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7. An altered plasma lipidome–phenome network characterizes heart failure with preserved ejection fraction.

Author

Jovanovic, Nina, Foryst‐Ludwig, Anna, Klose, Christian, da Conceicao, Cristina Rozados, Alasfar, Lina, Birkner, Till, Forslund, Sofia K., Kintscher, Ulrich, and Edelmann, Frank

Subjects
LEFT ventricular hypertrophy, BRAIN natriuretic factor, HEART failure, VENTRICULAR ejection fraction, BLOOD lipids, DIASTOLIC blood pressure
Abstract

Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial, multisystemic syndrome that involves alterations in lipid metabolism. This study aimed to test whether distinct plasma lipid profiles or lipid entities or both are associated with clinical and functional echocardiographic parameters in HFpEF. Methods and results: We examined the human plasma lipidome in HFpEF patients (n = 18) with left ventricular ejection fraction ≥50% and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) >125 pg/mL and control subjects (n = 12) using mass spectrometry‐based shotgun lipidomics. The cohort included 8 women and 22 men with average age of 67.8 ± 8.6 SD. The control and disease groups were not significantly different with respect to age, body mass index, systolic and diastolic blood pressure, and waist‐to‐hip ratio. The disease group experienced more fatigue (P < 0.001), had more often coronary artery disease (P = 0.04), and received more medications (beta‐blockers, P < 0.001). The disease group had significantly different levels of HFpEF‐relevant parameters, including NT‐proBNP (P < 0.001), left ventricular mass index (P = 0.005), left atrial volume index (P = 0.001), and left ventricular filling index (P < 0.001), and lower left ventricular end‐diastolic diameter (P = 0.014), with no difference in left ventricular ejection fraction. Significant differences in lipid profiles between HFpEF patients and controls could not be detected, including no significant differences in abundance of circulating lipids binned by carbon chain length or by double bonds, nor at the level of individual lipid species. However, there was a striking correlation between selected lipids with smoking status that was independent of disease status, as well as between specific lipids and hyperlipidaemia [with corresponding significance of either false discovery rate (FDR) <0.1 or FDR < 0.01]. In an exploratory network analysis of correlations, we observed significantly stronger correlations within the HFpEF group between individual lipids from the cholesterol ester and phosphatidylcholine (PC) classes and clinical/echocardiographic parameters such as left atrial volume index, left ventricular end‐diastolic diameters, and heart rate (FDR < 0.1). In contrast, the control group showed significantly stronger negative correlations (FDR < 0.1) between individual species from the PC and sphingomyelin classes and left ventricular mass index or systolic blood pressure. Conclusions: We did not find significant direct associations between plasma lipidomic parameters and HFpEF and therefore could not conclude that any specific lipids are biomarkers of HFpEF. The validation in larger cohort is needed to confidently conclude the absence of first‐order associations. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Accurate assessment of LV function using the first automated 2D-border detection algorithm for small animals - evaluation and application to models of LV dysfunction

Author

Grune, Jana, Ritter, Daniel, Kräker, Kristin, Pappritz, Kathleen, Beyhoff, Niklas, Schütte, Till, Ott, Christiane, John, Cathleen, van Linthout, Sophie, Tschöpe, Carsten, Dechend, Ralf, Muller, Dominik N., Haase, Nadine, Grune, Tilman, Kintscher, Ulrich, and Kuebler, Wolfgang M.

Published
2019
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22. Inflammatory Pathways Regulated by Tumor Necrosis Receptor–Associated Factor 1 Protect From Metabolic Consequences in Diet-Induced Obesity

Author

Anto Michel, Nathaly, Colberg, Christian, Buscher, Konrad, Sommer, Björn, Pramod, Akula Bala, Ehinger, Erik, Dufner, Bianca, Hoppe, Natalie, Pfeiffer, Katharina, Marchini, Timoteo, Willecke, Florian, Stachon, Peter, Hilgendorf, Ingo, Heidt, Timo, von zur Muhlen, Constantin, von Elverfeldt, Dominik, Pfeifer, Dietmar, Schüle, Roland, Kintscher, Ulrich, Brachs, Sebastian, Ley, Klaus, Bode, Christoph, Zirlik, Andreas, and Wolf, Dennis

Published
2018
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24. Assessment of Myocardial Microstructure in a Murine Model of Obesity-Related Cardiac Dysfunction by Diffusion Tensor Magnetic Resonance Imaging at 7T

Author

Lohr, David, primary, Thiele, Arne, additional, Stahnke, Max, additional, Braun, Vera, additional, Smeir, Elia, additional, Spranger, Joachim, additional, Brachs, Sebastian, additional, Klopfleisch, Robert, additional, Foryst-Ludwig, Anna, additional, Schreiber, Laura M., additional, Kintscher, Ulrich, additional, and Beyhoff, Niklas, additional

Published
2022
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25. Assessment of Myocardial Microstructure in a Murine Model of Obesity-Related Cardiac Dysfunction by Diffusion Tensor Magnetic Resonance Imaging at 7T

Author

Lohr, David, Thiele, Arne, Stahnke, Max, Braun, Vera, Smeir, Elia, Spranger, Joachim, Brachs, Sebastian, Klopfleisch, Robert, Foryst-Ludwig, Anna, Schreiber, Laura M., Kintscher, Ulrich, and Beyhoff, Niklas

Subjects
obesity, high-fat diet, cardiac dysfunction, obesity-related cardiac dysfunction, magnetic resonance imaging, diffusion tensor imaging, cardiac adipose tissue, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Abstract

Background: Obesity exerts multiple deleterious effects on the heart that may ultimately lead to cardiac failure. This study sought to characterize myocardial microstructure and function in an experimental model of obesity-related cardiac dysfunction. Methods: Male C57BL/6N mice were fed either a high-fat diet (HFD; 60 kcal% fat, n = 12) or standard control diet (9 kcal% fat, n = 10) for 15 weeks. At the end of the study period, cardiac function was assessed by ultra-high frequency echocardiography, and hearts were processed for further analyses. The three-dimensional myocardial microstructure was examined ex vivo at a spatial resolution of 100 × 100 × 100 μm3 by diffusion tensor magnetic resonance imaging (DT-MRI) at 7T. Myocardial deformation, diffusion metrics and fiber tract geometry were analyzed with respect to the different myocardial layers (subendocardium/subepicardium) and segments (base/mid-cavity/apex). Results were correlated with blood sample analyses, histopathology, and gene expression data. Results: HFD feeding induced significantly increased body weight combined with a pronounced accumulation of visceral fat (body weight 42.3 ± 5.7 vs. 31.5 ± 2.2 g, body weight change 73.7 ± 14.8 vs. 31.1 ± 6.6%, both P < 0.001). Obese mice showed signs of diastolic dysfunction, whereas left-ventricular ejection fraction and fractional shortening remained unchanged (E/e’ 41.6 ± 16.6 vs. 24.8 ± 6.0, P < 0.01; isovolumic relaxation time 19 ± 4 vs. 14 ± 4 ms, P < 0.05). Additionally, global longitudinal strain was reduced in the HFD group (−15.1 ± 3.0 vs. −20.0 ± 4.6%, P = 0.01), which was mainly driven by an impairment in basal segments. However, histopathology and gene expression analyses revealed no myocardial fibrosis or differences in cardiomyocyte morphology. Mean diffusivity and eigenvalues of the diffusion tensor were lower in the basal subepicardium of obese mice as assessed by DT-MRI (P < 0.05). The three-dimensional fiber tract arrangement of the left ventricle (LV) remained preserved. Conclusion: Fifteen weeks of high-fat diet induced alterations in myocardial diffusion properties in mice, whereas no remodeling of the three-dimensional myofiber arrangement of the LV was observed. Obese mice showed reduced longitudinal strain and lower mean diffusivity predominantly in the left-ventricular base, and further investigation into the significance of this regional pattern is required.

Published
2021

28. Spontaneous Degenerative Aortic Valve Disease in New Zealand Obese Mice

Author

Ott, Christiane, primary, Pappritz, Kathleen, additional, Hegemann, Niklas, additional, John, Cathleen, additional, Jeuthe, Sarah, additional, McAlpine, Cameron S., additional, Iwamoto, Yoshiko, additional, Lauryn, Jonathan H., additional, Klages, Jan, additional, Klopfleisch, Robert, additional, Van Linthout, Sophie, additional, Swirski, Fil, additional, Nahrendorf, Matthias, additional, Kintscher, Ulrich, additional, Grune, Tilman, additional, Kuebler, Wolfgang M., additional, and Grune, Jana, additional

Published
2021
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31. Liver X Receptor Agonist AZ876 Induces Beneficial Endogenous Cardiac Lipid Reprogramming and Protects Against Isoproterenol‐Induced Cardiac Damage

Author

Ritter, Daniel, Goeritzer, Madeleine, Thiele, Arne, Blumrich, Annelie, Beyhoff, Niklas, Luettges, Katja, Smeir, Elia, Kasch, Juliane, Grune, Jana, Müller, Oliver J., Klopfleisch, Robert, Jaeger, Carsten, Foryst‐Ludwig, Anna, and Kintscher, Ulrich

Subjects
Male, Mice, 129 Strain, Heart Diseases, heart failure, Molecular Cardiology, lipids, Mice, Animals, nuclear receptor, Original Research, Liver X Receptors, Aniline Compounds, Lipids and Cholesterol, Myocardium, Fatty Acids, Isoproterenol, Cellular Reprogramming, Fibrosis, Disease Models, Animal, Thiazoles, Echocardiography, cardiovascular system, lipids (amino acids, peptides, and proteins), diastolic dysfunction, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, Basic Science Research, liver X receptor
Abstract

Background: It is known that dietary intake of polyunsaturated fatty acids may improve cardiac function. However, relatively high daily doses are required to achieve sufficient cardiac concentrations of beneficial omega-3 fatty acids. The liver X receptor (LXR) is a nuclear hormone receptor and a crucial regulator of lipid homeostasis in mammals. LXR activation has been shown to endogenously reprogram cellular lipid profiles toward increased polyunsaturated fatty acids levels. Here we studied whether LXR lipid reprogramming occurs in cardiac tissue and exerts cardioprotective actions. Methods and Results: Male 129SV mice were treated with the LXR agonist AZ876 (20 mu mol/kg per day) for 11 days. From day 6, the mice were injected with the nonselective beta-agonist isoproterenol for 4 consecutive days to induce diastolic dysfunction and subendocardial fibrosis while maintaining systolic function. Treatment with isoproterenol led to a marked impairment of global longitudinal strain and the E/e' ratio of transmitral flow to mitral annular velocity, which were both significantly improved by the LXR agonist. Histological examination showed a significant reduction in isoproterenol-induced subendocardial fibrosis by AZ876. Analysis of the cardiac lipid composition by liquid chromatography-high resolution mass spectrometry revealed a significant increase in cardiac polyunsaturated fatty acids levels and a significant reduction in saturated fatty acids by AZ876. Conclusions: The present study provides evidence that the LXR agonist AZ876 prevents subendocardial damage, improves global longitudinal strain and E/e' in a mouse model of isoproterenol-induced cardiac damage, accompanied by an upregulation of cardiac polyunsaturated fatty acids levels. Cardiac LXR activation and beneficial endogenous cardiac lipid reprogramming may provide a new therapeutic strategy in cardiac disease with diastolic dysfunction.

Published
2021

33. Cardioprotective Effects of Palmitoleic Acid (C16:1n7) in a Mouse Model of Catecholamine-Induced Cardiac Damage Are Mediated by PPAR Activation

Author

Betz, Iris Rosa, primary, Qaiyumi, Sarah Julia, additional, Goeritzer, Madeleine, additional, Thiele, Arne, additional, Brix, Sarah, additional, Beyhoff, Niklas, additional, Grune, Jana, additional, Klopfleisch, Robert, additional, Greulich, Franziska, additional, Uhlenhaut, Nina Henriette, additional, Kintscher, Ulrich, additional, and Foryst-Ludwig, Anna, additional

Published
2021
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36. Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage

Author

Thiele, Arne, primary, Luettges, Katja, additional, Ritter, Daniel, additional, Beyhoff, Niklas, additional, Smeir, Elia, additional, Grune, Jana, additional, Steinhoff, Julia S, additional, Schupp, Michael, additional, Klopfleisch, Robert, additional, Rothe, Michael, additional, Wilck, Nicola, additional, Bartolomaeus, Hendrik, additional, Migglautsch, Anna K, additional, Breinbauer, Rolf, additional, Kershaw, Erin E, additional, Grabner, Gernot F, additional, Zechner, Rudolf, additional, Kintscher, Ulrich, additional, and Foryst-Ludwig, Anna, additional

Published
2021
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37. Arterial hypertension-What was important in 2020?

Author

Mahfoud, Felix, Boehm, Michael, Doerr, Oliver, Halbach, Marcel, Kintscher, Ulrich, Mahfoud, Felix, Boehm, Michael, Doerr, Oliver, Halbach, Marcel, and Kintscher, Ulrich

Abstract

Arterial hypertension remains the most significant risk factor for cardiovascular disease and associated disability worldwide. In the field of arterial hypertension the coronavirus disease 2019 (COVID-19) pandemic also determined major parts of the scientific debate. Arterial hypertension is associated with a severe course of COVID-19, whereas risk of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) does not appear to be increased in hypertensive individuals. According to current data, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 receptor blockers is not associated with an increased risk of SARS-CoV-2 infection or with a more severe course of COVID-19. A study on antihypertensive chronotherapy determined the scientific discourse on the medication treatment of hypertension. The HYGIA study concluded that bedtime medication reduces the cardiovascular risk in patients with arterial hypertension. Due to some study limitations, routine administration of bedtime antihypertensive medication cannot be recommended. Some of the reasons are discussed herein. Another scientific focus was on new renal denervation studies. Here, one can summarize that according to novel evidence, catheter-based renal denervation is an effective and safe procedure for the treatment of arterial hypertension, which could become established as an alternative to pharmaceutical blood pressure reduction in the near future.

Published
2021

39. Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage.

Author

Thiele, Arne, Luettges, Katja, Ritter, Daniel, Beyhoff, Niklas, Smeir, Elia, Grune, Jana, Steinhoff, Julia S, Schupp, Michael, Klopfleisch, Robert, Rothe, Michael, Wilck, Nicola, Bartolomaeus, Hendrik, Migglautsch, Anna K, Breinbauer, Rolf, Kershaw, Erin E, Grabner, Gernot F, Zechner, Rudolf, Kintscher, Ulrich, and Foryst-Ludwig, Anna

Subjects
ADIPOSE tissues, LIPASES, OLEIC acid, PALMITIC acid, TRIGLYCERIDES
Abstract

Aims Heart failure (HF) is characterized by an overactivation of β-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, β-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently, we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in mice. In this study, we investigated the cardioprotective effects of a new pharmacological inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-induced cardiac damage. Methods and results Male 129/Sv mice received repeated injections of isoproterenol (ISO, 25 mg/kg BW) to induce cardiac damage. Five days prior to ISO application, oral Atglistatin (2 mmol/kg diet) or control treatment was started. Two and twelve days after the last ISO injection cardiac function was analysed by echocardiography. The myocardial deformation was evaluated using speckle-tracking-technique. Twelve days after the last ISO injection, echocardiographic analysis revealed a markedly impaired global longitudinal strain, which was significantly improved by the application of Atglistatin. No changes in ejection fraction were observed. Further studies included histological-, WB-, and RT-qPCR-based analysis of cardiac tissue, followed by cell culture experiments and mass spectrometry-based lipidome analysis. ISO application induced subendocardial fibrosis and a profound pro-apoptotic cardiac response, as demonstrated using an apoptosis-specific gene expression-array. Atglistatin treatment led to a dramatic reduction of these pro-fibrotic and pro-apoptotic processes. We then identified a specific set of fatty acids (FAs) liberated from adipocytes under ISO stimulation (palmitic acid, palmitoleic acid, and oleic acid), which induced pro-apoptotic effects in cardiomyocytes. Atglistatin significantly blocked this adipocytic FA secretion. Conclusion This study demonstrates cardioprotective effects of Atglistatin in a mouse model of catecholamine-induced cardiac damage/dysfunction, involving anti-apoptotic and anti-fibrotic actions. Notably, beneficial cardioprotective effects of Atglistatin are likely mediated by non-cardiac actions, supporting the concept that pharmacological targeting of adipose tissue may provide an effective way to treat cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Published
2022
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41. eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction

Author

Liang, YongTian, primary, Piao, Chengji, additional, Beuschel, Christine B., additional, Toppe, David, additional, Kollipara, Laxmikanth, additional, Bogdanow, Boris, additional, Maglione, Marta, additional, Lützkendorf, Janine, additional, See, Jason Chun Kit, additional, Huang, Sheng, additional, Conrad, Tim O.F., additional, Kintscher, Ulrich, additional, Madeo, Frank, additional, Liu, Fan, additional, Sickmann, Albert, additional, and Sigrist, Stephan J., additional

Published
2021
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42. Myocardial Infarction After High-Dose Catecholamine Application—A Case Report From an Experimental Imaging Study

Author

Beyhoff, Niklas, Lohr, David, Thiele, Arne, Foryst-Ludwig, Anna, Klopfleisch, Robert, Schreiber, Laura M., and Kintscher, Ulrich

Subjects
myocardial infarction, speckle tracking, magnetic resonance imaging, case report, heart failure, echocardiography, ddc:610, Cardiovascular Medicine, diffusion tensor imaging, catecholamines, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Abstract

Although heart failure following myocardial infarction (MI) represents a major health burden, underlying microstructural and functional changes remain incompletely understood. Here, we report on a case of unexpected MI after treatment with the catecholamine isoproterenol in an experimental imaging study in mice using different state-of-the-art imaging modalities. The decline in cardiac function was documented by ultrahigh-frequency echocardiography and speckle-tracking analyses. Myocardial microstructure was studied ex vivo at a spatial resolution of 100 × 100 × 100 μm\(^{3}\) using diffusion tensor magnetic resonance imaging (DT-MRI) and histopathologic analyses. Two weeks after ISO treatment, the animal showed an apical aneurysm accompanied by reduced radial strain in corresponding segments and impaired global systolic function. DT-MRI revealed a loss of contractile fiber tracts together with a disarray of remaining fibers as corresponding microstructural correlates. This preclinical case report provides valuable insights into pathophysiology and morphologic–functional relations of heart failure following MI using emerging imaging technologies.

Published
2020

48. Obesity-related hypoxia via miR-128 decreases insulin-receptor expression in human and mouse adipose tissue promoting systemic insulin resistance

Author

Arcidiacono, Biagio, primary, Chiefari, Eusebio, additional, Foryst-Ludwig, Anna, additional, Currò, Giuseppe, additional, Navarra, Giuseppe, additional, Brunetti, Francesco S., additional, Mirabelli, Maria, additional, Corigliano, Domenica M., additional, Kintscher, Ulrich, additional, Britti, Domenico, additional, Mollace, Vincenzo, additional, Foti, Daniela P., additional, Goldfine, Ira D., additional, and Brunetti, Antonio, additional

Published
2020
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50. Serelaxin Improves Regional Myocardial Function in Experimental Heart Failure: An In Vivo Cardiac Magnetic Resonance Study

Author

Lapinskas, Tomas, primary, Kelle, Sebastian, additional, Grune, Jana, additional, Foryst‐Ludwig, Anna, additional, Meyborg, Heike, additional, Jeuthe, Sarah, additional, Wellnhofer, Ernst, additional, Elsanhoury, Ahmed, additional, Pieske, Burkert, additional, Gebker, Rolf, additional, Kintscher, Ulrich, additional, and Stawowy, Philipp, additional

Published
2020
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