Publications by authors named "Karl-Ludwig Laugwitz"

287 Publications

Subphenotyping of Patients With Aortic Stenosis by Unsupervised Agglomerative Clustering of Echocardiographic and Hemodynamic Data.

JACC Cardiovasc Interv 2021 Oct;14(19):2127-2140

Department of Cardiology, Deutsches Herzzentrum München, Technical University of Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

Objectives: The aim of this retrospective analysis was to categorize patients with severe aortic stenosis (AS) according to clinical presentation by applying unsupervised machine learning.

Background: Patients with severe AS present with heterogeneous clinical phenotypes, depending on disease progression and comorbidities.

Methods: Unsupervised agglomerative clustering was applied to preprocedural data from echocardiography and right heart catheterization from 366 consecutively enrolled patients undergoing transcatheter aortic valve replacement for severe AS.

Results: Cluster analysis revealed 4 distinct phenotypes. Patients in cluster 1 (n = 164 [44.8%]), serving as a reference, presented with regular cardiac function and without pulmonary hypertension (PH). Accordingly, estimated 2-year survival was 90.6% (95% CI: 85.8%-95.6%). Clusters 2 (n = 66 [18.0%]) and 4 (n = 91 [24.9%]) both comprised patients with postcapillary PH. Yet patients in cluster 2 with preserved left and right ventricular structure and function showed a similar survival as those in cluster 1 (2-year survival 85.8%; 95% CI: 76.9%-95.6%), whereas patients in cluster 4 with dilatation of all heart chambers and a high prevalence of mitral and tricuspid regurgitation (12.5% and 14.8%, respectively) died more often (2-year survival 74.9% [95% CI: 65.9%-85.2%]; HR for 2-year mortality: 2.8 [95% CI: 1.4-5.5]). Patients in cluster 3, the smallest (n = 45 [12.3%]), displayed the most extensive disease characteristics (ie, left and right heart dysfunction together with combined pre- and postcapillary PH), and 2-year survival was accordingly reduced (77.3% [95% CI: 65.2%-91.6%]; HR for 2-year mortality: 2.6 [95% CI: 1.1-6.2]).

Conclusions: Unsupervised machine learning aids in capturing complex clinical presentations as observed in patients with severe AS. Importantly, structural alterations in left and right heart morphology, possibly due to genetic predisposition, constitute an equally sensitive indicator of poor prognosis compared with high-grade PH.
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http://dx.doi.org/10.1016/j.jcin.2021.08.034DOI Listing
October 2021

Prognostic value of haemoglobin drop in patients with acute coronary syndromes.

Eur J Clin Invest 2021 Sep 20:e13670. Epub 2021 Sep 20.

Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

Background: The prognostic value of in-hospital haemoglobin drop in patients with acute coronary syndrome (ACS) undergoing invasive therapy remains insufficiently investigated.

Materials And Methods: This observational study included 3838 patients with ACS with admission and in-hospital nadir haemoglobin values available. Haemoglobin drop was defined as a positive difference between admission and nadir haemoglobin values. The primary endpoint was one-year all-cause mortality.

Results: In-hospital haemoglobin drop occurred in 3142 patients (82%). Patients were categorized into 4 groups: no haemoglobin drop (n = 696 patients), <3 g/dl haemoglobin drop (n = 2703 patients), 3 to <5 g/dl haemoglobin drop (n = 344 patients) and ≥5 g/dl haemoglobin drop (n = 95 patients). The primary endpoint occurred in 156 patients: 17 patients (2.5%) in the group with no haemoglobin drop, 81 patients (3.0%) in the group with <3g/dl haemoglobin drop, 37 patients (10.9%) in the group with 3 to <5 g/dl haemoglobin drop and 21 patients (22.2%) in the group with ≥5 g/dl haemoglobin (adjusted hazard ratio [HR] = 1.30, 95% confidence interval 1.17 to 1.45; p < .001 for one g/dl haemoglobin drop). The association of haemoglobin drop with one-year mortality remained significant after exclusion of patients with in-hospital overt bleeding (adjusted HR = 1.27 [1.11-1.46]; p < .001 for one g/dl haemoglobin drop). The lowest haemoglobin drop associated with mortality was 1.23 g/dl in all patients (HR = 1.03 [1.02-1.04]) and 1.13 g/dl in patients without overt bleeding (HR = 1.03 [1.01-1.04]).

Conclusions: In patients with ACS, in-hospital haemoglobin drop was associated with higher risk of one-year mortality even in the absence of overt bleeding.
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http://dx.doi.org/10.1111/eci.13670DOI Listing
September 2021

Prognostic value of glomerular function estimated by Cockcroft-Gault creatinine clearance, MDRD-4, CKD-EPI and European Kidney Function Consortium equations in patients with acute coronary syndromes.

Clin Chim Acta 2021 Sep 13;523:106-113. Epub 2021 Sep 13.

Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Germany.

Background: It remains unknown which equation used to assess the glomerular function is better for risk stratification in patients with acute coronary syndrome (ACS).

Methods: This study included 3985 patients with ACS. Glomerular function was assessed using 4 equations: the Cockcroft-Gault creatinine clearance (C-G), Modification of Diet in Renal Disease-4 (MDRD-4), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) equations. The primary outcome was one-year all-cause mortality.

Results: For each 30 ml/min decrement, the adjusted hazard ratio [HR] with 95% confidence interval [CI] for one-year mortality was 1.67 [1.27-2.25] for C-G, 1.45 [1.16-1.81] for MDRD-4, 1.76 [1.35-2.30] for CKD-EPI and 1.94 [1.44-2.63] for EKFC equation. Area under the receiver operating characteristic curve (AUC) for one-year mortality was 0.748 [0.709-0.788] for C-G, 0.670 [0.621-0.718] for estimated glomerular filtration rate (eGFR) calculated by MDRD-4 equation, 0.725 [0.684-0.765] for eGFR calculated by CKD-EPI equation and 0.741 [0.703-0.779] for eGFR calculated by EKFC equation (P = 0.342 for C-G, vs. EKFC equation and P ≤ 0.009 for all other AUC comparisons).

Conclusions: In patients with ACS, C-G and EKFC equations showed a similar discriminatory power regarding prediction of one-year mortality. Both equations were better than MDRD-4 and CKD-EPI equations for risk discrimination for mortality.

Clinical Trial Registration: NCT01944800.
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http://dx.doi.org/10.1016/j.cca.2021.09.007DOI Listing
September 2021

Long-term clinical outcomes after drug eluting stent implantation with and without stent overlap.

Catheter Cardiovasc Interv 2021 Sep 6. Epub 2021 Sep 6.

Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

Objective: The aim of this study was to investigate the impact of drug eluting stent (DES) overlap on clinical outcomes after percutaneous coronary intervention (PCI).

Background: While the use of overlapping bare metal stent has been associated with an increased risk of adverse clinical events, the long-term impact of DES overlap on clinical outcomes is not certain at present. Similarly, the effect of different DES generations and polymer types on DES overlap associated clinical outcomes has not previously been comprehensively elucidated.

Methods: We analyzed the angiographic and clinical outcomes of 5605 patients treated with DES in the setting of the ISAR-TEST 4 and ISAR-TEST 5 randomized control trials according to the presence or absence of stent overlap. The clinical endpoints assessed in this study were all-cause death, myocardial infarction (MI), target lesion revascularization (TLR), and definite or probable stent thrombosis at 10-years. We also compared rates of binary angiographic restenosis (BAR) at 6-8 months.

Results: At 10 years, all-cause mortality (Hazard ratios [HR] = 1.05 [0.95-1.16]; p = 0.348) did not differ between the stent overlap and no stent overlap groups. MI (8.4% vs. 5.2%; HR = 1.67 [1.35-2.07], p < 0.001) and TLR (23.7% vs. 16.3%; HR = 1.54 [1.36-1.74], p < 0.001) occurred more frequently in the stent overlap group. For MI, landmark analysis demonstrated that this increase in risk was primarily in the first 30 days post PCI. BAR at 6-8 months was also more frequent in the stent overlap group (16.0% vs. 10.3%; HR = 1.65 [1.41-1.92], p < 0.001).

Conclusion: DES overlap is associated with an increased risk of adverse clinical events post PCI.
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http://dx.doi.org/10.1002/ccd.29944DOI Listing
September 2021

Twelve-month clinical outcomes in patients with acute coronary syndrome undergoing complex percutaneous coronary intervention: insights from the ISAR-REACT 5 trial.

Eur Heart J Acute Cardiovasc Care 2021 Sep 1. Epub 2021 Sep 1.

Klinik für Herz-und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.

Aims: Complex percutaneous coronary intervention (PCI) is associated with a higher risk of ischaemic events. However, no study has analysed the effect of PCI complexity on outcomes in a contemporary cohort of acute coronary syndrome (ACS) patients treated with a dual anti-platelet therapy regimen based on potent P2Y12-inhibitors. Therefore, we performed the current analysis.

Methods And Results: This analysis included all ACS patients treated with PCI in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial. Complex PCI was defined as at least one of: multi-vessel PCI, ≥3 stents implanted, ≥3 lesions treated, and total stented length >60 mm. The primary endpoint was the composite of all-cause death, myocardial infarction (MI), or stroke at 12 months; the safety endpoint was Bleeding Academic Research Consortium types 3-5 bleeding at 12 months. Overall, 3377 patients were included in this analysis (complex PCI, n = 1429; non-complex PCI, n = 1948). The primary endpoint occurred more frequently in the complex PCI group than the non-complex PCI group [10.1% vs. 7.2%, hazard ratio (HR): 1.44, 95% confidence interval (CI) (1.14-1.82), P = 0.002], driven primarily by a higher risk of MI [HR: 1.62, (1.17-2.26), P = 0.004]. The safety endpoint was not statistically different between patients undergoing complex vs. non-complex PCI, although it was numerically higher in the complex PCI group [6.7% vs. 5.3%, HR: 1.28, (0.97-1.70), P = 0.08].

Conclusions: Acute coronary syndrome patients undergoing complex PCI have an increased incidence of ischaemic events compared with ACS patients undergoing non-complex PCI.

Clinical Trial Registration: NCT01944800, Prospective, Randomized Trial of Ticagrelor Vs. Prasugrel in Patients With Acute Coronary Syndrome-Full-Text View-ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01944800.
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http://dx.doi.org/10.1093/ehjacc/zuab077DOI Listing
September 2021

Ticagrelor or Prasugrel in Patients With Acute Coronary Syndrome in Relation to Estimated Glomerular Filtration Rate.

JACC Cardiovasc Interv 2021 Sep 23;14(17):1857-1866. Epub 2021 Aug 23.

Deutsches Herzzentrum München, Cardiology, and Technische Universität München, Munich, Germany.

Objectives: The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs).

Background: The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined.

Methods: Patients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m), intermediate eGFR (≥60 and <90 mL/min/1.73 m), and high eGFR (≥90 mL/min/1.73 m). The primary endpoint was a composite of all-cause death, myocardial infarction, and stroke; the secondary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding, both at 1 year.

Results: Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding.

Conclusions: These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800).
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http://dx.doi.org/10.1016/j.jcin.2021.06.028DOI Listing
September 2021

Optical coherence tomography tissue coverage and characterization at six months after implantation of bioresorbable scaffolds versus conventional everolimus eluting stents in the ISAR-Absorb MI trial.

Int J Cardiovasc Imaging 2021 Oct 21;37(10):2815-2826. Epub 2021 Aug 21.

Cardiovascular Research Institute Dublin, Mater Private Network, Dublin, Ireland.

Purpose: Data regarding vessel healing by optical coherence tomography (OCT) after everolimus-eluting bioresorbable scaffolds (BRS) or everolimus-eluting metallic stent (EES) implantation in acute myocardial infarction (AMI) patients is scarce. We compared OCT findings after BRS or EES implantation in patients with AMI enrolled in a randomized trial.

Methods: In ISAR-Absorb MI, AMI patients were randomized to BRS or EES implantation, with 6-8 month angiographic follow-up. This analysis includes patients who underwent OCT during surveillance angiography. Tissue characterization was done using grey-scale signal intensity analysis. The association between OCT findings and target lesion failure (TLF) at 2 years was investigated.

Results: OCT was analyzed in 103 patients (2237 frames, 19,827 struts) at a median of 216 days post-implantation. Of these, 70 were treated with BRS versus 32 with EES. Pre-(92.8 vs. 68.7%, p = 0.002) and post-dilation (51.4 vs. 12.5%, p < 0.001) were more common in BRS as compared to EES. Strut coverage was higher in BRS vs. EES (97.5% vs. 90.9%, p < 0.001). Mean neointimal thickness was comparable in both groups [85.5 (61.9, 124.1) vs. 69.5 (32.7, 127.5) µm, respectively, p = 0.20]. Mature neointimal regions were numerically more common in BRS (43.0% vs. 24.6%; p = 0.35); this difference was statistically significant in ST-elevation myocardial infarction patients (40.9% vs. 21.1%, p = 0.03). At two-years, 8 (7.8%) patients experienced TLF. Mean neointimal area [0.61 (0.21, 1.33) vs. 0.41 (0.11, 0.75) mm, p = 0.03] and mean neointimal coverage [106.1 (65.2, 214.8) vs. 80.5 (53.5, 122.1) µm, p < 0.01] were higher, with comparable tissue maturity, in lesions with versus without TLF.

Conclusions: In selected patients who underwent OCT surveillance 6-8 months after coronary intervention for AMI with differing implantation characteristics depending on the device type used, vessel healing was more advanced in BRS compared with EES, particularly in the STEMI subgroup.
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http://dx.doi.org/10.1007/s10554-021-02251-xDOI Listing
October 2021

Platelet Surface Protein Expression and Reactivity upon TRAP Stimulation after BNT162b2 Vaccination.

Thromb Haemost 2021 Aug 13. Epub 2021 Aug 13.

Department of Internal Medicine I, School of Medicine, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a coagulopathy characterized by platelet activation and a hypercoagulable state with an increased incidence of cardiovascular events. The viral spike protein S has been reported to enhance thrombosis formation, stimulate platelets to release procoagulant factors, and promote the formation of platelet-leukocyte aggregates even in absence of the virus. Although SARS-CoV-2 vaccines induce spike protein overexpression to trigger SARS-CoV-2-specific immune protection, thrombocyte activity has not been investigated in this context. Here, we provide the first phenotypic platelet characterization of healthy human subjects undergoing BNT162b2 vaccination. Using mass cytometry, we analyzed the expression of constitutive transmembrane receptors, adhesion proteins, and platelet activation markers in 12 healthy donors before and at five different time points within 4 weeks after the first BNT162b2 administration. We measured platelet reactivity by stimulating thrombocyte activation with thrombin receptor-activating peptide. Activation marker expression (P-selectin, LAMP-3, LAMP-1, CD40L, and PAC-1) did not change after vaccination. All investigated constitutive transmembrane proteins showed similar expressions over time. Platelet reactivity was not altered after BNT162b2 administration. Activation marker expression was significantly lower compared with an independent cohort of mild symptomatic COVID-19 patients analyzed with the same platform. This study reveals that BNT162b2 administration does not alter platelet protein expression and reactivity.
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http://dx.doi.org/10.1055/s-0041-1733934DOI Listing
August 2021

Early Bronchoscopy Improves Extubation Rates after Out-of-Hospital Cardiac Arrest: A Retrospective Cohort Analysis.

J Clin Med 2021 Jul 9;10(14). Epub 2021 Jul 9.

Department of Internal Medicine I, School of Medicine & Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.

Background: Patients suffering from out-of-hospital cardiac arrest (OHCA) frequently receive a bronchoscopy after being admitted to the ICU. We investigated the optimal timing and the outcome in these patients.

Methods: All patients who suffered from OHCA and were treated in our ICU from January 2013 to December 2018 were retrospectively analyzed. The data were collected from the patients' medical files, and included duration of mechanical ventilation, antibiotics, microbiological test results and neurological outcome. The outcome was the effect of early bronchoscopy (≤48 h after administration) on the rate of intubated patients on day five and day seven.

Results: From January 2013 to December 2018, 190 patients were admitted with OHCA. Bronchoscopy was performed in 111 patients out of the 164 patients who survived the first day. Late bronchoscopy >48 h was associated with higher rates of intubation on day five (OR 4.94; 95% CI 1.2-36.72, 86.7% vs. 55.0%, = 0.036) and day seven (OR 4.96; 95% CI 1.38-24.69; 80.0% vs. 43.3%, = 0.019).

Conclusion: This study shows that patients who suffered from OHCA might have a better outcome if they receive a bronchoscopy early after hospital admission. Our data suggests an association of early bronchoscopy with a shorter intubation period.
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http://dx.doi.org/10.3390/jcm10143055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306153PMC
July 2021

Ticagrelor or Prasugrel for Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention: A Prespecified Subgroup Analysis of a Randomized Clinical Trial.

JAMA Cardiol 2021 Oct;6(10):1121-1129

Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

Importance: It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI).

Objective: To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI.

Design, Setting, And Participants: A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle.

Interventions: Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization.

Main Outcomes And Measures: The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding.

Results: The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78; P = .005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34; P = .003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50; P = .54).

Conclusions And Relevance: Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings.

Trial Registration: ClinicalTrials.gov Identifier: NCT01944800.
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http://dx.doi.org/10.1001/jamacardio.2021.2228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246339PMC
October 2021

Comparison of Vascular Closure Devices vs Manual Compression After Femoral Artery Puncture in Patients on Oral Anticoagulation - Post Hoc Analysis of the ISAR-CLOSURE Trial.

J Invasive Cardiol 2021 Sep 25;33(9):E709-E715. Epub 2021 Jun 25.

Klinik fuer Herz- und Kreislauferkrankungen, Deutsches Herzzentrum Muenchen, Lazarettstr. 36, 80363 Muenchen, Germany.

Objectives: To compare vascular closure devices (VCD) with manual compression (MC) in patients on chronic oral anticoagulation (OAC) who undergo diagnostic coronary angiography in terms of vascular access-site complications.

Methods: This is a subanalysis of 604 patients that had undergone transfemoral diagnostic coronary angiography and were randomly assigned to arteriotomy closure with either VCDs (intravascular FemoSeal VCD or extravascular EXOSEAL VCD) or MC within the large scale, randomized ISAR-CLOSURE trial. Primary endpoint was the composite of access-site-related vascular complications at 30 days. Secondary endpoints were time to hemostasis and repeat MC.

Results: Vascular access-site complications were similar in patients assigned to VCDs compared to MC (8.2% vs 10.6%; P=.33). There was no interaction of treatment effect and OAC (P interaction = 0.59). Rates of pseudoaneurysms were lower with VCDs (0.8% vs 3.2%; P=.02). Time to hemostasis was significantly shortened with VCDs compared to MC (1 [IQR 0.5-2.0] min vs 12 [IQR 10-15] min; P<.001). There was no difference regarding repeat MC in both groups (VCD 1.5% vs MC 0.5%; P=.23). Time to hemostasis (0.5 [0.2-1.0] min, vs 2.0 [1.75-2.0] min; P<.001) and closure device failure (3.7% vs 17.2%; P<.001) were lower with the intravascular VCD, compared with the extravascular VCD.

Conclusions: In patients on chronic OAC undergoing transfemoral diagnostic coronary angiography, the use of VCDs was comparable to MC regarding the primary combined endpoint of vascular access-site related complications. VCDs reduced the occurrence of pseudoaneurysms and time to hemostasis.
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September 2021

Ten-year clinical outcomes of polymer-free versus durable polymer new-generation drug-eluting stent in patients with coronary artery disease with and without diabetes mellitus : Results of the Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol- and Zotarolimus-Eluting Stents (ISAR-TEST 5) trial.

Clin Res Cardiol 2021 Oct 22;110(10):1586-1598. Epub 2021 Jun 22.

Deutsches Herzzentrum München, Klinik Für Herz- Und Kreislauferkrankungen, an der Technischen Universität München, Lazarettstrasse 36, 80636, Munich, Germany.

Background: Very long-term outcomes according to diabetic status of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES) are scant. Both, the durable polymer zotarolimus-eluting stent (DP-ZES), the first DES to gain FDA-approval for specific use in patients with diabetes mellitus, and the polymer-free sirolimus- and probucol-eluting stent (PF-SES), with a unique design that enables effective drug release without the need of a polymer offer the potential to enhance clinical long-term outcomes especially in patients with diabetes mellitus.

Methods: We investigate 10-year clinical outcomes of the prespecified subgroups of patients with and without diabetes mellitus, randomly assigned to treatment with PF-SES versus DP-ZES in the ISAR-TEST 5 trial. The primary endpoint of interest was major adverse cardiac events (MACE), defined as the composite of all-cause death, any myocardial infarction or any revascularization. Further endpoints of interest were cardiac death, myocardial infarction related to the target vessel and target lesion revascularization as well as the individual components of the primary composite endpoint and the incidence of definite or probable stent thrombosis at 10 years.

Results: This analysis includes a total of 3002 patients randomly assigned to PF-SES (n = 2002) or DP-ZES (n = 1000). Prevalence of diabetes mellitus was high and comparable, 575 Patients (28.7%) in PF-SES group and 295 patients (29.5%) in DP-ZES group (P = 0.66). At 10 years 53.5% of patients with diabetes mellitus and 68.5% of patients without diabetes mellitus were alive. Regarding major adverse cardiac events, PF-SES as compared to DP-ZES showed comparable event rates in patients with diabetes mellitus (74.8% vs. 79.6%; hazard ratio 0.86; 95% CI 0.73-1.02; P = 0.08) and in patients without diabetes (PF-SES 62.5% vs. DP-ZES 62.2%; hazard ratio 0.99; 95% CI 0.88-1.11; P = 0.88).

Conclusion: At 10 years, both new-generation DES show comparable clinical outcome irrespective of diabetic status or polymer strategy. Event rates after PCI in patients with diabetes mellitus are considerable higher than in patients without diabetes mellitus and continue to accrue over time.

Trial Registration: ClinicalTrials.gov, NCT00598533, Registered 10 January 2008, https://clinicaltrials.gov/ct2/show/NCT00598533?term=NCT00598533 Kaplan-Meier estimates of endpoints of interest for patients with vs. without diabetes mellitus treated with PF-SES vs. DP-ZES. Bar graphs: Kaplan-Meier estimates as percentages. PF-SES: polymer-free sirolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; DM: diabetes mellitus. Comparison of event rates of individual endpoints in patients with and without diabetes mellitus treated with PF-SES vs. DP-ZES all without statistically significant differences. Comparison of event rates of individual endpoints in overall patients with vs. without diabetes mellitus significantly different (P ≤ 0.01 for all comparisons).
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http://dx.doi.org/10.1007/s00392-021-01854-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484170PMC
October 2021

Accuracy of high-sensitive troponin depending on renal function for clinical outcome prediction in patients with acute heart failure.

Heart Vessels 2021 Jun 21. Epub 2021 Jun 21.

Klinik Und Poliklinik Für Innere Medizin I, Klinikum Rechts Der Isar, Technical University of Munich, Munich, Germany.

High-sensitive troponin T (hs-TnT) is increasingly used for clinical outcome prediction in patients with acute heart failure (AHF). However, there is an ongoing debate regarding the potential impact of renal function on the prognostic accuracy of hs-TnT in this setting. The aim of the present study was to assess the prognostic value of hs-TnT within 6 h of admission for the prediction of 30-day mortality depending on renal function in patients with AHF. Patients admitted to our institution due to AHF were retrospectively included. Clinical information was gathered from electronic and paper-based patient charts. Patients with myocardial infarction were excluded. A total of 971 patients were enrolled in the present study. A negative correlation between estimated glomerular filtration rate (eGFR) and hsTnT was identified (Pearson r = - 0.16; p < 0.001) and eGFR was the only variable to be independently associated with hsTnT. The area under the curve (AUC) of hs-TnT for the prediction of 30-mortality was significantly higher in patients with an eGFR ≥ 45 ml/min (AUC 0.74) compared to those with an eGFR < 45 ml/min (AUC 0.63; p = 0.049). Sensitivity and specificity of the Youden Index derived optimal cut-off for hs-TnT was higher in patients with an eGFR ≥ 45 ml/min (40 ng/l: sensitivity 73%, specificity 71%) compared to patients with an eGFR < 45 ml/min (55 ng/l: sensitivity 63%, specificity 62%). Prognostic accuracy of hs-TnT in patients hospitalized for AHF regarding 30-day mortality is significantly lower in patients with reduced renal function.
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http://dx.doi.org/10.1007/s00380-021-01890-3DOI Listing
June 2021

Human BIN1 isoforms grow, maintain and regenerate excitation-contraction couplons in adult rat and human stem cell-derived cardiomyocytes.

Cardiovasc Res 2021 Jun 21. Epub 2021 Jun 21.

Molecular Cell Biology, Centre for Molecular Signaling (PZMS), Medical Faculty, Saarland University, 66421, Homburg, Germany.

Aims: In ventricular myocytes, Transverse-tubules (T-tubules) are instrumental for excitation-contraction (EC) coupling and their disarray is a hallmark of cardiac diseases. BIN1 is a key contributor to their biogenesis. Our study set out to investigate the role of human BIN1 splice variants in the maintenance and regeneration of EC-coupling in rat adult ventricular myocytes and human induced pluripotent stem cell-derived cardiac myocytes (hiPS-CMs).

Methods And Results: In heart samples from healthy human donors expression patterns of 5 BIN1 splice variants were identified. Following viral transduction of human BIN1 splice variants in cellular models of T-tubular disarray we employed high-speed confocal calcium imaging and Ca-CLEAN analysis to identify functional EC-coupling sites and T-tubular architecture. Adult rat ventricular myocytes were used to investigate the regeneration after loss and maintenance of EC-coupling while we studied the enhancement of EC-coupling in hiPS-CMs. All five human BIN1 splice variants induced de novo generation of T-tubules in both cell types. Isoforms with the phosphoinositide binding motif (PI) were most potent in maintenance and regeneration of T-tubules and functional EC-coupling in adult rat myocytes. In hiPSC-CMs, BIN1 variants with PI motiv induced de-novo generation of T-tubules, functional EC-coupling sites and enhanced calcium handling.

Conclusion(s): BIN1 is essential for the maintenance, regeneration, and de-novo generation of functional T-tubules, especially isoforms with PI motifs. These T-tubules trigger the development of functional EC couplons resulting in enhanced calcium handling.

Translational Perspective: Cardiomyopathy and heart failure are among the most frequent causes of death in modern societies. Gene therapies and hiPSC technology are becoming increasingly promising, both for treatment and therapy development. On the cellular level, one of the common denominators of cardiac diseases is the concurrent loss of T-tubules essential for efficient EC-coupling. While initial approaches in animal models employing gene therapy with BIN1 have depicted encouraging improvements the expression pattern of BIN1 isoforms in the human heart is still elusive. The present study identifies a unique set of five distinct BIN1 isoforms in healthy human hearts and demonstrates their potency in both, T-tubule maintenance and re-generation after loss resulting in efficient EC-coupling. Noteworthy, PI-motif containing isoforms were potent trigger of de-novo generation of T-tubules and establishment of efficient EC-coupling in hiPSC-CMs. Therefore, the expression of BIN1 might be novel and promising for pharmaceutical treatment and gene therapy.
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http://dx.doi.org/10.1093/cvr/cvab195DOI Listing
June 2021

Efficacy and safety of ticagrelor versus prasugrel in smokers and nonsmokers with acute coronary syndromes.

Int J Cardiol 2021 09 11;338:8-13. Epub 2021 Jun 11.

Deutsches Herzzentrum München, Technische Universität München, Germany. Electronic address:

Background: The efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with acute coronary syndromes (ACS) are not known. We assessed the efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with ACS undergoing invasive management.

Methods: This pre-specified analysis of the ISAR-REACT 5 trial included 1349 smokers and 2652 nonsmokers randomized to receive ticagrelor or prasugrel. The primary endpoint was the incidence of death, myocardial infarction, or stroke; the secondary endpoint was the incidence of Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding (both endpoints assessed at 12 months).

Results: There was no significant treatment arm-by-smoking status interaction regarding the efficacy outcome. The primary endpoint occurred in 47 patients (7.0%) in the ticagrelor group and 41 patients (6.2%) in the prasugrel group in smokers (hazard ratio [HR] = 1.15; 95% confidence interval [CI] 0.76-1.75; P = 0.510) and in 133 patients (10.2%) in the ticagrelor group and 94 patients (7.2%) in the prasugrel group in nonsmokers (HR = 1.44 [1.10-1.87]; P = 0.007; P for interaction = 0.378). The secondary endpoint occurred in 27 patients (4.6%) in the ticagrelor group and 33 patients (5.6%) in the prasugrel group in smokers (HR = 0.81 [0.49-1.35]; P = 0.412) and in 66 patients (6.0%) in the ticagrelor group and 46 patients (4.4%) in the prasugrel group in nonsmokers (HR = 1.38 [0.94-2.01]; P = 0.097).

Conclusions: In patients with ACS undergoing an invasive management strategy, the smoking status did not significantly interact with the relative treatment effect of ticagrelor vs. prasugrel.

Clinical Trial Registration: NCT01944800.
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http://dx.doi.org/10.1016/j.ijcard.2021.06.011DOI Listing
September 2021

AntimiR-132 Attenuates Myocardial Hypertrophy in an Animal Model of Percutaneous Aortic Constriction.

J Am Coll Cardiol 2021 Jun;77(23):2923-2935

Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address:

Background: Pathological cardiac hypertrophy is a result of afterload-increasing pathologies including untreated hypertension and aortic stenosis. It features progressive adverse cardiac remodeling, myocardial dysfunction, capillary rarefaction, and interstitial fibrosis often leading to heart failure.

Objectives: This study aimed to establish a novel porcine model of pressure-overload-induced heart failure and to determine the effect of inhibition of microribonucleic acid 132 (miR-132) on heart failure development in this model.

Methods: This study developed a novel porcine model of percutaneous aortic constriction by implantation of a percutaneous reduction stent in the thoracic aorta, inducing progressive remodeling at day 56 (d56) after pressure-overload induction. In this study, an antisense oligonucleotide specifically inhibiting miR-132 (antimiR-132), was regionally applied via intracoronary injection at d0 (percutaneous transverse aortic constriction induction) and d28.

Results: At d56, antimiR-132 treatment diminished cardiomyocyte cross-sectional area (188.9 ± 2.8 vs. 258.4 ± 9.0 μm in untreated hypertrophic hearts) and improved global cardiac function (ejection fraction 48.9 ± 1.0% vs. 36.1 ± 1.7% in control hearts). Moreover, at d56 antimiR-132-treated hearts displayed less increase of interstitial fibrosis compared with sham-operated hearts (Δsham 1.8 ± 0.5%) than control hearts (Δsham 10.8 ± 0.6%). Of note, cardiac platelet and endothelial cell adhesion molecule 1 capillary density was higher in the antimiR-132-treated hearts (647 ± 20 cells/mm) compared with in the control group (485 ± 23 cells/mm).

Conclusions: The inhibition of miR-132 is a valid strategy in prevention of heart failure progression in hypertrophic heart disease and may be developed as a treatment for heart failure of nonischemic origin.
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http://dx.doi.org/10.1016/j.jacc.2021.04.028DOI Listing
June 2021

Ten-Year Clinical Outcomes of Biodegradable Versus Durable Polymer New-Generation Drug-Eluting Stent in Patients With Coronary Artery Disease With and Without Diabetes Mellitus.

J Am Heart Assoc 2021 06 2;10(12):e020165. Epub 2021 Jun 2.

Deutsches Herzzentrum Muenchen an der Technische Universität Muenchen Klinik für Herz- und Kreislauferkrankungen Munich Germany.

Background Extended long-term follow-up data of new-generation drug-eluting stents in patients with diabetes mellitus is scant. The aim of this study is to assess the 10-year clinical outcome of new-generation biodegradable polymer-based sirolimus-eluting stents (Yukon Choice PC) versus permanent polymer-based everolimus-eluting stents (XIENCE) in patients with and without diabetes mellitus. Methods and Results In a prespecified subgroup analysis, outcomes of patients with or without diabetes mellitus treated with drug-eluting stents were compared. The primary end point of this analysis was major adverse cardiac event, the composite of death, myocardial infarction, or target lesion revascularization. The analysis includes a total of 1951 patients (560 patients with and 1391 patients without diabetes mellitus) randomized to treatment with Yukon Choice PC (n=1299) or Xience (n=652). Regarding the primary end point, at 10 years patients with diabetes mellitus showed significantly higher major adverse cardiac event rates than patients without diabetes mellitus (<0.001; hazard ratio [HR], 1.41; 95% CI, 1.22-1.63). There was no significant difference between patients treated with Yukon Choice PC versus Xience, neither in the subgroup of patients with (=0.91; HR, 1.01; 95% CI, 0.79-1.30) nor without diabetes mellitus (=0.50; HR, 0.94; 95% CI, 0.79-1.21). Rates of definite/probable stent thrombosis were 2.3% in patients with and 1.9% in patients without diabetes mellitus (HR, 1.27; 95% CI, 0.34-2.60; =0.52), without significant differences between study devices. Conclusions The clinical outcome of patients with diabetes after percutaneous coronary intervention with different new-generation drug-eluting stents is considerably worse than that of patients without diabetes mellitus, with event rates constantly increasing out to 10 years. Registration URL: https://clinicaltrials.gov. Unique Identifier: NCT00598676.
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http://dx.doi.org/10.1161/JAHA.120.020165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477883PMC
June 2021

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Cardiovasc Res 2021 Apr 20. Epub 2021 Apr 20.

Estonian Genome Center, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.

Aims: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.

Methods And Results: We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio [OR]=1.37, p = 1.07 × 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 × 10-4), aortic stenosis (OR = 1.47, p = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.

Conclusions: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.

Translational Perspective: Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease.
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http://dx.doi.org/10.1093/cvr/cvab136DOI Listing
April 2021

Association between duration of drug-coated balloon inflation and efficacy in patients with drug-eluting stent restenosis.

Coron Artery Dis 2021 Apr 19. Epub 2021 Apr 19.

Deutsches Herzzentrum München, an der Technische Universität München Herzzentrum der Segeberger Kliniken Erste medizinisch Klinik, Bad Segeberg, Klinikum rechts der Isar, Technische Universität München DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich Universitäts-Herzzentrum Freiburg-Bad Krozingen, Germany.

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http://dx.doi.org/10.1097/MCA.0000000000001045DOI Listing
April 2021

Efficacy and Safety of Ticagrelor Versus Prasugrel in Women and Men with Acute Coronary Syndrome: A Pre-specified, Sex-Specific Analysis of the ISAR-REACT 5 Trial.

J Atheroscler Thromb 2021 Apr 16. Epub 2021 Apr 16.

Deutsches Herzzentrum München, Cardiology, and Technische Universität München.

Aim: Sex-specific analyses of direct head-to-head comparisons between newer P2Y inhibitors are limited. This study was conducted to assess the efficacy and safety of ticagrelor versus prasugrel in women and men with acute coronary syndromes (ACS) planned for an invasive strategy.

Methods: This pre-specified analysis of the ISAR-REACT 5 trial included 956 women and 3,062 men with ACS randomly assigned to either ticagrelor or prasugrel. The primary endpoint was the 12-month incidence of death, myocardial infarction, or stroke; the safety endpoint was the 12-month incidence of bleeding (type 3-5 according to the Bleeding Academic Research Consortium [BARC]).

Results: The primary endpoint occurred in 42 women (8.9%) in the ticagrelor group and 39 women (8.3%) in the prasugrel group (hazard ratio [HR]=1.10, 95% confidence interval [CI] 0.71-1.70, P=0.657) and in 142 men (9.4%) in the ticagrelor group and 98 men (6.5%) in the prasugrel group (HR=1.47 [1.13-1.90], P=0.004; P for interaction [P]=0.275). BARC type 3-5 bleeding occurred in 36 women (9.7%) in the ticagrelor group and 34 women (9.7%) in the prasugrel group (HR=1.04 [0.65-1.67], P=0.856) and in 59 men in the ticagrelor group (4.4%) and 46 men (3.6%) in the prasugrel group (HR=1.24 [0.85-1.83], P=0.266; P=0.571).

Conclusions: Although there was no significant interaction between sex and treatment effect of study drugs, the superior efficacy of prasugrel was more evident among men. No difference in bleeding between the two study groups was seen for both women and men.
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http://dx.doi.org/10.5551/jat.62776DOI Listing
April 2021

Imaging of cardiac fibroblast activation in a patient after acute myocardial infarction using Ga-FAPI-04.

J Nucl Cardiol 2021 Apr 15. Epub 2021 Apr 15.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.

Our previous study has demonstrated the feasibility of noninvasive imaging of fibroblast activation protein (FAP)-expression after myocardial infarction (MI) in MI-territory in a rat model with Ga-FAPI-04-PET. In the current extended clinical case, we sought to delineate cardiac uptake of Ga-FAPI-04 in a patient after MI with clinical indication for the evidence of fibroblast activation. Carcinoma patients without cardiac disease underwent Ga-FAPI-04-PET/CT as control. The patient with one-vessel disease underwent dynamic Ga-FAPI-04-cardiac-PET/CMR for 60 minutes. Correlation of cardiac Ga-FAPI-04 uptake with clinical findings, ECG, echocardiography, coronary-arteriography and enhanced cardiac-MRI with T1 MOLLI and ECV mapping were performed. No uptake was found in normal myocardium and in mature scar. A focal intense Ga-FAPI-04 uptake with continuous wash-out in the infarct territory of coronary occlusion correlating with T1 and ECV mapping was observed. The uptake of Ga-FAPI-04 extends beyond the actual infarcted area and overestimates the infarct size as confirmed by follow-up CMR.
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http://dx.doi.org/10.1007/s12350-021-02603-zDOI Listing
April 2021

Changes of Right Ventricular Function After Transcatheter Aortic Valve Replacement and Association With Outcomes.

J Card Fail 2021 Apr 8. Epub 2021 Apr 8.

Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany. Electronic address:

Background: Baseline right ventricular (RV) dysfunction represents a predictor for poor outcome in patients undergoing transcatheter aortic valve replacement (TAVR). However, RV function may improve after TAVR, which could have important implications on outcomes. The aim of the present study was to assess changes in RV function after TAVR and its prognostic value regarding clinical outcome.

Methods And Results: Patients undergoing TAVR at our institution were consecutively enrolled and categorized into 4 groups according to changes in RV function during echocardiographic follow-up at 6 months. A total of 188 patients were included. Of those showing normal function at baseline, 87% (130/149) had preserved RV function at follow-up (group 1), whereas 13% (19/149) developed new RV dysfunction (group 2). Of those with RV dysfunction at baseline (39 patients), RV function normalized in 46% (18/39) (group 3) and remained impaired in 54% (21/39) (group 4). The Kaplan-Meier estimated survival at 3 years was highest in patients in group 1 (83%), intermediate in group 2 (65%) and 3 (69%), whereas group 4 had the worst survival (37%; P < .001). Furthermore, new or persistent RV dysfunction was identified to be independently associated with mortality during follow-up (hazard ratio 2.55; interquartile range 1.03-6.47, P = .004).

Conclusions: Patients with preserved RV function have a high 3-year survival. Normalization of RV function showed improved survival compared with patients with persistent RV dysfunction, who had a dismal prognosis despite TAVR.
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http://dx.doi.org/10.1016/j.cardfail.2021.03.007DOI Listing
April 2021

Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial.

JAMA Cardiol 2021 Jul;6(7):753-761

Department of Cardiology, Medizinische Klinik und Poliklinik I, Munich University Clinic, Ludwig-Maximilian University of Munich, Munich, Germany.

Importance: The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant.

Objective: To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI.

Design, Setting, And Participants: A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI).

Interventions: Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy.

Main Outcomes And Measures: The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days.

Results: Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5'-diphosphate-induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36).

Conclusions And Relevance: Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms.

Trial Registration: ClinicalTrials.gov Identifier: NCT03312855.
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http://dx.doi.org/10.1001/jamacardio.2021.0475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014195PMC
July 2021

Deciphering the Role of Wnt and Rho Signaling Pathway in iPSC-Derived ARVC Cardiomyocytes by In Silico Mathematical Modeling.

Int J Mol Sci 2021 Feb 18;22(4). Epub 2021 Feb 18.

Department of Clinical and Experimental Medicine, Magna Græcia University, 88100 Catanzaro, Italy.

Arrhythmogenic Right Ventricular cardiomyopathy (ARVC) is an inherited cardiac muscle disease linked to genetic deficiency in components of the desmosomes. The disease is characterized by progressive fibro-fatty replacement of the right ventricle, which acts as a substrate for arrhythmias and sudden cardiac death. The molecular mechanisms underpinning ARVC are largely unknown. Here we propose a mathematical model for investigating the molecular dynamics underlying heart remodeling and the loss of cardiac myocytes identity during ARVC. Our methodology is based on three computational models: firstly, in the context of the Wnt pathway, we examined two different competition mechanisms between β-catenin and Plakoglobin (PG) and their role in the expression of adipogenic program. Secondly, we investigated the role of RhoA-ROCK pathway in ARVC pathogenesis, and thirdly we analyzed the interplay between Wnt and RhoA-ROCK pathways in the context of the ARVC phenotype. We conclude with the following remark: both Wnt/β-catenin and RhoA-ROCK pathways must be inactive for a significant increase of expression, suggesting that a crosstalk mechanism might be responsible for mediating ARVC pathogenesis.
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http://dx.doi.org/10.3390/ijms22042004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923182PMC
February 2021

Impact of sinus rhythm versus atrial fibrillation on left ventricular remodeling after transcatheter aortic valve replacement.

Clin Res Cardiol 2021 May 10;110(5):689-698. Epub 2021 Feb 10.

Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der isar, Technical University of Munich, Munich, Germany.

Aims: Atrial fibrillation (AF) is associated with increased mortality after transcatheter aortic valve replacement (TAVR). Cerebrovascular complications and bleeding events associated with anticoagulation therapy are discussed to be possible causes for this increased mortality. The present study sought to assess whether AF is associated with impaired left ventricular (LV) reverse remodeling representing another possible mechanism for poor outcome.

Methods: All patients who underwent TAVR in our institution and had 1-year echocardiography follow-up were included. LV mass index (LVMI) at baseline and follow-up as well as LVMI change at 1 year were assessed with respect to the presence of AF (either at baseline or during hospitalization after TAVR) and sinus rhythm (SR).

Results: A total of 213 patients (n = 95 in AF; n = 118 in SR) were enrolled in the present study. Patients with AF had higher LVMI at 1 year compared to those with SR (173 ± 61 g/m vs. 154 ± 55 g/m; p = 0.02) and they showed lower relative LVMI change at 1 year (- 2 ± 28% vs. - 9 ± 29%; p = 0.04). In linear regression analysis, AF was independently associated with relative LVMI change (regression coefficient ß 0.076 [95% CI 0.001-0.150]; p = 0.04). With respect to clinical outcome depending on AF and LVMI regression, the Kaplan-Meier estimated event-free of death or cardiac rehospitalization at 3 years was lowest among patients with AF and no LVMI regression.

Conclusions: The present study identified a significant association of AF with changes in LVMI after TAVR, which was also shown to be associated with clinical outcome.
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http://dx.doi.org/10.1007/s00392-021-01810-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099831PMC
May 2021

Effect of plasma exchange on colchicine elimination in overdose - a case report.

Clin Toxicol (Phila) 2021 09 8;59(9):849-850. Epub 2021 Feb 8.

Division of Clinical Toxicology, Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.1080/15563650.2021.1877298DOI Listing
September 2021

Nocturnal respiratory rate predicts ICD benefit: A prospective, controlled, multicentre cohort study.

EClinicalMedicine 2021 Jan 21;31:100695. Epub 2020 Dec 21.

Klinikum rechts der Isar, Medizinische Klinik und Poliklinik I, Technical University of Munich, Munich, Germany.

Background: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. ICD implantation decisions are currently based on reduced left ventricular ejection fraction (LVEF≤35%). However, in some patients, the non-arrhythmic death risk predominates thus diminishing ICD-therapy benefits. Based on previous observations, we tested the hypothesis that compared to the others, patients with nocturnal respiratory rate (NRR) ≥18 breaths per minute (brpm) benefit less from prophylactic ICD implantations.

Methods: This prospective cohort study was a pre-defined sub-study of EU-CERT-ICD trial conducted at 44 centers in 15 EU countries between May 12, 2014, and September 6, 2018. Patients with ischaemic or non-ischaemic cardiomyopathy were included if meeting primary prophylactic ICD implantation criteria. The primary endpoint was all-cause mortality. NRR was assessed blindly from pre-implantation 24-hour Holters. Multivariable models and propensity stratification evaluated the interaction between NRR and the ICD mortality effect. This study is registered with ClinicalTrials.gov (NCT0206419).

Findings: Of the 2,247 EU-CERT-ICD patients, this sub-study included 1,971 with complete records. In 1,363 patients (61.7 (12) years; 244 women) an ICD was implanted; 608 patients (63.2 (12) years; 108 women) were treated conservatively. During a median 2.5-year follow-up, 202 (14.8%) and 95 (15.6%) patients died in the ICD and control groups, respectively. NRR statistically significantly interacted with the ICD mortality effect ( = 0.0070). While the 1,316 patients with NRR<18 brpm showed a marked ICD benefit on mortality (adjusted HR 0.529 (95% CI 0.376-0.746);  = 0.0003), no treatment effect was demonstrated in 655 patients with NRR≥18 brpm (adjusted HR 0.981 (95% CI 0.669-1.438);  = 0.9202).

Interpretation: In the EU-CERT-ICD trial, patients with NRR≥18 brpm showed limited benefit from primary prophylactic ICD implantation. Those with NRR<18 brpm benefitted substantially.

Funding: European Community's 7th Framework Programme FP7/2007-2013 (602299).
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http://dx.doi.org/10.1016/j.eclinm.2020.100695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846675PMC
January 2021

Calcium scoring using virtual non-contrast images from a dual-layer spectral detector CT: comparison to true non-contrast data and evaluation of proportionality factor in a large patient collective.

Eur Radiol 2021 Aug 20;31(8):6193-6199. Epub 2021 Jan 20.

Department of Diagnostic and Interventional Radiology, School of Medicine & Klinikum rechts der Isar, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany.

Objective: Determination of coronary artery calcium scoring (CACS) in non-contrast computed tomography (CT) images has been shown to be an important prognostic factor in coronary artery disease (CAD). The objective of this study was to evaluate the accuracy of CACS from virtual non-contrast (VNC) imaging generated from spectral data in comparison to standard (true) non-contrast (TNC) imaging in a representative patient cohort with clinically approved software.

Methods: One hundred three patients referred to coronary CTA with suspicion of CAD were investigated on a dual-layer spectral detector CT (SDCT) scanner. CACS was calculated from both TNC and VNC images by software certified for medical use. Patients with a CACS of 0 were excluded from analysis.

Results: The mean age of the study population was 61 ± 11 years with 48 male patients (67%). Inter-quartile range of clinical CACS was 22-282. Correlation of measured CACS from true- and VNC images was high (0.95); p < 0.001. The slope was 3.83, indicating an underestimation of VNC CACS compared to TNC CACS by that factor. Visual analysis of the Bland-Altman plot of CACS showed good accordance with both methods after correction of VNC CACS by the abovementioned factor.

Conclusions: In clinical diagnostics of CAD, the determination of CACS is feasible using VNC images generated from spectral data obtained on a dual-layer spectral detector CT. When multiplied by a correction factor, results were in good agreement with the standard technique. This could enable radiation dose reductions by obviating the need for native scans typically used for CACS.

Key Points: • Calcium scoring is feasible from contrast-enhanced CT images using a dual-layer spectral detector CT scanner. • When multiplied by a correction factor, calcium scoring from virtual non-contrast images shows good agreement with the standard technique. • Omitting native scans for calcium scoring could enable radiation dose reduction.
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http://dx.doi.org/10.1007/s00330-020-07677-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270810PMC
August 2021

SARS-CoV-2 infection is associated with a pro-thrombotic platelet phenotype.

Cell Death Dis 2021 01 5;12(1):50. Epub 2021 Jan 5.

Department of Internal Medicine I, School of Medicine, University hospital rechts der Isar, Technical University of Munich, Munich, Germany.

Novel coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, characterized by abnormal coagulation parameters and by increased incidence of cardiovascular complications. With this study, we aimed to investigate the activation state and the expression of transmembrane proteins in platelets of hospitalized COVID-19 patients. We investigated transmembrane proteins expression with a customized mass cytometry panel of 21 antibodies. Platelets of 8 hospitalized COVID-19 patients not requiring intensive care support and without pre-existing conditions were compared to platelets of healthy controls (11 donors) with and without in vitro stimulation with thrombin receptor-activating peptide (TRAP). Mass cytometry of non-stimulated platelets detected an increased surface expression of activation markers P-Selectin (0.67 vs. 1.87 median signal intensity for controls vs. patients, p = 0.0015) and LAMP-3 (CD63, 0.37 vs. 0.81, p = 0.0004), the GPIIb/IIIa complex (4.58 vs. 5.03, p < 0.0001) and other adhesion molecules involved in platelet activation and platelet-leukocyte interactions. Upon TRAP stimulation, mass cytometry detected a higher expression of P-selectin in COVID-19 samples compared to controls (p < 0.0001). However, we observed a significantly reduced capacity of COVID-19 platelets to increase the expression of activation markers LAMP-3 and P-Selectin upon stimulation with TRAP. We detected a hyperactivated phenotype in platelets during SARS-CoV-2 infection, consisting of highly expressed platelet activation markers, which might contribute to the hypercoagulopathy observed in COVID-19. In addition, several transmembrane proteins were more highly expressed compared to healthy controls. These findings support research projects investigating antithrombotic and antiplatelet treatment regimes in COVID-19 patients, and provide new insights on the phenotypical platelet expression during SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41419-020-03333-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790351PMC
January 2021
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