Impaired myocardial t-PA release in patients with coronary artery disease.

AIMS: Myocardial ischemia remains a significant perioperative complication in coronary artery disease (CAD) patients. We hypothesized that noxious stimuli during major surgery are associated with an acute release of tissue-type plasminogen activator (t-PA) into the coronary circulation, and that this response is reduced by CAD. METHODS AND RESULTS: Two patient groups, with (n=14) and without (n=8) CAD, were studied during the initial phase of heart surgery. After retrograde great cardiac vein catheterizations during closed-chest conditions, coronary arterial-venous concentration gradients of t-PA and plasminogen activator inhibitor type-1 (PAI-1) were measured together with coronary blood flow measurements, allowing derivation of coronary net release rates. Pre-surgery atrial pacing, performed to evaluate the influence of increases in heart rate (+ 40 beats/min) and coronary blood flow (+ 80 ml/min), did not significantly alter coronary net release of t-PA or PAI-1 in either patient group. Sternotomy induced a prominent increase in coronary net release of both total and active t-PA in the non-CAD group. This response was considerably reduced in the CAD group. CONCLUSIONS: This study provides the first analysis of coronary t-PA release during major surgery and demonstrates a deficient local endothelial t-PA release in patients with CAD. This suggests a reduced local fibrinolytic capacity in CAD patients, which may explain the increased risk for coronary thrombosis in this patient group.

Myocardial ischemia induces coronary t-PA release in the pig.

BACKGROUND: Tissue-type plasminogen activator (t-PA) is the key factor in initiating endogenous fibrinolysis in the vascular compartment. Regulated release of t-PA from endothelial stores is rapidly induced by several humoral factors as well as coagulation activation products. The aim of the present study was to test the hypothesis that regional myocardial ischemia induces regulated release of t-PA in the coronary vasculature in vivo. METHODS: Healthy anesthetized (pentobarbital) pigs (n=8) were studied before and after a 10-min left anterior descending region coronary artery occlusion (LAD). Coronary fluxes of lactate, total t-PA antigen (ELISA, detecting both complex bound and free fraction) and active t-PA (functional assay detecting biological free fraction) were determined at 1, 3, 5 and 10 min of reflow. RESULTS: Coronary occlusion induced myocardial lactate production in all animals. Net coronary release of total t-PA, which was 21 ng/min during control, increased rapidly during reflow with a peak after only 1 min (136 ng/min), and returned to baseline within 3 min. Net release of active t-PA mirrored the overall net release response, but fell short of statistical significance. CONCLUSION: Data indicate a local myocardial profibrinolytic response following regional ischemia, which may serve as a prompt defence against coronary thromboembolic events.

The cardiac effects of intracoronary angiotensin II infusion.

UNLABELLED: Angiotensin II (Ang II) is a potent vasoconstrictor, which recently has been shown to also have significant inotropic effects. Previous results regarding the mechanisms of the acute inotropic effects of Ang II are not conclusive. We designed this study to investigate the local cardiac effects of intracoronary Ang II infusion in doses not affecting systemic circulation. Ang II (2.5-40 microg/h) was infused in the left coronary artery of Yorkshire pigs (n = 9) reaching calculated intracoronary Ang II concentrations of 842 +/- 310, 3342 +/- 1238, and 12448 +/- 4393 pg/mL, respectively. Cardiac systolic and diastolic function was evaluated by analysis of the left ventricular pressure-volume relationship. Coronary flow was measured by using a coronary sinus catheter and the retrograde thermodilution technique. No significant changes were seen in the systolic and diastolic function variables of heart rate, end-systolic elastance, preload recruitable stroke work, the time constant for isovolumetric relaxation, or in coronary vascular resistance and flow. The positive inotropic and chronotropic effects of Ang II seen in previous studies seem thus to be mediated via extracardiac actions of Ang II. Coronary vascular tone is not affected by local Ang II infusion in anesthetized pigs. IMPLICATIONS: The positive inotropic and chronotropic effects of angiotension II (Ang II) seen in previous studies seem to be mediated via extracardiac actions of Ang II. Coronary vascular tone is not affected by local Ang II infusion in anesthetized pigs.

Surgical stress induces acute coronary release of tissue-type plasminogen activator in the pig.

BACKGROUND: Tissue-type plasminogen activator (t-PA) is an endothelium derived key enzyme in the initiation of endogenous fibrinolysis. Acute regulated release of active t-PA occurs within minutes in response to threatening thrombotic vessel occlusion. The aim of this study was to investigate the impact of surgical stimulation on the kinetics of t-PA release in the coronary vascular bed in the pig. METHODS: In anaesthetised pigs (n=16), arterio-venous concentration gradients of t-PA, and plasma flows (retrograde thermodilution) were obtained across the coronary vascular bed before (control) and at 1, 3, 5 and 10 min after sternotomy. RESULTS: At control, no significant coronary net flux (release or uptake) of t-PA was observed, while sternotomy induced a rapid net release of total t-PA (132.6 ng x min(-1)), with an associated increase in active t-PA (93.6 ng x min(-1)). This response, evident already after 1 min, showed a peak at 5 min and returned towards baseline levels within 10 min. No concurrent alterations in aortic levels of active t-PA were found and haemodynamic variables were unaltered. CONCLUSION: The rapidly increasing and transient net coronary release of t-PA after sternotomy suggests that the endothelium actively promotes local endogenous fibrinolysis during surgery. Such events could reflect a dynamic responsiveness to protect the coronary circulation during stress.

Reduced cancer incidence among the blind.

Melatonin is a hormone primarily produced by the pineal gland at night and is suppressed by exposure to light. Experimental studies have indicated that melatonin may protect against cancer development. In the majority of totally blind people, melatonin is never suppressed by light exposure. The aim of this study was to test the hypothesis that blind people have a decreased cancer incidence, and that this effect is more pronounced in the totally blind than in the severely visually impaired. We identified a cohort of 1,567 totally blind and 13,292 severely visually impaired subjects and obtained information about cancer incidence from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) based on the number of person-years and incidence rates specific for national age, sex, and calendar year. Totally blind people had a lower incidence of all cancers combined [SIR = 0.69; 95% confidence interval (CI) = 0.59-0.82]. The risk reduction was observed in both men and women and was equally pronounced in hormone-dependent tumors as in other types of cancer. In the severely visually impaired, SIR was 0.95 (95% CI = 0.91-1.00). The findings support the hypothesis that blind people have a lower cancer incidence, although other explanations than the higher melatonin exposure must also be considered.

A new method of using gas exchange measurements for the noninvasive determination of cardiac output: clinical experiences in adults following cardiac surgery.

New mathematical algorithms have been applied to a computer controlled closed breathing circuit system for non-invasive measurement of cardiac output (COniv). This system has been described in an animal study. Forty patients were studied 5 and 18 hours after cardiac surgery using the thermodilution technique as the reference (COtd). The variables entered into the algorithms for COniv were oxygen uptake, carbon dioxide elimination, end-tidal carbon dioxide partial pressure, tidal volume and arterial oxygen saturation. Mixed venous carbon dioxide partial pressure was obtained from an automatically implemented short rebreathing manoeuvre. Pulmonary perfusion was calculated by a modified Fick equation for carbon dioxide and the shunt flow added to obtain COniv. During mechanical ventilation, there was a good agreement between COtd and COniv (r = 0.8). The bias was -0.14 l/min and the precision was 0.77 l/min. The reproducibility of COniv was 0.03 l/min and for COtd -0.03 l/min with a standard deviation of the difference being 0.35 l/min for COniv and 0.31 l/min for COtd. In awake, but sedated extubated patients, the method proved unsatisfactory on account for uneven tidal volumes and difficulties with leakage around the mouth piece. We conclude that this new technique provides reliable and reproducible measures of cardiac output in sedated, ventilated patients.

A malonyl-CoA-binding protein from liver.

A soluble protein that binds malonyl-CoA without requiring cofactors has been purified from rat liver. Until saturated, it competes with fatty acid synthetase for free malonyl-CoA, temporarily reducing the rate of fatty acid synthesis at low levels of malonyl-CoA, as in fatty acid synthetase--coupled assays for acetyl-CoA carboxylase. These assays yield low estimates for carboxylase activity with crude and partially purified homogenates containing the malonyl-CoA-binding protein. The protein does not inhibit assays for carboxylase activity that measure nonvolatile radioactivity incorporated from bicarbonate or NADH oxidation coupled to ADP formation. It has an Mr of 180,000 and a subunit of 90,000. It has a lower affinity for ATP, ADP, and acetyl-CoA and none for CO2 or fatty acid synthetase. No enzymatic function has been identified. The protein may regulate malonyl-CoA-binding enzymes.

Crystallization of glycogen debranching enzyme.

Crystals of glycogen debranching enzyme from rabbit skeletal muscle have been obtained from solutions of polyethylene glycol 8000 (pH 7.3) containing 10 mM-linear oligosaccharides of lengths from three to seven glucose units in alpha-1,4 linkage. Preliminary X-ray precession photographs indicate an orthorhombie unit cell with dimensions of a = 106.4 A, b = 195.7 A and c = 93.0 A. The space group is P212121 with one monomer per asymmetric unit.