TY - JOUR A1 - Heuschmann, Peter U. A1 - Montellano, Felipe A. A1 - Ungethüm, Kathrin A1 - Rücker, Viktoria A1 - Wiedmann, Silke A1 - Mackenrodt, Daniel A1 - Quilitzsch, Anika A1 - Ludwig, Timo A1 - Kraft, Peter A1 - Albert, Judith A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Haeusler, Karl Georg A1 - Kleinschnitz, Christoph T1 - Prevalence and determinants of systolic and diastolic cardiac dysfunction and heart failure in acute ischemic stroke patients: The SICFAIL study JF - ESC Heart Failure N2 - Aims Ischaemic stroke (IS) might induce alterations of cardiac function. Prospective data on frequency of cardiac dysfunction and heart failure (HF) after IS are lacking. We assessed prevalence and determinants of diastolic dysfunction (DD), systolic dysfunction (SD), and HF in patients with acute IS. Methods and results The Stroke‐Induced Cardiac FAILure in mice and men (SICFAIL) study is a prospective, hospital‐based cohort study. Patients with IS underwent a comprehensive assessment of cardiac function in the acute phase (median 4 days after IS) including clinical examination, standardized transthoracic echocardiography by expert sonographers, and determination of blood‐based biomarkers. Information on demographics, lifestyle, risk factors, symptoms suggestive of HF, and medical history was collected by a standardized personal interview. Applying current guidelines, cardiac dysfunction was classified based on echocardiographic criteria into SD (left ventricular ejection fraction < 52% in men or <54% in women) and DD (≥3 signs of DD in patients without SD). Clinically overt HF was classified into HF with reduced, mid‐range, or preserved ejection fraction. Between January 2014 and February 2017, 696 IS patients were enrolled. Of them, patients with sufficient echocardiographic data on SD were included in the analyses {n = 644 patients [median age 71 years (interquartile range 60–78), 61.5% male]}. In these patients, full assessment of DD was feasible in 549 patients without SD (94%). Prevalence of cardiac dysfunction and HF was as follows: SD 9.6% [95% confidence interval (CI) 7.6–12.2%]; DD in patients without SD 23.3% (95% CI 20.0–27.0%); and clinically overt HF 5.4% (95% CI 3.9–7.5%) with subcategories of HF with preserved ejection fraction 4.35%, HF with mid‐range ejection fraction 0.31%, and HF with reduced ejection fraction 0.78%. In multivariable analysis, SD and fulfilment of HF criteria were associated with history of coronary heart disease [SD: odds ratio (OR) 3.87, 95% CI 1.93–7.75, P = 0.0001; HF: OR 2.29, 95% CI 1.04–5.05, P = 0.0406] and high‐sensitive troponin T at baseline (SD: OR 1.78, 95% CI 1.31–2.42, P = 0.0003; HF: OR 1.66, 95% CI 1.17–2.33, P = 0.004); DD was associated with older age (OR 1.08, 95% CI 1.05–1.11, P < 0.0001) and treated hypertension vs. no hypertension (OR 2.84, 95% CI 1.23–6.54, P = 0.0405). Conclusions A substantial proportion of the study population exhibited subclinical and clinical cardiac dysfunction. SICFAIL provides reliable data on prevalence and determinants of SD, DD, and clinically overt HF in patients with acute IS according to current guidelines, enabling further clarification of its aetiological and prognostic role. KW - Stroke KW - Heart failure KW - Cardiac dysfunction| Brain natriuretic peptide KW - Troponin Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225656 VL - 8 IS - 2 ER - TY - THES A1 - Maimari, Theopisti T1 - The influence of N-terminal peptides of G-protein coupled receptor kinase (GRK) 2, 3 and 5 on β-adrenergic signaling T1 - Der Einfluss von N-terminalen Peptiden der G-Protein gekoppelten Rezeptorkinasen (GRK) 2, 3 und 5 in der β-adrenergen Signaltransduktion N2 - G protein coupled receptor kinases (GRK) phosphorylate and thereby desensitize G protein coupled receptors (GPCR) including β-adrenergic receptors (βAR), which are critical regulators of cardiac function. We identified the Raf kinase inhibitor protein (RKIP) as an endogenous inhibitor of GRK2 that leads to increased cardiac contractility via βAR activation. RKIP binds to the N-terminus (aa1-185) of GRK2, which is important for the GRK2/receptor interaction. Thereby it interferes with the GRK2/receptor interaction without interference with cytosolic GRK2 target activation. In this project, the RKIP/GRK interface was investigated to develop strategies that simulate the effects of RKIP on βAR. RKIP binding to different isoforms of GRK expressed in the heart was analyzed by protein interaction assays using full-length and N-termini of GRK2, GRK3 and GRK5: 1-53, 54-185 and 1-185. Co-immunoprecipitation (Co-IPs) and pull-down assays revealed that RKIP binds to the peptides of GRK2 and GRK3 but not to the ones of GRK5, which suggests the existence of several binding sites of RKIP within the N-termini of GRK2 and GRK3. To analyze whether the peptides of GRK2 and GRK3 are able to simulate the RKIP mediated interference of the GRK2/receptor interaction, we analyzed the β2-AR phosphorylation in the absence and presence of the peptides. Interestingly, N-termini (aa1-185) of GRK2 and GRK3 reduced β2AR phosphorylation to a comparable extent as RKIP. In line with reduced receptor phosphorylation, the peptides also reduced isoproterenol-stimulated receptor internalization as shown by [3H] CGP-12177 radioligand binding assay and fluorescence microscopy compared to control cells. Subsequently, these peptides increased downstream signaling of β2AR, i.e. the phosphorylation of the PKA substrate phosducin. In an attempt to elucidate the mechanism behind the observed effects, Co-IPs were performed in order to investigate whether the peptides bind directly to the β2-AR and block its phosphorylation by GRK2. Indeed, GRK2 1-185 and GRK3 1-185 could bind the receptor, suggesting that this way GRK2 is prevented from inhibiting the receptor. To investigate the physiological effect of GRK2 1-185, GRK3 1-185 and GRK5 1-185, their effect on neonatal mouse cardiomyocyte contractility and hypertrophy was analyzed. After long-term isoproterenol stimulation, in the presence of GRK2 1 185 and GRK3 1-185 the cross-sectional area of the cardiomyocytes showed no significant increase in comparison to the unstimulated control cells. In addition, upon isoproterenol stimulation, GRK2 1-185 and GRK3 1-185 increased the beat rate in cardiomyocytes, mimicking RKIP while the base impedance, an indicator of viability, remained stable. The N-termini (1-185) of GRK2 and GRK3 simulated RKIP’s function and had a significant influence on β2AR phosphorylation, on its downstream signaling and internalization, could bind β2-AR, increased beat rate and did not significantly induce hypertrophy, suggesting that they may serve as a model for the generation of new and more specific targeting strategies for GRK mediated receptor regulation. N2 - G-Protein gekoppelte Rezeptorkinasen (GRK) phosphorylieren und desensitisieren G-Protein gekoppelte Rezeptoren (GPCR), einschließlich β-adrenerge Rezeptoren (βAR), welche wichtige Regulatoren der Herzfunktion sind. Raf Kinase Inhibitor Protein (RKIP) ist ein endogener Inhibitor von GRK2, der zur Aktivierung von βAR führt und dadurch zur Steigerung der Herzkontraktilität. RKIP bindet N-terminal (1-185) an GRK2; der GRK2 N-Terminus ist wichtig für die GRK2/Rezeptor Interaktion. Durch diese Bindung wird GRK2 inhibiert und derer Interaktion mit den Rezeptor gestört, allerdings bleiben die zytosolische GRK2 Substrate unbeeinflusst. In diesem Projekt wurde die Interaktion zwischen RKIP und GRK untersucht, um neue Targeting Strategien zu entwickeln, die die positiven Effekte von RKIP auf βAR Signalwege simulieren. Die Bindung von RKIP an verschiedene, im Herzen lokalisierte GRK-Isoformen wurde über protein interaction assays untersucht: mit GRK2, GRK3 und GRK5 und mit deren N-terminalen Peptiden 1-53, 54-185, 1-185. Die Co-Immunopräzipitationen (Co-IPs) und die pull-down Versuche haben gezeigt, dass RKIP sowohl GRK2 und GRK3 als auch deren N-Termini bindet, GRK5 und dessen N-termini hingegen nicht. Daraus lässt sich schlussfolgern, dass sich mehrere RKIP Bindungsstellen an dem GRK2 N-Terminus befinden. Um zu analysieren, ob die GRK2- und GRK3-Peptide eine ähnliche Wirkung wie RKIP auf die Interaktion von GRK2 und Rezeptor aufweisen, wurde die Rezeptorphosphorylierung ermittelt. Es konnte gezeigt werden, dass GRK2 1-185 und GRK3 1-185 die Phosphorylierung des βAR reduzieren können. Radioligandbindungsassays mit [3H] CGP-12177 und Fluoreszenzmikroskopie zeigten zudem, dass GRK2 1-185 und GRK3 1-185 auch die Internalisierungsrate des βAR senken können. Anschließend hatten GRK2 1-185 und GRK3 1-185 einen positiven Effekt auf einem βAR downstream Signalmolekül. Hierbei handelte es sich um die Phosphorylierung von Phosducin, was ein PKA-Substrat ist. Um die Wirkungsweise der N-termini zu erläutern, wurde untersucht, ob diese direkt den β2AR binden und somit die GRK2 vermittelte Phosphorylierung hindern. Interessanterweise konnte gezeigt werden, dass GRK2 1-185 und GRK3 1- 185 den β2AR binden und dementsprechend einen Einfluss auf die Phosphorylierung haben. Des Weiteren, wurden die Effekte der Peptide auf Kontraktilität und Hypertrophie in neonatalen Mauskardiomyozyten analysiert. In Anwesenheit von GRK2 1-185 und GRK3 1-185 war die Querschnittsfläche der Mauskardiomyozyten nicht signifikant größer im Vergleich zu den unstimulierten Kontrollzellen. Außerdem wurde eine signifikante Erhöhung der Kontraktilität in den Mauskardiomyozyten mit GRK2 1-185 und GRK3 1-185 beobachtet. Insgesamt, konnten GRK2 1-185 und GRK3 1-185 RKIPs Funktion simulieren: sie hatten einen signifikanten Effekt auf β2AR-Phosphorylierung, Internalisierung und downstream Signaling. Zudem konnten sie die Kontraktilität erhöhen und hatten keinen Einfluss auf Hypertrophie. Somit könnten sie als Prototyp für die Entwicklung neuer Targeting Strategien für die GRK-vermittelte Rezeptor Regulation, genutzt werden. KW - G protein-coupled receptor kinase KW - Raf kinase inhibitor protein KW - Inhibition KW - Heart failure KW - Peptides Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199322 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Wakabayashi, Hiroshi A1 - Chen, Xinyu A1 - Hayakawa, Nobuyuki A1 - Lapa, Constantin A1 - Rowe, Steven P. A1 - Javadi, Mehrbod S. A1 - Robinson, Simon A1 - Higuchi, Takahiro T1 - Ventricular distribution pattern of the novel sympathetic nerve PET radiotracer \(^{18}\)F-LMI1195 in Rabbit Hearts JF - Scientific Reports N2 - We aimed to determine a detailed regional ventricular distribution pattern of the novel cardiac nerve PET radiotracer \(^{18}\)F-LMI1195 in healthy rabbits. Ex-vivo high resolution autoradiographic imaging was conducted to identify accurate ventricular distribution of \(^{18}\)F-LMI1195. In healthy rabbits, \(^{18}\)F-LMI1195 was administered followed by the reference perfusion marker \(^{201}\)Tl for a dual-radiotracer analysis. After 20 min of \(^{18}\)F-LMI1195 distribution time, the rabbits were euthanized, the hearts were extracted, frozen, and cut into 20-μm short axis slices. Subsequently, the short axis sections were exposed to a phosphor imaging plate to determine \(^{18}\)F-LMI1195 distribution (exposure for 3 h). After complete \(^{18}\)F decay, sections were re-exposed to determine 201Tl distribution (exposure for 7 days). For quantitative analysis, segmental regions of Interest (ROIs) were divided into four left ventricular (LV) and a right ventricular (RV) segment on mid-ventricular short axis sections. Subendocardial, mid-portion, and subepicardial ROIs were placed on the LV lateral wall. \(^{18}\)F-LMI1195 distribution was almost homogeneous throughout the LV wall without any significant differences in all four LV ROIs (anterior, posterior, septal and lateral wall, 99 ± 2, 94 ± 5, 94 ± 4 and 97 ± 3%LV, respectively, n.s.). Subepicardial \(^{201}\)Tl uptake was significantly lower compared to the subendocardial portion (subendocardial, mid-portion, and subepicardial activity: 90 ± 3, 96 ± 2 and *80 ± 5%LV, respectively, *p < 0.01 vs. mid-portion). This was in contradistinction to the transmural wall profile of \(^{18}\)F-LMI1195 (90 ± 4, 96 ± 5 and 84 ± 4%LV, n.s.). A slight but significant discrepant transmural radiotracer distribution pattern of \(^{201}\)Tl in comparison to \(^{18}\)F-LMI1195 may be a reflection of physiological sympathetic innervation and perfusion in rabbit hearts. KW - Cardiovascular diseases KW - Heart failure Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202707 VL - 9 ER - TY - JOUR A1 - Eisele, Marion A1 - Boczor, Sigrid A1 - Rakebrandt, Anja A1 - Blozik, Eva A1 - Trader, Jens-Martin A1 - Stork, Stefan A1 - Herrmann-Lingen, Christoph A1 - Scherer, Martin T1 - General practitioners' awareness of depressive symptomatology is not associated with quality of life in heart failure patients - cross-sectional results of the observational RECODE-HF Study JF - BMC Family Practice N2 - Background Depression is a common comorbidity in patients with chronic heart failure (HF) and linked to a wider range of symptoms which, in turn, are linked to a decreased health-related quality of life (HRQOL). Treatment of depression might improve HRQOL but detecting depression is difficult due to the symptom overlap between HF and depression. Therefore, clinical guidelines recommend to routinely screen for depression in HF patients. No studies have so far investigated the treatment after getting aware of a depressive symptomatology and its correlation with HRQOL in primary care HF patients. Therefore, we examined the factors linked to depression treatment and those linked to HRQOL in HF patients. We hypothesized that GPs’ awareness of depressive symptomatology was associated with depression treatment and HRQOL in HF patients. Methods For this observational study, HF patients were recruited in primary care practices and filled out a questionnaire including PHQ-9 and HADS. A total of 574 patients screened positive for depressive symptomatology. Their GPs were interviewed by phone regarding the patients’ comorbidities and potential depression treatment. Descriptive and regression analysis were performed. Results GPs reported various types of depression treatments (including dialogue/counselling by the GP him/herself in 31.8% of the patients). The reported rates differed considerably between GP-reported initiated treatment and patient-reported utilised treatment regarding psychotherapy (16.4% vs. 9.5%) and pharmacotherapy (61.2% vs. 30.3%). The GPs' awareness of depressive symptomatology was significantly associated with the likelihood of receiving pharmacotherapy (OR 2.8; p < 0.001) but not psychotherapy. The patient’s HRQOL was not significantly associated with the GPs' awareness of depression. Conclusion GPs should be aware of the gap between GP-initiated and patient-utilised depression treatments in patients with chronic HF, which might lead to an undersupply of depression treatment. It remains to be investigated why GPs’ awareness of depressive symptomatology is not linked to patients’ HRQOL. We hypothesize that GPs are aware of cases with reduced HRQOL (which improves under depression treatment) and unaware of cases whose depression do not significantly impair HRQOL, resulting in comparable levels of HRQOL in both groups. This hypothesis needs to be further investigated. KW - Medicine KW - Depression KW - Heart failure KW - Recognition of depression KW - Quality of life KW - Depression treatment KW - Observational study KW - Primary care KW - Healthcare research KW - Depressive symptomatology Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172445 VL - 18 ER - TY - JOUR A1 - Sack, Stefan A1 - Wende, Christian Michael A1 - Nägele, Herbert A1 - Katz, Amos A1 - Bauer, Wolfgang Rudolf A1 - Barr, Craig Scott A1 - Malinowski, Klaus A1 - Schwacke, Harald A1 - Leyva, Francisco A1 - Proff, Jochen A1 - Berdyshev, Sergey A1 - Paul, Vincent T1 - Potential value of automated daily screening of cardiac resynchronization therapy defibrillator diagnostics for prediction of major cardiovascular events: results from Home-CARE (Home Monitoring in Cardiac Resynchronization Therapy) study JF - European Journal of Heart Failure N2 - Aim To investigate whether diagnostic data from implanted cardiac resynchronization therapy defibrillators (CRT-Ds) retrieved automatically at 24 h intervals via a Home Monitoring function can enable dynamic prediction of cardiovascular hospitalization and death. Methods and results Three hundred and seventy-seven heart failure patients received CRT-Ds with Home Monitoring option. Data on all deaths and hospitalizations due to cardiovascular reasons and Home Monitoring data were collected prospectively during 1-year follow-up to develop a predictive algorithm with a predefined specificity of 99.5%. Seven parameters were included in the algorithm: mean heart rate over 24 h, heart rate at rest, patient activity, frequency of ventricular extrasystoles, atrial–atrial intervals (heart rate variability), right ventricular pacing impedance, and painless shock impedance. The algorithm was developed using a 25-day monitoring window ending 3 days before hospitalization or death. While the retrospective sensitivities of the individual parameters ranged from 23.6 to 50.0%, the combination of all parameters was 65.4% sensitive in detecting cardiovascular hospitalizations and deaths with 99.5% specificity (corresponding to 1.83 false-positive detections per patient-year of follow-up). The estimated relative risk of an event was 7.15-fold higher after a positive predictor finding than after a negative predictor finding. Conclusion We developed an automated algorithm for dynamic prediction of cardiovascular events in patients treated with CRT-D devices capable of daily transmission of their diagnostic data via Home Monitoring. This tool may increase patients’ quality of life and reduce morbidity, mortality, and health economic burden, it now warrants prospective studies. KW - Remote device monitoring KW - Multiparameter predictor KW - Cardiovascular hospitalizations KW - Heart failure KW - Home monitoring KW - Cardiac resynchronization therapy defibrillator Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141709 VL - 13 IS - 9 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Meinitzer, Andreas A1 - Pilz, Stefan A1 - Krane, Vera A1 - Tomaschitz, Andreas A1 - Ritz, Eberhard A1 - März, Winfried A1 - Wanner, Christoph T1 - Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients JF - European Journal of Heart Failure N2 - Aims Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. Methods and results This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95% CI 2.0–4.9), attenuating slightly in multivariate models (HR 2.4; 95% CI 1.5–3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. Conclusion Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies. KW - Homoarginine KW - Sudden cardiac death KW - Heart failure KW - Amino acids KW - Haemodialysis Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140495 VL - 13 IS - 8 ER -