Wolfgang Dietl

Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardium

Background  Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c‐kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium.

The anti-angiogenic factor PEDF is present in the human heart and is regulated by anoxia in cardiac myocytes and fibroblasts

Cardiac diseases such as myocardial infarction and heart failure are among the leading causes of death in western societies. Therapeutic angiogenesis has been suggested as a concept to combat these diseases. The biology of angiogenic factors expressed in the heart such as vascular endothelial growth factor (VEGF) is well studied, whereas data on anti‐angiogenic mediators in the heart are scarce. Here we study the expression of the anti‐angiogenic factor pigment epithelium‐derived factor (PEDF) in the human heart and in human cardiac cells. PEDF expression could be detected in human cardiac tissue on the protein and mRNA levels. PEDF mRNA levels were significantly lower in explanted human ischemic hearts as compared to healthy hearts. Our in vitro experiments showed that human adult cardiac myocytes and fibroblasts constitutively secrete PEDF. In addition to anoxic conditions, cobalt chloride, 2,2′dipyridyl and dimethoxally glycine, which stabilize hypoxia inducible factor‐α decreased PEDF expression. Furthermore we show that PEDF inhibits VEGF‐induced sprouting. We have identified PEDF in healthy and ischemic human hearts and we show that PEDF expression is down‐regulated by low oxygen levels. Therefore, we suggest a role for PEDF in the regulation of angiogenesis in the heart and propose PEDF as a possible therapeutic target in heart disease.

Bβ15-42 Protects against Acid-induced Acute Lung Injury and Secondary Pseudomonas Pneumonia In Vivo

RATIONALE Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bbeta(15-42) was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bbeta(15-42) in ALI has not been addressed so far. OBJECTIVES To investigate the therapeutic potential of Bbeta(15-42) in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. METHODS The effect of the fibrin-derived peptide Bbeta(15-42) was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bbeta(15-42) on inflammation, bacterial clearance, and survival were evaluated. MEASUREMENTS AND MAIN RESULTS After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bbeta(15-42). Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bbeta(15-42) during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. CONCLUSIONS The fibrin-derived peptide Bbeta(15-42) exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.

Improved myocardial protection in the failing heart by selective endothelin-A receptor blockade

OBJECTIVE Ischemia/reperfusion injury caused by cardioplegic arrest is still a major challenge in patients with reduced left ventricular function. We investigated the effect of chronic versus acute administration of the selective endothelin-A receptor antagonist (ERA) TBC-3214Na during ischemia/reperfusion in failing hearts. METHODS Male Sprague-Dawley rats underwent coronary ligation. Three days after myocardial infarction (MI), 19 randomly assigned animals (ERA chronic) were administered TBC-3214Na continuously with their drinking water, 29 MI rats received placebo, and 3 rats died during the observation period. Six weeks after infarction, hearts were evaluated in a blood-perfused working heart model during 60 minutes of ischemia and 30 minutes of reperfusion. In 14 MI rats, TBC-3214Na (ERA acute) was added to the cardioplegic solution during ischemia. Thirteen MI rats served as control. RESULTS At a similar infarct size, postischemic recovery of cardiac output (ERA chronic: 91% +/- 10%, ERA acute: 86% +/- 11% vs control: 52% +/- 15%; P < .05) and external heart work (ERA chronic: 90% +/- 10%, ERA acute: 85% +/- 13% vs control: 51% +/- 17%; P < .05) was significantly enhanced in both TBC-3214Na-treated groups whereas recovery of coronary flow was only improved in ERA acute rats (ERA acute: 121% +/- 23% vs ERA chronic: 75% +/- 13%; control: 64% +/- 15%; P < .05). Blood gas measurements showed enhanced myocardial oxygen delivery and consumption with acute TBC-3214Na therapy. Additionally, high-energy phosphates (phosphocreatine) were significantly higher and transmission electron microscopy revealed less ultrastructural damage under acute TBC-3214Na administration. CONCLUSION Acute endothelin-A receptor blockade is superior to chronic blockade in attenuating ischemia/reperfusion injury in failing hearts. Therefore, acute endothelin-A receptor blockade might be an interesting option for patients with heart failure undergoing cardiac surgery.

Functional alterations in NO, PGI2 and EDHF pathways in the aortic endothelium after myocardial infarction in rats

Previous work on endothelial dysfunction in post‐MI heart failure has shown conflicting results.

Introducing a mouse model of brain death

Experimental animal models of brain death increasing intracranial pressure (ICP) by inflating an intracranial placed balloon-catheter are well established and used in transplant-associated studies. Our aim was to develop an experimental mouse model of brain death (BD) and to compare explosive and gradual brain death induction under ICP monitoring. We therefore induced BD in female OF-1 mice by injecting 40 microl saline every 5 min into an intracranial placed balloon increasing ICP rapidly [BD ex, n=7], or gradually [BD grad, n=7] with 20 microl volume every 5 min under electroencephalogram (EEG) and ICP monitoring until BD occurred. The major criterion for BD was a flat-line-EEG, confirmed by cessation of spontaneous respiration and maximally dilated and fixed pupils. ICP, central activity and heart rate were continuously monitored during the entire 6h follow-up. In sham-operated controls [control, n=7] a burr hole was drilled but no balloon inserted. The BD groups showed equal ICP levels at the time of BD. Both groups had increased heart rates (HR) 15 min after BD, HR decreased to 402+/-29.39 bpm (beats per minute) [BD ex] and 409.33+/-26.46 bpm [BD grad] (n.s. vs. control) by 30 min after the inflation of the balloon, but only BD ex showed a significant decrease in HR compared to control, progressively decreasing thereafter. On the basis of these results, we conclude that the mouse model of brain death can be performed in a standardized, reproducible and successful way.

Short-term clinical outcomes between intermittent cold versus intermittent warm blood cardioplegia in 2200 adult cardiac surgery patients.

BACKGROUND Aim of the present study was to compare clinical outcome of intermittent cold (ICC) versus intermittent warm (IWC) blood cardioplegia in different cardiosurgical procedures. METHODS Two thousand one hundred and eighty-eight patients were retrospectively divided into 5 groups: isolated coronary artery bypass surgery (CABG; N.=1203), isolated aortic valve surgery (AVR; N.=374), isolated mitral valve surgery (MVR; N.=151), combined AVR+CABG (N.=390), and combined MVR+CABG (N.=70). Myocardial protection was performed by ICC (N.=1578) or IWC (N.=610) blood cardioplegia. In logistic regression models the effect of cardioplegia on 30-day mortality, IABP/ECLS (intraaortic balloon-pump/extracorporal life support) implantation, transient neurological deficit, stroke, renal failure, new-onset atrial fibrillation, and troponin T release was estimated. Potential modifications of the effect of cardioplegia by logistic EuroSCORE, cross-clamping time, ejection fraction, and op-status elective versus urgent/emergent were investigated. RESULTS There were no statistically significant differences between ICC and IWC regarding 30-day mortality (odds ratio [OR]=0.70; 95% CI: 0.39-1.23; P=0.219), IABP/ECLS support (OR=0.60; 95% CI: 0.23-1.55; P=0.294), transient neurological deficit (OR=0.90; 95% CI: 0.65-1.24; P=0.541), stroke (OR=0.79; 95% CI: 0.40-1.54; P=0.495), renal failure (OR=1.07; 95% CI: 0.57-1.99; P=0.825), and atrial fibrillation (OR=0.96; 95% CI: 0.77-1.18; P=0.713) across all 5 groups. Troponin t release was significantly higher in ICC compared to IWC (by 0.029±0.015 ng/mL; P=0.046) in univariate analysis; this effect was lowered by risk-factor adjustment and lost statistical significance. The effect of cardioplegia was not significantly different between groups. In urgent/emergent surgery ICC resulted in a significantly higher 30-day mortality (OR=3.03; P=0.024) compared to IWC. CONCLUSIONS The comparison of IWC and ICC blood cardioplegia in different cardiosurgical procedures showed no statistical significant difference in myocardial protection. The use of ICC, however, appeared overall associated with a slightly better clinical outcome except in patients undergoing urgent/emergent CABG where IWC led to a reduction in 30-day-mortality.

SiNiTang ? A Traditional Chinese Herbal Remedy Improves Cardiac Function Post-MI

SiNiTang is a well known traditional Chinese herbal remedy. It is used to treat cold extremities, weak pulse and lethargy: Symptoms that correspond with myocardial infarction and heart failure in western medicine. To examine potential beneficial effects on post-MI remodeling, a modified SiNiTang formula was tested using a well established model of myocardial infarction in Rats. Application of SiNiTang significantly reduced left ventricular dilation and thus preserved left ventricular function. However, it did not affect the hypertrophic response. Exploratory histopathological examination revealed better vascularization of infarct and peri-infarct areas in SiNiTang treated animals compared to placebo. HUVEC cells were treated with SiNiTang showed increased proliferation and tube formation. SiNiTang attenuates ventricular dilation post-MI and increases neoangiogenesis.

Protection of the Failing Heart

In the developed world, heart failure (HF) is the only cardiovascular disease that is steadily increasing. Both in Europe and the United States about five million people live with the diagnosis of HF, and about 400,000 patients are newly diagnosed every year. Several epidemiological and demographic factors contribute to this trend (Hunt et al.). (a) The development of HF goes parallel with the rise in life expectancy. HF is clearly a disease of the elderly because 80% of the patients admitted to hospital with the diagnosis of HF are older than 65 years (Katz and Konstam ). (b) Improved treatment regimens of acute myocardial infarction (MI) increase survival. Consequently, the survivors are more likely to develop HF due to postMI remodelling later in their life (Opie (c) A general increase in pharmacological and non-pharmacological treatment modalities heightens the number of patients living with HF and/or reaching later stages of HF.