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Vertreter der Hochschulmedizin, Bildungs- und Forschungspolitik und der Industrie sind sich einig: Clinician Scientists, forschende Ärztinnen und Ärzte, sind Schlüssel und Antrieb der Translation und Implementierung innovativer Therapiekonzepte in die klinische Praxis. Der Forschung an kardiovaskulären Erkrankungen, welche weiterhin für die meisten Todesfälle weltweit verantwortlich sind, muss dabei eine herausragende Rolle beigemessen werden. Die Deutsche Gesellschaft für Kardiologie – Herz- und Kreislaufforschung e. V. hat im Rahmen interner Diskussionen und auf Basis von Umfragen unter Ärztinnen und Ärzten an deutschen Universitätskliniken und kliniknahen Forschungsinstituten die aktuelle und zukünftige Situation und Bedeutung forschender Kliniker*innen in der kardiovaskulären Medizin intensiv beleuchtet. Die Analyse ergab, dass die moderne Kardiologie an Universitätskliniken von einem hohen Maß an Arbeitsverdichtung bei steigenden Patientenfallzahlen, kürzeren Liegezeiten und immer komplexeren interventionellen Eingriffen geprägt ist, die viele forschungsinteressierte Ärztinnen und Ärzte und Einrichtungsleiter*innen vor große Herausforderungen bei der Integration wissenschaftlicher Tätigkeiten in den klinischen Alltag und die Ausbildung stellt. Mögliche Verbesserungen der Rahmenbedingungen und die Schaffung konkreter Karriereperspektiven für Clinician Scientistsin der kardiovaskulären Medizin werden in diesem Positionspapier erörtert.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)Cmice 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.

An increased sympathoadrenergic activation is thought to contribute to the maintenance of elevated blood pressure levels in hypertension. Therefore, the regulation of cardiac presynaptic sympathetic neurotransmission was investigated in spontaneously hypertensive (SHR) and Wistar–Kyoto rats (WKY).

An impairment of norÍepinephrine (NE) re-uptake by the neuronal NE transporter (NET) has been shown to contribute to the increased cardiac net-release of NE in congestive heart failure (CHF). The present study investigated which mechanisms are involved in the impairment of NET. Rats with supracoronary aortic banding characterized by myocardial hypertrophy, elevated left ventricular end diastolic pressures and severe pulmonary congestion were used as an experimental model for CHF. Compared to sham-operated controls, aortic-banded rats had enhanced plasma NE concentrations and decreased cardiac NE stores. In isolated perfused hearts of aortic-banded rats, functional impairment of NET was indicated by a 37% reduction in [3H]-NE-uptake. In addition, pharmacological blockade of NET with desipramine led to a markedly attenuated increase in the overflow of endogenous NE from hearts of aortic-banded rats. Determination of cardiac NET protein and of NET mRNA in the left stellate ganglion by [3H]-desipramine binding and competitive RT-PCR, respectively, revealed a 41% reduction of binding sites but no difference in gene expression. The density of sympathetic nerve fibers within the heart was unchanged, as shown by glyoxylic acid-induced histofluorescence. In conclusion, as impairment of intracardiac NE re-uptake by a reduction of NET binding sites is neither mediated by a decreased NET gene expression nor by a loss of noradrenergic nerve terminals, a posttranscriptional downregulation of NET per neuron is suggested in CHF.

Introduction:Ca2+/calmodulin-dependent protein kinase II (CaMK2) is a recognized driver of pathological cardiac remodeling and heart failure, but its role in the metabolic reprogramming of heart failure remains unclear, as do the molecular processes that trigger this pathologic switch.Hypothesis:Myocardial CaMKIIδ drives the pathological remodeling of cardiac metabolic substrate preference.Methods and Results:Adeno-associated viral (ssAAV9) overexpression of constitutively-active cytosolic (CaMK2δC) and nuclear (CaMK2δB) CaMK2δ isoforms, as well as the catalytic PKA subunit (PKAca), were created under the control of the cardiac troponin-T promoter and introduced via tail-vein injection into 12-week old mice (1 x 1012v.g., n = 5). In vivometabolic phenotyping via 18-fluorodeoxyglucose (18FDG)-based positron emission tomography (PET) revealed a 3.4-fold (P = 0.02) higher glucose uptake among mice receiving ssAAV9-TnnT-CaMK2δC commensurate with cardiac CaMK2δC expression. In contrast, no differences were seen in glucose uptake following AAV overexpression of cardiac CaMK2δB or PKAca relative to luciferase control vector. Echocardiography subsequently revealed a 14.6% decrease in left ventricular ejection fraction at 6 weeks following CaMK2δC overexpression (P = 0.047), whereas no changes were seen following CaMK2δB or PKAca overexpression in systolic or diastolic cardiac parameters. Conversely, transcriptomic analysis of hearts from mice lacking cardiac CaMK2δC expression revealed disproportionate up-regulation of fatty acid oxidative genes (P < 0.001).Conclusion:Taken together, these preliminary findings implicate CaMK2δC as a crucial regulator of the cardiac metabolic reprogramming that likely precedes the hemodynamic manifestations of cardiac dysfunction in heart failure.

The glyoxalase system is a highly conserved and ubiquitously expressed enzyme system, which is responsible for the detoxification of methylglyoxal (MG), a spontaneous by-product of energy metabolism. This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax). Additionally, we observe proteasomal degradation of non-phosphorylated Glo1 via ubiquitination does occur more rapidly as compared with native Glo1. The absence of CamKIIδ is associated with poor detoxification capacity and decreased protein content of Glo1 in a murine CamKIIδ knockout model. Therefore, phosphorylation of T107 in the Glo1 protein by CamKIIδ is a quick and precise mechanism regulating Glo1 activity, which is experimentally linked to an altered Glo1 status in cancer, diabetes, and during aging.

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Sperm-egg interaction at fertilization results in a rise in the intracellular concentration of Ca2+that triggers a series of events known as egg activation. Several calcium-dependent proteins have been postulated to mediate the different events. One of them is calcium/calmodulin-dependent protein kinase II (CaMKII). In Xenopuseggs, the involvement of CaMKII in metaphase II exit has been recently demonstrated. However, whether the same signaling cascade operates in mice is unknown. Moreover, CaMKII's role in triggering other events of egg activation and the identity of the isoform/s present in mouse eggs are still unclear. Here we show that CaMKIIγ is the only isoform present in mouse eggs. We generated CaMKIIγ-deficient mice and report that they are viable, but CaMKIIγ-/-females are infertile. While CaMKIIγ-/-eggs exhibit a normal pattern of calcium oscillations, they fail to get fertilized or parthenogenetically activated. Instead, they remain arrested at metaphase II with high mitogen-activated protein kinase (MAPK) and maturation-promoting factor (MPF) activities. Maternal mRNA recruitment does not occur in CaMKIIγ-deficient eggs. On the other hand, null eggs are able to mount a post-fertilization block to polyspermy, as revealed by their ability to proteolytically cleave the zona pellucidaprotein ZP2. This demonstrates that while cell cycle resumption and mRNA recruitment are CaMKII-dependent, the block to polyspermy is not. Additionally, we report that the egg activation defects observed in CaMKIIγ-/-eggs can be reversed by introduction of either CaMKIIγ or CaMKIIδ mRNA into mouse oocytes, suggesting that CaMKII's role during egg activation is not isoform-specific.(platform)