Publications by authors named "Lars S Maier"

243 Publications

The impact of epicardial adipose tissue in patients with acute myocardial infarction.

Clin Res Cardiol 2021 May 12. Epub 2021 May 12.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Aims: Epicardial adipose tissue (EAT) has been linked to impaired reperfusion success after percutaneous coronary intervention (PCI). Whether EAT predicts myocardial damage in the early phase after acute myocardial infarction (MI) is unclear. Therefore, we investigated whether EAT in patients with acute MI is associated with more microvascular obstruction (MVO), greater ST-deviation, larger infarct size and reduced myocardial salvage index (MSI).

Methods And Results: This retrospective analysis of a prospective observational study including patients with acute MI (n = 54) undergoing PCI and 12 healthy matched controls. EAT, infarct size and MSI were analyzed with cardiac magnetic resonance imaging, conducted 3-5 days and 12 weeks after MI. Patients with acute MI showed higher EAT volume than healthy controls (46 [25.;75. percentile: 37;59] vs. 24 [15;29] ml, p < 0.001). The high EAT group (above median) showed significantly more MVO (2.22 [0.00;5.38] vs. 0.0 [0.00;2.18] %, p = 0.004), greater ST-deviation (0.38 [0.22;0.55] vs. 0.15 [0.03;0.20] mV×10, p = 0.008), larger infarct size at 12 weeks (23 [17;29] vs. 10 [4;16] %, p < 0.001) and lower MSI (40 [37;54] vs. 66 [49;88] %, p < 0.001) after PCI than the low EAT group. After accounting for demographic characteristics, body-mass index, heart volume, infarct location, TIMI-flow grade as well as apnea-hypopnea index, EAT was associated with infarct size at 12 weeks (B = 0.38 [0.11;0.64], p = 0.006), but not with MSI.

Conclusions: Patients with acute MI showed higher volume of EAT than healthy individuals. High EAT was linked to more MVO and greater ST-deviation. EAT was associated with infarct size, but not with MSI.
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http://dx.doi.org/10.1007/s00392-021-01865-4DOI Listing
May 2021

Transient hypoglycemia as a rare cause of recurring transient loss of consciousness: a case report.

J Med Case Rep 2021 May 6;15(1):261. Epub 2021 May 6.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

Background: Syncopes and transient loss of consciousness affect a large number of patients. Determining the underlying mechanism of a syncope is key to effectively treating and preventing future events. However, given the broad differential diagnosis of transient loss of consciousness, it can be challenging to determine the exact etiology.

Case Presentation: This case presents a 42-year-old Caucasian female patient with recurrent transient loss of consciousness due to a hitherto undiagnosed impaired glucose tolerance and hyperinsulinism. The patient had been thoroughly tested for all typical causes of syncope without finding any causal explanation. An oral glucose tolerance test confirmed rapidly dropping blood glucose levels associated with rapidly fading consciousness as the underlying cause of transient loss of consciousness. Further diagnostic workup revealed that the patient suffered from impaired glucose tolerance and subsequent hyperinsulinism without overt diabetes mellitus. Nutritional counseling including reduction of glucose intake and frequently eating smaller meal portions led to a significant reduction in the frequency of transient loss of consciousness and overall improvement in quality of life.

Conclusions: The current European Society of Cardiology (ESC) guideline on syncope does not list hypoglycemia as a cause of transient loss of consciousness. However, this case report stresses that metabolic dysregulation can indeed lead to self-limited transient loss of consciousness. Thus, in the case of recurrent syncope with an unclear underlying mechanism, physicians should consider transient hypoglycemia and metabolic workup as a possible differential diagnosis.
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http://dx.doi.org/10.1186/s13256-021-02844-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101148PMC
May 2021

Argatroban versus heparin in patients without heparin-induced thrombocytopenia during venovenous extracorporeal membrane oxygenation: a propensity-score matched study.

Crit Care 2021 04 29;25(1):160. Epub 2021 Apr 29.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

Background: During venovenous extracorporeal membrane oxygenation (vvECMO), direct thrombin inhibitors are considered by some potentially advantageous over unfractionated heparin (UFH). We tested the hypothesis that Argatroban is non-inferior to UFH regarding thrombosis and bleeding during vvECMO.

Methods: We conducted a propensity-score matched observational non-inferiority study of consecutive patients without heparin-induced-thrombocytopenia (HIT) on vvECMO, treated between January 2006 and March 2019 in the medical intensive care unit at the University Hospital Regensburg. Anticoagulation was realized with UFH until August 2017 and with Argatroban from September 2017 onwards. Target activated partial thromboplastin time was 50 ± 5seconds in both groups. Primary composite endpoint was major thrombosis and/or major bleeding. Major bleeding was defined as a drop in hemoglobin of ≥ 2 g/dl/day or in transfusion of ≥ 2 packed red cells/24 h, or retroperitoneal, cerebral, or pulmonary bleeding. Major thrombosis was defined as obstruction of > 50% of the vessel lumen diameter by means of duplex sonography. We also assessed technical complications such as oxygenator defects or pump head thrombosis, the time-course of platelets, and the cost of anticoagulation (including HIT-testing).

Results: Out of 465 patients receiving UFH, 78 were matched to 39 patients receiving Argatroban. The primary endpoint occurred in 79% of patients in the Argatroban group and in 83% in the UFH group (non-inferiority for Argatroban, p = 0.026). The occurrence of technical complications was equally distributed (Argatroban 49% vs. UFH 42%, p = 0.511). The number of platelets was similar in both groups before ECMO therapy but lower in the UFH group after end of ECMO support (median [IQR]: 141 [104;198]/nl vs. 107 [54;171]/nl, p = 0.010). Anticoagulation costs per day of ECMO were higher in the Argatroban group (€26 [13.8;53.0] vs. €0.9 [0.5;1.5], p < 0.001) but not after accounting for blood products and HIT-testing (€63 [42;171) vs. €40 [17;158], p = 0.074).

Conclusion: In patients without HIT on vvECMO, Argatroban was non-inferior to UFH regarding bleeding and thrombosis. The occurrence of technical complications was similarly distributed. Argatroban may have less impact on platelet decrease during ECMO, but this finding needs further evaluation. Direct drug costs were higher for Argatroban but comparable to UFH after accounting for HIT-testing and transfusions.
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http://dx.doi.org/10.1186/s13054-021-03581-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081564PMC
April 2021

Successful weight loss reduces endothelial activation in individuals with severe obesity participating in a multimodal weight loss program.

Obes Res Clin Pract 2021 Apr 10. Epub 2021 Apr 10.

Clinic for Internal Medicine II, University Hospital of Regensburg, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany. Electronic address:

Introduction: Endothelial dysfunction is a very common finding in obesity and metabolic syndrome. The aim of our study was to investigate if longterm weight reduction (WR) success may reverse endothelial activation in individuals with severe obesity participating in a multimodal WR program.

Methods: Participants with obesity (øBMI 40.3 ±7.5 kg/m) underwent a standardized non-surgical 1-year WR program. Carotid artery studies and determination of endothelial function biomarkers were performed at baseline and after 1 year. Individuals were dichotomized in "successful WR" (% WR≥10% of initial body weight) and "failed WR" (% WR<10% of initial body weight).

Results: From 191 people with obesity, 115 achieved successful WR. Compared to controls without obesity (n=44) participants with obesity had higher carotid intima media thickness as well as higher sICAM-1, sE-selectin, MMP-9, hsCRP and IL-6 levels. After 12 months follow up delta values of inflammation and endothelial adhesion markers were significantly different between participants with obesity and successful WR and participants with obesity and failed WR, in favour of the successful WR group (mean ± standard deviation): ΔhsCRP (-5.2 mg/L ±7.8 vs. 1.1 mg/L ±5.1, P<0.001; P=0.009), ΔIL-6 (-1.0 pg/mL ±3.4 vs. 0.5 pg/mL ±2.6, P<0.001; P=0.057), ΔsE-selectin (-19.0 ng/mL ±24.4 vs. 39.2 ng/mL ±20.3, P<0.001; P<0.001), ΔsICAM-1 (-26.4 ng/mL ±68.8 vs. 10.6 ng/mL ±73.9, P=0.004; P=0.805) and ΔoxLDL (-4 mg/dL ±30 vs. 5 mg/dL ±25, P=0.004; P=0.473). In linear regression analysis reduction of BMI was significantly associated with improvement of several endothelial dysfunction biomarkers with the strongest effects for ΔsE-selectin and ΔhsCRP.

Conclusion: Our data corroborate the finding that obesity leads to endothelial dysfunction. Furthermore, successful non-surgical WR may at least partially reverse endothelial activation implicating cardiovascular health benefits of WR in people with severe obesity.
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http://dx.doi.org/10.1016/j.orcp.2021.03.013DOI Listing
April 2021

Urinary N-terminal pro-brain natriuretic peptide: prognostic value in patients with acute chest pain.

ESC Heart Fail 2021 Jun 6;8(3):2293-2305. Epub 2021 Apr 6.

Department of Internal Medicine II (Cardiology), University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93053, Germany.

Aims: The objective of this study was to investigate the prognostic value of urinary N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with plasma NT-proBNP in patients presenting with acute chest pain in the emergency department.

Methods And Results: We measured simultaneously plasma and urinary NT-proBNP at admission in 301 patients with acute chest pain. In our cohort, 174 patients suffered from acute coronary syndrome (ACS). A follow-up (median of 55 months) was performed regarding the endpoints all-cause mortality and major adverse cardiac events (mortality, congestive heart failure, ACS with the necessity of a coronary intervention, and stroke). Fifty-four patients died during follow-up; 98 suffered from the combined endpoint. A significant and positive correlation of urinary and plasma NT-proBNP was found (r = 0.87, P < 0.05). Patients with troponin positive ACS had significantly elevated levels of plasma and urinary NT-proBNP compared with those with unstable angina pectoris or chest wall syndrome (each P < 0.05). The highest levels of both biomarkers were found in patients with congestive heart failure (each P < 0.05). According to Kaplan-Meier analysis, plasma and urinary NT-proBNP were significant predictors for mortality and the combined endpoint in the whole study cohort and in the subgroup of patients with ACS (each P < 0.05). Regarding Cox regression analysis, plasma and urinary NT-proBNP were independent predictors for mortality and the combined endpoint (each P < 0.05).

Conclusions: Urinary NT-proBNP seems to provide a significant predictive value regarding the endpoints all-cause mortality and major adverse cardiac events in patients with acute chest pain and those with ACS.
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http://dx.doi.org/10.1002/ehf2.13332DOI Listing
June 2021

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry.

ESC Heart Fail 2021 Jun 13;8(3):1924-1932. Epub 2021 Mar 13.

Department of Cardiology, Charité, Campus Rudolf Virchow, Berlin, Germany.

Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes.

Methods And Results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002).

Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.
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http://dx.doi.org/10.1002/ehf2.13165DOI Listing
June 2021

Mapping genetic changes in the cAMP-signaling cascade in human atria.

J Mol Cell Cardiol 2021 Feb 22;155:10-20. Epub 2021 Feb 22.

Université Paris-Saclay, Inserm, UMR-S 1180, Châtenay-Malabry, France; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.

Aim: To obtain a quantitative expression profile of the main genes involved in the cAMP-signaling cascade in human control atria and in different cardiac pathologies.

Methods And Results: Expression of 48 target genes playing a relevant role in the cAMP-signaling cascade was assessed by RT-qPCR. 113 samples were obtained from right atrial appendages (RAA) of patients in sinus rhythm (SR) with or without atrium dilation, paroxysmal atrial fibrillation (AF), persistent AF or heart failure (HF); and left atrial appendages (LAA) from patients in SR or with AF. Our results show that right and left atrial appendages in donor hearts or from SR patients have similar expression values except for AC7 and PDE2A. Despite the enormous chamber-dependent variability in the gene-expression changes between pathologies, several distinguishable patterns could be identified. PDE8A, PI3Kγ and EPAC2 were upregulated in AF. Different phosphodiesterase (PDE) families showed specific pathology-dependent changes.

Conclusion: By comparing mRNA-expression patterns of the cAMP-signaling cascade related genes in right and left atrial appendages of human hearts and across different pathologies, we show that 1) gene expression is not significantly affected by cardioplegic solution content, 2) it is appropriate to use SR atrial samples as controls, and 3) many genes in the cAMP-signaling cascade are affected in AF and HF but only few of them appear to be chamber (right or left) specific.

Topic: Genetic changes in human diseased atria.

Translational Perspective: The cyclic AMP signaling pathway is important for atrial function. However, expression patterns of the genes involved in the atria of healthy and diseased hearts are still unclear. We give here a general overview of how different pathologies affect the expression of key genes in the cAMP signaling pathway in human right and left atria appendages. Our study may help identifying new genes of interest as potential therapeutic targets or clinical biomarkers for these pathologies and could serve as a guide in future gene therapy studies.
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http://dx.doi.org/10.1016/j.yjmcc.2021.02.006DOI Listing
February 2021

Long-term effects of a standardized feedback-driven quality improvement program for timely reperfusion therapy in regional STEMI care networks.

Eur Heart J Acute Cardiovasc Care 2020 Jul 29. Epub 2020 Jul 29.

German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.

Aims: Current European Society of Cardiology guidelines state that repetitive monitoring and feedback should be implemented for ST-elevation myocardial infarction (STEMI) treatment, but no evidence is available supporting this recommendation. We aimed to analyze the long-term effects of a formalized data assessment and systematic feedback on performance and mortality within the prospective, multicenter Feedback Intervention and Treatment Times in STEMI (FITT-STEMI) study.

Methods: Regular interactive feedback sessions with local STEMI management teams were performed at six participating German percutaneous coronary intervention (PCI) centers over a 10-year period starting from October 2007.

Results: From the first to the 10th year of study participation, all predefined key-quality indicators for performance measurement used for feedback improved significantly in all 4926 consecutive PCI-treated patients - namely, the percentages of patients with pre-hospital electrocardiogram (ECG) recordings (83.3% vs 97.1%, p < 0.0001) and ECG recordings within 10 minutes after first medical contact (41.7% vs 63.8%, p < 0.0001), pre-announcement by telephone (77.0% vs 85.4%, p = 0.0007), direct transfer to the catheterization laboratory bypassing the emergency department (29.4% vs 64.2%, p < 0.0001), and contact-to-balloon times of less than 90 minutes (37.2% vs 53.7%, p < 0.0001). Moreover, this feedback-related continuous improvement of key-quality indicators was linked to a significant reduction in in-hospital mortality from 10.8% to 6.8% (p = 0.0244). Logistic regression models confirmed an independent beneficial effect of duration of study participation on hospital mortality (odds ratio = 0.986, 95% confidence interval = 0.976-0.996, p = 0.0087). In contrast, data from a nationwide PCI registry showed a continuous increase in in-hospital mortality in all PCI-treated STEMI patients in Germany from 2008 to 2015 (n = 398,027; 6.7% to 9.2%, p < 0.0001).

Conclusions: Our results indicate that systematic data assessment and regular feedback is a feasible long-term strategy and may be linked to improved performance and a reduction in mortality in STEMI management.
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http://dx.doi.org/10.1177/2048872620907323DOI Listing
July 2020

Extracorporeal life support in patients with acute myocardial infarction complicated by cardiogenic shock - Design and rationale of the ECLS-SHOCK trial.

Am Heart J 2021 04 8;234:1-11. Epub 2021 Jan 8.

University Clinic Düsseldorf, Düsseldorf, Germany.

Background: In acute myocardial infarction complicated by cardiogenic shock the use of mechanical circulatory support devices remains controversial and data from randomized clinical trials are very limited. Extracorporeal life support (ECLS) - venoarterial extracorporeal membrane oxygenation - provides the strongest hemodynamic support in addition to oxygenation. However, despite increasing use it has not yet been properly investigated in randomized trials. Therefore, a prospective randomized adequately powered clinical trial is warranted.

Study Design: The ECLS-SHOCK trial is a 420-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare whether treatment with ECLS in addition to early revascularization with percutaneous coronary intervention or alternatively coronary artery bypass grafting and optimal medical treatment is beneficial in comparison to no-ECLS in patients with severe infarct-related cardiogenic shock. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of ECLS-SHOCK is 30-day mortality. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, a longer follow-up at 6 and 12 months will be performed including quality of life assessment. Safety endpoints include peripheral ischemic vascular complications, bleeding and stroke.

Conclusions: The ECLS-SHOCK trial will address essential questions of efficacy and safety of ECLS in addition to early revascularization in acute myocardial infarction complicated by cardiogenic shock.
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http://dx.doi.org/10.1016/j.ahj.2021.01.002DOI Listing
April 2021

Secondary hemophagocytic lymphohistiocytosis and severe liver injury induced by hepatic SARS-CoV-2 infection unmasking Wilson's disease: Balancing immunosuppression.

Int J Infect Dis 2021 Feb 4;103:624-627. Epub 2021 Jan 4.

Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.

A 21-year-old woman was hospitalized due to coronavirus disease 2019 (COVID-19)-associated respiratory and hepatic impairment concomitant with severe hemolytic anemia. Upon diagnosis of secondary hemophagocytic lymphohistiocytosis, immunosuppression with anakinra and steroids was started, leading to a hepatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and viremia. Subsequent liver biopsy revealed virus particles in hepatocytes by electron microscopy and SARS-CoV-2 virus could be isolated and cultured. Immunosuppression was stopped and convalescent donor plasma given. In the differential diagnosis, an acute crisis of Wilson's disease was raised by laboratory and genetic testing. This case highlights the complexity of balancing immunosuppression to control hyperinflammation versus systemic SARS-CoV-2 dissemination.
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http://dx.doi.org/10.1016/j.ijid.2020.12.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781512PMC
February 2021

Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites.

J Gen Physiol 2021 Feb;153(2)

Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France.

Phosphorylation of the voltage-gated Na+ (NaV) channel NaV1.5 regulates cardiac excitability, yet the phosphorylation sites regulating its function and the underlying mechanisms remain largely unknown. Using a systematic, quantitative phosphoproteomic approach, we analyzed NaV1.5 channel complexes purified from nonfailing and failing mouse left ventricles, and we identified 42 phosphorylation sites on NaV1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic NaV1.5 mutants revealed the roles of three phosphosites in regulating NaV1.5 channel expression and gating. The phosphorylated serines S664 and S667 regulate the voltage dependence of channel activation in a cumulative manner, whereas the nearby S671, the phosphorylation of which is increased in failing hearts, regulates cell surface NaV1.5 expression and peak Na+ current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, our results demonstrate that ventricular NaV1.5 is highly phosphorylated and that the phosphorylation-dependent regulation of NaV1.5 channels is highly complex, site specific, and dynamic.
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http://dx.doi.org/10.1085/jgp.202012646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797897PMC
February 2021

Acquired von Willebrand syndrome and factor VIII in patients with moderate to severe mitral regurgitation undergoing transcatheter mitral valve repair.

Clin Cardiol 2021 Feb 29;44(2):261-266. Epub 2020 Dec 29.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Background And Hypothesis: The acquired von Willebrand syndrome (AvWS), which predisposes to bleeding events, is often related to valvular heart diseases. We investigated possible implications of AvWS and factor VIII levels in patients with moderate to severe mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR).

Methods And Results: 123 patients with moderate to severe MR were prospectively enrolled. Complete measurements of von Willebrand Factor activity (vWFAct), von Willebrand Factor antigen (vWFAg), and factor VIII expression before and 4 weeks after TMVR were available in 85 patients. At baseline, seven patients had a history of gastrointestinal bleeding, two patients suffered bleeding events during their hospital stay, and one patient had a bleeding 4 weeks after TMVR. Even though vWFAct, vWFAct/vWFAg ratio and vWFAg values did not change after TMVR, we observed a significantly lower vWFAct/vWFAg ratio in patients with primary MR as compared to patients with secondary MR both at baseline (p = 0.022) and 4 weeks following the TMVR procedure (p = 0.003). Additionally, patients with a mean mitral valve gradient ≥4 mmHg after TMVR had significantly lower vWFAct/vWFAg ratios as compared to patients with a mean mitral valve gradient <4 mmHg (p = 0.001).

Conclusions: MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, morphological changes leading to postprocedural transmitral gradients ≥4 mmHg were related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Alterations of the vWFAct/vWFAg ratio in turn did not translate into a greater risk for bleeding events.
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http://dx.doi.org/10.1002/clc.23538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852171PMC
February 2021

Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

BMC Cardiovasc Disord 2020 12 9;20(1):516. Epub 2020 Dec 9.

Careggi University Hospital, University of Florence, Florence, Italy.

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.

Methods: As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.

Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p = 0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p = 0.085). Laboratory analyses revealed normal levels of creatinine (85.5 ± 18.3 vs. 81.3 ± 16.4 µmol/l; p = 0.487) and blood urea nitrogen (10.2 ± 15.6 vs. 6.9 ± 3.9 mmol/l; p = 0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p = 0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p = 0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p = 0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8 ± 3.3, MYH7 13.9 ± 6.9, p = 0.079).

Conclusions: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.
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http://dx.doi.org/10.1186/s12872-020-01807-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727200PMC
December 2020

Decreased GLUT1/NHE1 RNA expression in whole blood predicts disease severity in patients with COVID-19.

ESC Heart Fail 2021 02 20;8(1):309-316. Epub 2020 Nov 20.

Department of Internal Medicine II (Cardiology), University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, 93053, Germany.

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 COVID-19 patients.

Methods And Results: Whole-blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS-CoV-2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID-19 patients. NHE1 expression is up-regulated in whole blood of patients with COVID-19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID-19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID-19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID-19 in comparison with the myocardium of non-infected donors.

Conclusions: NHE1 and GLUT1 may be critically involved in the disease progression of SARS-CoV-2 infection. We show here that SARS-CoV-2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID-19.
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http://dx.doi.org/10.1002/ehf2.13063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835506PMC
February 2021

Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation.

Front Cell Dev Biol 2020 22;8:592893. Epub 2020 Oct 22.

Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany.

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of density, a 69.5% reduction of Na1.5 expression, and the impaired localization of Na1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The in BrS-CMs was significantly augmented, and the window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.
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http://dx.doi.org/10.3389/fcell.2020.592893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642519PMC
October 2020

Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms.

J Clin Invest 2021 Jan;131(2)

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Diabetes mellitus (DM) and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF. However, the mechanism(s) underlying this clinical association is unknown. ROS and protein O-GlcNAcylation (OGN) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by ROS (oxidized CaMKII, ox-CaMKII) and OGN (OGN-CaMKII). We induced type 1 (T1D) and type 2 DM (T2D) in a portfolio of genetic mouse models capable of dissecting the role of ROS and OGN at CaMKII and global OGN in diabetic AF. Here, we showed that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both required ox-CaMKII to increase AF; however, we did not detect OGN-CaMKII or a role for OGN-CaMKII in diabetic AF. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by a CaMKII-independent mechanism(s). These results provide insights into the mechanisms for increased AF in DM and suggest potential benefits for future CaMKII and OGN targeted therapies.
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http://dx.doi.org/10.1172/JCI95747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810480PMC
January 2021

Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes.

J Mol Med (Berl) 2020 12 9;98(12):1689-1700. Epub 2020 Oct 9.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

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. IPSC from 3 donors, differentiated into pure iPSC-CM (4 differentiations), were treated with a clinically relevant concentration of empagliflozin (0.5 μmol/l) or vehicle control. Treatment, data acquisition, and analysis were conducted externally blinded. Epifluorescence microscopy measurements in iPSC-CM showed that empagliflozin has neutral effects on Ca transient amplitude, diastolic Ca levels, Ca transient kinetics, or sarcoplasmic Ca load after 2 weeks or 8 weeks of treatment. Confocal microscopy determining possible effects on proarrhythmogenic diastolic Ca release events showed that in iPSC-CM, Ca spark frequency and leak was not altered after chronic treatment with empagliflozin. Finally, in patch-clamp experiments, empagliflozin did not change action potential duration, amplitude, or resting membrane potential compared with vehicle control after long-term treatment. Next-generation RNA sequencing (NGS) and mapped transcriptome profiles of iPSC-CMs untreated and treated with empagliflozin for 8 weeks showed no differentially expressed EC-coupling genes. In line with NGS data, Western blots indicate that empagliflozin has negligible effects on key EC-coupling proteins. In this blinded study, direct treatment of iPSC-CM with empagliflozin for a clinically relevant duration of 2 months did not influence cardiomyocyte EC-coupling and electrophysiology. Therefore, it is likely that other mechanisms independent of cardiomyocyte EC-coupling are responsible for the beneficial treatment effect of empagliflozin. KEY MESSAGES: This blinded study investigated the clinically relevant long-term effects (up to 2 months) of empagliflozin on cardiomyocyte excitation-contraction (EC)-coupling. Human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) were used to study a human model including a high repetition number of experiments. Empagliflozin has neutral effects on cardiomyocyte Ca transients, sarcoplasmic Ca load, and diastolic sarcoplasmic Ca leak. In patch-clamp experiments, empagliflozin did not change the action potential. Next-generation RNA sequencing, mapped transcriptome profiles, and Western blots of iPSC-CM untreated and treated with empagliflozin showed no differentially expressed EC-coupling candidates.
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http://dx.doi.org/10.1007/s00109-020-01989-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679329PMC
December 2020

Effects of visualization of successful revascularization on chest pain and quality of life in chronic coronary syndrome: study protocol for the multi-center, randomized, controlled PLA-pCi-EBO-pilot-trial.

Trials 2020 Oct 8;21(1):838. Epub 2020 Oct 8.

University Heart Centre Regensburg, Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Background: Stable coronary artery disease (CAD), recently termed chronic coronary syndrome (CCS), is a highly prevalent disease. Current treatment strategies often include a relevant placebo effect. The hypothesis is that visual angiographic demonstration of the coronary arteries before and after successful percutaneous coronary intervention (PCI) by itself reduces the symptom burden of stable CAD/CCS.

Design And Methods: The PLA-pCi-EBO-pilot-trial is a prospective, multi-center, randomized, controlled investigator-initiated pilot trial to study the effect of visual demonstration of successful PCI on quality of life (QoL) and angina pectoris (AP) in patients with symptomatic stable CAD/CCS. All patients with stable CAD/CCS and successful PCI will be screened. One hundred forty four patients with a frequency of AP ≥ 2/week will be randomized 1:1 stratified for AP frequency > 1/day. The control group will receive the common written procedural report on the procedure. Patients in the intervention group will additionally be given a printout picture of their coronary angiogram both before and after PCI. Primary endpoints are change in the Seattle Angina Questionnaire (SAQ)-derived QoL score 1 and 6 months after PCI. Secondary endpoints are changes in other SAQ-derived scores and dyspnea (NYHA score) 1 and 6 months after PCI.

Discussion: The PLA-pCi-EBO-pilot-trial evaluates the effect of visual angiographic result demonstration on disease symptoms and QoL in patients with stable CAD/CCS on top of PCI. A positive outcome of our study would encourage the routine use of angiographic picture demonstration and has thus the potential to change daily routine in the catheterization laboratory.

Trial Registration: German Clinical Trials Register DRKS00017524 . Registered on 5 July 2019.
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http://dx.doi.org/10.1186/s13063-020-04710-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542727PMC
October 2020

Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardiovascular disease.

Eur J Heart Fail 2020 12 20;22(12):2248-2257. Epub 2020 Oct 20.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Aims: Coronavirus disease 2019 (COVID-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic.

Methods And Results: We have measured ACE2 mRNA expression using real-time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression.

Conclusion: Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression.
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http://dx.doi.org/10.1002/ejhf.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675329PMC
December 2020

Empagliflozin inhibits Na /H exchanger activity in human atrial cardiomyocytes.

ESC Heart Fail 2020 Sep 18. Epub 2020 Sep 18.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Aims: Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na /H exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes.

Methods And Results: Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 μmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 μmol/L, 10 min).

Conclusions: This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.
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http://dx.doi.org/10.1002/ehf2.13024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755005PMC
September 2020

Effects of ON-Hours Versus OFF-Hours Admission on Outcome in Patients With Myocardial Infarction and Cardiogenic Shock: Results From the CULPRIT-SHOCK Trial.

Circ Cardiovasc Interv 2020 09 4;13(9):e009562. Epub 2020 Sep 4.

Department of Internal Medicine II, University Medical Center Regensburg, Germany (C.M.S., L.S.M.).

Background: The management of patients with acute myocardial infarction complicated by cardiogenic shock is highly complex, and outcomes may depend on the time of hospital admission and subsequent intervention (ie, ON-hours versus OFF-hours). The CULPRIT-SHOCK trial (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock) demonstrated superior outcome for culprit-lesion-only versus immediate multivessel percutaneous coronary intervention in patients presenting with acute myocardial infarction, multivessel disease, and cardiogenic shock. However, it is unknown whether the time of hospital admission affects the overall outcome of these high-risk patients.

Methods: We analyzed patients from the CULPRIT-SHOCK trial with respect to the time of hospital admission. We divided patients in ON-hours and OFF-hours groups and further stratified them according to their individual revascularization strategy. Outcome measures consisted of a composite end point of death or renal-replacement therapy within 30 days and mortality within 1 year.

Results: Out of 686 patients randomized in the CULPRIT-SHOCK trial, 444 patients (64.7%) presented during ON-hours, whereas 242 patients (35.3%) presented during OFF-hours. Death or renal-replacement therapy at 30 days occurred to a similar extent in patients admitted during ON-hours (51.0%) and OFF-hours (50.0%; =0.80). Similarly, 1-year mortality was not affected by the time of hospital admission (54.4% ON-hours versus 51.7% OFF-hours, =0.49). Regardless of admission time, patients had a benefit from culprit-lesion-only as compared to immediate multivessel percutaneous coronary intervention. The composite end point at 30 days occurred in 45.1% versus 57.6% of patients admitted ON-hours and in 47.7% versus 51.9% of patients admitted OFF-hours (=0.29). Death within 1 year occurred in 49.4% versus 60.0% of patients admitted during ON-hours and in 51.4% versus 51.9% of patients admitted OFF-hours (=0.20).

Conclusions: Among patients with myocardial infarction and cardiogenic shock, the risk of death or renal-replacement therapy at 30 days, and mortality at 1 year did not differ significantly according to the time of hospital admission. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01927549.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009562DOI Listing
September 2020

Adaptive servo-ventilation in patients with chronic heart failure and sleep disordered breathing: predictors of usage.

Sleep Breath 2020 Sep 3. Epub 2020 Sep 3.

Department of Internal Medicine II, Cardiology and Pneumology, Center for Sleep Medicine, University Medical Center Regensburg, Regensburg, Germany.

Purpose: Adaptive servo-ventilation (ASV) is a therapy designed for patients with central sleep apnea (CSA) and Cheyne Stokes respiration. The aim of this study was to find predictors of ASV usage in patients with CSA in a routine sleep clinic cohort.

Methods: In this retrospective study, consecutive patients in whom ASV therapy was initiated at the University Hospital Regensburg between 2011 and 2015, were analyzed. Analysis included polysomnographies of diagnostic and ASV initiation nights, a phone questionnaire on ASV usage, readout of the ASV device 1 month after initiation ("early ASV usage," 1 month after ASV initiation), and the readout of the last month before a reappointment date set in 2015 ("late ASV usage," median 17 months after ASV initiation).

Results: In 69 consecutive patients, the mean early and late ASV usage per night was 4.8 ± 2.5 h and 4.1 ± 3.0 h, respectively. Seventeen months after initiation, 57% of patients used the device ≥ 4 h per night, and of those 91% reported a subjective benefit from ASV therapy. Early ASV usage was significantly associated with late ASV usage (univariable regression: Beta 0.8, 95%CI [0.6; 1.0] p < 0.001). In multivariable regression analysis, short duration of slow wave sleep (N3) during diagnostic polysomnography (Beta - 6.2, 95%CI [- 11.0; - 1.5]; p = 0.011) and subjective benefit from ASV (Beta 174.0, 95%CI [68.6; 279.5]; p = 0.002) were significantly associated with longer late ASV usage.

Conclusion: Early ASV usage predicts late ASV usage. In addition, low slow wave sleep before ASV initiation and subjective benefit from ASV may contribute to higher late ASV usage.
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http://dx.doi.org/10.1007/s11325-020-02182-2DOI Listing
September 2020

RNA-expression of adrenomedullin is increased in patients with severe COVID-19.

Crit Care 2020 08 28;24(1):527. Epub 2020 Aug 28.

Department of Internal Medicine II (Cardiology), University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

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http://dx.doi.org/10.1186/s13054-020-03246-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453369PMC
August 2020

Association of Culprit Lesion Location With Outcomes of Culprit-Lesion-Only vs Immediate Multivessel Percutaneous Coronary Intervention in Cardiogenic Shock: A Post Hoc Analysis of a Randomized Clinical Trial.

JAMA Cardiol 2020 Dec;5(12):1329-1337

Wilhelminenspital, Department of Cardiology, Vienna, Austria.

Importance: Myocardial infarction with a culprit lesion located in the left main or proximal left anterior descending artery compared with other coronary segments is associated with more myocardium at risk and worse clinical outcomes.

Objective: To evaluate the association of culprit lesion location with outcomes of culprit-lesion-only percutaneous coronary intervention with optional staged revascularization vs immediate multivessel percutaneous coronary intervention in patients with multivessel disease, myocardial infarction, and cardiogenic shock.

Design, Setting, And Participants: Post hoc analysis of the Culprit Lesion Only Coronary Intervention vs Multivessel Coronary Intervention in Cardiogenic Shock (CULPRIT-SHOCK), an investigator-initiated randomized, open-label clinical trial. Patients with multivessel disease, acute myocardial infarction, and cardiogenic shock were enrolled at 83 European centers from April 2013 through April 2017.

Interventions: Patients were randomized to culprit-lesion-only percutaneous coronary intervention with optional staged revascularization or immediate multivessel percutaneous coronary intervention (1:1). For this analysis, patients were stratified by culprit lesion location in the left main or proximal left anterior descending artery group and other-culprit-lesion location group.

Main Outcomes And Measures: End points included a composite of death or kidney replacement therapy at 30 days and death at 1 year.

Results: The median age of the study population was 70 (interquartile range, 60-78 years) and 524 of the study participants were men (76.4%). Of the 685 patients, 33.4% constituted the left main or proximal left anterior descending artery group and 66.6% the other-culprit-lesion location group. The left main or proximal left anterior descending artery group had worse outcomes compared with the other-culprit-lesion location group (56.8% vs 47.5%; P = .02 for the composite end point at 30 days and 59.8% vs 50.1%; P = .02 for death at 1 year). In both groups, culprit-lesion-only vs immediate multivessel percutaneous coronary intervention was associated with a reduced risk of the composite end point at 30 days (49.1% vs 64.3% and 44.1% vs 50.9%; P for interaction = .27). At 1 year, culprit-lesion-only vs immediate multivessel percutaneous coronary intervention was associated with a significantly reduced risk of death in the left main or proximal left anterior descending artery but not the other-culprit-lesion location group (50.0% vs 69.6%; P = .003 and 49.8% vs 50.4%; P = .89; P for interaction = 0.02).

Conclusions And Relevance: In patients with multivessel disease with myocardial infarction and cardiogenic shock, a culprit lesion located in the left main or proximal left anterior descending artery vs other coronary segments was associated with worse outcomes. These patients may especially benefit from culprit-lesion-only percutaneous coronary intervention with optional staged revascularization, although further investigation is needed to confirm this finding.

Trial Registration: ClinicalTrials.gov Identifier: NCT01927549.
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http://dx.doi.org/10.1001/jamacardio.2020.3377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450400PMC
December 2020

Toward a Long-Term Artificial Lung.

ASAIO J 2020 08;66(8):847-854

Department of Anesthesiology, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Only a very small portion of end-stage organ failures can be treated by transplantation because of the shortage of donor organs. Although artificial long-term organ support such as ventricular assist devices provide therapeutic options serving as a bridge-to-transplantation or destination therapy for end-stage heart failure, suitable long-term artificial lung systems are still at an early stage of development. Although a short-term use of an extracorporeal lung support is feasible today, the currently available technical solutions do not permit the long-term use of lung replacement systems in terms of an implantable artificial lung. This is currently limited by a variety of factors: biocompatibility problems lead to clot formation within the system, especially in areas with unphysiological flow conditions. In addition, proteins, cells, and fibrin are deposited on the membranes, decreasing gas exchange performance and thus, limiting long-term use. Coordinated basic and translational scientific research to solve these problems is therefore necessary to enable the long-term use and implantation of an artificial lung. Strategies for improving the biocompatibility of foreign surfaces, for new anticoagulation regimes, for optimization of gas and blood flow, and for miniaturization of these systems must be found. These strategies must be validated by in vitro and in vivo tests, which remain to be developed. In addition, the influence of long-term support on the pathophysiology must be considered. These challenges require well-connected interdisciplinary teams from the natural and material sciences, engineering, and medicine, which take the necessary steps toward the development of an artificial implantable lung.
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http://dx.doi.org/10.1097/MAT.0000000000001139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386861PMC
August 2020

Long-term effects of a standardized feedback-driven quality improvement program for timely reperfusion therapy in regional STEMI care networks.

Eur Heart J Acute Cardiovasc Care 2020 Jul 29:2048872620907323. Epub 2020 Jul 29.

German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.

Aims: Current European Society of Cardiology guidelines state that repetitive monitoring and feedback should be implemented for ST-elevation myocardial infarction (STEMI) treatment, but no evidence is available supporting this recommendation. We aimed to analyze the long-term effects of a formalized data assessment and systematic feedback on performance and mortality within the prospective, multicenter Feedback Intervention and Treatment Times in STEMI (FITT-STEMI) study.

Methods: Regular interactive feedback sessions with local STEMI management teams were performed at six participating German percutaneous coronary intervention (PCI) centers over a 10-year period starting from October 2007.

Results: From the first to the 10th year of study participation, all predefined key-quality indicators for performance measurement used for feedback improved significantly in all 4926 consecutive PCI-treated patients - namely, the percentages of patients with pre-hospital electrocardiogram (ECG) recordings (83.3% vs 97.1%, < 0.0001) and ECG recordings within 10 minutes after first medical contact (41.7% vs 63.8%, < 0.0001), pre-announcement by telephone (77.0% vs 85.4%, = 0.0007), direct transfer to the catheterization laboratory bypassing the emergency department (29.4% vs 64.2%, < 0.0001), and contact-to-balloon times of less than 90 minutes (37.2% vs 53.7%, < 0.0001). Moreover, this feedback-related continuous improvement of key-quality indicators was linked to a significant reduction in in-hospital mortality from 10.8% to 6.8% ( = 0.0244). Logistic regression models confirmed an independent beneficial effect of duration of study participation on hospital mortality (odds ratio = 0.986, 95% confidence interval = 0.976-0.996, = 0.0087). In contrast, data from a nationwide PCI registry showed a continuous increase in in-hospital mortality in all PCI-treated STEMI patients in Germany from 2008 to 2015 ( = 398,027; 6.7% to 9.2%, < 0.0001).

Conclusions: Our results indicate that systematic data assessment and regular feedback is a feasible long-term strategy and may be linked to improved performance and a reduction in mortality in STEMI management.
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http://dx.doi.org/10.1177/2048872620907323DOI Listing
July 2020

The oral Ca/calmodulin-dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure.

ESC Heart Fail 2020 10 20;7(5):2871-2883. Epub 2020 Jul 20.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

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 available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC).

Methods And Results: In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 ± 3.7% (RA608) vs. 34.9 ± 2.6% (vehicle), n = 9 vs. n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKIIδ transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608, P < 0.05, 'n - 1' χ test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608, P < 0.05, 'n - 1' χ test.

Conclusions: RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in mice in vivo.
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http://dx.doi.org/10.1002/ehf2.12895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524064PMC
October 2020

Dysferlin links excitation-contraction coupling to structure and maintenance of the cardiac transverse-axial tubule system.

Europace 2020 07;22(7):1119-1131

Department of Child and Adolescent Health, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.

Aims: The multi-C2 domain protein dysferlin localizes to the T-Tubule system of skeletal and heart muscles. In skeletal muscle, dysferlin is known to play a role in membrane repair and in T-tubule biogenesis and maintenance. Dysferlin deficiency manifests as muscular dystrophy of proximal and distal muscles. Cardiomyopathies have been also reported, and some dysferlinopathy mouse models develop cardiac dysfunction under stress. Generally, the role and functional relevance of dysferlin in the heart is not clear. The aim of this study was to analyse the effect of dysferlin deficiency on the transverse-axial tubule system (TATS) structure and on Ca2+ homeostasis in the heart.

Methods And Results: We studied dysferlin localization in rat and mouse cardiomyocytes by immunofluorescence microscopy. In dysferlin-deficient ventricular mouse cardiomyocytes, we analysed the TATS by live staining and assessed Ca2+ handling by patch-clamp experiments and measurement of Ca2+ transients and Ca2+ sparks. We found increasing co-localization of dysferlin with the L-type Ca2+-channel during TATS development and show that dysferlin deficiency leads to pathological loss of transversal and increase in longitudinal elements (axialization). We detected reduced L-type Ca2+-current (ICa,L) in cardiomyocytes from dysferlin-deficient mice and increased frequency of spontaneous sarcoplasmic reticulum Ca2+ release events resulting in pro-arrhythmic contractions. Moreover, cardiomyocytes from dysferlin-deficient mice showed an impaired response to β-adrenergic receptor stimulation.

Conclusions: Dysferlin is required for TATS biogenesis and maintenance in the heart by controlling the ratio of transversal and axial membrane elements. Absence of dysferlin leads to defects in Ca2+ homeostasis which may contribute to contractile heart dysfunction in dysferlinopathy patients.
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http://dx.doi.org/10.1093/europace/euaa093DOI Listing
July 2020

Alterations of the renin angiotensin system in human end-stage heart failure before and after mechanical cardiac unloading by LVAD support.

Mol Cell Biochem 2020 Sep 20;472(1-2):79-94. Epub 2020 Jun 20.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Heart transplantation is often an unrealizable therapeutic option for end-stage heart failure, which is why mechanical left ventricular assist devices (LVADs) become an increasingly important therapeutic alternative. Currently, there is a lack of information about molecular mechanisms which are influenced by LVADs, particularly regarding the pathophysiologically critical renin angiotensin system (RAS). We, therefore, determined regulation patterns of key components of the RAS and the β-arrestin signaling pathways in left ventricular (LV) tissue specimens from 8 patients with end-stage ischemic cardiomyopathy (ICM) and 12 patients with terminal dilated cardiomyopathy (DCM) before and after LVAD implantation and compared them with non-failing (NF) left ventricular tissue samples: AT1R, AT2R, ACE, ACE2, MasR, and ADAM17 were analyzed by polymerase chain reaction. ERK, phosphorylated ERK, p38, phosphorylated p38, JNK, phosphorylated JNK, GRK2, β-arrestin 2, PI3K, Akt, and phosphorylated Akt were determined by Western blot analysis. Angiotensin I and Angiotensin II were quantified by mass spectrometry. Patients were predominantly middle-aged (53 ± 10 years) men with severely impaired LV function (LVEF 19 ± 8%), when receiving LVAD therapy for a mean duration of 331 ± 317 days. Baseline characteristics did not differ significantly between ICM and DCM patients. By comparing failing with non-failing left ventricles, i.e., before LVAD implantation, a downregulation of AT1R, AT2R, and MasR and an upregulation of ACE, ACE2, GRK, β-arrestin, ERK, PI3K, and Akt were seen. Following LVAD support, then angiotensin I, ACE2, GRK, and β-arrestin were downregulated and AT2R, JNK, and p38 were upregulated. ACE, angiotensin II, AT1R, ADAM17, MasR, ERK, PI3K, and Akt remained unchanged. Some regulation patterns were influenced by the underlying etiology of heart failure, the severity of LV dysfunction at baseline, and the duration of LVAD therapy. Key components of the RAS and β-arrestin signaling pathways were divergently altered in failing left ventricles both before and after LVAD implantation, whereas a remarkable fraction remained unchanged. This indicates a rather incomplete molecular reverse remodeling, whose functional relevance has to be further evaluated.
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http://dx.doi.org/10.1007/s11010-020-03787-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431447PMC
September 2020