Julian Mustroph

Julian Mustroph
University Hospital Regensburg | Uni Regensburg · Klinik und Poliklinik für Innere Medizin II

MD, PD Dr. med.

About

42
Publications
7,128
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Introduction
I am interested in novel approaches of cardiovascular pharmacotherapy. A specific focus of my work is the isolation and use of human atrial and ventricular cardiomyocytes for research. I am especially interested in human TTR amyloidosis and graft rejection after heart transplant. Current research projects also include alcohol-induced cardiomyopathy, cardiac signaling in hyperglycemia (& translational pharmacotherapy), and effects of antidiabetic drugs on cardiomyocytes.
Additional affiliations
July 2016 - March 2020
University Hospital Regensburg
Position
  • Medical Professional
May 2015 - July 2016
University Hospital Regensburg
Position
  • PhD Student
April 2012 - May 2015
Universitätsmedizin Göttingen
Position
  • PhD Student
Education
October 2009 - June 2016

Publications

Publications (42)
Article
Full-text available
Aims: Ethanol has acute negative inotropic and arrhythmogenic effects. The underlying mechanisms, however, are largely unknown. Sarcoplasmic reticulum Ca2+-leak is an important mechanism for reduced contractility and arrhythmias. Ca2+-leak can be induced by oxidative stress and Ca2+/Calmodulin-dependent protein kinase II (CaMKII). Therefore, we in...
Article
Full-text available
Aims The EMPA‐REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca²⁺‐dependent activation of Ca²⁺/calmodulin‐dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin...
Article
Rationale: Increased myocardial activity of Ca/calmodulin-dependent kinase II (CaMKII) leads to heart failure (HF) and arrhythmias. In Drosophila neurons, interaction of CaMKII with Ca/CaM-dependent serine protein kinase (CASK) has been shown to inhibit CaMKII activity, but the consequences of this regulation for HF and ventricular arrhythmias are...
Article
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Recently, it was published in Circulation that empagliflozin inhibits H2O2-induced cardiac late sodium current (late INa). Using computational modeling and point mutagenic approaches, Philippaert et al suggested a possible site of empagliflozin-binding within NaV1.5 similar to that of local anesthetics, supportive of direct drug binding to NaV1.5,...
Article
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Alcohol consumption is a major cause for de-novo and paroxysmal atrial fibrillation (AF). We have previously shown that ethanol activates Ca2+/calmodulin–dependent protein kinase II (CaMKII), inducing sarcoplasmic reticulum Ca2+ leak, delayed afterdepolarizations, and cellular arrhythmias in cardiomyocytes. CaMKII can induce the late component of c...
Article
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Aims Studies have reported a strongly varying co‐prevalence of aortic stenosis (AS) and cardiac amyloidosis (CA). We sought to histologically determine the co‐prevalence of AS and CA in patients undergoing transcatheter aortic valve replacement (TAVR). Consequently, we aimed to derive an algorithm to identify cases in which to suspect the co‐preval...
Article
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Background The aim of this study was to investigate whether bioactive adrenomedullin (bio-ADM) and interleukin-6 (IL-6) are related to acute kidney injury (AKI) and severe illness in COVID-19 patients. Methods 153 patients with COVID-19 admitted to the emergency department (ED) were included. Blood samples were collected from each patient at admis...
Article
Background Ethanol consumption is the most important self-triggered cause of atrial fibrillation (AF). As abstinence often fails, alternative therapies are needed. CaMKII-activation upon ethanol with consecutive Ca2+-leak from the sarcoplasmic reticulum (SR) appears to be an important pathomechanism for ethanol-induced AF, but is not a druggable ta...
Article
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Coronavirus SARS-CoV-2 spread worldwide, causing a respiratory disease known as COVID-19. The aim of the present study was to examine whether Dipeptidyl-peptidase 3 (DPP3) and the inflammatory biomarkers IL-6, CRP, and leucocytes are associated with COVID-19 and able to predict the severity of pulmonary infiltrates in COVID-19 patients versus non-C...
Article
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Introduction: The ongoing COVID-19 pandemic is placing an extraordinary burden on our health care system with its limited resources. Accurate triage of patients is necessary to ensure medical care for those most severely affected. In this regard, biomarkers could contribute to risk evaluation. The aim of this prospective observational clinical stu...
Article
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Spitzenforschung Herz-Kreislauf-Medizin. Innovationen und Auszeichnungen 2023: Neue Ansätze in der Herzinsuffizienztherapie: das Protein CASK als Negativregulator der Ca2+/Calmodulin-abhängigen Kinase II
Article
Introduction: The effects of empagliflozin on excitation-contraction coupling (ECC) have not been fully elucidated. We previously showed that empagliflozin directly reduces Ca ²⁺ /calmodulin kinase II (CaMKII) activity in human and murine heart failure, thereby improving contraction. Upon acute exposure, however, only subsarcolemmal [Na ⁺ ] is decr...
Article
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Introduction The respiratory illness triggered by severe acute respiratory syndrome virus-2 (SARS-CoV-2) is often particularly serious or fatal amongst patients with pre-existing heart conditions. Although the mechanisms underlying SARS-CoV-2-related cardiac damage remain elusive, inflammation (i.e. ‘cytokine storm’) and oxidative stress are likely...
Article
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Background: Sleep-disordered breathing (SDB) is associated with increased oxidant generation. Oxidized Ca/calmodulin kinase II (CaMKII) can contribute to atrial arrhythmias by the stimulation of sarcoplasmic reticulum Ca release events, i.e., Ca sparks. Methods: We prospectively enrolled 39 patients undergoing cardiac surgery to screen for SDB a...
Article
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An interplay between Ca ²⁺ /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na ⁺ current (I NaL ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na V 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na V...
Article
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Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventr...
Article
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During the current SARS-CoV-2-pandemic, involvement of multiple organs in addition to the respiratory tract has been observed. Cardiac manifestations, such as acute heart failure, arrhythmias or acute coronary syndrome, are known complications in severe disease courses. Multiple studies have reported hyperferritinemia in patients with COVID-19 inf...
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Aims The aim of the current study was to evaluate whether tubular markers kidney injury molecule-1 (KIM-1) and N-acetyl-ß-glucosaminidase (NAG) are related to acute kidney injury (AKI) and severe disease in patients with COVID-19. Methods and results In this prospective observational clinical trial we examined a cohort of 80 patients with proof of...
Article
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Arrhythmogenic right ventricular cardiomyopathy is a hereditary, rare disease with an increased risk for sudden cardiac death. The disease-causing mutations are located within the desmosomal complex and the highest incidence is found in plakophilin2. However, there are other factors playing a role for the disease progression unrelated to the genoty...
Article
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Background PKARIα (protein kinase A type I‐α regulatory subunit) is redox‐active independent of its physiologic agonist cAMP. However, it is unknown whether this alternative mechanism of PKARIα activation may be of relevance to cardiac excitation–contraction coupling. Methods and Results We used a redox‐dead transgenic mouse model with homozygous...
Article
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The SGLT2 inhibitor empagliflozin improved cardiovascular outcomes in patients with diabetes. As the cardiac mechanisms remain elusive, we investigated the long-term effects (up to 2 months) of empagliflozin on excitation-contraction (EC)-coupling in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) in a blinded manner. IPS...
Article
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Aims We aimed to assess whether expression of whole‐blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID‐19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COV...
Article
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Aims Excessive activation of Ca/calmodulin‐dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKIIδ/CaMKIIɣ‐selective, ATP‐competitive, orally...
Article
Aims: In atrial fibrillation (AF), an increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) mediated by calcium/calmodulin-dependent-protein-kinaseIIδC (CaMKII) can serve as a substrate for arrhythmia induction and persistence. Dantrolene has been shown to stabilize the cardiac ryanodine-receptor. This study investigated the effects o...
Article
ZUSAMMENFASSUNG SGLT-2-Inhibitoren sind in den letzten Jahren zunehmend in den Fokus der Diabetologen, aber auch der Kardiologen gerückt. Große Studien zeigen eine Verbesserung der kardiovaskulären Mortalität und Morbidität bei mit SGLT-2-Inhibitoren behandelten Typ-2-Diabetespatienten – insbesondere eine Reduktion der kardiovaskulären und gesamten...
Article
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Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (NaV1.8) in atrial electrophysiology. This study investigated the role and involve...
Article
Empagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has been shown to reduce mortality and hospitalization for heart failure in diabetic patients in the EMPA-REG-OUTCOME trial (Zinman et al., 2015). Surprisingly, dapagliflozin, another SGLT2 inhibitor, exerted comparable effects on clinical endpoints even in the absence of...
Article
Rationale: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased Ca/calmodulin-dependent protein kinase II (CaMKII) activity has been previously implicated in atrial arrhythmogenesis. Objective: We hypothesized that CaMKII-dependent dysregulation of Na current (I Na ) may contribute to atrial pro-arrhythmic ac...
Article
Rationale In atrial and ventricular rhythm disorders, an increased diastolic sarcoplasmatic reticulum (SR) calcium leak can induce a depolarizing transient inward current, serving as a trigger for cellular arrhythmias. Dantrolene has been shown to also stabilize the cardiac ryanodine receptor. However, the detailed mechanism of the mode of action r...
Article
Full-text available
The results of the Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients(EMPA-REG OUTCOME) showed that the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin reduced mortality and hospitalisation due to heart failure (HF) in high-risk diabetic patients. We have previously reported that empagliflozin impr...
Article
Full-text available
Ethanol can acutely and chronically alter cardiomyocyte and whole-organ function in the heart. Importantly, ethanol acutely and chronically predisposes to arrhythmias, while chronic abuse can induce heart failure. However, the molecular mechanisms of ethanol toxicity in the heart are incompletely understood. In this review, we summarize the current...
Article
Aims Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium‐dependent glucose co‐transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefor...
Article
Rationale: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillat...
Article
Full-text available
Objective: Pathologically increased activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the associated Ca2+-leak from the sarcoplasmic reticulum are recognized to be important novel pharmacotherapeutic targets in heart failure and cardiac arrhythmias. However, CaMKII-inhibitory compounds for therapeutic use are still lacking. We n...
Article
Calcium/calmodulin-dependent protein kinase II (CaMKII) has emerged as key enzyme in many cardiac pathologies, especially heart failure (HF), myocardial infarction and cardiomyopathies, thus leading to contractile dysfunction and malignant arrhythmias. While many pathways leading to CaMKII activation have been elucidated in recent years, hardly any...
Poster
Rationale: Excessive activation of Ca/calmodulin kinase II (CaMKII) is of critical importance in the development of heart failure (HF) as well as atrial fibrillation (AF). However, a clinically viable drug for the inhibition of CaMKII has not yet emerged. Objective: We tested the effects of RA123456 on the development of heart failure in a murine...
Article
Full-text available
Cardiac K channels are critical determinants of cardiac excitability. In hypertrophied and failing myocardium, alterations in the expression and activity of voltage-gated K channels are frequently observed and contribute to the increased propensity for life-threatening arrhythmias. Thus, understanding the mechanisms of disturbed K channel regulatio...

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