Levente Fazekas

Acute kidney injury is associated with higher morbidity and resource utilization in pediatric patients undergoing heart surgery.

BACKGROUND The RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification system was developed to standardize the definition of acute kidney injury (AKI) in adults. We hypothesized that AKI was associated with increased mortality and morbidity. METHODS Acute kidney injury was defined as a decrease in the amount of estimated creatinine clearance based on pediatric-modified RIFLE (pRIFLE) criteria. Using propensity score analysis, 325 patients who had AKI were matched to 325 patients who did not have AKI from a database of 1,510 consecutive pediatric patients who underwent cardiac surgery between January 2004 and December 2008 at a single center. The association between AKI and outcome was analyzed after propensity score matching of perioperative variables. RESULTS Four hundred eighty-one patients (31.9%) had AKI according to the RIFLE categories. Of those 1,510, 173 (11.5%) reached pRIFLE criteria for risk; 26 (1.7%) reached the criteria for injury; and 282 (18.7%) reached the criteria for failure. Fifty-five patients (3.6%) died. The 2 matched groups were well balanced in terms of measured perioperative variables. Mortality rate was 5.2% in the AKI and 2.5% in the matched control group (p=0.09). Occurrence of low cardiac output syndrome (p=0.002), need for dialysis (p<0.001), and infection (p=0.03) were significantly higher, and duration of mechanical ventilation (p<0.001) and length of intensive care unit stay (p<0.001) were significantly longer compared with the matched control group. CONCLUSIONS Acute kidney injury was independently associated with an increased occurrence of postoperative complications but not with mortality after pediatric cardiac surgery.

Endothelin-A and -B antagonists protect myocardial and endothelial function after ischemia/reperfusion in a rat heart transplantation model

OBJECTIVE Previous studies suggested that endothelin-1 (ET-1) may play a pathophysiological role in myocardial ischemia/reperfusion injury. This study was designed to investigate the effects of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia in a heterotopic rat heart transplantation model. METHODS Isogenic intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of cold ischemic preservation reperfusion was started either after application of placebo (control), BQ123 (3 mumol/kg/min). BQ788 (3 mumol/kg/min), ET-1 (8 pmol/kg/min) or simultaneous infusion of BQ123 or BQ788 and ET-1, respectively (n = 12 each). An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Myocardial blood flow (MBF) was assessed by the hydrogen-clearance method. Measurements were taken after 1 and 24 h of reperfusion. Endothelium-dependent vasodilation to acetylcholine (ACH) and endothelium-independent vasodilation to sodium nitroprusside were also determined. RESULTS Both BQ123 and BQ788 significantly improved myocardial and endothelial functional recovery during early reperfusion, whereas ET-1 significantly impaired myocardial and endothelial function. Simultaneous infusion of ET-1 diminished the effects of BQ123 and BQ788. Although myocardial function and baseline MBF were similar in all groups after 24 h of reperfusion, endothelium dependent vasodilation to ACH was still significantly higher in the BQ123 and BQ788 groups and lower in the ET-1 groups (p < 0.05). CONCLUSIONS These results suggest that endogenous ET release is involved in the pathogenesis of reperfusion injury after heart transplantation. ET-A and ET-B receptor antagonists may be useful to reduce ischemia/reperfusion injury.

Ventricular arrhythmias induced by endothelin-1 or by acute ischemia: a comparative analysis using three-dimensional mapping

OBJECTIVES To analyze three-dimensional activation patterns of ventricular arrhythmias induced by endothelin-1 in comparison with ischemia-induced tachycardias. METHODS Following AV node ablation, sixty pin electrodes containing four bipoles each were inserted into both ventricles of ten foxhounds. Using a computerized mapping system, this would allow to simultaneously record 240 endo-, epi- and midmyocardial electrograms for reconstruction of the three-dimensional activation pattern. In five dogs, endothelin-1 was infused into the LAD at 60 pmol/min. In another five animals, the LAD was ligated. During the following 40 min, all ventricular arrhythmias were recorded for subsequent analysis. Furthermore, left ventricular conduction times during constant pacing and local effective refractory periods at eight left ventricular sites were determined before and after either intervention. RESULTS Endothelin-1 had no significant effect on conduction time and refractoriness, whereas ligation prolonged both parameters significantly. Endothelin-1 as well as ligation induced multiple mono- and polymorphic nonsustained ventricular tachycardias. Endothelin-1-induced arrhythmias were exclusively based on focal mechanisms, whereas during ligation, macroreentrant mechanisms were involved in the maintenance of tachycardias in 29% of episodes. CONCLUSION The differences in the effects of endothelin-1 and LAD ligation on electrophysiologic properties and the difference in the mechanism of induced ventricular tachycardias support the hypothesis that, apart from vasoconstrictive properties, endothelin-1 exerts an intrinsic arrhythmogenic effect.

Enhanced accumulation of pericardial fluid adenosine and inosine in patients with coronary artery disease

Adenosine and inosine are believed to have cardioprotective effects. However, little is known about their possible role in the metabolic autoregulation of human coronaries and in pathologic conditions with supply/demand imbalance of the heart such as coronary artery disease. Since these low molecular weight nucleosides freely diffuse through the monolayer of the visceral pericardium, adenosine and inosine concentrations in pericardial fluid may well reflect the conditions in cardiac interstitium. The pericardial fluid and systemic venous blood adenosine and inosine concentrations were measured in 98 human subjects undergoing heart surgery for coronary artery disease or valvular heart disease. Adenosine and inosine concentrations were measured by HPLC with UV detection. In subjects with coronary artery disease pericardial fluid nucleoside concentrations were significantly higher than in patients with valvular heart disease (adenosine: 1545 (996-3146) nmol/L [median (25th-75th quartiles)] vs. 738 (390-2527) nmol/L, P<0.01; inosine: 658 (321-1331) nmol/L vs. 347 (159-1037) nmol/L, P<0.05), while in both patient groups pericardial fluid nucleoside concentrations were higher by an order of magnitude than in venous plasma. Our results show the enhanced release of adenosine and inosine by the ischemic myocardium as a marker of supply/demand imbalance and support the hypothesis that these cardiac nucleosides may have an important role in the adaptation of coronary blood flow in human coronary artery disease.

The Coronary Effects of Parathyroid Hormone

Objective: The aim of the present study was to characterize the role of the ATP-sensitive potassium channels (K+ATP) in the coronary dilator action of parathyroid hormone (PTH). Methods: Dose-response curves of intracoronary administrated PTH (0.15–1.33 nmol) were obtained in control phases and during continuous intracoronary administration of the K+ATP channel-selective antagonist glibenclamide (0.1–1.0 µmol/min) in dogs (n = 13). Results: Increments of integrated coronary conductance (excess coronary conductance) at PTH doses of 0.15 and 1.33 nmol were 1.17 versus 0.03 ml/mm Hg (p < 0.05) and 4.03 versus 0.94 ml/mm Hg (p < 0.05) in the control versus during maximal blockade, respectively. Conclusion: The results indicate that the activation of K+ATP channels significantly contributes to the PTH-induced coronary vasodilation.

Cardiothermographic assessment of arterial and venous revascularization

High blood-flow rate and considerable metabolic activity render the myocardium a possible candidate for infrared (IR) imaging. Cardiothermography is the term used for recording the heart surface temperature. It is a useful tool in monitoring coronary perfusion through epicardial heat emission changes. Elevated heat-emission indicates increased coronary blood flow, while decreased emission represents hypoperfusion. The aim of our study is the early intraoperative cardiothermographic evaluation of arterial and venous bypass graft patency and the quantitative assessment of the temperature changes of the revascularized area. Infrared imaging was complemented by electromagnetic flow measurements on the venous grafts.

Uneven Flow Distribution in the Heart Induced by Endothelin

The safety of cardiac energy balance depends on the equilibrium and near uniformity of the intramyocardial tissue oxygen level ensured by the coronary supply. Since the myocardium is deprived of the sufficient capacity of anaerobiosis, the most important function of the smooth muscle in the coronary vessel wall is to adapt continuously to the changing O2 demands of the heart muscle. At the same time, in contrast with expectations of conventional wisdom, the coronary vessels are well equipped with vasoconstrictor nervous elements: the effect of the local release of neurotransmitters, primarily norepinephrine, was found to be superimposed on the inherent, highly developed myogenic tone in the coronaries (Feigl, 1983). Traditionally, vasodilator modulation of this vascular tone is attributed (beside s-adrenergic influences) to metabolic factors produced by the myocardial tissue.

SIMULTANEOUS RECORDINGS OF THE MONOPHASIC ACTION POTENTIAL WITH SILVER CHLORIDE- AND IR-COATED ELECTRODES

Ag AgCI and Ir‐coated electrodes allow the recording of the monophasic action potential (MAP) due to their electrical properties like non‐polarisability. This study investigates the correlation of MAP recorded with both types of electrodes. In 20 mongrel dogs (18 ± 6 kg) an Ag/AgCI and an Ir‐coated catheter (Ir) were placed endo‐cardially in the apex of the right ventricle. The effects of isoproterenol and verapamil were investigated during spontaneous rhythm and stimulation simultaneously recorded with both types of electrodes in 10 dogs without AV‐node ablation. The correlation at different heart rates were investigated in 10 other dogs with complete AV‐block. The morphology and amplitudes of MAP were comparable (AgCl: 15±7 mV; Ir: 13±8 mV). Following an i.v. bolus of 2μg/kg isoproterenol the spontaneous rate increased (175±18 to 245±25 bpm). During stimulation with 250 ms cycle length the duration shortened (MAPd90: AgCl: 160 ± 11 to 130 ± 12 ms; Ir: 154 ± 18 to 128±15 ms). The alterations reversed after 20 mm. An i.v. bolus of 0.2 mg/kg verapamil decreased the spontaneous rate (167±11 to 104 ± 23 bpm) and lengthened the MAPd90 (AgCl: 182 ± 14 to 220±13 ms; Ir: 174 ± 16 to 216, 21 ms) at 300 ms stimulation. The correlation between the MAPd90 of both lead types was r=0.98 during all measurements. Under the effect of beta‐agonist and Ca2+ ‐antagonist medication MAP showed a strong correlation recorded with both types of electrodes. Thus, both leads allow the recording of MAP but only the Ir‐electrodes with their long‐term stability are implantable and allows us to control the effects of drugs with implantable devices.

Role of K+ ATP channels in the metabolic adaptation of the coronaries

In the coronary vascular bed multiple mechanisms interact with each other to control the blood supply of the heart muscle and oxygen transport to cardiac myocytes. Since the early works of Drury & Szent-Gyorgyi in 1929 and Berne in 1963 the most tempting hypothesis for this control is based on the metabolic theory. The intrinsic mechanism which matches coronary blood flow (CBF) to myocardial demand would be mediated by adenosine, a purine compound, released by cardiac myocytes in metabolic stress, which has a vasodilator effect on coronary vascular smooth muscle cells (VSMC). However, the natural P1 purinergic antagonist methylxantines, while blocking the exogenous adenosine effects, fail to antagonize the metabolic autoregulatory responses i.e., the functional hyperemia in the same vascular bed. This is the greatest flaw of the adenosine hypothesis of coronary autoregulation. In the myocardial tissue the presence of inosine, the first breakdown product of adenosine, may be responsible for this difference because inosine, which has a vasodilator action of its own, strongly potentiates adenosine-induced vasodilation (Kekesi et al., 1986). Accordingly, inosine may function as a co-transmitter. If so, the coronary vasodilator action of inosine—which is also remarkably resistant to methylxantine blockade—should be blocked by the K+ ATP channel antagonist sulfonylureas which effectively antagonize both adenosine vasodilation and reactive hyperemia.

Intraoperative IR imaging in the cardiac operating room

The high blood flow rate and the considerable metabolic activity render the myocardium a possible candidate for IR imaging. The study was aimed to test cardiothermography in evaluating arterial bypass graft patency and in assessing myocardial protection during open-heart surgery. Ten patients underwent arterial bypass grafting. Thermograms were obtained immediately before and after opening the grafts. As the bypasses were opened in hypothermia the warmer blood coming from the extracorporeal circulation readily delineated graft and coronary anatomy. By the end of the 5 min observation period, the revascularized area exhibited a temperature increase of 5.9 +/- 0.7 degrees C. The affectivity of antegrade cardioplegia was monitored in 38 patients undergoing either valve implantations or aorto- coronary bypass surgery. Thermographic imags were taken after sternotomy, before aortic cross-clamping and after administrating the 4 degrees C cardioplegic solution. Most of the patients displayed adequate myocardial cooling, moreover the bypass-group exhibited a more profound temperature-decrease. In conclusion, cardiothermography can visualize arterial grafts, recipient coronaries and collaterals seconds after opening by bypass, thus it properly evaluated arterial bypass graft patency. The obtained images could easily be analyzed for qualitative flow- and quantitative temperature changes. Myocardial protection could also be safely assessed with thermography.