Browsing by Author "Grefe, Clemens"

Background-Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo. Methods and Results-Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P < 0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P < 0.05). Increasing intracellular Ca stores using ISO (10(-8) M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P < 0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca](i) rose clearly on ISO in TG but not in wild-type cells (+20 +/- 5% versus +3 +/- 4% at 10(-6) M ISO, P < 0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9 +/- 0.5 versus 2.0 +/- 0.4 sparks per 100 mu m(-1).s(-1), P < 0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKII delta-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P < 0.05) and late (86% versus 43%, P < 0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P < 0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P < 0.05). Conclusions-We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKII delta(C) mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies. (Circ Heart Fail. 2009; 2: 664-675.)

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

Abstract Background Frailty is an indicator of a decline in quality of life and functional capacity in cardiac rehabilitation (CR) patients. Currently, there is no standardized assessment tool for frailty used in CR. The aim of this study was to determine if the Clinical Frailty Scale (CFS) is feasible for assessing frailty in CR. Methods Prospective, cross-sectional study within the framework of the ongoing multicenter prehabilitation study "PRECOVERY". Patients ≥75 years undergoing CR after cardiac procedure (n=122) were recruited in four German inpatient CR facilities. Assessments included: CFS, Katz-Index, hand grip strength (HGS), Short Physical Performance Battery (SPPB) and six-minute-walk test (6MWT). Outcomes were frailty (CFS≥4) and the correlation of frailty with assessments of functional capacity, activities of daily living and clinical parameters. Statistical analysis included descriptive statistics and correlations, using the spearman correlation coefficient and chi-square test to test for significance. Results Data from 101 patients (79.9±4.0 years; 63% male) were analyzed. The mean CFS score was 3.2±1.4; 41.6% were defined as frail (CFS≥4). The mean time required to assess the CFS was 0.20 minutes. The findings show that CFS correlates significantly (p<0.001) with the following factors: Katz-Index, HGS, SPPB-Score and 6MWT (r≤-0.575). In addition, CFS correlated with small to moderate effects with co-morbidities (r=0.250), as-needed medications and need for nursing assistance (r≤0.248). Conclusions The CFS assessment can be performed in under one minute and it correlates significantly with assessments of functional capacity, activities of daily living and clinical parameters in the CR setting. Trial registration German Clinical Trials Register (DRKS; http:// www. drks. de; DRKS00032256). Retrospectively registered on 13 July 2023.

Background: Podcasts are popular with medical students, but the impact of podcast use on learning outcomes in undergraduate medical education has not been studied in detail. Objective: Our aim was to assess the impact of podcasts accompanied by quiz questions and lecture attendance on short- and medium-term knowledge retention. Methods: Students enrolled for a cardio-respiratory teaching module were asked to prepare for 10 specific lectures by watching podcasts and submitting answers to related quiz questions before attending live lectures. Performance on the same questions was assessed in a surprise test and a retention test. Results: Watching podcasts and submitting answers to quiz questions (versus no podcast/quiz use) was associated with significantly better test performance in all items in the surprise test and 7 items in the retention test. Lecture attendance (versus no attendance) was associated with higher test performance in 3 items and 1 item, respectively. In a linear regression analysis adjusted for age, gender, and overall performance levels, both podcast/quiz use and lecture attendance were significant predictors of student performance. However, the variance explained by podcast/quiz use was greater than the variance explained by lecture attendance in the surprise test (38.7% vs 2.2%) and retention test (19.1% vs 4.0%). Conclusions: When used in conjunction with quiz questions, podcasts have the potential to foster knowledge acquisition and retention over and above the effect of live lectures.

Abstract Background Previous studies have demonstrated the efficacy of rehabilitation after a cardiovascular procedure. Especially older and multimorbid patients benefit from rehabilitation after a cardiac procedure. Prehabilitation prior to cardiac procedures may also have positive effects on patients’ pre- and postoperative outcomes. Results of a current meta-analysis show that prehabilitation prior to cardiac procedures can improve perioperative outcomes and alleviate adverse effects. Germany currently lacks a structured cardiac prehabilitation program for older patients, which is coordinated across healthcare sectors. Methods In a randomized, controlled, two-arm parallel group, assessor-blinded multicenter intervention trial (PRECOVERY), we will randomize 422 patients aged 75 years or older scheduled for an elective cardiac procedure (e.g., coronary artery bypass graft surgery or transcatheter aortic valve replacement). In PRECOVERY, patients randomized to the intervention group participate in a 2-week multimodal prehabilitation intervention conducted in selected cardiac-specific rehabilitation facilities. The multimodal prehabilitation includes seven modules: exercise therapy, occupational therapy, cognitive training, psychosocial intervention, disease-specific education, education with relatives, and nutritional intervention. Participants in the control group receive standard medical care. The co-primary outcomes are quality of life (QoL) and mortality after 12 months. QoL will be measured by the EuroQol 5-dimensional questionnaire (EQ-5D-5L). A health economic evaluation using health insurance data will measure cost-effectiveness. A mixed-methods process evaluation will accompany the randomized, controlled trial to evaluate dose, reach, fidelity and adaptions of the intervention. Discussion In this study, we investigate whether a tailored prehabilitation program can improve long-term survival, QoL and functional capacity. Additionally, we will analyze whether the intervention is cost-effective. This is the largest cardiac prehabilitation trial targeting the wide implementation of a new form of care for geriatric cardiac patients. Trial registration German Clinical Trials Register (DRKS; http://www.drks.de ; DRKS00030526). Registered on 30 January 2023.

The prevalence of sarcopenia and its impact in older patients undergoing inpatient cardiac rehabilitation (iCR) after cardiac procedure has been insufficiently studied. The main aim of this study was to evaluate the prevalence of sarcopenia and quantify the functional capacity of older sarcopenic and non-sarcopenic patients participating in iCR.

Objective: CaMKII contributes to impaired contractility in heart failure by inducing SR Ca2+-leak. CaMKII-inhibition in the heart was suggested to be a novel therapeutic principle. Different CaMKII isoforms exist. Specifically targeting CaMKII delta, the dominant isoform in the heart, could be of therapeutic potential without impairing other CaMKII isoforms. Rationale: We investigated whether cardiomyocyte function is affected by isoform-specific knockout (KO) of CaMKII delta under basal conditions and upon stress, i.e. upon beta-adrenergic stimulation and during acidosis. Results: Systolic cardiac function was largely preserved in the KO in vivo (echocardiography) corresponding to unchanged Ca2+-transient amplitudes and isolated myocyte contractility in vitro. CaMKII activity was dramatically reduced while phosphatase-1 inhibitor-1 was significantly increased. Surprisingly, while diastolic Ca2+-elimination was slower in KO most likely due to decreased phospholamban Thr-17 phosphorylation, frequency-dependent acceleration of relaxation was still present. Despite decreased SR Ca2+-reuptake at lower frequencies, SR Ca2+-content was not diminished, which might be due to reduced diastolic SR Ca2+-loss in the KO as a consequence of lower RyR Ser-2815 phosphorylation. Challenging KO myocytes with isoproterenol showed intact inotropic and lusitropic responses. During acidosis, SR Ca2+-reuptake and SR Ca2+-loading were significantly impaired in KO, resulting in an inability to maintain systolic Ca2+-transients during acidosis and impaired recovery. Conclusions: Inhibition of CaMKII delta appears to be safe under basal physiologic conditions. Specific conditions exist (e.g. during acidosis) under which CaMKII-inhibition might not be helpful or even detrimental. These conditions will have to be more clearly defined before CaMKII inhibition is used therapeutically. (C) 2013 Elsevier Ltd. All rights reserved.