Bernhard Korbmacher

Ca2+ sensitizer superior to catecholamine during myocardial stunning?

BACKGROUND After open-chest cardiac surgery, ventricular function remains depressed (myocardial stunning). Catecholamines (epinephrine) improve ventricular function by increasing the intracellular Ca(2+) concentration. In parallel, the oxygen consumption is increased, so that the hitherto intact myocardium can be jeopardized. In the very insufficient ventricle, epinephrine can even become ineffective. Since Ca(2+) sensitizers provide another therapeutic avenue, the effects of epinephrine and levosimendan on postischemic hemodynamics were investigated. METHODS After hemodynamic steady state, isolated, blood (erythrocyte-enriched Krebs-Henseleit solution)-perfused rabbit hearts were subjected to 25 min normothermic, no-flow ischemia and 20 min reperfusion. Heart rate (HR), cardiac output (CO), left ventricular pressure (LVP), coronary blood flow (CBF), and arterio-venous oxygen difference (AVDO(2)) were recorded during reperfusion and after administration of either epinephrine (n=16; 0.03 micromol), or levosimendan (n=11; 0.75 micromol) or epinephrine plus levosimendan (n=5). RESULTS Epinephrine increased HR (19%, p=0.01) and improved hemodynamics in terms of CO (62%, p=0.0006), stroke volume SV (46%, p=0.02), stroke work W (158%, p=0.01), LVP(max) (58%, p=0.0001), maximal pressure increase dP/dt(max)(140%, p=0.0004), minimal pressure increase dP/dt(min) (104%, p=0.0002), LVP(ed) (-26%, p=0.02), and increased coronary resistance CR (31%, p=0.05). Epinephrine impaired hemodynamics in terms of AVDO(2) (+63%, p=0.003), myocardial oxygen consumption MVO(2) (+67%, p=0.0003) and MVO(2)/beat (+36%, p=0.01). External efficiency eta was increased by 92% (p=0.02). Levosimendan in postischemic hearts increased HR (32%, p=0.009) and improved hemodynamics in terms of CO (85%, p=0.01), SV (44%, p=0.03), W (115%, p=0.04), LVP(max) (95%, p=0.04), dP/dt(max) (133%, p=0.009), dP/dt(min) (121%, p=0.007), LVP(ed) (-63%, p=0.0006), and CR (-17%; n.s., p=0.1). It altered hemodynamics in terms of AVDO(2) (+7.0%; n.s., p=0.3) and MVO(2) (+32%, p=0.007) and MVO(2)/beat (+2.3%; n.s., p=0.4). External efficiency was increased by 307% (p=0.04). In five additional extremely dysfunctional rabbit hearts, epinephrine was ineffective. Additional levosimendan increased hemodynamics in terms of HR (56%; n.s., p=0.1), CO (159%, p=0.04), SV (89%, p=0.03), W (588%, p=0.02), LVP(max) (168%, p=0.03), dP/dt(max) (102%, p=0.005), dP/dt(min) (78%, p=0.006), LVP(ed) (-98%, p=0.0006), and CR (-50%, p=0.02). It altered hemodynamics in terms of AVDO(2) (-11%; n.s., p=0.05), MVO(2) (+131%, p=0.04) and MVO(2)/beat (+171%, p=0.03). External efficiency was increased by 212% (p=0.04). CONCLUSION In contrast to epinephrine, levosimendan improves ventricular function without increasing oxygen demand, thereby considerably improving external efficiency. Even during epinephrine resistance in extremely dysfunctional hearts, levosimendan successfully improves ventricular function.

Cardiac stunning in the clinic: the full picture

Cardiac stunning refers to different dysfunctional levels occurring after an episode of acute ischemia, despite blood flow is near normal or normal. The phenomenon was initially identified in animal models, where it has been very well characterized. After being established in the experimental setting, it remained unclear, whether a similar syndrome occurs in humans. In addition, it remained controversial, whether stunning was of any clinical relevance as it is spontaneously reversible. Hence, many studies continue to focus on the properties and mechanisms of stunning, although therapies seem more relevant for attenuating and treating myocardial ischemia/reperfusion (I/R) injury, i.e. to bridge until recovery. This article reviews the different facets of cardiac stunning, i.e. myocardial, vascular/microvascular/endothelial, metabolic, neural/neuronal, and electrical stunning. This review also displays where these facets exist and which clinical relevance they might have. Particular attention is directed to the different therapeutic interventions that the various facets of this I/R-induced cardiac injury might require. A final outlook considers possible alternatives to further reduce the detrimental consequences of brief episodes of ischemia and reperfusion.

Right and left ventricular volume measurements in an animal heart model in vitro: first experiences with cardiac MRI at 1.0 T.

Abstract. The aim of this study was to determine the accuracy in quantifying right and left ventricular volumes using a 1.0-T system and commercially available, standard equipment. For exact comparison of MRI measurements and real volumes we used an animal heart model ex vivo. Eight pig hearts were explanted and prepared by removal of the atria. Aorta and pulmonary truncus were cannulated. Definable volumes were injected into the ventricles. Magnetic resonance imaging was performed at 1.0 T (Gyroscan T10 NT, Philips, Eindhoven, The Netherlands); sequence: fast field echo–echo planar (multishot EPI); body coil; MR software: Cardiac Application Package (Philips). Statistical analysis correlated the real volumes and MR measurements separately for both ventricles and two investigators (SAS, ANOVA). For both ventricles and both investigators the correlation between real volumes and MR measurements was greater than 0.99. There was no significant systematic false estimation for both ventricles. Magnetic resonance imaging at 1.0 T using standard hardware and software equipment enables the quantification of right and left ventricular volumes with high approximation to the real volumes in vitro. There is a clear restriction in translating these data into a clinical application because under experimental conditions no motion-induced artifacts existed.

Improved ventricular function by enhancing the Ca++ sensitivity in normal and stunned myocardium of isolated rabbit hearts.

SummaryA possible cause for the decreased function in postischemic reperfused (=stunned) myocardium could be a decrease in Ca++ sensitivity. To test this hypothesis, we used an agent with reportedly Ca++ sensitizing properties (EMD 57033) and performed experiments on a total of 17 isolated rabbit hearts that were perfused with an erythrocyte-containing medium in a modified Langendorff setting (hct=30%; Ca++=2.0 meq/l). The hearts were divided into two groups. In one group (n=9), the Ca++ sensitizer (30 μM) was administered to nonischemic myocardium, and in a second group (n=8), the Ca++ sensitizer was administered after 30 min of reperfusion that followed a period of 20 min normothermic, no-flow ischemia.In the nonischemic group, addition of the agent, improved left ventricular (LV) function significantly. In the ischemic group, LV-function was depressed at 30 min reperfusion compared to control. Again, the agent improved LV-function significantly. The increase in systolic and diastolic function was comparable in both groups as well as the oxygen consumption that was significantly increased after administration of the agent. In both groups, the agent neither exhibited significant, positive chronotropic nor arrhythmogenic effects.We summarize that the novel Ca++ sensitizer acts as a potent positive inotropic agent in the isolated blood-perfused rabbit heart. Because of the agents properties to ameliorate postischemic contractile dysfunction, this general strategy may be useful for treating poorly functioning reperfused myocardium.

Inotropic, Vasodilating and Preconditioning Actions of Levosimendan in the Heart

BACKGROUND Levosimendan improves ventricular function, induces vasodilation and induces myocardial preconditioning. We determined the external efficiency and assessed the effects on arrhythmias. METHODS In isolated, blood-perfused rabbit hearts, levosimendan (0.75 micromol) or placebo was administered, while hemodynamics were recorded. After no-flow ischemia and reperfusion, data were recorded again. RESULTS Placebo in normoxic hearts did not affect measurements, while levosimendan increased heart rate (+ 18 %) and improved coronary output (+ 52 %), stroke volume (+ 28 %), maximal left ventricular pressure (+ 30 %), maximal rate of pressure increase (+ 36 %), work (+ 68 %), minimal rate of pressure increase (+ 53 %), coronary blood flow (+ 41 %), coronary resistance (- 19 %) and external efficiency (33 %; P < 0.05). During reperfusion, hemodynamics in the levosimendan group were significantly better preserved compared with the placebo group. Early reperfusion arrhythmias were decreased (levosimendan group: 7 +/- 3 % vs. placebo group: 25 +/- 17 %; P < 0.05). CONCLUSIONS Levosimendan does not impair diastole, dilates coronary vessels, induces pharmacological preconditioning, improves external efficiency and exerts antiarrhythmic properties during reperfusion. As this drug protects the heart from reperfusion injury, it seems well suited for treating dysfunctional hearts after cardiac surgery.

Myocardial efficiency in stunned myocardium. Comparison of Ca2+-sensitization and PDE III-inhibition on energy consumption

OBJECTIVE In stunned myocardium oxygen consumption is relatively high compared with the reduced ventricular function. On the other hand, inotropic stimulation is frequently required to improve postischemic ventricular dysfunction. However, inotropic agents which act via intracellular increased calcium result in a higher oxygen demand. Therefore Ca(2+)-sensitization might be a favorable alternative. METHODS The effects of a novel Ca(2+)-sensitizer (EMD 60263, 10 microM, group 1) were compared with a phosphodiesterase (PDE) III-inhibitor (enoximon, 20 microM, group 2) on 14 isolated, blood-perfused rabbit hearts during reperfusion after a global ischemia of 20 min. Ventricular function, the pressure-volume area (PVA, a measure of total mechanical work), and total myocardial oxygen consumption (MVO(2)) were assessed. Contractile efficiency (EF(cont)), derived from the reciprocal of the slope of the MVO(2)-PVA relation, and external efficiency (EF(ex), stroke work/MVO(2)), were calculated. RESULTS At matched heart rate (group 1: 141+/-10 min(-1) group 2: 151+/-28 min(-1)) and end-diastolic volume (1.3+/-0.2 ml) systolic variables were significantly decreased in stunned myocardium: LVP(max) to 57+/-13% of control value in group 1 and to 76+/-7% in group 2, aortic flow to 20+/-4 vs. 25+/-8%. PVA was decreased to 57+/-13 and 67+/-11%, MVO(2) was non-significantly decreased to 73+/-22 and 88+/-14%. After administration of either inotropic agent LVP(max) was significantly improved to 96+/-12 vs. 90+/-8% compared with preischemic levels, aortic flow to 103+/-24 vs. 88+/-9%, and PVA 99+/-11 vs. 89+/-16%, respectively. EMD 60263 increased MVO(2) to control levels (107+/-9%), and enoximon raised MVO(2) even more significantly above control (139+/-13%). Both myocardial efficiency indices were significantly diminished during reperfusion: EF(ex) to 14+/-9 vs. 23+/-7% and EF(cont) to 71+/-7 vs. 65+/-9% compared with preischemic levels. EF(ex) (109+/-21%) was significantly, but EF(cont) only slightly (84+/-11%) increased after administration of EMD 60263, whereas EF(ex) (57+/-13%) and EF(cont) (71+/-12%) remained depressed after enoximon. CONCLUSIONS In stunned myocardium, the decreased efficiency indices show that energy utilization is disturbed. Both agents recruited an inotropic reserve, whereas Ca(2+)-sensitization seemed to be more favorable in terms of myocardial efficiency indices. These results indicate that alteration of myocardial calcium sensitivity contributes a major part to postischemic dysfunction. Therefore, Ca(2+)-sensitization may potentially be a superior method for inotropic support in the postischemic heart.

In vitro determination of cardiac ventricular volumes using MRI at 1.0 T in a porcine heart model.

Purpose: To determine the accuracy of a 1.0 T MR system with a standard gradient system for quantification of left and right ventricular volumes. A porcine heart model in vitro was used. Methods: In eight explanted porcine hearts the atria were removed and the aorta and the pulmonary truncus were cannulated. Defined volumes were injected into the ventricles. Magnetic resonance imaging (MRI): FFE-EPI (Multishot EPI) was used. Papillary muscles and trabeculae were excluded. True volumes and MR measurements were analysed separately for both ventricles and by both investigators. Results: The correlation of the true volumes and MR measurements was > 0.99. MRI was found to be investigator independent in assessing right and left ventricular volumes in vitro. Conclusions: MRI at 1.0 T using standard equipment can be used to quantitate cardiac ventricular volumes in vitro with high accuracy.

Left ventricular dysfunction and disturbed O2-utilization in stunned myocardium: influence of ischemic preconditioning

OBJECTIVE Myocardial dysfunction during postischemic reperfusion is frequently reported only in terms of left ventricular (LV) systolic properties. We additionally assessed diastolic properties, the cardiovascular tone and in particular, the relation between ventricular function and myocardial oxygen consumption. Moreover, these measures are investigated after cardioprotection via ischemic preconditioning (IP). However, this phenomenon is not fully understood, and therefore cardioprotective methods like ischemic preconditioning might provide only insufficient protection. METHODS In a total of 17 isolated rabbit hearts, perfused with an erythrocyte suspension (Hct 30%), we investigated the effect of 20 min low-flow ischemia also on diastolic properties, coronary resistance and cardiac energetics (n=9). During control and 30 min after the onset of reperfusion, LV systolic function was assessed in terms of aortic flow, dP/dt(max) and the end-systolic pressure-volume relation (ESPVR). Early relaxation was evaluated via dP/dt(min) and diastolic properties were assessed via the end-diastolic pressure-volume relation (EDPVR), i.e. using the equation LVP(ed)=c.exp(m.LVV(ed)), where c equals the LVP(ed)-axis intercept and m equals LV stiffness. In addition, coronary resistance (R(cor)) and the pressure-volume area (PVA) were calculated. Total oxygen consumption (MVO(2)) was calculated as well as the contractile efficiency (E = inverse slope of the MVO(2)-PVA relation). In a second series (n=8) the effect of ischemic preconditioning (3 min no-flow and 8 min reperfusion before the 20 min low-flow ischemia) was tested. RESULTS In the first series, systolic function was impaired during reperfusion: aortic flow to 32% of control, dP/dt(max) to 74% and the slope of ESPVR to 73%. Early relaxation in terms of dP/dt(min) decreased to 76%. The slope of the EDPVR was steeper in stunned myocardium with an increase of the ventricular stiffness (m increased from 3.2 to 4.1) and with an upward shift of the EDPVR (c from 0.6 to 2.4 mmHg). Coronary resistance was increased (from 0.9 to 1.4 mmHg/ml per min) and PVA was significantly decreased to 68%, whereas MVO(2) was not, indicating also a decrease in contractile efficiency E from 28 to 14%. In the second series, recovery of systolic function was significantly improved by IP compared with the first series (aortic flow 56% of preischemic control, dP/dt(max) to 91% and ESPVR to 78%). LV stiffness m was also slightly increased from 3.1 to 3.9 and again, c was elevated, indicating no beneficial effect for diastolic properties including dP/dt(min) (77%). But IP improved R(cor) significantly (from 0.9 to only 1.0 mmHg/ml per min) and efficiency E to 21% (from 27% during control). CONCLUSION Brief episodes of ischemia not only induce systolic but also diastolic and vascular stunning at almost maintained MVO(2). The decreased contractile efficiency clearly indicates an impaired O(2)-utilization of the contractile apparatus. Ischemic preconditioning did not improve diastolic function during reperfusion, but it provided protection with respect to vascular stunning and myocardial energetics.

Change of sternal perfusion following preparation of the internal thoracic artery – a scintigraphical study

BACKGROUND Today the internal thoracic artery (ITA) is the bypass graft of choice due to its superior long-term patency rate. It was the aim of this present prospective study to investigate possible perfusion disturbances and consecutive impaired wound healing induced by the ITA preparation. The sternal perfusion was assessed by bone scintigraphy. METHODS Forty-four patients were included in the study. There were three groups: group I (control, no ITA preparation; n = 12); group II (preparation of the left ITA; n = 21); group III (preparation of both ITAs; n = 11). In all patients a median sternotomy was performed. A bone scintigraphy was performed 4 days before and 12 days after the bypass procedure. Scintigraphical pictures of all patients were assessed visually (one specialized investigator) and the impulse rate was counted by the aid of a computer program. RESULTS Results of both evaluation methods showed congruently that neither the use of the left nor of both ITAs causes a statistically significant impairment of sternal perfusion. The percentage of postoperative increase of the rate of impulses was in group I: total sternum 55%; right side 56%; left side 55%. The respective numbers for group II were 58, 63 and 53%, and for group III 54, 52 and 56%. Surprisingly, perfusion scans in group II revealed an increase in the right sternal half after left ITA preparation. This may be due to the additional blood flow demand of collaterals branching between the right ITA and contralateral intercostal arteries representing a compensatory mechanism of the loss of the left ITA. During the observed postoperative time frame (mean 15 days) no healing disturbance of the sternal wound occurred in any patient. CONCLUSION According to the present data the use of one or both ITAs does not cause an increase of healing disturbances, consecutive to a postoperatively decreased sternal blood perfusion.

A case of lethal spontaneous massive hemothorax in a patient with neurofibromatosis 1

Neurofibromatosis type 1 is an autosomal dominant disease characterized by multiple dermatological disorders amongst others. Among the less frequent manifestations are vascular abnormalities. Here, we present a case of spontaneous massive hemothorax in a 39-year-old Caucasian woman with neurofibromatosis 1 and a thoracic meningocele with a lethal outcome despite extensive surgical intervention as well as intensive care measures. Spontaneous hemothorax is a rare, but potentially lethal complication of neurofibromatosis type 1, which necessitates quick and decisive intervention; endovascular embolization where possible, otherwise aggressive surgical intervention in unstable patients.