Publications by authors named "Bernhard Unsöld"

32 Publications

Acquired von Willebrand syndrome and factor VIII in patients with moderate to severe mitral regurgitation undergoing transcatheter mitral valve repair.

Clin Cardiol 2021 Feb 29;44(2):261-266. Epub 2020 Dec 29.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Background And Hypothesis: The acquired von Willebrand syndrome (AvWS), which predisposes to bleeding events, is often related to valvular heart diseases. We investigated possible implications of AvWS and factor VIII levels in patients with moderate to severe mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR).

Methods And Results: 123 patients with moderate to severe MR were prospectively enrolled. Complete measurements of von Willebrand Factor activity (vWFAct), von Willebrand Factor antigen (vWFAg), and factor VIII expression before and 4 weeks after TMVR were available in 85 patients. At baseline, seven patients had a history of gastrointestinal bleeding, two patients suffered bleeding events during their hospital stay, and one patient had a bleeding 4 weeks after TMVR. Even though vWFAct, vWFAct/vWFAg ratio and vWFAg values did not change after TMVR, we observed a significantly lower vWFAct/vWFAg ratio in patients with primary MR as compared to patients with secondary MR both at baseline (p = 0.022) and 4 weeks following the TMVR procedure (p = 0.003). Additionally, patients with a mean mitral valve gradient ≥4 mmHg after TMVR had significantly lower vWFAct/vWFAg ratios as compared to patients with a mean mitral valve gradient <4 mmHg (p = 0.001).

Conclusions: MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, morphological changes leading to postprocedural transmitral gradients ≥4 mmHg were related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Alterations of the vWFAct/vWFAg ratio in turn did not translate into a greater risk for bleeding events.
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http://dx.doi.org/10.1002/clc.23538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852171PMC
February 2021

The role of diabetes in cardiomyopathies of different etiologies-Characteristics and 1-year follow-up results of the EVITA-HF registry.

PLoS One 2020 11;15(6):e0234260. Epub 2020 Jun 11.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Background: Type 2 diabetes is a major risk factor for cardiovascular diseases, e.g. coronary artery disease (CAD). But it has also been shown that diabetes can cause heart failure independently of ischemic heart disease (IHD) by causing diabetic cardiomyopathy. In contrast to diabetes and IHD, limited data exist regarding patients with diabetes and dilated cardiomyopathy (DCM).

Methods: EVIdence based TreAtment in Heart Failure (EVITA-HF) comprises web-based case report data on demography, diagnostic measures, adverse events and 1-year follow-up of patients hospitalized for chronic heart failure and an ejection fraction ≤40%. In the present study we focused on the results of patients with diabetes and heart failure.

Results: Between February 2009 and November 2015, 4101 patients with chronic heart failure were included in 16 tertiary care centers in Germany. The mortality in patients with diabetes and DCM (n = 323) was more than double (15.2%) than that of DCM patients without diabetes (6.5%, p<0.001, n = 885). In contrast the mortality rate of patients with IHD was not influenced by the presence of diabetes (17.6% in patients with IHD and diabetes n = 945, vs. 14.7% in patients with IHD and no diabetes, n = 1236, p = 0.061). The results also remained stable after performing a multivariable analysis (unadjusted p-value for interaction = 0.002, adjusted p = 0.046).

Conclusion: The influence of diabetes on the mortality rate is only significant in patients with DCM not in patients with CAD. Therefore, the underlying mechanisms of this effect should be studied in greater detail to improve patient care and outcome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289353PMC
August 2020

Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation.

PLoS One 2020 28;15(5):e0232817. Epub 2020 May 28.

Department of Internal Medicine I, Klinikum St. Marien, Amberg, Germany.

Background And Objectives: MitraClip implantation is an established therapy for secondary mitral regurgitation (MR) in high-risk patients and has shown to improve several important outcome parameters such as functional capacity. Patient selection is both challenging and crucial for achieving therapeutic success. This study investigated baseline predictors of functional improvement as it was quantified by the six-minute walk distance (6MWD) after transcatheter mitral valve repair.

Methods And Results: We retrospectively analyzed 79 patients with secondary MR treated with MitraClip implantation at an academic tertiary care center. Before and four weeks after the procedure, all patients underwent comprehensive clinical assessment, six-minute walk tests and echocardiography. 6MWD significantly improved after MitraClip therapy (295 m vs. 265 m, p < 0.001). A linear regression model including seven clinical baseline variables significantly predicted the change in 6MWD (p = 0.002, R2 = 0.387). Female gender, diabetes mellitus and arterial hypertension were found to be significant negative predictors of 6MWD improvement. At baseline, female patients had significant higher left ventricular ejection fraction (49% vs. 42%, p = 0.019) and lower 6MWD (240 m vs. 288 m, p = 0.034) than male patients.

Conclusion: MitraClip implantation in secondary MR significantly improves functional capacity in high-risk patients even in the short term of four weeks after the procedure. Female gender, diabetes mellitus and arterial hypertension are baseline predictors of a less favourable functional outcome. While further validation in a larger cohort is recommended, these parameters may improve patient selection for MitraClip therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232817PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255600PMC
July 2020

A machine learning approach for the prediction of pulmonary hypertension.

PLoS One 2019 25;14(10):e0224453. Epub 2019 Oct 25.

Clinic for Cardiology and Pulmonology/Heart Center, University Medical Center Göttingen, Göttingen, Germany.

Background: Machine learning (ML) is a powerful tool for identifying and structuring several informative variables for predictive tasks. Here, we investigated how ML algorithms may assist in echocardiographic pulmonary hypertension (PH) prediction, where current guidelines recommend integrating several echocardiographic parameters.

Methods: In our database of 90 patients with invasively determined pulmonary artery pressure (PAP) with corresponding echocardiographic estimations of PAP obtained within 24 hours, we trained and applied five ML algorithms (random forest of classification trees, random forest of regression trees, lasso penalized logistic regression, boosted classification trees, support vector machines) using a 10 times 3-fold cross-validation (CV) scheme.

Results: ML algorithms achieved high prediction accuracies: support vector machines (AUC 0.83; 95% CI 0.73-0.93), boosted classification trees (AUC 0.80; 95% CI 0.68-0.92), lasso penalized logistic regression (AUC 0.78; 95% CI 0.67-0.89), random forest of classification trees (AUC 0.85; 95% CI 0.75-0.95), random forest of regression trees (AUC 0.87; 95% CI 0.78-0.96). In contrast to the best of several conventional formulae (by Aduen et al.), this ML algorithm is based on several echocardiographic signs and feature selection, with estimated right atrial pressure (RAP) being of minor importance.

Conclusions: Using ML, we were able to predict pulmonary hypertension based on a broader set of echocardiographic data with little reliance on estimated RAP compared to an existing formula with non-inferior performance. With the conceptual advantages of a broader and unbiased selection and weighting of data our ML approach is suited for high level assistance in PH prediction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224453PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814224PMC
March 2020

Control of p21Cip by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival.

Cardiovasc Res 2020 03;116(3):592-604

Department of Cardiology and Pulmonology, Georg-August University, Robert-Koch Str. 40, 37075 Göttingen, Germany.

Aims: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation.

Methods And Results: General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis.

Conclusion: By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.
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http://dx.doi.org/10.1093/cvr/cvz177DOI Listing
March 2020

Echocardiographic Estimation of Mean Pulmonary Artery Pressure: A Comparison of Different Approaches to Assign the Likelihood of Pulmonary Hypertension.

J Am Soc Echocardiogr 2018 01 23;31(1):89-98. Epub 2017 Nov 23.

Clinic for Cardiology and Pneumology/Heart Center, University Medical Center Göttingen, Göttingen, Germany; German Centre for Cardiovascular Research, Partner Site Göttingen, Göttingen, Germany. Electronic address:

Background: Current guidelines advise using echocardiography for noninvasive estimation of the likelihood that a patient has pulmonary hypertension (PH). To estimate the echocardiographic probability of PH, the maximal tricuspid regurgitation velocity (TR Vmax) is recommended as the main parameter to use over more complex algorithms that provide an estimation of pulmonary artery pressure. This preference is based on concerns about inaccuracies and amplification of measurement errors that can occur from using derived variables. However, this has not been examined systematically.

Methods: A retrospective database analysis was performed of invasively determined measurements of right heart pressure in 90 patients, corresponding echocardiographic estimations of pulmonary artery pressure, and additional parameters obtained within 24 hours. Several algorithms were compared for their correlations and accuracy parameters.

Results: Although a Bland-Altman analysis demonstrated that all examined algorithms exhibited inaccuracies that could be clinically relevant in individuals, algorithms estimating mean pulmonary artery pressure (PAPm) on the basis of tricuspid regurgitation generally exhibited stronger correlations with invasively determined PAPm and more accurate identification of PH than did TR Vmax. Echocardiographic estimation of right atrial pressure >15 mm Hg exhibited the highest odds ratio for invasively confirmed PH, suggesting that this parameter is of additional diagnostic value. Indeed, algorithms that also considered right atrial pressure performed best, whereas empirical algorithms, TR Vmax, and methods relying on pulmonary acceleration time exhibited weaker performance.

Conclusions: Although all methods are associated with inaccuracies, echocardiographically determined PAPm was superior to the current guideline recommendation of using TR Vmax with regard to its correlation with invasively determined PAPm and the presence of PH. PAPm may be considered as an alternative to TR Vmax for evaluating the echocardiographic probability of PH.
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http://dx.doi.org/10.1016/j.echo.2017.09.009DOI Listing
January 2018

Pericardiectomy for Constrictive Pericarditis: An Institution's 21 Years Experience.

Thorac Cardiovasc Surg 2018 11 6;66(8):645-650. Epub 2017 Aug 6.

Department of Cardiothoracic Surgery, University Medical Center Regensburg, Regensburg, Germany.

Background: The aim of this retrospective study was to evaluate our experience with the surgical pericardiectomy procedure for patients suffering from isolated severe constrictive pericarditis.

Methods: From 1995 to 2016, 39 patients underwent isolated pericardiectomy for constrictive pericarditis. Fifteen patients were excluded because of concomitant surgery. There were 31 male (79.5%) patients and 8 female (20.5%) patients, 28 to 76 years old (mean, 56.6 ± 13.6 years). The underlying etiologies were idiopathic pericarditis (74.5%), infection (10%), rheumatic disorders (8%), status post cardiac surgery (2.5%), tuberculosis (2.5%), and status post mediastinal irradiation (2.5%).

Results: Pericardiectomy was performed through midline sternotomy in all cases. Sixteen patients (41%) underwent pericardiectomy electively employing cardiopulmonary bypass with the heart beating, and 23 patients (59%) had surgery without extracorporeal circulation (ECC). The overall 30-day mortality rate was 50% if cardiopulmonary bypass was used (13.8% since 2007). If surgery was performed without a heart-lung machine, mortality was 0%. On-pump patients had a significantly longer intensive care unit (ICU) stay (12 ± 9 vs. 4 ± 4 days,  = 0.013). Likewise, the duration of mechanical ventilation was much longer (171 ± 246 vs. 21 ± 40 hours,  = 0.04). The hospital stay was comparable with 28 ± 10 and 24 ± 18 days ( = 0.21).

Conclusion: The present study demonstrates that pericardiectomy, without the use of cardiopulmonary bypass as treatment for constrictive pericarditis, is a safe procedure with an excellent outcome in critically ill patients.
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http://dx.doi.org/10.1055/s-0037-1604303DOI Listing
November 2018

Enhanced cardiac TBC1D10C expression lowers heart rate and enhances exercise capacity and survival.

Sci Rep 2016 Sep 26;6:33853. Epub 2016 Sep 26.

Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.

TBC1D10C is a protein previously demonstrated to bind and inhibit Ras and Calcineurin. In cardiomyocytes, also CaMKII is inhibited and all three targeted enzymes are known to promote maladaptive cardiomyocyte hypertrophy. Here, in accordance with lack of Calcineurin inhibition in vivo, we did not observe a relevant anti-hypertrophic effect despite inhibition of Ras and CaMKII. However, cardiomyocyte-specific TBC1D10C overexpressing transgenic mice exhibited enhanced longevity. Ejection fraction and exercise capacity were enhanced in transgenic mice, but shortening of isolated cardiomyocytes was not increased. This suggests longevity resulted from enhanced cardiac performance but independent of cardiomyocyte contractile force. In further search for mechanisms, a transcriptome-wide analysis revealed expressional changes in several genes pertinent to control of heart rate (HR) including Hcn4, Scn10a, Sema3a and Cacna2d2. Indeed, telemetric holter recordings demonstrated slower atrial conduction and significantly lower HR. Pharmacological reduction of HR was previously demonstrated to enhance survival in mice. Thus, in addition to inhibition of stress signaling, TBC1D10C economizes generation of cardiac output via HR reduction, enhancing exercise capacity and survival. TBC1D10C may be a new target for HR reduction and longevity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036039PMC
http://dx.doi.org/10.1038/srep33853DOI Listing
September 2016

Sensing Cardiac Electrical Activity With a Cardiac Myocyte--Targeted Optogenetic Voltage Indicator.

Circ Res 2015 Aug 15;117(5):401-12. Epub 2015 Jun 15.

From the Institute of Pharmacology (M.-L.C.L., S.D., E. Wettwer, W.-H.Z.), Clinic for Cardiology and Pulmonology (N.R., E. Wagner, B.U., K.S.-B., K.G., S.W., S.E.L., L.S.M.), and Microarray and Deep-Sequencing Facility (B.R.D.), University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany (M.-L.C.L., N.R., E. Wagner, K.S.-B., S.L., K.G., S.E.L., W.S., W.-H.Z.); Institute of Biomechanics, Technical University Hamburg-Harburg, Hamburg, Germany (M.-L.C.L., M.M.M.); Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands (T.P.d.B., I.A., T.v.V.); Laboratory of Neuronal Circuit Dynamics, RIKEN Brain Science Institute, Saitama, Japan (H.M., T.K.); Max-Planck-Institutes for Dynamics and Self Organization (N.R., C.R., S.L.) and Experimental Medicine (W.S.), Göttingen, Germany; Department of Internal Medicine II, University Hospital of Regensburg, Regensburg, Germany (B.U., S.W., L.S.M.); Department of Medicine and Centre for Neurotechnology, Imperial College London, United Kingdom (T.K.).

Rationale: Monitoring and controlling cardiac myocyte activity with optogenetic tools offer exciting possibilities for fundamental and translational cardiovascular research. Genetically encoded voltage indicators may be particularly attractive for minimal invasive and repeated assessments of cardiac excitation from the cellular to the whole heart level.

Objective: To test the hypothesis that cardiac myocyte-targeted voltage-sensitive fluorescence protein 2.3 (VSFP2.3) can be exploited as optogenetic tool for the monitoring of electric activity in isolated cardiac myocytes and the whole heart as well as function and maturity in induced pluripotent stem cell-derived cardiac myocytes.

Methods And Results: We first generated mice with cardiac myocyte-restricted expression of VSFP2.3 and demonstrated distinct localization of VSFP2.3 at the t-tubulus/junctional sarcoplasmic reticulum microdomain without any signs for associated pathologies (assessed by echocardiography, RNA-sequencing, and patch clamping). Optically recorded VSFP2.3 signals correlated well with membrane voltage measured simultaneously by patch clamping. The use of VSFP2.3 for human action potential recordings was confirmed by simulation of immature and mature action potentials in murine VSFP2.3 cardiac myocytes. Optical cardiograms could be monitored in whole hearts ex vivo and minimally invasively in vivo via fiber optics at physiological heart rate (10 Hz) and under pacing-induced arrhythmia. Finally, we reprogrammed tail-tip fibroblasts from transgenic mice and used the VSFP2.3 sensor for benchmarking functional and structural maturation in induced pluripotent stem cell-derived cardiac myocytes.

Conclusions: We introduce a novel transgenic voltage-sensor model as a new method in cardiovascular research and provide proof of concept for its use in optogenetic sensing of physiological and pathological excitation in mature and immature cardiac myocytes in vitro and in vivo.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.306143DOI Listing
August 2015

Long term biventricular support with Berlin Heart Excor in a Septuagenarian with giant-cell myocarditis.

J Cardiothorac Surg 2015 Jan 31;10:14. Epub 2015 Jan 31.

Giant-cell myocarditis (GCM) is known as a rare, rapidly progressive, and frequently fatal myocardial disease in young and middle-aged adults. We report about a 76 year old male patient who underwent implantation with a biventricular Berlin Heart Excor system at the age of 74 due to acute biventricular heart failure caused by giant-cell myocarditis. The implantation was without any surgical problems; however, a difficulty was the immunosuppressive therapy after implantation. Meanwhile the patient is 76 years old and lives with circulatory support for about 3 years without major adverse events. Also, in terms of mobility in old age there are no major limitations. It seems that in even selected elderly patients an implantation of a long term support with the biventricular Berlin Heart Excor is a useful therapeutic option with an acceptable outcome.
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http://dx.doi.org/10.1186/s13019-015-0218-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320566PMC
January 2015

Negative hemodynamic effects of pantoprazole at high infusion rates in mice.

Cardiovasc Ther 2015 Feb;33(1):20-6

Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Background: Pantoprazole has been shown to exert a negative inotropic effect in isolated myocardium. The purpose of this study was to evaluate the hemodynamic effects of pantoprazole in vivo in healthy myocardium and in the setting of heart failure.

Methods And Results: Healthy mice and mice with heart failure 4 weeks after myocardial infarction induced by permanent LAD ligation were instrumented with a Millar Mikrotip conductance catheter to record pressure-volume loops. Pantoprazole was infused at rates of 3 and 10 mg/kg/min intravenously, and hemodynamic parameters were recorded. Infusion of pantoprazole at increasing rates lead to a significant decline of end systolic LV pressure by decreasing heart rate, myocardial contractility and arterial elastance. These effects were quick, beginning immediately with the infusion and usually reaching a plateau after 2 or 3 min of infusion. The effects on blood pressure and heart rate were of comparable size in healthy mice and mice with MI. However, in sham-operated mice, there was a compensatory increase in stroke volume that sufficed to maintain cardiac output at a constant level, which was missing in mice with MI. In 4 of 13 mice with MI infusion of 10 mg/kg/min pantoprazole lead to pump failure, which was lethal in 2 of these animals.

Conclusion: At higher infusion rates, pantoprazole is able to induce negative hemodynamic responses. In particular, in the setting of heart failure, these effects can lead to significant impairment of cardiac function. Therefore, high infusion rates of pantoprazole should be avoided especially in heart failure patients.
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http://dx.doi.org/10.1111/1755-5922.12102DOI Listing
February 2015

Differential PI3K signal transduction in obesity-associated cardiac hypertrophy and response to ischemia.

Obesity (Silver Spring) 2015 Jan 30;23(1):90-9. Epub 2014 Aug 30.

Department of Cardiology and Pulmonary Medicine, University Medical Center of the Georg August University of Goettingen, Germany.

Objective: Elevated insulin and inflammatory cytokine levels in obesity may chronically activate signaling pathways regulating cardiac growth and contractility. Our aim was to examine the effect of obesity on cardiac PI3K isoform and Akt activation during left ventricular (LV) hypertrophy and heart failure.

Methods: Wild-type mice were fed normal chow or high-fat diet (HFD) for 2, 4, or 6 months. A subset of mice was subjected to chronic myocardial ischemia (MI).

Results: Echocardiography revealed a progressive increase in LV mass, wall thickness, and diameters in obese mice. Systolic pump function was not impaired. Increased cardiac levels of PI3Kγ, phosphorylated Akt, GSK3β, and Epac were observed after HFD for 2 months but gradually declined and were normal or reduced after 6 months, paralleled by elevated PP2A and SOCS3 levels. MI resulted in heart failure, independent of obesity, but compensatory LV hypertrophy was absent in obese mice. Histochemical analyses revealed similar increases in cardiac fibrosis, inflammation, apoptosis, and angiogenesis in lean and obese mice.

Conclusions: Our findings suggest that activation of Akt initially contributes to cardiac hypertrophy and that chronic metabolic and inflammatory stimulation and overexpression of inhibitory mediators decrease PI3Kγ-mediated Akt signaling and blunt compensatory hypertrophy after MI.
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http://dx.doi.org/10.1002/oby.20888DOI Listing
January 2015

Enhanced late INa induces proarrhythmogenic SR Ca leak in a CaMKII-dependent manner.

J Mol Cell Cardiol 2014 Nov 27;76:94-105. Epub 2014 Aug 27.

Department of Internal Medicine II, University of Regensburg, Germany.

Objective: Enhanced late Na current (late INa) induces Na-dependent Ca overload as well as proarrhythmogenic events on the cellular level that include spatio-temporally uncoordinated diastolic Ca release from the sarcoplasmic reticulum (SR) and delayed afterdepolarizations (DADs). The Ca/calmodulin-dependent protein kinase II (CaMKII) gets activated upon increases in [Ca]i and mediates diastolic SR Ca leak as well as DADs.

Rationale: We hypothesized that increased late INa (in disease-comparable ranges) exerts proarrhythmogenic events in isolated ventricular mouse myocytes in a manner depending on CaMKII-dependent SR Ca leak. We further tested whether inhibition of disease-related late INa may reduce proarrhythmogenic SR Ca leak in myocytes from failing human hearts.

Methods: Ventricular myocytes were isolated from healthy wildtype (WT), failing CaMKIIδC transgenic (TG) mouse, and failing human hearts. ATX-II (0.25-10 nmol/L) was used to enhance late INa. Spontaneous Ca loss from the SR during diastole (Ca sparks), DADs, non-triggered diastolic Ca transients in myocytes and premature beats of isometrically twitching papillary muscles were used as readouts for proarrhythmogenic events. CaMKII autophosphorylation was assessed by immunoblots. Late INa was inhibited using ranolazine (Ran, 10 μmol/L) or TTX (2 μmol/L), and CaMKII by KN-93 (1 μmol/L) or AIP (1 μmol/L).

Results: In WT myocytes, sub-nanomolar ATX-II exposure (0.5 nmol/L) enhanced late INa by ~60%, which resulted in increased diastolic SR Ca loss despite unaltered SR Ca content. In parallel, DADs and non-triggered diastolic Ca transients arose. Inhibition of enhanced late INa by RAN or TTX significantly attenuated diastolic SR Ca loss and suppressed DADs as well as mechanical alternans in mouse and diastolic SR Ca loss in failing human myocytes. ATX-II caused Ca-dependent CaMKII-activation without changes in protein expression, which was reversible by Ran or AIP. Conversely, CaMKII-inhibition decreased diastolic SR Ca loss, DADs and non-triggered diastolic Ca transients despite ATX-II-exposure. Finally, failing mouse myocytes with increased CaMKII activity (TG CaMKIIδC) showed an even aggravated diastolic SR Ca loss that was associated with an increased frequency of non-triggered diastolic Ca transients upon enhanced late INa.

Conclusions: Increased late INa (in disease-comparable ranges) induces proarrhythmogenic events during diastole in healthy and failing mouse myocytes, which are mediated via CaMKII-dependent SR Ca loss. Inhibition of late INa not only attenuated these cellular arrhythmias in mouse myocytes but also in failing human myocytes indicating some antiarrhythmic potential for an inhibition of the elevated late INa/CaMKII signaling pathway in this setting.
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http://dx.doi.org/10.1016/j.yjmcc.2014.08.016DOI Listing
November 2014

Erythropoietin responsive cardiomyogenic cells contribute to heart repair post myocardial infarction.

Stem Cells 2014 Sep;32(9):2480-91

Institute of Pharmacology, University Medical Center, Georg-August-Universität Göttingen, Göttingen, Germany.

The role of erythropoietin (Epo) in myocardial repair after infarction remains inconclusive. We observed high Epo receptor (EPOR) expression in cardiac progenitor cells (CPCs). Therefore, we aimed to characterize these cells and elucidate their contribution to myocardial regeneration on Epo stimulation. High EPOR expression was detected during murine embryonic heart development followed by a marked decrease until adulthood. EPOR-positive cells in the adult heart were identified in a CPC-enriched cell population and showed coexpression of stem, mesenchymal, endothelial, and cardiomyogenic cell markers. We focused on the population coexpressing early (TBX5, NKX2.5) and definitive (myosin heavy chain [MHC], cardiac Troponin T [cTNT]) cardiomyocyte markers. Epo increased their proliferation and thus were designated as Epo-responsive MHC expressing cells (EMCs). In vitro, EMCs proliferated and partially differentiated toward cardiomyocyte-like cells. Repetitive Epo administration in mice with myocardial infarction (cumulative dose 4 IU/g) resulted in an increase in cardiac EMCs and cTNT-positive cells in the infarcted area. This was further accompanied by a significant preservation of cardiac function when compared with control mice. Our study characterized an EPO-responsive MHC-expressing cell population in the adult heart. Repetitive, moderate-dose Epo treatment enhanced the proliferation of EMCs resulting in preservation of post-ischemic cardiac function.
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http://dx.doi.org/10.1002/stem.1741DOI Listing
September 2014

Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction.

Cardiovasc Res 2014 Jan 15;101(1):97-107. Epub 2013 Oct 15.

Department of Cardiology, University of Göttingen, Heart Research Center Göttingen, Göttingen, Germany.

Aims: Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach.

Methods And Results: Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusin's overexpression strongly reduced mortality (43.2% in wild-type vs. 27.3% in melusin-TG, P = 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility.

Conclusions: Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling.
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http://dx.doi.org/10.1093/cvr/cvt235DOI Listing
January 2014

Parthenogenetic stem cells for tissue-engineered heart repair.

J Clin Invest 2013 Mar 22;123(3):1285-98. Epub 2013 Feb 22.

Institute of Pharmacology, University Medical Center Göttingen, Göttingen, Germany.

Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair.
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http://dx.doi.org/10.1172/JCI66854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582145PMC
March 2013

Age-dependent changes in contractile function and passive elastic properties of myocardium from mice lacking muscle LIM protein (MLP).

Eur J Heart Fail 2012 Apr 26;14(4):430-7. Epub 2012 Feb 26.

Department of Cardiology and Pneumology, Georg-August University of Göttingen, Germany.

Aims: Muscle LIM protein (MLP) null mice are often used as a model for human dilated cardiomyopathy. So far, little is known about the time course and pathomechanisms leading to the development of the adult phenotype.

Methods And Results: We systematically analysed the contractile phenotype, myofilament calcium (Ca(2)(+)) responsiveness, passive myocardial mechanics, histology, and mRNA expression in mice aged 4 and 12 weeks. In 4-week-old animals, there was no significant difference in the force-frequency relationship (FFR) and catecholamine response of intact isolated papillary muscles between wild-type (WT) and MLP null myocardium. In 12-week-old animals, WT myocardium exhibited a significantly positive FFR, while that of MLP null mice was significantly negative, and the inotropic response to catecholamines was significantly reduced in MLP null mice. This time course of decline in contractile function was confirmed in vivo by echocardiography. Whereas at 4 weeks of age MLP null mice and WT littermates showed similar levels of SERCA2a (sarcoplasmic reticulum Ca(2+) ATPase) expression, the expression was significantly lower in 12-week-old MLP null mice compared with littermate controls. Myofilament Ca(2)(+) responsiveness was not affected by the lack of MLP, irrespective of age. Whereas in 4-week-old animals MLP null myocardium showed a trend to an increased compliance compared with the WT, myocardium of 12-week-old MLP null mice was significantly less compliant than WT myocardium. Parallel to the decrease in compliance there was an increase in fibrosis in the MLP null animals.

Conclusion: Our data suggest that MLP deficiency does not primarily influence myocardial contractility. A lack of MLP leads to an age-dependent impairment of excitation-contraction coupling with resulting contractile dysfunction and secondary fibrosis.
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http://dx.doi.org/10.1093/eurjhf/hfs020DOI Listing
April 2012

Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.

Circ Res 2011 Sep 28;109(7):758-69. Epub 2011 Jul 28.

Imperial College, National Heart & Lung Institute, British Heart Foundation, Centre for Research Excellence, Myocardial Genetics, London, UK.

Rationale: Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function.

Objective: Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation.

Methods And Results: By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts.

Conclusions: Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.111.245787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664427PMC
September 2011

Limitations of FKBP12.6-directed treatment strategies for maladaptive cardiac remodeling and heart failure.

J Mol Cell Cardiol 2011 Jan 24;50(1):33-42. Epub 2010 Aug 24.

Department of Cardiology and Pneumology, Heart Center, University of Göttingen, Germany.

Sarcoplasmic reticulum (SR) calcium (Ca) leak can be reduced by enhancing FKBP12.6 binding to SR Ca release channels (RyR2) and expression of a "sticky" FKBP12.6(D37S) mutant may correct reduced binding stoichiometry in RyR2 from failing hearts. Both calcium/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and protein kinase A (PKA) are activated in heart failure and promote SR Ca leak at RyR2. It is possible that FKBP12.6 dissociation from RyR2 may promote remodeling and that interventions to reassociate FKBP12.6 with RyR2 reflect a future therapeutic strategy. We created transgenic (TG) mice expressing FKBP12.6(D37S) and tested their capacity to improve intracellular Ca handling and pathological remodeling in vivo. FKBP12.6(D37S) TG mice were cross-bred with CaMKIIδc TG mice, which are known to exhibit pronounced RyR2 dysfunction and heart failure. We observed a significant improvement of post-rest Ca transients and a higher SR Ca content in FKBP12.6(D37S) TG mice. In double-TG mice, a marked reduction of SR Ca spark frequency indicated reduced SR Ca leak but neither SR Ca transient amplitude, SR Ca content nor morphological or functional parameters improved in vivo. Likewise, FKBP12.6(D37S) TG mice subjected to increased afterload after aortic banding exhibited higher SR Ca load but did not exhibit any improvement in hypertrophic growth or functional decline. Enhancement of FKBP12.6-RyR2 binding markedly reduced RyR2 Ca leak in CaMKIIδc-induced heart failure and in pressure overload. Our data suggest that activation of CaMKIIδc and pressure overload confer significant resistance towards approaches aiming at FKBP12.6-RyR2 reconstitution in heart failure and maladaptive remodeling, although RyR2 Ca leak can be reduced.
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http://dx.doi.org/10.1016/j.yjmcc.2010.08.016DOI Listing
January 2011

Differential cardiac remodeling in preload versus afterload.

Circulation 2010 Sep 23;122(10):993-1003. Epub 2010 Aug 23.

Department of Cardiology and Pneumology, Georg-August-University Goettingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

Background: Hemodynamic load regulates myocardial function and gene expression. We tested the hypothesis that afterload and preload, despite similar average load, result in different phenotypes.

Methods And Results: Afterload and preload were compared in mice with transverse aortic constriction (TAC) and aortocaval shunt (shunt). Compared with sham mice, 6 hours after surgery, systolic wall stress (afterload) was increased in TAC mice (+40%; P<0.05), diastolic wall stress (preload) was increased in shunt (+277%; P<0.05) and TAC mice (+74%; P<0.05), and mean total wall stress was similarly increased in TAC (69%) and shunt mice (67%) (P=NS, TAC versus shunt; each P<0.05 versus sham). At 1 week, left ventricular weight/tibia length was significantly increased by 22% in TAC and 29% in shunt mice (P=NS, TAC versus shunt). After 24 hours and 1 week, calcium/calmodulin-dependent protein kinase II signaling was increased in TAC. This resulted in altered calcium cycling, including increased L-type calcium current, calcium transients, fractional sarcoplasmic reticulum calcium release, and calcium spark frequency. In shunt mice, Akt phosphorylation was increased. TAC was associated with inflammation, fibrosis, and cardiomyocyte apoptosis. The latter was significantly reduced in calcium/calmodulin-dependent protein kinase IIdelta-knockout TAC mice. A total of 157 mRNAs and 13 microRNAs were differentially regulated in TAC versus shunt mice. After 8 weeks, fractional shortening was lower and mortality was higher in TAC versus shunt mice.

Conclusions: Afterload results in maladaptive fibrotic hypertrophy with calcium/calmodulin-dependent protein kinase II-dependent altered calcium cycling and apoptosis. Preload is associated with Akt activation without fibrosis, little apoptosis, better function, and lower mortality. This indicates that different loads result in distinct phenotype differences that may require specific pharmacological interventions.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.110.943431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955196PMC
September 2010

BNP controls early load-dependent regulation of SERCA through calcineurin.

Basic Res Cardiol 2010 Nov 15;105(6):795-804. Epub 2010 Aug 15.

Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Robert-Koch-Str. 40, 37075, Göttingen, Germany.

Heart failure is characterised by reduced expression of sarcoplasmic reticulum calcium-ATPase (SERCA) and increased expression of B-type natriuretic peptide (BNP). The present study was performed to investigate causality of this inverse relationship under in vivo conditions in the transversal aortic constriction mouse model (TAC). Left ventricular SERCA-mRNA expression was significantly upregulated in TAC by 32% after 6 h, but not different from sham after 24 h. Serum proANP and BNP levels were increased in TAC after 24 h (BNP +274%, p < 0.01; proANP +60%, p < 0.05), but only proANP levels were increased after 6 h (+182%, p < 0.01). cGMP levels were only increased 24 h after TAC (+307%, p < 0.01), but not 6 h after TAC. BNP infusion inhibited the increase in SERCA expression 6 h after TAC. In BNP-receptor-knockout animals (GC-A), the expression of SERCA was still significantly increased 24 h after TAC at the mRNA level by 35% (p < 0.05), as well as at the protein level by 25% (p < 0.05). MCIP expression as an indicator of calcineurin activity was regulated in parallel to SERCA after 6 and 24 h. MCIP-mRNA was increased by 333% 6 h after TAC, but not significantly different from sham after 24 h. In the GC-A-KO mice, MCIP-mRNA was significantly increased in TAC compared to WT after 24 h. In mice with BNP infusion, MCIP was significantly lower 6 h after TAC compared to control animals. In conclusion, mechanical load leads to an upregulation of SERCA expression. This is followed by upregulation of natriuretic peptides with subsequent suppression of SERCA upregulation. Elevated natriuretic peptides may suppress SERCA expression by inhibition of calcineurin activity via activation of GC-A.
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http://dx.doi.org/10.1007/s00395-010-0115-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965361PMC
November 2010

Effects of mild hypothermia on hemodynamics in cardiac arrest survivors and isolated failing human myocardium.

Clin Res Cardiol 2010 May 4;99(5):267-76. Epub 2010 Feb 4.

Department of Cardiology und Pneumology, Heart Center, Georg-August-University, Robert-Koch-Strasse 40, 37075, Göttingen, Germany.

Post-cardiac arrest myocardial dysfunction is a common phenomenon after return of spontaneous circulation (ROSC) and contributes to hemodynamic instability and low survival rates after cardiac arrest. Mild hypothermia for 24 h after ROSC has been shown to significantly improve neurologic recovery and survival rates. In the present study we investigate the influence of therapeutic hypothermia on hemodynamic parameters in resuscitated patients and on contractility in failing human myocardium. We analyzed hemodynamic data from 200 cardiac arrest survivors during the hypothermia period. The initial LVEF was 32.6 +/- 1.2% indicating a significantly impaired LV function. During hypothermia induction, the infusion rate of epinephrine could be significantly reduced from 9.1 +/- 1.3 microg/min [arrival intensive care unit (ICU) 35.4 degrees C] to 4.6 +/- 1.0 microg/min (34 degrees C) and 2.8 +/- 0.5 microg/min (33 degrees C). The dobutamine and norepinephrine application rates were not changed significantly. The mean arterial blood pressure remained stable. The mean heart rate significantly decreased from 91.8 +/- 1.7 bpm (arrival ICU) to 77.3 +/- 1.5 bpm (34 degrees C) and 70.3 +/- 1.4 bpm (33 degrees C). In vitro we investigated the effect of hypothermia on isolated ventricular muscle strips from explanted failing human hearts. With decreasing temperature, the contractility increased to a maximum of 168 +/- 23% at 27 degrees C (n = 16, P < 0.05). Positive inotropic response to hypothermia was accompanied by moderately increased rapid cooling contractures as a measure of sarcoplasmic reticulum (SR) Ca(2+) content, but can be elicited even when the SR Ca(2+) release is blocked in the presence of ryanodine. Contraction and relaxation kinetics are prolonged with hypothermia, indicating increased Ca(2+) sensitivity as the main mechanism responsible for inotropy. In conclusion, mild hypothermia stabilizes hemodynamics in cardiac arrest survivors which might contribute to improved survival rates in these patients. Mechanistically, we demonstrate that hypothermia improves contractility in failing human myocardium most likely by increasing Ca(2+)-sensitivity.
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http://dx.doi.org/10.1007/s00392-010-0113-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858797PMC
May 2010

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging.

J Clin Invest 2010 Feb 11;120(2):617-26. Epub 2010 Jan 11.

Institute of Experimental and Clinical Pharmacology and Toxicology, Cardiovascular Research Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.
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http://dx.doi.org/10.1172/JCI40545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810086PMC
February 2010

Effects of large volume, ice-cold intravenous fluid infusion on respiratory function in cardiac arrest survivors.

Resuscitation 2009 Nov 11;80(11):1223-8. Epub 2009 Aug 11.

Department of Cardiology and Pneumology, Georg-August-University, Göttingen, Germany.

International guidelines for cardiopulmonary resuscitation recommend mild hypothermia (32-34 degrees C) for 12-24h in comatose survivors of cardiac arrest. To induce therapeutic hypothermia a variety of external and intravascular cooling devices are available. A cheap and effective method for inducing hypothermia is the infusion of large volume, ice-cold intravenous fluid. There are concerns regarding the effects of rapid infusion of large volumes of fluid on respiratory function in cardiac arrest survivors. We have retrospectively studied the effects of high volume cold fluid infusion on respiratory function in 52 resuscitated cardiac arrest patients. The target temperature of 32-34 degrees C was achieved after 4.1+/-0.5h (cooling rate 0.48 degrees C/h). During this period 3427+/-210 mL ice-cold fluid was infused. Despite significantly reduced LV-function (EF 35.8+/-2.2%) the respiratory status of these patients did not deteriorate significantly. On intensive care unit admission the mean PaO(2) was 231.4+/-20.6 mmHg at a F(i)O(2) of 0.82+/-0.03 (PaO(2)/F(i)O(2)=290.0+/-24.1) and a PEEP level of 7.14+/-0.31 mbar. Until reaching the target temperature of
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http://dx.doi.org/10.1016/j.resuscitation.2009.06.032DOI Listing
November 2009

Recent in vitro findings of negative inotropy of pantoprazole did not translate into clinically relevant effects on left ventricular function in healthy volunteers.

Clin Res Cardiol 2009 Jun 20;98(6):391-9. Epub 2009 Mar 20.

Herzzentrum, Kardiologie und Pneumologie, Universitätsmedizin Göttingen, Germany.

Purpose: Reports on cardiac problems with oral proton pump inhibitors have caused extensive safety reviews by the US Food and Drug Administration. We provide additional data on acute cardiac effects of an intravenous application.

Methods: Echocardiography was performed in 18 healthy volunteers after administration of a common high-dose regimen of pantoprazole (80 mg i.v. bolus followed by 8 mg/h for 1 h) or placebo.

Design: The design included a randomized, double-blind, placebo-controlled cross-over trial.

Results: Ejection fraction (%, mean +/- SE) in the treatment group (placebo group) was 60.7 +/- 1.1 (61.2 +/- 1.7) at baseline, and 62.6 +/- 1.1 (62.1 +/- 1.9), 64.7 +/- 1.6 (63.5 +/- 1.3), 62.6 +/- 1.6 (61.0 +/- 1.6) and 63.0 +/- 1.4 (61.8 +/- 1.5) at 7.5, 15, 30 and 60 min after bolus application, respectively (p = n.s.). Similarly, no significant changes were found for cardiac output, cardiac index, blood pressure and heart rate. In contrast, gastric pH that was used as a treatment control was significantly increased 60 min after the application of pantoprazole as compared to baseline and to placebo.

Conclusions: Pantoprazole as injection is safe in healthy subjects with respect to cardiac contractile function. However, in view of recent reports of negative inotropy of the drug, further studies in heart failure patients are required.
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http://dx.doi.org/10.1007/s00392-009-0012-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698968PMC
June 2009

Exercise intolerance and systemic manifestations of pulmonary emphysema in a mouse model.

Respir Res 2009 Jan 28;10. Epub 2009 Jan 28.

Kardiologie und Pneumologie, Georg-August-Universität, Göttingen, Germany.

Background: Systemic effects of chronic obstructive pulmonary disease (COPD) significantly contribute to severity and mortality of the disease. We aimed to develop a COPD/emphysema model exhibiting systemic manifestations of the disease.

Methods: Female NMRI mice were treated 5 times intratracheally with porcine pancreatic elastase (emphysema) or phosphate-buffered saline (control). Emphysema severity was quantified histologically by mean linear intercept, exercise tolerance by treadmill running distance, diaphragm dysfunction using isolated muscle strips, pulmonary hypertension by measuring right ventricular pressure, and neurohumoral activation by determining urinary norepinephrine concentration.

Results: Mean linear intercept was higher in emphysema (260.7 +/- 26.8 microm) than in control lungs (24.7 +/- 1.7 microm). Emphysema mice lost body weight, controls gained weight. Running distance was shorter in emphysema than in controls. Diaphragm muscle length was shorter in controls compared to emphysema. Fatigue tests of muscle strips revealed impaired relaxation in emphysema diaphragms. Maximum right ventricular pressure and norepinephrine were elevated in emphysema compared to controls. Linear correlations were observed between running distance changes and intercept, right ventricular weight, norepinephrine, and diaphragm length.

Conclusion: The elastase mouse model exhibited severe emphysema with consecutive exercise limitation, and neurohumoral activation. The model may deepen our understanding of systemic aspects of COPD.
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http://dx.doi.org/10.1186/1465-9921-10-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2644670PMC
January 2009

Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy.

Cardiovasc Res 2008 Dec 8;80(3):396-406. Epub 2008 Aug 8.

Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Aims: Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response.

Methods And Results: We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection.

Conclusion: Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.
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http://dx.doi.org/10.1093/cvr/cvn208DOI Listing
December 2008