Publications by authors named "Uwe Primessnig"

18 Publications

  • Page 1 of 1

Right-ventricular dysfunction in HFpEF is linked to altered cardiomyocyte Ca homeostasis and myofilament sensitivity.

ESC Heart Fail 2021 Aug 17;8(4):3130-3144. Epub 2021 May 17.

Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany.

Aims: Heart failure with preserved ejection fraction (HFpEF) is frequently (30%) associated with right ventricular (RV) dysfunction, which increases morbidity and mortality in these patients. Yet cellular mechanisms of RV remodelling and RV dysfunction in HFpEF are not well understood. Here, we evaluated RV cardiomyocyte function in a rat model of metabolically induced HFpEF.

Methods And Results: Heart failure with preserved ejection fraction-prone animals (ZSF-1 obese) and control rats (Wistar Kyoto) were fed a high-caloric diet for 13 weeks. Haemodynamic characterization by echocardiography and invasive catheterization was performed at 22 and 23 weeks of age, respectively. After sacrifice, organ morphometry, RV histology, isolated RV cardiomyocyte function, and calcium (Ca ) transients were assessed. ZSF-1 obese rats showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end-diastolic pressures and E/e' ratio), and preserved LV ejection fraction. ZSF-1 obese animals developed RV dilatation (50% increased end-diastolic area) and mildly impaired RV ejection fraction (42%) with evidence of RV hypertrophy. In isolated RV cardiomyocytes from ZSF-1 obese rats, cell shortening amplitude was preserved, but cytosolic Ca transient amplitude was reduced. In addition, augmentation of cytosolic Ca release with increased stimulation frequency was lost in ZSF-1 obese rats. Myofilament sensitivity was increased, while contractile kinetics were largely unaffected in intact isolated RV cardiomyocytes from ZSF-1 obese rats. Western blot analysis revealed significantly increased phosphorylation of cardiac myosin-binding protein C (Ser282 cMyBP-C) but no change in phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium from ZSF-1 obese rats.

Conclusions: Right ventricular dysfunction in obese ZSF-1 rats with HFpEF is associated with intrinsic RV cardiomyocyte remodelling including reduced cytosolic Ca amplitudes, loss of frequency-dependent augmentation of Ca release, and increased myofilament Ca sensitivity.
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http://dx.doi.org/10.1002/ehf2.13419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318431PMC
August 2021

Effects of different exercise modalities on cardiac dysfunction in heart failure with preserved ejection fraction.

ESC Heart Fail 2021 06 25;8(3):1806-1818. Epub 2021 Mar 25.

Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, Berlin, 13353, Germany.

Aims: Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent disease. Physical exercise has been shown to alter disease progression in HFpEF. We examined cardiomyocyte Ca homeostasis and left ventricular function in a metabolic HFpEF model in sedentary and trained rats following 8 weeks of moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT).

Methods And Results: Left ventricular in vivo function (echocardiography) and cardiomyocyte Ca transients (CaTs) (Fluo-4, confocal) were compared in ZSF-1 obese (metabolic syndrome, HFpEF) and ZSF-1 lean (control) 21- and 28-week-old rats. At 21 weeks, cardiomyocytes from HFpEF rats showed prolonged Ca reuptake in cytosolic and nuclear CaTs and impaired Ca release kinetics in nuclear CaTs. At 28 weeks, HFpEF cardiomyocytes had depressed CaT amplitudes, decreased sarcoplasmic reticulum (SR) Ca content, increased SR Ca leak, and elevated diastolic [Ca ] following increased pacing rate (5 Hz). In trained HFpEF rats (HIIT or MICT), cardiomyocyte SR Ca leak was significantly reduced. While HIIT had no effects on the CaTs (1-5 Hz), MICT accelerated early Ca release, reduced the amplitude, and prolonged the CaT without increasing diastolic [Ca ] or cytosolic Ca load at basal or increased pacing rate (1-5 Hz). MICT lowered pro-arrhythmogenic Ca sparks and attenuated Ca -wave propagation in cardiomyocytes. MICT was associated with increased stroke volume in HFpEF.

Conclusions: In this metabolic rat model of HFpEF at an advanced stage, Ca release was impaired under baseline conditions. HIIT and MICT differentially affected Ca homeostasis with positive effects of MICT on stroke volume, end-diastolic volume, and cellular arrhythmogenicity.
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http://dx.doi.org/10.1002/ehf2.13308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120378PMC
June 2021

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF.

Cardiovasc Diabetol 2021 01 7;20(1). Epub 2021 Jan 7.

Department of Internal Medicine and Cardiology, Charité University Medicine, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany.

Background: Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.

Methods: 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca release were recorded by ratiometric microscopy using Ca-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student's t-test, as applicable.

Results: Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca accumulation upon glycolytic inhibition.

Conclusion: The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca buffer capacity, diastolic Ca accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.
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http://dx.doi.org/10.1186/s12933-020-01208-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792219PMC
January 2021

Increased mortality and worse cardiac outcome of acute myocardial infarction during the early COVID-19 pandemic.

ESC Heart Fail 2021 02 6;8(1):333-343. Epub 2020 Dec 6.

Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany.

Aims: This study aimed to evaluate the impact of coronavirus disease 2019 (Covid-19) outbreak on admissions for acute myocardial infarction (AMI) and related mortality, severity of presentation, major cardiac complications and outcome in a tertiary-care university hospital in Berlin, Germany.

Methods And Results: In a single-centre cross-sectional observational study, we included 355 patients with AMI containing ST-elevation or non-ST-elevation myocardial infarction (STEMI or NSTEMI), admitted for emergency cardiac catheterization between January and April 2020 and the equivalent time in 2019. During the early phase of the Covid-19 pandemic (e-COV) in Berlin (March and April 2020), admissions for AMI halved compared with those in the pre-Covid-19 time (January and February 2020; pre-COV) and with those in the corresponding months in 2019. However, mortality for AMI increased substantially from 5.2% pre-COV to 17.7% (P < 0.05) during e-COV. Severity of presentation for AMI was more pronounced during e-COV [increased levels of cardiac enzymes, reduced left ventricular ejection fraction (LVEF), an increase in the need of inotropic support by 25% (P < 0.01)], while patients' demographic and angiographic characteristics did not differ between pre-COV and e-COV. Time from symptom onset to first medical contact was prolonged in all AMI during e-COV (presentation > 72 h +21% in STEMI, p = 0.04 and presentation > 72 h in NSTEMI +22%, p = 0.02). Door to balloon time was similar in STEMI patients, while time from first medical contact to revascularization was significantly delayed in NSTEMI patients (p = 0.02). Major cardiac complications after AMI occurred significantly more often, and cardiac recovery was worse in e-COV than in pre-COV, demonstrated by a significantly lower LVEF (39 ± 16 vs. 46 ± 16, p < 0.05) at hospital discharge and substantially higher NTproBNP levels.

Conclusions: The Covid-19 outbreak affects hospital admissions for acute coronary syndromes. During the first phase of the pandemia, significantly less patients with AMI were admitted, but those admitted presented with a more severe phenotype and had a higher mortality, more complications, and a worse short-term outcome. Therefore, our data indicate that Covid-19 had relevant impact on non-infectious disease states, such as acute coronary syndromes.
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http://dx.doi.org/10.1002/ehf2.13075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835606PMC
February 2021

Left ventricular dysfunction in heart failure with preserved ejection fraction-molecular mechanisms and impact on right ventricular function.

Cardiovasc Diagn Ther 2020 Oct;10(5):1541-1560

DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany.

The current classification of heart failure (HF) based on left ventricular (LV) ejection fraction (EF) identifies a large group of patients with preserved ejection fraction (HFpEF) with significant morbidity and mortality but without prognostic benefit from current HF therapy. Co-morbidities and conditions such as arterial hypertension, diabetes mellitus, chronic kidney disease, adiposity and aging shape the clinical phenotype and contribute to mortality. LV diastolic dysfunction and LV structural remodeling are hallmarks of HFpEF, and are linked to remodeling of the cardiomyocyte and extracellular matrix. Pulmonary hypertension (PH) and right ventricular dysfunction (RVD) are particularly common in HFpEF, and mortality is up to 10-fold higher in HFpEF patients with without RV dysfunction. Here, we review alterations in cardiomyocyte function (i.e., ion homeostasis, sarcomere function and cellular metabolism) associated with diastolic dysfunction and summarize the main underlying cellular pathways. The contribution and interaction of systemic and regional upstream signaling such as chronic inflammation, neurohumoral activation, and NO-cGMP-related pathways are outlined in detail, and their diagnostic and therapeutic potential is discussed in the context of preclinical and clinical studies. In addition, we summarize prevalence and pathomechanisms of RV dysfunction in the context of HFpEF and discuss mechanisms connecting LV and RV dysfunction in HFpEF. Dissecting the molecular mechanisms of LV and RV dysfunction in HFpEF may provide a basis for an improved classification of HFpEF and for therapeutic approaches tailored to the molecular phenotype.
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http://dx.doi.org/10.21037/cdt-20-477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666919PMC
October 2020

Long-term effects of a food pattern on cardiovascular risk factors and age-related changes of muscular and cognitive function.

Medicine (Baltimore) 2020 Sep;99(39):e22381

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin.

Introduction: The mean age of the German population increased over the last years, which resulted in a higher prevalence of cardiovascular diseases, type 2 diabetes, cognitive impairment, sarcopenia and bone fractures. Current evidence indicates a preservation of human wellbeing in the elderly by a healthy diet, although the recommended macronutrient composition and quality remains unclear and needs further long-term investigation. In this context we investigate the effect of a specific dietary pattern on age-related disorders in a randomized controlled multi-center trial (RCT).

Methods: We assess the effect of a specific dietary pattern (NutriAct) with a high proportion of unsaturated fat, plant proteins and fibres (fat 35%-40% of total energy (%E) of which 15%E-20%E monounsaturated fatty acids (MUFA) and 10%E-15%E polyunsaturated fatty acids (PUFA), 15%E-25%E proteins, ≥30 g fibres per day and 35%E-45%E carbohydrates) on age-related impairment of health within a 36-months RCT conducted in the region of Berlin and Potsdam. 502 eligible men (n = 183) and women (n = 319), aged 50 to 80 years, with an increased risk to develop age-related diseases were randomly assigned to either an intervention group focusing on NutriAct dietary pattern or a control group focusing on usual care and dietary recommendations in accordance to the German Nutrition Society (DGE). In the intervention group, 21 nutrition counsellings as well as supplementation of rapeseed oil, oil cake and specific designed foods are used to achieve the intended NutriAct dietary pattern.The primary outcome is a composite endpoint of age-related disorders, including cardiovascular morbidity, decline of cognitive function as well as clinical features of sarcopenia. Secondary outcomes include diet-induced effects on quality of life, depression, frailty, cardiovascular function, bone density, fat distribution pattern, glucose, lipid and energy metabolism, as well as the identification of biomarkers linked with age-related disorders.

Discussion: The findings of this trial will provide clinically relevant information regarding dietary effects on age-related impairment of health and will contribute to the definition of the optimal macronutrient composition in the context of healthy aging in the German population.
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http://dx.doi.org/10.1097/MD.0000000000022381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523819PMC
September 2020

Oxidative Stress and Inflammatory Modulation of Ca Handling in Metabolic HFpEF-Related Left Atrial Cardiomyopathy.

Antioxidants (Basel) 2020 Sep 14;9(9). Epub 2020 Sep 14.

Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, Charité University Medicine, 13353 Berlin, Germany.

Metabolic syndrome-mediated heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by left atrial (LA) cardiomyopathy, significantly affecting morbidity and mortality. We evaluate the role of reactive oxygen species (ROS) and intrinsic inflammation (TNF-α, IL-10) related to dysfunctional Ca homeostasis of LA cardiomyocytes in a rat model of metabolic HFpEF. ZFS-1 obese rats showed features of HFpEF and atrial cardiomyopathy in vivo: increased left ventricular (LV) mass, E/e' and LA size and preserved LV ejection fraction. In vitro, LA cardiomyocytes exhibited more mitochondrial-fission (MitoTracker) and ROS-production (H2DCF). In wildtype (WT), pro-inflammatory TNF-α impaired cellular Ca homeostasis, while anti-inflammatory IL-10 had no notable effect (confocal microscopy; Fluo-4). In HFpEF, TNF-α had no effect on Ca homeostasis associated with decreased TNF-α receptor expression (western blot). In addition, IL-10 substantially improved Ca release and reuptake, while IL-10 receptor-1 expression was unaltered. Oxidative stress in metabolic syndrome mediated LA cardiomyopathy was increased and anti-inflammatory treatment positively affected dysfunctional Ca homeostasis. Our data indicates, that patients with HFpEF-related LA dysfunction might profit from IL-10 targeted therapy, which should be further explored in preclinical trials.
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http://dx.doi.org/10.3390/antiox9090860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555173PMC
September 2020

Long-term effects of Na /Ca exchanger inhibition with ORM-11035 improves cardiac function and remodelling without lowering blood pressure in a model of heart failure with preserved ejection fraction.

Eur J Heart Fail 2019 12 24;21(12):1543-1552. Epub 2019 Nov 24.

Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.

Aims: Heart failure with preserved ejection fraction (HFpEF) is increasingly common but there is currently no established pharmacological therapy. We hypothesized that ORM-11035, a novel specific Na /Ca exchanger (NCX) inhibitor, improves cardiac function and remodelling independent of effects on arterial blood pressure in a model of cardiorenal HFpEF.

Methods And Results: Rats were subjected to subtotal nephrectomy (NXT) or sham operation. Eight weeks after intervention, treatment for 16 weeks with ORM-11035 (1 mg/kg body weight) or vehicle was initiated. At 24 weeks, blood pressure measurements, echocardiography and pressure-volume loops were performed. Contractile function, Ca transients and NCX-mediated Ca extrusion were measured in isolated ventricular cardiomyocytes. NXT rats (untreated) showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV end-diastolic pressure (LVEDP) elevation, increased brain natriuretic peptide (BNP) levels, preserved ejection fraction and pulmonary congestion. In cardiomyocytes from untreated NXT rats, early relaxation was prolonged and NCX-mediated Ca extrusion was decreased. Chronic treatment with ORM-11035 significantly reduced LV hypertrophy and cardiac remodelling without lowering systolic blood pressure. LVEDP [14 ± 3 vs. 9 ± 2 mmHg; NXT (n = 12) vs. NXT + ORM (n = 12); P = 0.0002] and BNP levels [71 ± 12 vs. 49 ± 11 pg/mL; NXT (n = 12) vs. NXT + ORM (n = 12); P < 0.0001] were reduced after ORM treatment. LV cardiomyocytes from ORM-treated rats showed improved active relaxation and diastolic cytosolic Ca decay as well as restored NCX-mediated Ca removal, indicating NCX modulation with ORM-11035 as a promising target in the treatment of HFpEF.

Conclusion: Chronic inhibition of NCX with ORM-11035 significantly attenuated cardiac remodelling and diastolic dysfunction without lowering systemic blood pressure in this model of HFpEF. Therefore, long-term treatment with selective NCX inhibitors such as ORM-11035 should be evaluated further in the treatment of heart failure.
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http://dx.doi.org/10.1002/ejhf.1619DOI Listing
December 2019

The role of fibroblast - Cardiomyocyte interaction for atrial dysfunction in HFpEF and hypertensive heart disease.

J Mol Cell Cardiol 2019 06 18;131:53-65. Epub 2019 Apr 18.

Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

Aims: Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent.

Methods And Results: Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca and slowed Ca removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity.

Conclusions: Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.
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http://dx.doi.org/10.1016/j.yjmcc.2019.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065048PMC
June 2019

Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix.

J Am Heart Assoc 2018 10;7(20):e010025

2 Cardiac Surgery Medical University of Innsbruck Austria.

Background Mechanical stimulation of acute ischemic myocardium by shock wave therapy ( SWT ) is known to improve cardiac function by induction of angiogenesis. However, SWT in chronic heart failure is poorly understood. We aimed to study whether mechanical stimulation upon SWT improves heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis and to dissect underlying mechanisms. Methods and Results SWT was applied in a mouse model of chronic myocardial ischemia. To study effects of SWT on postnatal vasculogenesis, wild-type mice received bone marrow transplantation from green fluorescence protein donor mice. Underlying mechanisms were elucidated in vitro in endothelial cells and murine aortic rings. Echocardiography and pressure/volume measurements revealed improved left ventricular ejection fraction, myocardial contractility, and diastolic function and decreased myocardial fibrosis after treatment. Concomitantly, numbers of capillaries and arterioles were increased. SWT resulted in enhanced expression of the chemoattractant stromal cell-derived factor 1 in ischemic myocardium and serum. Treatment induced recruitment of bone marrow-derived endothelial cells to the site of injury. In vitro, SWT resulted in endothelial cell proliferation, enhanced survival, and capillary sprouting. The effects were vascular endothelial growth factor receptor 2 and heparan sulfate proteoglycan dependent. Conclusions SWT positively affects heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis. SWT upregulated pivotal angiogenic and vasculogenic factors in the myocardium in vivo and induced proliferative and anti-apoptotic effects on endothelial cells in vitro. Mechanistically, these effects depend on vascular endothelial growth factor signaling and heparan sulfate proteoglycans. SWT is a promising treatment option for regeneration of ischemic myocardium.
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http://dx.doi.org/10.1161/JAHA.118.010025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474945PMC
October 2018

Cellular mechanisms of metabolic syndrome-related atrial decompensation in a rat model of HFpEF.

J Mol Cell Cardiol 2018 02 28;115:10-19. Epub 2017 Dec 28.

Department of Internal Medicine and Cardiology, Charité University Medicine, Campus Virchow-Klinikum, 13353 Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany.

Heart failure (HF) with preserved ejection fraction (HFpEF) is present in about 50% of HF patients. Atrial remodeling is common in HFpEF and associated with increased mortality. We postulate that atrial remodeling is associated with atrial dysfunction in vivo related to alterations in cardiomyocyte Calcium (Ca) signaling and remodeling. We examined atrial function in vivo and Ca transients (CaT) (Fluo4-AM, field stim) in atrial cardiomyocytes of ZSF-1 rats without (Ln; lean hypertensive) and with metabolic syndrome (Ob; obese, hypertensive, diabetic) and HFpEF.

Results: At 21weeks Ln showed an increased left ventricular (LV) mass and left ventricular end-diastolic pressure (LVEDP), but unchanged left atrial (LA) size and preserved atrial ejection fraction vs. wild-type (WT). CaT amplitude in atrial cardiomyocytes was increased in Ln (2.9±0.2 vs. 2.3±0.2F/F in WT; n=22 cells/group; p<0.05). Studying subcellular Ca release in more detail, we found that local central cytosolic CaT amplitude was increased, while subsarcolemmal CaT amplitudes remained unchanged. Moreover, Sarcoplasmic reticulum (SR) Ca content (caffeine) was preserved while Ca spark frequency and tetracaine-dependent SR Ca leak were significantly increased in Ln. Ob mice developed a HFpEF phenotype in vivo, LA area was significantly increased and atrial in vivo function was impaired, despite increased atrial CaT amplitudes in vitro (2.8±0.2; p<0.05 vs. WT). Ob cells showed alterations of the tubular network possibly contributing to the observed phenotype. CaT kinetics as well as SR Ca in Ob were not significantly different from WT, but SR Ca leak remained increased. Angiotensin II (Ang II) reduced in vitro cytosolic CaT amplitudes and let to active nuclear Ca release in Ob but not in Ln or WT.

Summary: In hypertensive ZSF-1 rats, a possibly compensatory increase of cytosolic CaT amplitude and increased SR Ca leak precede atrial remodeling and HFpEF. Atrial remodeling in ZSF-1 HFpEF is associated with an altered tubular network in-vitro and atrial contractile dysfunction in vivo, indicating insufficient compensation. Atrial cardiomyocyte dysfunction in vitro is induced by the addition of angiotensin II.
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http://dx.doi.org/10.1016/j.yjmcc.2017.12.012DOI Listing
February 2018

Shockwaves prevent from heart failure after acute myocardial ischaemia via RNA/protein complexes.

J Cell Mol Med 2017 04 20;21(4):791-801. Epub 2016 Dec 20.

Department for Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria.

Shock wave treatment (SWT) was shown to induce regeneration of ischaemic myocardium via Toll-like receptor 3 (TLR3). The antimicrobial peptide LL37 gets released by mechanical stress and is known to form complexes with nucleic acids thus activating Toll-like receptors. We suggested that SWT in the acute setting prevents from the development of heart failure via RNA/protein release. Myocardial infarction in mice was induced followed by subsequent SWT. Heart function was assessed 4 weeks later via transthoracic echocardiography and pressure-volume measurements. Human umbilical vein endothelial cells (HUVECs) were treated with SWT in the presence of RNase and proteinase and analysed for proliferation, tube formation and LL37 expression. RNA release and uptake after SWT was evaluated. We found significantly improved cardiac function after SWT. SWT resulted in significantly higher numbers of capillaries and arterioles and less left ventricular fibrosis. Supernatants of treated cells activated TLR3 reporter cells. Analysis of the supernatant revealed increased RNA levels. The effect could not be abolished by pre-treatment of the supernatant with RNase, but only by a sequential digestion with proteinase and RNase hinting strongly towards the involvement of RNA/protein complexes. Indeed, LL37 expression as well as cellular RNA uptake were significantly increased after SWT. We show for the first time that SWT prevents from left ventricular remodelling and cardiac dysfunction via RNA/protein complex release and subsequent induction of angiogenesis. It might therefore develop a potent regenerative treatment alternative for ischaemic heart disease.
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http://dx.doi.org/10.1111/jcmm.13021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345685PMC
April 2017

Cardioprotection and lifespan extension by the natural polyamine spermidine.

Nat Med 2016 12 14;22(12):1428-1438. Epub 2016 Nov 14.

Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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http://dx.doi.org/10.1038/nm.4222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806691PMC
December 2016

Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction.

Eur J Heart Fail 2016 08 2;18(8):987-97. Epub 2016 May 2.

Department of Cardiology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.

Aims: Heart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na(+) /Ca(2+) exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) with HFpEF.

Methods And Results: Male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). After 8 and 24 weeks, in vivo (haemodynamics, echocardiography) and in vitro function (LV cardiomyocyte cell shortening (CS), and Ca(2+) transients (CaT)) were determined without and with SEA0400. In a subgroup of rats, SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. NXT resulted in stable compensated CKD and HFpEF [hypertrophied left ventricle, prolonged LV isovolumetric relaxation constant TAU (IVRc TAU), elevated end diastolic pressure (EDP), increased lung weight (pulmonary congestion), and preserved LV systolic function (EF, dP/dt)]. In NXT cardiomyocytes, the amplitude of CS and CaT were unchanged but relaxation and CaT decay were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. NCX forward mode activity (caffeine response) was progressively reduced, while NCX protein expression was up-regulated, suggesting increased NCX reverse mode activity in NXT. SEA0400 acutely improved relaxation in NXT in vivo and in cardiomyocytes and improved cardiac remodelling and diastolic function when given chronically.

Conclusions: This model of renal HFpEF is associated with slowed relaxation of LV cardiomyocytes. Treatment with SEA0400 improved cardiomyocyte function, remodelling, and HFpEF.
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http://dx.doi.org/10.1002/ejhf.524DOI Listing
August 2016

AMP-activated protein kinase α1-sensitive activation of AP-1 in cardiomyocytes.

J Mol Cell Cardiol 2016 08 19;97:36-43. Epub 2016 Apr 19.

Department of Physiology & Cardiology and Cardiovascular Medicine, University of Tübingen, Gmelinstr.5/Otfried-Mueller-Str. 10, 72076, Tübingen, Germany. Electronic address:

AMP-activated protein kinase (Ampk) regulates myocardial energy metabolism and plays a crucial role in the response to cell stress. In the failing heart, an isoform shift of the predominant Ampkα2 to the Ampkα1 was observed. The present study explored possible isoform specific effects of Ampkα1 in cardiomyocytes. To this end, experiments were performed in HL-1 cardiomyocytes, as well as in Ampkα1-deficient and corresponding wild-type mice and mice following AAV9-mediated cardiac overexpression of constitutively active Ampkα1. As a result, in HL-1 cardiomyocytes, overexpression of constitutively active Ampkα1 increased the phosphorylation of Pkcζ. Constitutively active Ampkα1 further increased AP-1-dependent transcriptional activity and mRNA expression of the AP-1 target genes c-Fos, Il6 and Ncx1, effects blunted by Pkcζ silencing. In HL-1 cardiomyocytes, angiotensin-II activated AP-1, an effect blunted by silencing of Ampkα1 and Pkcζ, but not of Ampkα2. In wild-type mice, angiotensin-II infusion increased cardiac Ampkα1 and cardiac Pkcζ protein levels, as well as c-Fos, Il6 and Ncx1 mRNA expression, effects blunted in Ampkα1-deficient mice. Pressure overload by transverse aortic constriction (TAC) similarly increased cardiac Ampkα1 and Pkcζ abundance as well as c-Fos, Il6 and Ncx1 mRNA expression, effects again blunted in Ampkα1-deficient mice. AAV9-mediated cardiac overexpression of constitutively active Ampkα1 increased Pkcζ protein abundance and the mRNA expression of c-Fos, Il6 and Ncx1 in cardiac tissue. In conclusion, Ampkα1 promotes myocardial AP-1 activation in a Pkcζ-dependent manner and thus contributes to cardiac stress signaling.
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http://dx.doi.org/10.1016/j.yjmcc.2016.04.009DOI Listing
August 2016

TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.

Cardiovasc Res 2015 Apr 28;106(1):163-73. Epub 2015 Jan 28.

Ludwig Boltzmann Institute of Translational Heart Failure Research, Graz, Austria Institute of Biophysics, Medical University of Graz, Harrachgasse 21, Graz 8010, Austria

Aim: TRPC3 is a non-selective cation channel, which forms a Ca2+ entry pathway involved in cardiac remodelling. Our aim was to analyse acute electrophysiological and contractile consequences of TRPC3 activation in the heart.

Methods And Results: We used a murine model of cardiac TRPC3 overexpression and a novel TRPC3 agonist, GSK1702934A, to uncover (patho)physiological functions of TRPC3. GSK1702934A induced a transient, non-selective conductance and prolonged action potentials in TRPC3-overexpressing myocytes but lacked significant electrophysiological effects in wild-type myocytes. GSK1702934A transiently enhanced contractility and evoked arrhythmias in isolated Langendorff hearts from TRPC3-overexpressing but not wild-type mice. Interestingly, pro-arrhythmic effects outlasted TRPC3 current activation, were prevented by enhanced intracellular Ca2+ buffering, and suppressed by the NCX inhibitor 3',4'-dichlorobenzamil hydrochloride. GSK1702934A substantially promoted NCX currents in TRPC3-overexpressing myocytes. The TRPC3-dependent electrophysiologic, pro-arrhythmic, and inotropic actions of GSK1702934A were mimicked by angiotensin II (AngII). Immunocytochemistry demonstrated colocalization of TRPC3 with NCX1 and disruption of local interaction upon channel activation by either GSK1702934A or AngII.

Conclusion: Cardiac TRPC3 mediates Ca2+ and Na+ entry in proximity of NCX1, thereby elevating cellular Ca2+ levels and contractility. Excessive activation of TRPC3 is associated with transient cellular Ca2+ overload, spatial uncoupling between TRPC3 and NCX1, and arrhythmogenesis. We propose TRPC3-NCX micro/nanodomain communication as determinant of cardiac contractility and susceptibility to arrhythmogenic stimuli.
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http://dx.doi.org/10.1093/cvr/cvv022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362401PMC
April 2015

AMP-activated protein kinase α1 regulates cardiac gap junction protein connexin 43 and electrical remodeling following pressure overload.

Cell Physiol Biochem 2015 14;35(1):406-18. Epub 2015 Jan 14.

Department of Physiology, University of Tübingen, Tübingen, Germany.

Background/aims: Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling.

Methods: Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by "transverse aortic constriction" (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy.

Results: TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1(-/-) mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1(-/-) mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPK(WT) and constitutively active AMPK(γR70Q), but not by catalytically inactive AMPK(αK45R).

Conclusion: Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.
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http://dx.doi.org/10.1159/000369706DOI Listing
September 2015

Bile acids induce arrhythmias in human atrial myocardium--implications for altered serum bile acid composition in patients with atrial fibrillation.

Heart 2013 Nov 26;99(22):1685-92. Epub 2013 Jul 26.

Division of Cardiology, Medical University of Graz, , Graz, Austria.

Objective: High bile acid serum concentrations have been implicated in cardiac disease, particularly in arrhythmias. Most data originate from in vitro studies and animal models. We tested the hypotheses that (1) high bile acid concentrations are arrhythmogenic in adult human myocardium, (2) serum bile acid concentrations and composition are altered in patients with atrial fibrillation (AF) and (3) the therapeutically used ursodeoxycholic acid has different effects than other potentially toxic bile acids.

Methods And Results: Multicellular human atrial preparations ('trabeculae') were exposed to primary bile acids and the incidence of arrhythmic events was assessed. Bile acid concentrations were measured in serum samples from 250 patients and their association with AF and ECG parameters analysed. Additionally, we conducted electrophysiological studies in murine myocytes. Taurocholic acid (TCA) concentration-dependently induced arrhythmias in atrial trabeculae (14/28 at 300 µM TCA, p<0.01) while ursodeoxycholic acid did not. Patients with AF had significantly decreased serum levels of ursodeoxycholic acid conjugates and increased levels of non-ursodeoxycholic bile acids. In isolated myocytes, TCA depolarised the resting membrane potential, enhanced Na(+)/Ca(2+) exchanger (NCX) tail current density and induced afterdepolarisations. Inhibition of NCX prevented arrhythmias in atrial trabeculae.

Conclusions: High TCA concentrations induce arrhythmias in adult human atria while ursodeoxycholic acid does not. AF is associated with higher serum levels of non-ursodeoxycholic bile acid conjugates and low levels of ursodeoxycholic acid conjugates. These data suggest that higher levels of toxic (arrhythmogenic) and low levels of protective bile acids create a milieu with a decreased arrhythmic threshold and thus may facilitate arrhythmic events.
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http://dx.doi.org/10.1136/heartjnl-2013-304163DOI Listing
November 2013
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