TY - THES A1 - Cellini, Antonella T1 - Die Rolle der Na\(^+\)/K\(^+\)-ATPase in der Herzinsuffizienz T1 - The Na\(^+\)/K\(^+\)-ATPase and its role in heart failure N2 - Die Na+ /K+ -ATPase (NKA) ist maßgeblich an der Regulation der kardialen Na+ -Homöostase beteilligt. Im Myokard werden hauptsächlich zwei Isoformen exprimiert: die α1 (NKA-α1) und die α2-Isoform (NKA-α2). Diese beiden Isoformen unterscheiden sich sowohl in ihrer Lokalisation als auch in ihrer zellulären Funktion. So ist die NKA-α1 recht homogen entlang des Sarkolemms zu finden und ist verantwortlich für die Regulation der globalen intrazellulären Na+ -Konzentration ([Na+ ]i). Die NKA-α2 hingegen konzentriert sich hauptsächlich in den T-Tubuli und beeinflusst über Veränderung der lokalen [Na+ ]i die Ca2+ -Transienten und die Kontraktilität. Im Rahmen einer Herzinsuffizienz wurde eine verminderte Expression und Aktivität der NKA beobachtet. Gleichzeitig werden Inhibitoren der NKA, sogenannte Digitalisglykoside, in fortgeschrittenen Herzinsuffizienz-Stadien eingesetzt. Die Studienlage über den Einsatz dieser Therapeutika ist recht uneinheitlich und reicht von einer verringerten Hospitalisierung bis hin zu einer erhöhten Mortalität. Ziel dieser Arbeit war es die Folgen einer NKA-α2 Aktivierung während einer Herzinsuffizienz mit Hilfe eines murinen Überexpressionsmodells zu analysieren. 11-Wochen alte Mäuse mit einer kardialen NKA-α2 Überexpression (NKA-α2) und Wildtyp (WT) Versuchstiere wurden einem 8-wöchigen Myokardinfarkt (MI) unterzogen. NKA-α2 Versuchstiere waren vor einem pathologischem Remodeling und einer kardialen Dysfunktion geschützt. NKA-α2 Kardiomyozyten zeigten eine erhöhte Na+ /Ca2+ -Austauscher (NCX) Aktivität, die zu niedrigeren diastolischen und systolischen Ca2+ -Spiegeln führte und einer Ca2+ -Desensitisierung der Myofibrillen entgegenwirkte. WT Versuchstiere zeigten nach chronischem MI eine sarkoplasmatische Ca2+ -Akkumulation, die in NKA-α2 Kardiomyozyten ausblieb. Gleichzeitig konnte in der NKA-α2 MI Kohorte im Vergleich zu den WT MI Versuchstieren eine erhöhte Expression von β1-adrenergen Rezeptoren (β1AR) beobachtet werden, die eine verbesserte Ansprechbarkeit gegenüber β-adrenergen Stimuli bewirkte. Zudem konnte in unbehandelten Versuchstieren eine Interaktion zwischen NKA-α2 und dem β1AR nachgewiesen werden, welche in der WT Kohorte größer ausfiel als in der NKA-α2 Versuchsgruppe. Gleichzeitig zeigten unbehandelte NKA-α2 Kardiomyozyten eine erhöhte Sensitivität gegenüber β-adrenerger Stimulation auf, welche nicht mit einer erhöhten Arrhythmie-Neigung oder vermehrten Bildung reaktiver Sauerstoffspezies einherging. Diese Untersuchungen zeigen, dass eine NKA-α2 Überexpression vor pathologischem Remodeling und einer kardialen Funktionbeeinträchtigung schützt, indem eine systolische, diastolische und sarkoplasmatische Ca2+ -Akkumulation verhindert wird. Gleichzeitig wird die β1AR Expression stabilisert, wodurch es zu einer verminderten neurohumoralen Aktivierung und einer Durchbrechung des Circulus vitiosus kommen könnte. Insgesamt scheint eine Aktivierung der NKA-α2 durchaus ein vielversprechendes Target in der Herzinsuffizienz Therapie darzustellen. Therapie darzustellen. N2 - The Na+ /K+ -ATPase (NKA) is significantly involved in the regulation of the cardiac Na+ homeostasis. Two isoforms are mainly expressed in the myocardium: the α1- (NKA-α1) and the α2-isoform (NKA-α2). These two isoforms differ regarding their localization as well as their cellular function. The NKA-α1 is located along the sarcolemma and is responsible for the regulation of the global intracellular Na+ concentration ([Na+ ]i). In contrast , the NKA-α2 is concentrated mostly in the t-tubules and influences the Ca2+ transients and contractility by changing the local [Na+ ]i. During heart failure, a reduced activity and expression of the NKA has been observed. At the same time, inhibitors of the NKA, so-called digitalis glycosides, are used in the treatment of advanced stages of heart failure. The current evidence for the use of these substances remains still inconsistent ranging from decreased hospitalization to increased mortality. The aim of this project was to analyze the consequences of an NKA-α2 activation during heart failure by using a murine overexpression system. 11-weeks old mice with a cardiac-specific overexpression of the NKA-α2 (NKA-α2) and wildtype (WT) animals were subjected to 8 weeks of myocardial infarction (MI). NKA-α2 mice were protected against pathological remodeling and functional impairment. NKA-α2 cardiomyocytes showed an increased Na+ /Ca2+ -exhanger (NCX) activity, which led to a reduction of the diastolic and systolic Ca2+ levels and prevented a Ca2+ desensitization of the myofilaments. WT animals showed a sarcoplasmic Ca2+ accumulation after MI, which did not occur in NKA-α2 cardiomyoctes. At the same time, NKA-α2 MI mice showed an increased expression of β1-adrenergic receptor (β1AR), which induced an improved response towards β-adrenergic stimuli. In addition, an interaction between the NKA-α2 and the β1AR was detected in untreated animals, which was tighter in the WT cohort than in the NKA-α2 group. Furthermore, untreated NKA-α2 cardiomyocytes showed an increased sensitivity towards β-adrenergic stimulation, which was not associated with a higher arrhythmic tendency or augmented generation of reative oxygen species. These results show that an NKA-α2 overexpression protects against pathological remodeling and cardiac dysfunction by preventing systolic, diastolic and sarcoplasmic Ca2+ accumulation. Concurrently, a β1AR downregulation is countercated, probably inducing a reduced neurohormonal activation and an ending of the vicious circle. Altogether, it seems that an activation of the NKA-α2 might be a promising target in the therapy of heart failure. KW - Herzinsuffizienz KW - Natrium-Kalium-Pumpe KW - Herzmuskelzelle KW - Na+/K+-ATPase KW - heart failure KW - myocardial infarction KW - Myokardinfarkt Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297894 ER - TY - JOUR A1 - Steinhardt, Maximilian J. A1 - Cejka, Vladimir A1 - Chen, Mengmeng A1 - Bäuerlein, Sabrina A1 - Schäfer, Julia A1 - Adrah, Ali A1 - Ihne-Schubert, Sandra M. A1 - Papagianni, Aikaterini A1 - Kortüm, K. Martin A1 - Morbach, Caroline A1 - Störk, Stefan T1 - Safety and tolerability of SGLT2 inhibitors in cardiac amyloidosis — a clinical feasibility study JF - Journal of Clinical Medicine N2 - Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients. KW - heart failure KW - chronic kidney disease KW - amyloidosis KW - SGLT2 inhibitors Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-356024 SN - 2077-0383 VL - 13 IS - 1 ER - TY - JOUR A1 - Gerhardt, Louisa M. S. A1 - Kordsmeyer, Maren A1 - Sehner, Susanne A1 - Güder, Gülmisal A1 - Störk, Stefan A1 - Edelmann, Frank A1 - Wachter, Rolf A1 - Pankuweit, Sabine A1 - Prettin, Christiane A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Angermann, Christiane E. T1 - Prevalence and prognostic impact of chronic kidney disease and anaemia across ACC/AHA precursor and symptomatic heart failure stages JF - Clinical Research in Cardiology N2 - Background The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A–D. Methods and results 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1%/35.3%/32.9% and 23.7% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( – ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3%/23.6%/31.6%/54.7%; anaemia: 3.0%/7.9%/21.7%/33.2%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95% confidence intervals] for all-cause mortality were 2.1 [1.8–2.6] for CKD + , 1.7 [1.4–2.0] for anaemia, and 3.6 [2.9–4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4%, 30.8% and 34.7%, respectively). Conclusions Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF. KW - anaemia KW - ACC/AHA classification KW - chronic kidney disease KW - comorbidity KW - heart failure KW - mortality Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323990 VL - 112 IS - 7 ER - TY - JOUR A1 - Traub, Jan A1 - Frey, Anna A1 - Störk, Stefan T1 - Chronic neuroinflammation and cognitive decline in patients with cardiac disease: evidence, relevance, and therapeutic implications JF - Life N2 - Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target. KW - neuroinflammation KW - cognitive impairment KW - dementia KW - myocardial infarction KW - heart failure KW - hypertension KW - coronary artery disease KW - atrial fibrillation KW - cardiac arrest KW - aortic valve stenosis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304869 SN - 2075-1729 VL - 13 IS - 2 ER - TY - JOUR A1 - Kerwagen, Fabian A1 - Riemer, Uwe A1 - Wachter, Rolf A1 - von Haehling, Stephan A1 - Abdin, Amr A1 - Böhm, Michael A1 - Schulz, Martin A1 - Störk, Stefan T1 - Impact of the COVID-19 pandemic on implementation of novel guideline-directed medical therapies for heart failure in Germany: a nationwide retrospective analysis JF - The Lancet Regional Health - Europe N2 - Background Guideline-directed medical therapy (GDMT) is the cornerstone in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) and novel substances such as sacubitril/valsartan (S/V) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated marked clinical benefits. We investigated their implementation into real-world HF care in Germany before, during, and after the COVID-19 pandemic period. Methods The IQVIA LRx data set is based on ∼80% of 73 million people covered by the German statutory health insurance. Prescriptions of S/V were used as a proxy for HFrEF. Time trends were analysed between Q1/2016 and Q2/2023 for prescriptions for S/V alone and in combination therapy with SGLT2i. Findings The number of patients treated with S/V increased from 5260 in Q1/2016 to 351,262 in Q2/2023. The share of patients with combination therapy grew from 0.6% (29 of 5260) to 14.2% (31,128 of 219,762) in Q2/2021, and then showed a steep surge up to 54.8% (192,429 of 351,262) in Q2/2023, coinciding with the release of the European Society of Cardiology (ESC) guidelines for HF in Q3/2021. Women and patients aged >80 years were treated less often with combined therapy than men and younger patients. With the start of the COVID-19 pandemic, the number of patients with new S/V prescriptions dropped by 17.5% within one quarter, i.e., from 26,855 in Q1/2020 to 22,145 in Q2/2020, and returned to pre-pandemic levels only in Q1/2021. Interpretation The COVID-19 pandemic was associated with a 12-month deceleration of S/V uptake in Germany. Following the release of the ESC HF guidelines, the combined prescription of S/V and SGLT2i was readily adopted. Further efforts are needed to fully implement GDMT and strengthen the resilience of healthcare systems during public health crises. KW - health policy KW - oncology KW - internal medicine KW - heart failure KW - COVID-19 KW - sacubitril-valsartan KW - sodium-glucose co-transporter-2 inhibitors KW - guideline-directed medical therapy KW - evidence-based practice KW - real-world Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350510 SN - 2666-7762 VL - 35 ER - TY - JOUR A1 - Traub, Jan A1 - Otto, Markus A1 - Sell, Roxane A1 - Göpfert, Dennis A1 - Homola, György A1 - Steinacker, Petra A1 - Oeckl, Patrick A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Pham, Mirko A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Serum phosphorylated tau protein 181 and neurofilament light chain in cognitively impaired heart failure patients JF - Alzheimer's Research & Therapy N2 - Background Chronic heart failure (HF) is known to increase the risk of developing Alzheimer’s dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. Methods Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). Results Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = − 0.21; p = 0.013) and pTau (ρ = − 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = − 2.4 for pTau; T = − 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = − 3.1). Conclusions pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers. KW - Alzheimer’s dementia KW - heart failure KW - cognitive impairment KW - neurofilament light chain KW - phosphorylated tau protein KW - renal function KW - age Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300515 VL - 14 ER - TY - JOUR A1 - Kayvanpour, Elham A1 - Wisdom, Michael A1 - Lackner, Maximilian K. A1 - Sedaghat-Hamedani, Farbod A1 - Boeckel, Jes-Niels A1 - Müller, Marion A1 - Eghbalian, Rose A1 - Dudek, Jan A1 - Doroudgar, Shirin A1 - Maack, Christoph A1 - Frey, Norbert A1 - Meder, Benjamin T1 - VARS2 depletion leads to activation of the integrated stress response and disruptions in mitochondrial fatty acid oxidation JF - International Journal of Molecular Sciences N2 - Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) have been reported in patients with mitochondriopathies: most commonly encephalopathy, but also cardiomyopathy. Through a GWAS, we showed possible associations between mitochondrial valyl-tRNA synthetase (VARS2) dysregulations and non-ischemic cardiomyopathy. We aimed to investigate the possible consequences of VARS2 depletion in zebrafish and cultured HEK293A cells. Transient VARS2 loss-of-function was induced in zebrafish embryos using Morpholinos. The enzymatic activity of VARS2 was measured in VARS2-depleted cells via northern blot. Heterozygous VARS2 knockout was established in HEK293A cells using CRISPR/Cas9 technology. BN-PAGE and SDS-PAGE were used to investigate electron transport chain (ETC) complexes, and the oxygen consumption rate and extracellular acidification rate were measured using a Seahorse XFe96 Analyzer. The activation of the integrated stress response (ISR) and possible disruptions in mitochondrial fatty acid oxidation (FAO) were explored using RT-qPCR and western blot. Zebrafish embryos with transient VARS2 loss-of-function showed features of heart failure as well as indications of CNS and skeletal muscle involvements. The enzymatic activity of VARS2 was significantly reduced in VARS2-depleted cells. Heterozygous VARS2-knockout cells showed a rearrangement of ETC complexes in favor of complexes III\(_2\), III\(_2\) + IV, and supercomplexes without significant respiratory chain deficiencies. These cells also showed the enhanced activation of the ISR, as indicated by increased eIF-2α phosphorylation and a significant increase in the transcript levels of ATF4, ATF5, and DDIT3 (CHOP), as well as disruptions in FAO. The activation of the ISR and disruptions in mitochondrial FAO may underlie the adaptive changes in VARS2-depleted cells. KW - VARS2 KW - heart failure KW - integrated stress response KW - mitochondrial FAO Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284590 SN - 1422-0067 VL - 23 IS - 13 ER - TY - JOUR A1 - Montellano, Felipe A. A1 - Kluter, Elisabeth J. A1 - Rücker, Viktoria A1 - Ungethüm, Kathrin A1 - Mackenrodt, Daniel A1 - Wiedmann, Silke A1 - Dege, Tassilo A1 - Quilitzsch, Anika A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Haeusler, Karl Georg A1 - Kleinschnitz, Christoph A1 - Heuschmann, Peter U. T1 - Cardiac dysfunction and high-sensitive C-reactive protein are associated with troponin T elevation in ischemic stroke: insights from the SICFAIL study JF - BMC Neurology N2 - Background Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables. Methods Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, Würzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L. Results We report results from 543 IS patients recruited between 01/2014–02/2017. Of those, 203 (37%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95% CI 1.02–1.08), male sex (OR 2.65; 95% CI 1.54–4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95% CI 0.61–0.84), systolic dysfunction (OR 2.79; 95% CI 1.22–6.37), diastolic dysfunction (OR 2.29; 95% CI 1.29–4.02), atrial fibrillation (OR 2.30; 95% CI 1.25–4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95% CI 1.22–1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables. Conclusion Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors. KW - echocardiography KW - ischemic stroke KW - troponin KW - heart failure KW - biomarkers Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300119 VL - 22 IS - 1 ER - TY - JOUR A1 - Güder, Gülmisal A1 - Wilkesmann, Joana A1 - Scholz, Nina A1 - Leppich, Robert A1 - Düking, Peter A1 - Sperlich, Billy A1 - Rost, Christian A1 - Frantz, Stefan A1 - Morbach, Caroline A1 - Sahiti, Floran A1 - Stefenelli, Ulrich A1 - Breunig, Margret A1 - Störk, Stefan T1 - Establishing a cardiac training group for patients with heart failure: the "HIP-in-Würzburg" study JF - Clinical Research in Cardiology N2 - Background Exercise training in heart failure (HF) is recommended but not routinely offered, because of logistic and safety-related reasons. In 2020, the German Society for Prevention&Rehabilitation and the German Society for Cardiology requested establishing dedicated ""HF training groups."" Here, we aimed to implement and evaluate the feasibility and safety of one of the first HF training groups in Germany. Methods Twelve patients (three women) with symptomatic HF (NYHA class II/III) and an ejection fraction ≤ 45% participated and were offered weekly, physician-supervised exercise training for 1 year. Patients received a wrist-worn pedometer (M430 Polar) and underwent the following assessments at baseline and after 4, 8 and 12 months: cardiopulmonary exercise test, 6-min walk test, echocardiography (blinded reading), and quality of life assessment (Kansas City Cardiomyopathy Questionnaire, KCCQ). Results All patients (median age [quartiles] 64 [49; 64] years) completed the study and participated in 76% of the offered 36 training sessions. The pedometer was worn ≥ 1000 min per day over 86% of the time. No cardiovascular events occurred during training. Across 12 months, NT-proBNP dropped from 986 pg/ml [455; 1937] to 483 pg/ml [247; 2322], and LVEF increased from 36% [29;41] to 41% [32;46]%, (p for trend = 0.01). We observed no changes in exercise capacity except for a subtle increase in peak VO2% predicted, from 66.5 [49; 77] to 67 [52; 78]; p for trend = 0.03. The physical function and social limitation domains of the KCCQ improved from 60 [54; 82] to 71 [58; 95, and from 63 [39; 83] to 78 [64; 92]; p for trend = 0.04 and = 0.01, respectively. Positive trends were further seen for the clinical and overall summary scores. Conclusion This pilot study showed that the implementation of a supervised HF-exercise program is feasible, safe, and has the potential to improve both quality of life and surrogate markers of HF severity. This first exercise experiment should facilitate the design of risk-adopted training programs for patients with HF. KW - m exercise training KW - heart failure KW - cardiac training group KW - heart failure training group Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266678 SN - 1861-0692 VL - 111 ER - TY - JOUR A1 - Lorenz, Kristina A1 - Rosner, Marsha Rich T1 - Harnessing RKIP to combat heart disease and cancer JF - Cancers N2 - Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity. KW - RKIP KW - ERK1/2 KW - PKA KW - βAR KW - heart failure KW - cancer Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262185 SN - 2072-6694 VL - 14 IS - 4 ER -