoconstrictors of the IMA, through interaction with mainly ETAreceptors, in stable as well as unstable patients. In study VI, the myocardial metabolic disturbance during on-pump CABG, as well as the cardiac outflow of vasoactive substances (ET-1, NO and PGI2) following on-pump CABG, and local ET blockade, was determined. The coronary vasoreactivity following intracoronary infusion of ETblockers subsequent to CABG, and the effects of ET-receptor blockade on the coronary blood flow subsequent to CABG was also investigated. A myocardial lactate release, as well as an increased outflow of PG12 was observed. ET-receptor blockade after ischaemia did not improve endotheliumdependent vasodilatation. ET-receptor antagonists (ETA-blockade alone or combined with ETBblockade) did not influence cardiac outflow of ETA and did not improve immediate myocardial blood flow following CABG. Conclusions: Based on the present study it may be concluded that: (i) Off-pump CABG is less harmful compared to on-pump CABG in terms of cardiac endothelial and metabolic integrity; (ii) Unstable angina pectoris is associated with augmented ET-metabolism which is reversed by CABG; (iii) ET content, action and receptor activation are similar in arterial grafts commonly used in CABG; (iv) Coronary perfusion immediately following on-pump CABG is not dependent on ET-receptor activation.