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Due to an increasing prevalence of heart failure and persistent shortage of donor hearts, the number of left ventricular assist device (LVAD) implantations is growing. As more patients live with LVADs for prolonged periods of time, psychosocial outcomes are becoming more relevant. This particularly applies to destination therapy (DT) patients, who live with the LVAD for the rest of their lives.We used a cross-sectional qualitative design to explore psychological burden, coping strategies, and resources from the perspective of DT patients. Data were collected via semi-structured in-depth interviews with 18 patients who lived with the LVAD for 3 months to over 10 years. These were analyzed using an inductive content analysis. Due to the COVID-19 pandemic, changes to the recruitment strategy and data collection strategies of the original study protocol were applied. Patients and clinicians were involved throughout the research process to ensure the validity of the results and implications.We synthesized 10 psychosocial, health, and treatment-related burdens and identified 15 problem- and emotion-focused coping strategies and 5 personal and environmental resources patients used to cope with the burden.The findings provide deeper insights into the complex and specific situation of LVAD patients to better address the patient situation in health care and promote positive psychosocial outcomes. So far, health care practice and quality vary significantly between clinics due to individual treatment protocols. Our results highlight the need to improve medical and psychosocial care. Overarching care concepts may be developed based on the implications.

ZusammenfassungDesorientierung kann ein frühes Merkmal eines Delirs sein. Für die Überwachung eines Delirs testet die im deutschsprachigen Raum weit verbreitete „Confusion Assessment Method for Intensive Care Unit“ (CAM-ICU) die Orientierung nicht, da intubierte Intensivpatienten sich nicht verbal äußern können. Die Mehrheit der Patienten auf deutschen Intensivstationen ist aber nicht beatmet, sie könnten hinsichtlich ihrer Orientiertheit befragt werden. Die vorliegende Studie untersuchte, ob sich durch das Kriterium „Desorientierung“ bei extubierten Patienten im Vergleich zur CAM-ICU divergierende Befunde ergeben und ob sich die Sensitivität der CAM-ICU durch Kombination mit dem Merkmal „Desorientierung“ („CAM-IMC“) erhöhen lassen. Insgesamt 86 gepaarte Untersuchungen fanden bei 50 extubierten Patienten statt. Ein Delir fand sich bei 19,8 % (n = 17) aller Untersuchungen. Die CAM-ICU hatte eine Sensitivität von 71 % (95%-KI: 44–90 %) und eine Spezifität von 100 % (95–100 %). Für „Desorientierung“ als alleiniges Delir-Merkmal fand sich eine Sensitivität von 77 % (50–93 %) und eine Spezifität von 93 % (89–100 %). Die CAM-IMC erreichte eine Sensitivität von 88 % (64–99 %) bei einer Spezifität von 100 % (95–100 %). Die „Receiver-Operating-Characteristics(ROC)-Analyse“ fand mit einer „area under the curve“ (AUC) von 0,941 (95%-KI: 0,851–1,000) für die CAM-IMC den höchsten Wert im Vergleich zu den anderen Delir-Tests (CAM-ICU, AUC 0,853 [0,720–0,986]; Desorientierung, AUC 0,868 [0,745–0,991]). Diese Arbeit unterstreicht die Wertigkeit des Merkmals „Desorientierung“ für Delir-Tests bei verbal kommunikationsfähigen Patienten und erklärt einige diskrepante Beurteilungen schwierig einzuschätzender Patienten in der täglichen Praxis. Die CAM-IMC scheint als Delir-Test für extubierte Patienten günstigere Eigenschaften als die CAM-ICU zu haben und sollte eingehender überprüft werden.

Die Mortalitat von Patienten mit isoliert auftretenden angeborenen Zwerchfellhernien liegt in spezialisierten Zentren bei 20–40%. Wesentliche, das Outcome beeinflussende Faktoren, sind die bestehende Lungenhypoplasie, eine daraus resultierende pulmonale Hypertonie, sowie das Vorliegen weiterer Fehlbildungen. Begleitfehlbildungen wie angeborene Herzfehler treten bei ca. 18% aller Neonaten mit Zwerchfellhernie auf. Schwere angeborene Herzfehler wie das hypoplastische Linksherz Syndrom zeigen sich in ca. 8% der Falle. In einer retrospektiven Analyse des Patientenkollektivs unserer Klinik zwischen 01/2012 und 12/2018 wurde das pra- und postnatale Management, sowie das Outcome von Neugeborenen mit der Kombination aus angeborenen Herzfehlern und Zwerchfellhernien untersucht. Im Studienzeitraum wurden in unserer Klinik 156 Neugeborene mit Zwerchfellhernie behandelt. Bei 10 Patienten (6,4%) lag zusatzlich ein schwerer, bei 11 Patienten (7,1%) ein moderater Herzfehler vor. 6/21 Patienten verstarben im Verlauf des Krankenhausaufenthaltes, davon 3 am ersten Lebenstag. Es zeigte sich eine deutlich geringere Mortalitat bei Patienten mit Zwerchfellhernie und moderatem Herzfehler im Vergleich zu schwerem Herzfehler (9 vs. 50%). Besonders hoch lag die Mortalitat bei Kindern mit einem univentrikularen Herzen. Trotz einer deutlich reduzierten Prognose bei der Kombination aus angeborenem Herzfehler und Zwerchfellhernie muss nicht generell mit einer infausten Prognose gerechnet werden. In spezialisierten Zentren kann ein kurativer Ansatz erfolgen. The mortality of patients with isolated congenital diaphragmatic hernia (CDH) in specialized centers is 20–40%. The main factors influencing the outcome are the underlying pulmonary hypoplasia, the resulting pulmonary hypertension and the presence of other malformations. Concomitant malformations such as congenital heart defects occur in around 18% of all neonates with a diaphragmatic hernia. Serious congenital heart defects such as hypoplastic left heart syndrome occur in approximately 8% of cases. In a retrospective analysis of the patient collective of our hospital between 01/2012 and 12/2018, the prenatal and postnatal management as well as the outcome of newborns with a combination of congenital heart defects and diaphragmatic hernias were examined. During the study period, 156 newborns with diaphragmatic hernias were treated at our institution. In 10 patients (6.4%) there was also a severe, and in 11 patients (7.1%) a moderate heart defect. 6/21 patients died during their hospital stay, 3 of them on the first day of life. There was a significantly lower mortality in patients with diaphragmatic hernia and moderate heart defects compared to severe heart defects (9 vs. 50%). The mortality in children with a univentricular heart was particularly high. Despite a significantly reduced prognosis for the combination of congenital heart defects and diaphragmatic hernia, generally a poor prognosis does not have to be expected. A curative approach can be achieved in specialized centers.

Background Right ventricular outflow tract (RVOT) stenosis after repair of tetralogy of Fallot has been linked with favorable right ventricular remodeling but adverse outcomes. The aim of our study was to assess the hemodynamic impact and prognostic relevance of right ventricular pressure load in this population. Methods and Results A total of 296 patients with repaired tetralogy of Fallot (mean age, 17.8±7.9 years) were included in a prospective cardiovascular magnetic resonance multicenter study. Myocardial strain was quantified by feature tracking technique at study entry. Follow‐up, including the need for pulmonary valve replacement, was assessed. The combined end point consisted of ventricular tachycardia and cardiac death. A higher echocardiographic RVOT peak gradient was significantly associated with smaller right ventricular volumes and less pulmonary regurgitation, but lower biventricular longitudinal strain. During a follow‐up of 10.1 (0.1–12.9) years, the primary end point was reached in 19 of 296 patients (cardiac death, n=6; sustained ventricular tachycardia, n=2; and nonsustained ventricular tachycardia, n=11). A higher RVOT gradient was associated with the combined outcome (hazard ratio [HR], 1.03; 95% CI, 1.00–1.06; P =0.026), and a cutoff gradient of ≥25 mm Hg was predictive for cardiovascular events (HR, 3.69; 95% CI, 1.47–9.27; P =0.005). In patients with pulmonary regurgitation ≥25%, a mild residual RVOT gradient (15–30 mm Hg) was not associated with a lower risk for pulmonary valve replacement. Conclusions Higher RVOT gradients were associated with less pulmonary regurgitation and smaller right ventricular dimensions but were related to reduced biventricular strain and emerged as univariate predictors of adverse events. Mild residual pressure gradients did not protect from pulmonary valve replacement. These results may have implications for the indication for RVOT reintervention in this population.

Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). The aim of this study was to investigate whether postconditioning with the cytosine-phosphate-guanine (CpG)-containing Toll-like receptor-9 (TLR9) ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Thirty minutes of left descending coronary artery (LAD) occlusion was conducted in 12-wk-old C57BL/6 mice. Mice were treated with CpG intraperitoneally 5 min before reperfusion. The control group received PBS; the sham group did not undergo ischemia. M-mode echocardiography (3, 7, and 28 days) and Millar left ventricular (LV) catheterization were performed (7 and 28 days) before the hearts were excised and harvested for immunohistochemical (6 h, 24 h, 3 days, 7 days, and 28 days), gene expression (6 h, 24 h, and 3 days; Taqman RT-qPCR), protein, and FACS analysis (24 h and 3 days). Mice treated with CpG showed significantly better LV function after 7 and 28 days of reperfusion. Protein and mRNA expressions of proinflammatory and anti-inflammatory cytokines were significantly induced after CpG treatment. Histology revealed fewer macrophages in CpG mice after 24 h, confirmed by FACS analysis with a decrease in both classically M1- and alternative M2a-monocytes. CpG treatment reduced apoptosis and cardiomyocyte loss and was associated with induction of adaptive mechanisms, e.g., of heme-oxigenase-1 and β-/α-myosin heavy chain (MHC) ratio. Profibrotic markers collagen type Iα (Col-Ια) and Col-III induction was abrogated in CpG mice, accompanied by fewer myofibroblasts. This led to the formation of a smaller scar. Differential matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a Toll-like receptor 1- and TLR9-dependent manner. Our study suggests a cardioprotective mechanism of CpG postconditioning, involving Toll-like receptor-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV function.NEW & NOTEWORTHY Cytosine-phosphate-guanine (CpG) postconditioning seems to mediate inflammation via Toll-like receptor-1 and Toll-like receptor-9 signaling. Enhanced cytokine and chemokine expressions are partly attenuated by IL-10 and matrix metalloproteinase-8 (MMP8) induction, being associated with lower macrophage infiltration and M1-monocyte differentiation. Furthermore, switch from α- to β-MHC and balanced MMP/TIMP expression led to lesser cardiomyocyte apoptosis, smaller scar size, and preserved cardiac function. Data of pharmacological postconditioning have been widely disappointing to date. Our study suggests a new pathway promoting myocardial postconditioning via Toll-like receptor activation.

Opioid dosage for general anaesthesia and sedation relies on surrogate parameters such as heartrate and blood pressure. This implies the risk of both under- and overdosing. A promising tool to provide target-oriented opioid dosing is measuring the nociceptive flexion reflex threshold (NFRT). The aim of this study was to investigate the individual trajectories and to determine this methods' clinical practicability in the perioperative setting of cardiac surgery. NFRT was measured preoperatively (twice as baseline), immediately after surgery and later in the general ward (primary outcomes). No intraoperative measurements were performed since neuromuscular blockade hinders NFRT assessment. Administered analgesics and pain scores were also recorded (secondary outcomes). Data were collected from August 2019 to March 2020. 264 patients scheduled for cardiac surgery were screened for eligibility. 55 patients were included, 30 rendered datasets for analysis. Thresholds after conclusion of surgery [T

Background Adaptation to aortic valve stenosis leads to myocardial hypertrophy, which has been associated with inflammation, fibrosis and activation of the endocannabinoid system. Since the endocannabinoid system and the CB2 receptor provide cardioprotection and modulate immune response in experimental ischemia, we investigated the role of CB2 in a mouse model of cardiac pressure overload. Methods Transverse aortic constriction was performed in CB2 receptor-deficient (Cnr2−/−) mice and their wild-type littermates (Cnr2+/+). After echocardiography and Millar left heart catheter hemodynamic evaluation hearts were processed for histological, cellular and molecular analyses. Results The endocannabinoid system showed significantly higher anandamide production and CB2 receptor expression in Cnr2+/+ mice. Histology showed non-confluent, interstitial fibrosis with rare small areas of cardiomyocyte loss in Cnr2+/+ mice. In contrast, extensive cardiomyocyte loss and confluent scar formation were found in Cnr2−/− mice accompanied by significantly increased apoptosis and left ventricular dysfunction when compared with Cnr2+/+ mice. The underlying cardiac maladaptation in Cnr2−/− mice was associated with significantly reduced expression of myosin heavy chain isoform beta and less production of heme oxygenase-1. Cnr2−/− hearts presented after 7 days with stronger proinflammatory response including significantly higher TNF-alpha expression and macrophage density, but lower density of CD4+ and B220+ cells. At the same time, we found increased apoptosis of macrophages and adaptive immune cells. Higher myofibroblast accumulation and imbalance in MMP/TIMP-regulation indicated adverse remodeling in Cnr2−/− mice. Conclusions Our study provides mechanistic evidence for the role of the endocannabinoid system in myocardial adaptation to pressure overload in mice. The underlying mechanisms include production of anandamide, adaptation of contractile elements and antioxidative enzymes, and selective modulation of immune cells action and apoptosis in order to prevent the loss of cardiomyocytes.

Physiological and pathological cardiac stress induced by exercise and hypertension, respectively, increase the hemodynamic load for the heart and trigger specific hypertrophic signals in cardiomyocytes leading to adaptive or maladaptive cardiac hypertrophy responses involving a mechanosensitive remodeling of the contractile cytoskeleton. Integrins sense load and have been implicated in cardiac hypertrophy, but how they discriminate between the two types of cardiac stress and translate mechanical loads into specific cytoskeletal signaling pathways is not clear. Here, we report that the focal adhesion protein β-parvin is highly expressed in cardiomyocytes and facilitates the formation of cell protrusions, the serial assembly of newly synthesized sarcomeres, and the hypertrophic growth of neonatal rat ventricular cardiomyocytes (NRVCs) in vitro. In addition, physiological mechanical loading of NRVCs by either the application of cyclic, uni-axial stretch, or culture on physiologically stiff substrates promotes NRVC elongation in a β-parvin-dependent manner, which is achieved by binding of β-parvin to α/β-PIX, which in turn activates Rac1. Importantly, loss-of-function studies in mice also revealed that β-parvin is essential for the exercise-induced cardiac hypertrophy response in vivo. Our results identify β-parvin as a novel mechano-responsive signaling hub in hypertrophic cardiomyocytes that drives cell elongation in response to physiological mechanical loads.

OBJECTIVES Cardiac biomarkers are indicators of irreversible cell damage. Current myocardial infarction (MI) definitions require concomitant clinical characteristics. For perioperative MI, a correlation of biomarker elevations and mortality has been suggested. Definitions emerged relying on cardiac biomarker release only. This approach is questionable as several clinical and experimental scenarios exist where relevant biomarker release can occur apart from MI. METHODS We reviewed the clinical and basic science literature and revealed important aspects regarding the use and interpretation of cardiac biomarker release with special focus on their interpretation in the perioperative setting. RESULTS Ischaemic biomarkers may be released without cell death in multiple conditions, such as after endurance runs in athletes, temporary inotropic stimulation in animal models and flow variations in in vitro cell models. In addition, access through atrial tissue during cannulation or concomitant valve procedures adds sources of enzyme release that may not be related to ventricular ischaemia (i.e. MI). Such non-cell death-related mechanisms may explain the lack of poor correlations of enzyme release and long-term outcomes in recent trials. In addition, the 3 main biomarkers, troponin T, I and creatine kinase myocardial band, differ in their release kinetics, which may differentially trigger MI events in trial patients. CONCLUSIONS The identification of irreversible myocardial injury in cardiac surgery based only on biomarker release is unreliable. Cell death- and non-cell death-related mechanisms create a mix in the perioperative setting that requires additional markers for proper identification of MI. In addition, the 3 most common ischaemic biomarkers display different release kinetics adding to the confusion. We review the topic.

Die Mortalität von Patienten mit isoliert auftretenden angeborenen Zwerchfellhernien liegt in spezialisierten Zentren bei 20-40%. Wesentliche, das Outcome beeinflussende Faktoren, sind die bestehende Lungenhypoplasie, eine daraus resultierende pulmonale Hypertonie, sowie das Vorliegen weiterer Fehlbildungen. Begleitfehlbildungen wie angeborene Herzfehler treten bei ca. 18% aller Neonaten mit Zwerchfellhernie auf. Schwere angeborene Herzfehler wie das hypoplastische Linksherz Syndrom zeigen sich in ca. 8% der Fälle. In einer retrospektiven Analyse des Patientenkollektivs unserer Klinik zwischen 01/2012 und 12/2018 wurde das prä- und postnatale Management, sowie das Outcome von Neugeborenen mit der Kombination aus angeborenen Herzfehlern und Zwerchfellhernien untersucht. Im Studienzeitraum wurden in unserer Klinik 156 Neugeborene mit Zwerchfellhernie behandelt. Bei 10 Patienten (6,4%) lag zusätzlich ein schwerer, bei 11 Patienten (7,1%) ein moderater Herzfehler vor. 6/21 Patienten verstarben im Verlauf des Krankenhausaufenthaltes, davon 3 am ersten Lebenstag. Es zeigte sich eine deutlich geringere Mortalität bei Patienten mit Zwerchfellhernie und moderatem Herzfehler im Vergleich zu schwerem Herzfehler (9 vs. 50%). Besonders hoch lag die Mortalität bei Kindern mit einem univentrikulären Herzen. Trotz einer deutlich reduzierten Prognose bei der Kombination aus angeborenem Herzfehler und Zwerchfellhernie muss nicht generell mit einer infausten Prognose gerechnet werden. In spezialisierten Zentren kann ein kurativer Ansatz erfolgen.The mortality of patients with isolated congenital diaphragmatic hernia (CDH) in specialized centers is 20-40%. The main factors influencing the outcome are the underlying pulmonary hypoplasia, the resulting pulmonary hypertension and the presence of other malformations. Concomitant malformations such as congenital heart defects occur in around 18% of all neonates with a diaphragmatic hernia. Serious congenital heart defects such as hypoplastic left heart syndrome occur in approximately 8% of cases. In a retrospective analysis of the patient collective of our hospital between 01/2012 and 12/2018, the prenatal and postnatal management as well as the outcome of newborns with a combination of congenital heart defects and diaphragmatic hernias were examined. During the study period, 156 newborns with diaphragmatic hernias were treated at our institution. In 10 patients (6.4%) there was also a severe, and in 11 patients (7.1%) a moderate heart defect. 6/21 patients died during their hospital stay, 3 of them on the first day of life. There was a significantly lower mortality in patients with diaphragmatic hernia and moderate heart defects compared to severe heart defects (9 vs. 50%). The mortality in children with a univentricular heart was particularly high. Despite a significantly reduced prognosis for the combination of congenital heart defects and diaphragmatic hernia, generally a poor prognosis does not have to be expected. A curative approach can be achieved in specialized centers.

Disorientation may present as a warning sign of developing delirium. The most commonly used delirium assessment tool in Germany, the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), does not rate "disorientation", since intubated patients cannot communicate verbally. However, the majority of German ICU patients are not orally intubated, so they could be examined for their orientation. This study was carried out to investigate whether the delirium feature "disorientation" in extubated patients yields diverging findings in comparison to the CAM-ICU and whether the sensitivity of the CAM-ICU may be improved when combined with the feature "disorientation" (CAM-IMC). A total of 86 paired assessments were completed in 50 extubated patients. Delirium was found in 19.8% (N = 17). The CAM-ICU had a sensitivity of 71% (95% confidence interval [CI] 44-90%) and a specificity of 100% (95-100%). Disorientation, if taken as the only delirium feature, had a sensitivity of 77% (50-93%) and a specificity of 93% (89-100%). The CAM-IMC reached a sensitivity of 88% (64-99%) and a specificity of 100% (95-100%). The receiver operating characteristics (ROC) analyses found an area under the curve (AUC) of 0.941 (95%CI 0.851-1.000) for the CAM-IMC, which was the highest compared to the other delirium tests (CAM-ICU, AUC 0.853 [0.720-0.986]; disorientation, AUC 0.868 [0.745-0.991]). This research emphasizes the importance of the feature "disorientation" for delirium assessments in patients able to verbally communicate and explains some controversial delirium ratings in daily practice. The CAM-IMC appears to be an attractive tool for delirium assessment in nonintubated patients and deserves further research.Desorientierung kann ein frühes Merkmal eines Delirs sein. Für die Überwachung eines Delirs testet die im deutschsprachigen Raum weit verbreitete „Confusion Assessment Method for Intensive Care Unit“ (CAM-ICU) die Orientierung nicht, da intubierte Intensivpatienten sich nicht verbal äußern können. Die Mehrheit der Patienten auf deutschen Intensivstationen ist aber nicht beatmet, sie könnten hinsichtlich ihrer Orientiertheit befragt werden. Die vorliegende Studie untersuchte, ob sich durch das Kriterium „Desorientierung“ bei extubierten Patienten im Vergleich zur CAM-ICU divergierende Befunde ergeben und ob sich die Sensitivität der CAM-ICU durch Kombination mit dem Merkmal „Desorientierung“ („CAM-IMC“) erhöhen lassen. Insgesamt 86 gepaarte Untersuchungen fanden bei 50 extubierten Patienten statt. Ein Delir fand sich bei 19,8 % (n = 17) aller Untersuchungen. Die CAM-ICU hatte eine Sensitivität von 71 % (95%-KI: 44–90 %) und eine Spezifität von 100 % (95–100 %). Für „Desorientierung“ als alleiniges Delir-Merkmal fand sich eine Sensitivität von 77 % (50–93 %) und eine Spezifität von 93 % (89–100 %). Die CAM-IMC erreichte eine Sensitivität von 88 % (64–99 %) bei einer Spezifität von 100 % (95–100 %). Die „Receiver-Operating-Characteristics(ROC)-Analyse“ fand mit einer „area under the curve“ (AUC) von 0,941 (95%-KI: 0,851–1,000) für die CAM-IMC den höchsten Wert im Vergleich zu den anderen Delir-Tests (CAM-ICU, AUC 0,853 [0,720–0,986]; Desorientierung, AUC 0,868 [0,745–0,991]). Diese Arbeit unterstreicht die Wertigkeit des Merkmals „Desorientierung“ für Delir-Tests bei verbal kommunikationsfähigen Patienten und erklärt einige diskrepante Beurteilungen schwierig einzuschätzender Patienten in der täglichen Praxis. Die CAM-IMC scheint als Delir-Test für extubierte Patienten günstigere Eigenschaften als die CAM-ICU zu haben und sollte eingehender überprüft werden.

Cardiac surgery and subsequent treatment in the intensive care unit (ICU) has been shown to be associated with functional decline, especially in elderly patients. Due to the different assessment tools and assessment periods, it remains yet unclear what parameters determine unfavorable outcomes. This study sought to identify risk factors during the entire perioperative period and focused on the decline in activity of daily living (ADL) half a year after cardiac surgery. Follow-ups of 125 patients were available. It was found that in the majority of patients (60%), the mean ADL declined by 4.9 points (95% CI, &minus, 6.4 to &minus, 3.5, p &lt, 0.000). In the &ldquo, No decline&rdquo, group, the ADL rose by 3.3 points (2.0 to 4.6, 0.001). A multiple regression analysis revealed that preoperative cognitive impairment (MMSE &le, 26, Exp(B) 2.862 (95%CI, 1.192&ndash, 6.872), p = 0.019) and duration of postoperative delirium &ge, 2 days (Exp(B) 3.534 (1.094&ndash, 11.411), p = 0.035) was independently associated with ADL decline half a year after the operation and ICU. Of note, preoperative ADL per se was neither associated with baseline cognitive function nor a risk factor for functional decline. We conclude that the preoperative assessment of cognitive function, rather than functional assessments, should be part of risk stratification when planning complex cardiosurgical procedures.

Objective. Myocardial ischemia and reperfusion (I/R) injury is associated with oxidative stress and inflammation, leading to scar development and malfunction. The marine omega-3 fatty acids (ω-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are mediating cardioprotection and improving clinical outcomes in patients with heart disease. Therefore, we tested the hypothesis that docosahexaenoic acid (DHA) supplementation prior to LAD occlusion-induced myocardial injury (MI) confers cardioprotection in mice. Methods. C57BL/6N mice were placed on DHA or control diets (CD) beginning 7 d prior to 60 min LAD occlusion-induced MI or sham surgery. The expression of inflammatory mediators was measured via RT-qPCR. Besides FACS analysis for macrophage quantification and subtype evaluation, macrophage accumulation as well as collagen deposition was quantified in histological sections. Cardiac function was assessed using a pressure-volume catheter for up to 14 d. Results. DHA supplementation significantly attenuated the induction of peroxisome proliferator-activated receptor-α (PPAR-α) (2.3±0.4 CD vs. 1.4±0.3 DHA) after LAD occlusion. Furthermore, TNF-α (4.0±0.6 CD vs. 1.5±0.2 DHA), IL-1β (60.7±7.0 CD vs. 11.6±1.9 DHA), and IL-10 (223.8±62.1 CD vs. 135.5±38.5 DHA) mRNA expression increase was diminished in DHA-supplemented mice after 72 h reperfusion. These changes were accompanied by a less prominent switch in α/β myosin heavy chain isoforms. Chemokine mRNA expression was stronger initiated (CCL2 6 h: 32.8±11.5 CD vs. 78.8±13.6 DHA) but terminated earlier (CCL2 72 h: 39.5±7.8 CD vs. 8.2±1.9 DHA; CCL3 72 h: 794.3±270.9 CD vs. 258.2±57.8 DHA) in DHA supplementation compared to CD mice after LAD occlusion. Correspondingly, DHA supplementation was associated with a stronger increase of predominantly alternatively activated Ly6C-positive macrophage phenotype, being associated with less collagen deposition and better LV function (EF 14 d: 17.6±2.6 CD vs. 31.4±1.5 DHA). Conclusion. Our data indicate that DHA supplementation mediates cardioprotection from MI via modulation of the inflammatory response with timely and attenuated remodeling. DHA seems to attenuate MI-induced cardiomyocyte injury partly by transient PPAR-α downregulation, diminishing the need for antioxidant mechanisms including mitochondrial function, or α- to β-MHC isoform switch.

Background Patients with acute myocardial infarction (AMI) are at high risk when undergoing emergency coronary artery bypass graft (CABG)-surgery. Their outcome remains poor despite increased use of extracorporeal membrane oxygenation (ECMO). We investigated the impact of timing for perioperative ECMO-support in these patients. Methods In this retrospective double-center study, we evaluated 201 patients with AMI undergoing CABG, dividing them into the following groups: No-ECMO (n = 101), preoperative ECMO (pre-ECMO, n = 6), intraoperative ECMO (ECC-ECMO, n = 67), and postoperative ECMO (post-ECMO, n = 27). We evaluated the impact of ECMO timing on postoperative mortality, organ function, and length of stay, comparing these to predicted outcome using different risk-scores. Results Post-ECMO patients showed lowest 30-day-survival (40.7%), while earlier ECMO-start was associated with better outcome (50.7% in extracorporeal circulation [ECC]-ECMO and 66.7% in pre-ECMO patients). On admission, only pre-ECMO and ECC-ECMO patients showed higher surgery- and intensive-care-unit (ICU)-related risk-scores. In pre- and ECC-ECMO patients, the first significant increase in lactate-levels (>4 mmol/L) was observed preoperatively, while this occurred 1 hour postoperatively in post-ECMO patients. Bilirubin was increased in all patients, decreasing after 3 and 12 days in pre- and ECC-ECMO patients, respectively, but only after 18 days in post-ECMO patients. Multiple ICU risk-scores did not discriminate survival-probability correctly. Only the ECMO-related survival after veno-arterial-ECMO-score correctly predicted the significantly lower survival in post-ECMO patients. Conclusion Our study shows that timely ECMO-support is associated with earlier bilirubin-downtrend and higher survival in patients with AMI after CABG. Lactate-increase greater than 4 mmol/L seems to be a helpful threshold to trigger the timely onset of ECMO-therapy, providing better survival.

Pediatric cardiac surgeries involving aortic arch reconstruction are complex and require long cardiopulmonary bypass (CPB) times with deep hypothermic circulatory arrest (DHCA). Selective perfusion techniques have been developed to prevent the deleterious consequences of DHCA associated hypoperfusion. The effectivity of low body perfusion through cannulation of the femoral artery with an arterial sheath remains to be elucidated. We compared perfusion and inflammation in patients receiving selective antegrade cerebral perfusion (ACP) only to low body perfusion (LBP) in addition to ACP during DHCA for aortic arch reconstruction surgery. There was no difference in patient characteristics, cardiac pathologies, or performed procedures between ACP and LBP groups. Lactate levels increased after cardiac arrest in both groups. However, lactate levels were lower after 1 h reperfusion, at the end of extracorporeal circulation (ECC), and after surgery in LBP group compared to ACP only. Furthermore, creatinine was increased in ACP group on postoperative day 1 compared to LBP group but no acute kidney injury was observed in any group. IL-6 concentration increased in ACP group, while remained unchanged in LBP group compared to pre surgical values and were significantly lower compared to ACP group on postoperative days 1 and 2. LBP via an arterial sheath during cardiac arrest for aortic arch reconstruction surgery in addition to ACP, improves post ECC tissue perfusion as indicated by lower lactate levels and reduces creatinine levels suggesting milder kidney injury. LBP seems to prevent postoperative inflammation through a reduction in procedural duration or enhanced perfusion and thereby improves the outcome after aortic arch reconstruction surgery.

Aims Pulmonary hypertension (PH) leads to right ventricular (RV) adaptation and remodeling and has deleterious long-term effects on RV function. The endocannabinoid receptor CB2 has been associated with protective effects in adaptation and remodeling of the left ventricle after ischemia. Therefore, we investigated the role of CB2 receptor in RV adaptation after occlusion of the left pulmonary artery (LPA) in a murine model. Main methods C57/Bl6 (WT)- and CB2 receptor-deficient (Cnr2−/−)-mice underwent paramedian sternotomy and LPA was occluded using a metal clip. Right heart hemodynamic study (Millar®) preceded organ harvesting for immunohistochemistry and mRNA analysis 7 and 21 days (d) post-occlusion. Key findings LPA occlusion led to higher RV systolic pressure in Cnr2−/−-hearts, while hemodynamics were comparable with WT-hearts after 21d. Cnr2−/−-hearts showed higher macrophage infiltration and lower interleukin-10 expression after 7 d, but otherwise a comparable inflammatory mediator expression profile. Cardiomyocyte-hypertrophy was stronger in Cnr2−/−-mice, presenting with higher tenascin-C expression than WT-hearts. Planimetry revealed higher collagen area in Cnr2−/−-hearts and small areas of cardiomyocyte-loss. Surrounding cardiomyocytes were cleaved caspase-3- and TUNEL positive in Cnr2−/−-hearts. This was associated by maladaptation of myosin heavy-chain isoforms and lower reactive oxygen scavenger enzymes induction in Cnr2−/−-hearts. We found comparable morphological changes in both lungs between the two genotypes. Significance LPA occlusion led to increased systolic pressure and adaptation of RV in CB2-deficient mice. CB2 receptor seems to modulate RV adaptation through expression of contractile elements, reactive oxygen scavenger enzymes, and inflammatory response in order to prevent cardiomyocyte apoptosis.

Background Survival of neonates with intrauterine renal insufficiency and oligo- or anhydramnios correlates with the severity of secondary pulmonary hypoplasia. Early prenatal diagnosis together with repetitive amnioinfusions and modern intensive care treatment have improved the prognosis of these neonates. Extracorporeal membrane oxygenation is an established treatment option, mainly applied to neonates with pulmonary hypoplasia caused by congenital diaphragmatic hernia. However, a few case reports of extracorporeal membrane oxygenation in neonates with lower urinary tract obstruction have been published. Case presentation We describe a case of a Caucasian male infant with prenatally diagnosed lower urinary tract obstruction and secondary pulmonary hypoplasia who was delivered spontaneously at 36 + 2 weeks of gestation. Venovenous extracorporeal membrane oxygenation was initiated on the first day of life for severe respiratory failure and consecutive hypoxemia despite treatment with inhaled nitric oxide and high-frequency oscillation. The patient was supported by extracorporeal membrane oxygenation for 10 days and extubated 6 weeks later. Hemofiltration was required on the second day of life because of renal insufficiency and was later replaced by peritoneal dialysis. The child was discharged after 4 months with nasal high-flow mild oxygen therapy and peritoneal dialysis. Conclusion Neonatal extracorporeal membrane oxygenation support is a possible treatment option for neonates with lower urinary tract obstruction and pulmonary hypoplasia.

Aims The endocannabinoid system and cannabinoid receptor 2 (CB2 receptor) have been associated with modulation of inflammatory response and myocardial adaptation after ischemic injury. In order to elucidate CB2 receptor-related effects during cellular interactions, we investigated cardiomyocyte survival and macrophage function in vitro. Main methods Murine embryonic (eCM) and adult (CM) cardiomyocytes, murine macrophages (MO), and their subtypes M1 (M1-MO) and M2 (M2-MO) were derived from wildtype- (WT) and CB2 receptor-deficient (Cnr2−/−) mice. Cells were cultured separately or in co-culture under normoxia or hypoxia (2% O2) and pro-inflammatory stimulation using interferon (IFN)γ. Besides immunohistochemistry, we also measured mRNA expression (Taqman®) and performed FACS-analysis of cardiomyocytes. Macrophage migration was assessed using Boyden chamber assay. Key findings We found a significant induction of CB2 receptor mRNA and protein in murine eCM as well as M1- and M2-MO in vitro following cultivation under hypoxia or stimulation with IFNγ. A significantly higher amount of apoptotic Cnr2−/−-CMs was found after incubation under hypoxia when compared to WT-CMs. We observed a significantly stronger migration potential in Cnr2−/−-M1-MOs towards the supernatant of apoptotic CM, than in corresponding WT-cells. Co-culture revealed a significantly higher loss of eCMs and induction of their apoptosis after cultivation with Cnr2−/−-M1-MOs. Production of TNF-α in M1-MOs was dependent on CB2 receptor stimulation by anandamide. Significance Our data provide novel insights into CB2 receptor-mediated protection of cardiomyocytes during hypoxia and pro-inflammatory stimulation. We show CB2 receptor-dependent effects on migration and function of M1-MOs in interaction with cardiomyocytes, thereby influencing their survival.

SummaryBackground Anesthesia for pediatric cardiac surgery requires a high level of expert knowledge. There are currently no recommendations and standards for anesthetic management for congenital cardiac surgery in Germany. Aim The aim of the present study was to assess the current status of structural and personnel anesthetic standards at pediatric cardiac surgery centers in Germany. Method All cardiac surgical centers in Germany were reviewed for an active program for congenital heart surgery. Centers with an active program were invited to respond to an online survey. The questionnaire containing 55 items in 16 categories assessed current practice in pediatric cardiac anesthesia. Results An active program for pediatric cardiac surgery was identified at 27 centers. The response rate to the survey was 96.3%. A specialized group of anesthesiologists for pediatric cardiac anesthesia was reported from 26 centers (92.3%). The mean size of this group was 4.8 anesthesiologists per center. However, the annual case load of centers and relative annual case load per specialized anesthesiologist varied considerably between 12.5 and 250. Nonanesthesiologists performed sedation and general anesthesia for diagnostic and therapeutic interventions outside the operating theater in children with congenital heart diseases in 24 centers (77%). Although special equipment, for example, pediatric TEE, near-infrared spectroscopy, and devices for mechanical auto transfusion were available in most centers, their routine use was not always part of standard operating procedures. The proposal for mean adequate training in pediatric cardiac anesthesia as estimated by the participating centers was 10.8 months. Conclusion The present study represents the current structural situation for anesthesia at German pediatric cardiac surgery centers.

Objective:Echocardiography is the most important tool to assess infants with congenital diaphragmatic hernia (CDH) for pulmonary hypertension (PH). The pattern of blood flow in the pulmonary artery [described as time to peak velocity (TPV)/right ventricular ejection time (RVET) ratio] provides distinct information about pulmonary arterial pressure. The aim of our study was to investigate the correlation of TPV/RVET measurements with the most commonly used classification system for PH in CDH newborns and the association of these measurements with outcome parameters.Methods:Echocardiographic measurements were obtained in 40 CDH newborns within 6 h of life. The obtained measurements were correlated with the decision for or against extracorporeal membrane oxygenation (ECMO); early mortality; total duration of mechanical ventilation and total duration of oxygen supplementation.Results:The correlation coefficient between severity of PH and TPV/RVET measurements was −0.696 (PConclusions:TPV/RVET is a feasible parameter to assess PH in CDH newborns with close correlation to outcome parameters.

Repetitive brief ischemia and reperfusion (I/R) is associated with ventricular dysfunction in pathogenesis of murine ischemic cardiomyopathy and human hibernating myocardium. We investigated the role of matricellular protein osteopontin-1 (OPN) in murine model of repetitive I/R. One 15-min LAD-occlusion followed by reperfusion was performed daily over 3, 5, and 7 consecutive days in C57/Bl6 wildtype- (WT-) and OPN−/−-mice (n=8/group). After echocardiography hearts were processed for histological and mRNA-studies. Cardiac fibroblasts were isolated, cultured, and stimulated with TGF-β1. WT-mice showed an early, strong, and cardiomyocyte-specific osteopontin-expression leading to interstitial macrophage infiltration and consecutive fibrosis after 7 days I/R in absence of myocardial infarction. In contrast, OPN−/−-mice showed small, nontransmural infarctions after 3 days I/R associated with significantly worse ventricular dysfunction. OPN−/−-mice had different expression of myocardial contractile elements and antioxidative mediators and a lower expression of chemokines during I/R. OPN−/−-mice showed predominant collagen deposition in macrophage-rich small infarctions. We found lower induction of tenascin-C, MMP-9, MMP-12, and TIMP-1, whereas MMP-13-expression was higher in OPN−/−-mice. Cultured OPN−/−-myofibroblasts confirmed these findings. In conclusion, osteopontin seems to modulate expression of contractile elements, antioxidative mediators, and inflammatory response and subsequently remodel in order to protect cardiomyocytes in murine ischemic cardiomyopathy.

AIM Venous stasis is a well-known risk factor for the development of venous thromboembolism. It is likely that stasis increases the risk of thrombosis by inducing hypercoagulability via the hypoxic procoagulant activation of endothelial and mononuclear cells and the accumulation of activated clotting factors. However, increased rates of thrombin formation have not been demonstrated in response to venous stasis in vivo. METHODS In this study, we used the venous occlusion (VO) test to determine, if stasis triggers thrombin formation in healthy individuals (n=25) and patients with additional thrombotic risk factors, such as inherited thrombophilia (n=19) and symptomatic atherosclerosis (n=15). Thrombin formation was monitored by measuring plasma levels of free thrombin using a highly sensitive oligonucleotide enzyme capture assay (OECA) in addition to the plasma levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin-complexes (TAT). The plasma levels of activated protein C (APC) were additionally measured using an APC-OECA. RESULTS VO induced a significant (p

Results from different studies showing CB2 receptor-associated cardioprotective action are still fairly controversial and no single specific mechanism could be identified. Several groups investigated the involvement of the endocannabinoid system in cellular systems and function of cardiomyocytes, fibroblasts, macrophages and endothelial cells. While some studies are limited in their translational relevance, a few recent studies describe a myocardial ischemia and reperfusion scenario in a fashion comparable to the clinical situation. Recent studies provided evidence for involvement of the CB2 receptor–endocannabinoid axis in prevention of cardiomyocyte apoptosis including modulation of antioxidative enzymes and contractile elements expression. CB2 receptor has further been shown to specifically modulate the inflammatory response and macrophage function after myocardial ischemia. These effects have an impact on the subsequent myocardial remodeling, where the CB2 receptor modulates function of myofibroblasts, collagen production and limitation of myocardial infarction size. Recent experimental and clinical data showed the association of the endocannabinoid system in myocardial hypertrophy. In conclusion, increasing amount of evidence supports a crucial role of the endocannabinoid system in cardioprotection and myocardial remodeling, while some of them even suggest model-independent systemic effects in adaptation of cardiomyocytes or components of the extracellular matrix.

BACKGROUND: Pressure-volume loops (PVL) provide vital information regarding ventricular performance and pathophysiology in cardiac disease. Unfortunately, acquisition of PVL by conductance technology is not feasible in neonates and small children due to the available human catheter size and resulting invasiveness. The aim of the study was to validate the accuracy of PVL in small hearts using volume data obtained by real-time three-dimensional echocardiography (3DE) and simultaneously acquired pressure data. METHODS: In 17 piglets (weight range: 3.6–8.0 kg) left ventricular PVL were generated by 3DE and simultaneous recordings of ventricular pressure using a mini pressure wire (PVL3D). PVL3D were compared to conductance catheter measurements (PVLCond) under various hemodynamic conditions (baseline, alpha-adrenergic stimulation with phenylephrine, beta-adrenoreceptor-blockage using esmolol). In order to validate the accuracy of 3D volumetric data, cardiac magnetic resonance imaging (CMR) was performed in another 8 piglets. RESULTS: Correlation between CMR- and 3DE-derived volumes was good (enddiastolic volume: mean bias -0.03ml ±1.34ml). Computation of PVL3D in small hearts was feasible and comparable to results obtained by conductance technology. Bland-Altman analysis showed a low bias between PVL3D and PVLCond. Systolic and diastolic parameters were closely associated (Intraclass-Correlation Coefficient for: systolic myocardial elastance 0.95, arterial elastance 0.93, diastolic relaxation constant tau 0.90, indexed end-diastolic volume 0.98). Hemodynamic changes under different conditions were well detected by both methods (ICC 0.82 to 0.98). Inter- and intra-observer coefficients of variation were below 5% for all parameters. CONCLUSIONS: PVL3D generated from 3DE combined with mini pressure wire represent a novel, feasible and reliable method to assess different hemodynamic conditions of cardiac function in hearts comparable to neonate and infant size. This methodology may be integrated into clinical practice and cardiac catheterization programs and has the capability to contribute to clinical decision making even in small hearts.

Myocardial remodeling determines the degree of left ventricular dysfunction and mortality after transmural chronic myocardial infarction (CMI). Noninvasive characterization and quantitation of myocardial borderzone and collagenous scar are therefore parameters of clinical interest. The aims of this study were (i) to measure accuracy of reconstructive 3-D echocardiography (3DE) in scar and myocardial borderzone size assessment and (ii) to investigate the incremental value of low-dose dobutamine stress. 3DE was performed in 14 immunodeficient rats (rnu-rnu, 180-200 g) with anterior CMI 25 d after coronary ligation. Briefly, consecutive parallel short-axis cineloops were obtained electrocardiogram-gated starting from base to the apex. Morphology (mass, surface) and function (contractility, contractile reserve) of different compartments were assessed and correlated with 3-D histomorphometry. Histology was done using picrosirius red for collagen staining. 3DE left ventricular mass correlated closely with histomorphometry (y = 0.89x + 155, p0.0001, r = 0.80). Hypo- and akinetic myocardial surface correlated well with borderzone myocardium (y = 0.34x + 17, p = 0.009, r = 0.62) and collagenous scar (y = 1.9x + 4.4, p0.0001, r = 0.79), respectively. Extent of abnormal wall motion was closely related to borderzone and scar tissue area (y = 0.82x + 7, p0.0001, r = 0.77). 3DE quantitation of borderzone myocardium, but not collagenous scar, was more closely correlated to histomorphometry during inotropic stimulation. Global contractile reserve is positively associated with the size of myocardial borderzone. Regional contractile reserve of borderzone myocardium is not negatively associated with its collagen content. 3DE allows precise quantitation of myocardial borderzone and identification of transmural scar tissue noninvasively. Assessment of contractile reserve improves characterization and estimation of myocardial borderzone after CMI.

Cellular replacement therapy has emerged as a novel strategy for the treatment of heart failure. The aim of our study was to determine the fate of injected mesenchymal stem cells (MSCs) and whole bone marrow (BM) cells in the infarcted heart. MSCs were purified from BM of transgenic mice and characterized using flow cytometry and in vitro differentiation assays. Myocardial infarctions were generated in mice and different cell populations including transgenic MSCs, unfractionated BM cells, or purified hematopoietic progenitors were injected. Encapsulated structures were found in the infarcted areas of a large fraction of hearts after injecting MSCs (22 of 43, 51.2%) and unfractionated BM cells (6 of 46, 13.0%). These formations contained calcifications and/or ossifications. In contrast, no pathological abnormalities were found after injection of purified hematopoietic progenitors (0 of 5, 0.0%), fibroblasts (0 of 5, 0.0%), vehicle only (0 of 30, 0.0%), or cytokine-induced mobilization of BM cells (0 of 35, 0.0%). We conclude that the developmental fate of BM-derived cells is not restricted by the surrounding tissue after myocardial infarction and that the MSC fraction underlies the extended bone formation in the infarcted myocardium. These findings seriously question the biologic basis and clinical safety of using whole BM and in particular MSCs to treat nonhematopoietic disorders.

Resolution of inflammation is an active counter-regulatory mechanism involving polyunsaturated fatty acid-derived proresolving lipid mediators. Postoperative intestinal motility disturbances, clinically known as postoperative ileus, occur frequently after abdominal surgery and are mediated by a complex inflammation of the intestinal muscularis externa. Herein, we tested the hypothesis that proresolving lipid mediators are involved in the resolution of postoperative ileus. In a standardized experimental model of postoperative ileus, we detected strong expression of 12/15-lipoxygenase within the postoperative muscularis externa of C57BL/6 mice, predominately located within CX3CR1+/Ly6C+ infiltrating monocytes rather than Ly6G+ neutrophils. Mass spectrometry analyses demonstrated that a 12/15-lipoxygenase increase was accompanied by production of docosahexaenoic acid-derived lipid mediators, particularly protectin DX and resolvin D2, and their common precursor 17-hydroxy docosahexaenoic acid. Perioperative administration of protectin DX, but not resolvin D2 diminished blood-derived leukocyte infiltration into the surgically manipulated muscularis externa and improved the gastrointestinal motility. Flow cytometry analyses showed impaired Ly6G+/Ly6C+ neutrophil extravasation after protectin DX treatment, whereas Ly6G-/Ly6C+ monocyte numbers were not affected. 12/15-lipoxygenase-deficient mice, lacking endogenous protectin DX synthesis, demonstrated increased postoperative leukocyte levels. Preoperative intravenous administration of a docosahexaenoic acid-rich lipid emulsion reduced postoperative leukocyte infiltration in wild-type mice but failed in 12/15-lipoxygenase-deficient mice mice. Protectin DX application reduced leukocyte influx and rescued 12/15-lipoxygenase-deficient mice mice from postoperative ileus. In conclusion, our results show that 12/15-lipoxygenase mediates postoperative ileus resolution via production of proresolving docosahexaenoic acid-derived protectin DX. Perioperative, parenteral protectin DX or docosahexaenoic acid supplementation, as well as modulation of the 12/15-lipoxygenase pathway, may be instrumental in prevention of postoperative ileus.

Human aortic aneurysms have been associated with inflammation and vascular remodeling. Since the endocannabinoid system modulates inflammation and tissue remodeling, we investigated its components in human aortic aneurysms. We obtained anterior aortic wall samples from patients undergoing elective surgery for aortic aneurysm or coronary artery disease as controls. Histological and molecular analysis (RT-qPCR) was performed, and endocannabinoid concentration was determined using LC-MRM. Patient characteristics were comparable between the groups except for a higher incidence of arterial hypertension and diabetes in the control group. mRNA level of cannabinoid receptors was significantly higher in aneurysms than in controls. Concentration of the endocannabinoid 2-arachidonoylglycerol was significantly higher, while the second endocannabinoid anandamide and its metabolite arachidonic acid and palmitoylethanolamide were significantly lower in aneurysms. Histology revealed persistent infiltration of newly recruited leukocytes and significantly higher mononuclear cell density in adventitia of the aneurysms. Proinflammatory environment in aneurysms was shown by significant upregulation of M-CSF and PPARγbut associated with downregulation of chemokines. We found comparable collagen-stained area between the groups, significantly decreased mRNA level of CTGF, osteopontin-1, and MMP-2, and increased TIMP-4 expression in aneurysms. Our data provides evidence for endocannabinoid system activation in human aortic aneurysms, associated with persistent low-level inflammation and vascular remodeling.

Echocardiography is an established method to estimate left-ventricular mass (LVM) in mice. Accuracy is determined by cardiac size and morphology and influenced by mathematical models. We investigated accuracy of three common algorithms in three early developmental stages. High-resolution echocardiography was performed in 35 C57/BL6-mice. Therefore, two-dimensional-guided M-mode echocardiography and parasternal short- and long-axis views in B-mode were obtained. LVM was assessed in vivo applying Penn (P), Area Length (AL), and Truncated Ellipsoid (TE) algorithms and validated with histomorphometry. Regression analysis of all mice showed fair estimation of LVM assessed with M-mode-based Penn algorithm (y = 0.6*x - 0.12, r: 0.71). In contrast two-dimensional assessment of LVM revealed close linear relationship with histomorphometry (y(AL)= 1.21*x - 12.1, r: 0.88, y(TE)= 1.38*x - 2.88, r: 0.86). Bias was lowest for LVM-AL at diastole underestimating 3.2%. In concordance with the summarized data, LVM-P revealed lower regression coefficients and significant underestimation in all three subgroups. Small hearts (

Objective: Cardiac surgery causes induction and release of inflammatory mediators that may be regulated by genetic background. Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator that is known to be up-regulated in patients undergoing cardiac operations. Here we analyzed genotype distribution and allele frequency of the MIF-173*G/C single nucleotide polymorphism (SNP) and MIF plasma levels in patients undergoing surgical revascularization with (on-pump, n = 45) and without (off-pump, n = 34) cardiopulmonary bypass (CPB). Methods: Genotyping was performed using a real-time PCR-based system with a hybridization probe system specific for the MIF-173*G/C SNP. In on-pump patients, blood samples were drawn before start of CPB, after termination of CPB and 12 h postoperatively. In off-pump patients, blood samples were collected before stabilizer placement, after removal of the stabilizer and 12 h postoperatively. MIF levels were measured using ELISA technique. Results: Genotype distribution and allele frequencies were comparable between on-pump and off-pump patients. When comparing patients according to MIF genotype, a significant increase of MIF plasma levels after completed coronary bypass grafting using CPB was found in patients heterozygous for the MIF-173*G/C SNP (p < 0.05). Moreover, on-pump patients showed significantly decreased MIF plasma levels after 12 h postoperatively (p < 0.05). In off-pump patients, MIF plasma levels were not significantly different over the time-course and were independent of the genotype. Conclusions: Patients carrying the C-allele showed significantly increased levels of the proinflammatory cytokine MIF compared to G/G homozygous when revascularization was carried out using CPB. The G/C genotype may be associated with a severe inflammatory reaction and therefore preoperative screening could be beneficial for patients undergoing cardiac surgery using CPB.

The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 has potent mononuclear cell chemo-attractant properties, modulates fibroblast and endothelial cell phenotype and may play an important role in wound healing. In order to examine whether MCP-1 critically regulates myocardial infarct healing, we studied the effects of MCP-1 gene disruption and antibody neutralization in a closed-chest model of reperfused murine myocardial infarction. MCP-1−/−mice had decreased and delayed macrophage infiltration in the healing infarct and demonstrated delayed replacement of injured cardiomyocytes with granulation tissue. In contrast, the time course and density of neutrophil infiltration was similar in MCP-1 null and wild-type animals. MCP-1−/−infarcts had decreased mRNA expression of the cytokines TNF-α, IL-1β, TGF-β2, -β3, and IL-10 and demonstrated defective macrophage differentiation evidenced by decreased Osteopontin-1 expression. MCP-1 deficiency diminished myofibroblast accumulation but did not significantly affect infarct angiogenesis. Despite showing delayed phagocytotic removal of dead cardiomyocytes, MCP-1−/−mice had attenuated left ventricular remodeling, but similar infarct size when compared with wild-type animals. MCP-1 antibody inhibition resulted in defects comparable with the pathological findings noted in infarcted MCP-1−/−animals without an effect on macrophage recruitment. MCP-1 has important effects on macrophage recruitment and activation, cytokine synthesis and myofibroblast accumulation in healing infarcts. Absence of MCP-1 results in attenuated post-infarction left ventricular remodeling, at the expense of a prolonged inflammatory phase and delayed replacement of injured cardiomyocytes with granulation tissue.