Jochen D. Schipke

Gene expression in acute Stanford type A dissection: a comparative microarray study

BackgroundWe compared gene expression profiles in acutely dissected aorta with those in normal control aorta.Materials and methodsAscending aorta specimen from patients with an acute Stanford A-dissection were taken during surgery and compared with those from normal ascending aorta from multiorgan donors using the BD Atlas™ Human1.2 Array I, BD Atlas™ Human Cardiovascular Array and the Affymetrix HG-U133A GeneChip®. For analysis only genes with strong signals of more than 70 percent of the mean signal of all spots on the array were accepted as being expressed. Quantitative real-time polymerase chain reaction (RT-PCR) was used to confirm regulation of expression of a subset of 24 genes known to be involved in aortic structure and function.ResultsAccording to our definition expression profiling of aorta tissue specimens revealed an expression of 19.1% to 23.5% of the genes listed on the arrays. Of those 15.7% to 28.9% were differently expressed in dissected and control aorta specimens. Several genes that encode for extracellular matrix components such as collagen IV α2 and -α5, collagen VI α3, collagen XIV α1, collagen XVIII α1 and elastin were down-regulated in aortic dissection, whereas levels of matrix metalloproteinases-11, -14 and -19 were increased. Some genes coding for cell to cell adhesion, cell to matrix signaling (e.g., polycystin1 and -2), cytoskeleton, as well as several myofibrillar genes (e.g., α-actinin, tropomyosin, gelsolin) were found to be down-regulated. Not surprisingly, some genes associated with chronic inflammation such as interleukin -2, -6 and -8, were up-regulated in dissection.ConclusionOur results demonstrate the complexity of the dissecting process on a molecular level. Genes coding for the integrity and strength of the aortic wall were down-regulated whereas components of inflammatory response were up-regulated. Altered patterns of gene expression indicate a pre-existing structural failure, which is probably a consequence of insufficient remodeling of the aortic wall resulting in further aortic dissection.

Potential role of endothelin-1 and endothelin antagonists in cardiovascular diseases

Abstract The endothelins comprise a family of three isopeptides ET-1, ET-2 and ET-3, whereby ET-1 appears to be the most relevant in humans. They act in a paracrine manner on ETA and ETB receptors. ET-1 plays an important role in the cardiovascular system. In addition, it modulates vasomotion and growth processes, and it participates in thrombogenesis and neutrophil adhesion. This review summarizes some of the current literature pertaining to the physiological and pathophysiological significance of ET-1, focusing the assets and drawbacks of elevated ET-1 levels. In this regard, modulation of the endothelin system by either receptor blockade or by inhibition of endothelin converting enzyme is expected to provide novel therapeutic drug strategies.

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.

[Postconditioning: a brief review].

ZusammenfassungDie Präkonditionierung ist die wirksamste Form der Kardioprotektion. Sie kann durch unterschiedliche Interventionen ausgelöst werden: kurze Ischämien, Pharmaka und volatile Anästhetika. Eine kurze Ischämie an einem anderen Organ—also nicht am Herzen selbst—kann ebenfalls zu einem Schutz des Herzens führen: heterotope Präkonditionierung. Nach jüngeren Befunden können auch kurze Ischämien während der Reperfusion nach einer andauernden Ischämie die postischämische Dysfunktion verbessern. Eine solche Postkonditionierung lässt sich ebenfalls durch eine kurze Ischämie an einem anderen Organ auslösen. Entsprechend wird dieses Phänomen als heterotope Postkonditionierung bezeichnet. Ziel dieser kurzen Übersichtsarbeit ist, Präkonditionierung und Postkonditionierung zunächst zu charakterisieren, mögliche Mechanismen zu nennen und auf die klinische Relevanz aufmerksam zu machen.AbstractPreconditioning is the most effective form of cardioprotection that can be induced via different interventions before a longer-lasting ischemia (= index ischemia). Preconditioning can be induced by short bouts of ischemia, several pharmaceuticals (e.g., adenosine), and volatile anesthetics. A brief ischemia of an organ other than the heart can likewise initiate protection of the heart, which has been called preconditioning at a distance or remote preconditioning. According to the more recent literature, short bouts of ischemia after an index ischemia can also initiate cardioprotection, e.g., improve postischemic dysfunction or reduce infarct size, which has been called postconditioning. Such a postconditioning can also be elicited at a distant organ, termed remote postconditioning. It is the aim of this short review to characterize preconditioning and in particular postconditioning, describe possible mechanisms, and call attention to the clinical relevance.

Independency of myocardial stunning of endothelial stunning

Background and objectiveVascular endothelial cells play an important role in the control of vascular tone. The reasons for coronary endothelial dysfunction are complex and may involve ischemia/reperfusion injury. We investigated whether endothelial, smooth muscle, and myocardial dysfunction are independent phenomena.MethodsRabbit hearts were rapidly excised without intermittent ischemia, connected to a modified Langendorff apparatus, and perfused with a modified Krebs-Henseleit solution containing bovine erythrocytes. Normoxic control hearts (n = 16) were perfused for 125 min. Postischemic hearts (n = 15) were perfused for 45 min, submitted to global ischemia (20 min) and reperfused (60 min). Both the normoxic and the postischemic hearts were divided into three groups that received either 0.9% NaCl (placebo), or 3-morpholinosydnonimine (SIN-1; 100 μM),or substance P (SP; 5 nM).ResultsAfter SIN-1, CBF in the normoxic hearts was increased by maximum 63% and after SP by 62%. 60 min after the onset of reperfusion, the postischemic hearts of both groups had recovered to 95% LVPmax. In the postischemic hearts, SIN-1 increased CBF still by 58%, while the endothelium-dependent vasomotion was impaired: SP improved CBF by only 9%.Summary and conclusionsThe particular protocol permitted differentiation between myocardial and vascular stunning. The results show that, while myocardial function has already recovered, endothelial cells are more severely impaired than smooth muscle cells, and that this injury persists beyond myocardial stunning. Thus, endothelial-dependent dysfunction can still impair vasodilatation while ventricular dysfunction has already resolved.

Effect of changes in aortic pressure and in coronary arterial pressure on left ventricular geometry and function Anrep vs. gardenhose effect

SummarySudden increases in aortic pressure (AoP, mmHg) are associated with increases in left ventricular (LV) function which persist even after diastolic volume has returned to its initial value (Anrep effect). Likewise, increases in coronary arterial pressure (CAP, mmHg) are associated with improved LV function (gardenhose effect). In situ, increases in AoP are paralleled by increases in both CAP and coronary blood flow, i.e., oxygen supply. We investigated the individual contributions of AoP and CAP increases on function (peak systolic pressure: LVPmax, mm Hg; dP/dtmax, mm Hg/s; end-diastolic pressure: LVPed, mm Hg) and end-diastolic geometry (inner diameter: IDed, mm; wall thickness: WTed, mm; sonomicrometry). CAP-induced increases in coronary flow were prevented by admixing dextran to the perfusate. The experiments were performed on isolated, saline-perfused, working rabbit hearts. Increasing CAP from 60 to 80 mm Hg (n=11) resulted in improved function: LVPmax 89±3 vs. 94±3, dP/dtmax 1160±50 vs. 1250±50, LVPed 17±1 vs. 16±1 (mean±SEM). IDed decreased from 9.96±0.25 to 9.64±0.33 and WTed increased from 6.02±0.16 to 6.15±0.17. In a second series, AoP was increased from 60 to 80 (n=9). Both LVPmax, dP/dtmax and LVPed increased (90±4 vs. 97±3, 1170±70 vs. 1270±90 and 18±1 vs. 19±1). IDed increased from 9.76±0.39 to 9.99±0.37 and WTed decreased from 6.08±0.22 to 5.86±0.25. After additionally increasing CAP to 80, function further improved (LVPmax: 101±3, dP/dtmax: 1310±80) while LVPed decreased (18±1). This time, IDed decreased to 9.71±0.36 and WTed increased to 6.03±0.26. Increases in CAP improve LV function via the gardenhose effect and likely do not depend on simultaneous increases in coronary flow or oxygen supply. On the other hand, increases in AoP alone improve systolic function via the Frank-Starling mechanism. Increases in both pressures together amplify this effect. Increases in CAP and in AoP have opposing effects on IDed and WTed. In conclusion, the homeometric Anrep effect-at least in part — can be viewed as synergistic action of the Frank-Starling mechanism and the gardenhose effect for this experimental model.

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.

An easy and quick implantation procedure for the measurement of myocardial wall thickness using sonomicrometry

SummaryUltrasonic techniques for the measurement of ventricular dimensions are widely used in acute and chronic experiments. Implantation of ultrasonic crystals is associated with reversible and irreversible myocardial damage which might limit the interpretation of the obtained results, in particular during acute experiments. We therefore developed a sonomicrometric device which can be easily and quickly implanted, and thus reduces the reversible myocardial damage induced by prolonged surgical implantation.

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.