Publications by authors named "Heribert Schunkert"

613 Publications

Risk Prediction of Cardiovascular Events by Exploration of Molecular Data with Explainable Artificial Intelligence.

Int J Mol Sci 2021 Sep 24;22(19). Epub 2021 Sep 24.

Department of Cardiology, Deutsches Herzzentrum München, Technical University Munich, Lazarettstrasse 36, 80636 Munich, Germany.

Cardiovascular diseases (CVD) annually take almost 18 million lives worldwide. Most lethal events occur months or years after the initial presentation. Indeed, many patients experience repeated complications or require multiple interventions (recurrent events). Apart from affecting the individual, this leads to high medical costs for society. Personalized treatment strategies aiming at prediction and prevention of recurrent events rely on early diagnosis and precise prognosis. Complementing the traditional environmental and clinical risk factors, multi-omics data provide a holistic view of the patient and disease progression, enabling studies to probe novel angles in risk stratification. Specifically, predictive molecular markers allow insights into regulatory networks, pathways, and mechanisms underlying disease. Moreover, artificial intelligence (AI) represents a powerful, yet adaptive, framework able to recognize complex patterns in large-scale clinical and molecular data with the potential to improve risk prediction. Here, we review the most recent advances in risk prediction of recurrent cardiovascular events, and discuss the value of molecular data and biomarkers for understanding patient risk in a systems biology context. Finally, we introduce explainable AI which may improve clinical decision systems by making predictions transparent to the medical practitioner.
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http://dx.doi.org/10.3390/ijms221910291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508897PMC
September 2021

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

Impact of Tele-Coaching During the COVID-19 Pandemic on Risk-Reduction Behavior of Patients with Heart Failure.

Telemed J E Health 2021 Oct 7. Epub 2021 Oct 7.

Deutsches Herzzentrum München (German Heart Centre Munich), Cardiology Department, Technical University Munich, Munich, Germany.

Our study assessed the effectiveness of tele-coaching over written information in educating patients with chronic heart failure (CHF) at high risk of hospitalization about corona virus disease 2019 (COVID-19). We analyzed the impact on number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and self-reported behavior change. In April 2020, a tele-coaching module and written summary about COVID-19, risk-reduction measures for prevention of COVID-19, and appropriate consultation of medical attention during the pandemic were integrated into an established tele-coaching program. Three hundred seventy-eight patients who had received both tele-coaching and written information 3 weeks earlier were interviewed using a structured questionnaire and compared with 1,748 patients who had only received written information at this point. Tele-coaching had no short-term effect on numbers of SARS-CoV-2 infections. However, patients receiving tele-coaching reported significantly more behavioral changes, including increased room ventilation (88% vs. 78%, < 0.0001), surface cleaning (80% vs. 70%,  = 0.0006), wearing of face masks (59% vs. 51%,  = 0.013), and reduced usage of public transport (77% vs. 68%,  = 0.0003), despite no observed difference in recall about risk-reduction measures. Moreover, tele-coaching improved patients' knowledge about how to seek medical help in an emergency (46% vs. 36%,  = 0.0006), with a significant reduction in self-reported doctors' appointments (304 vs. 413 per 1,000 patients,  = 0.002) and hospital visits (50 vs. 87 per 1,000,  = 0.033) during the first peak of the pandemic. In a population of patients with CHF at high risk of hospitalization, COVID-19-specific tele-coaching effectively supported behavioral changes and significantly reduced face-to-face medical contacts in a short-term follow-up period.
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http://dx.doi.org/10.1089/tmj.2021.0324DOI Listing
October 2021

[Cardiovascular interventions].

Herz 2021 Oct 30;46(5):397-398. Epub 2021 Sep 30.

Klinik für Innere Medizin/Kardiologie, Herzzentrum Leipzig - Universität Leipzig, Strümpellstr. 39, 04289, Leipzig, Deutschland.

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http://dx.doi.org/10.1007/s00059-021-05066-7DOI 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

Cardiac MRI shows an association of lower cardiorespiratory fitness with decreased myocardial mass and higher cardiac stiffness in the general population - The Sedentary's Heart.

Prog Cardiovasc Dis 2021 Sep 16. Epub 2021 Sep 16.

Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany.

Background: The heart has the capacity to adapt to different demands. The pathophysiological mechanisms involved with sedentarism are not fundamentally the opposite of those related with physical activity and regular exercise. We investigated the impact of lower cardiorespiratory fitness (CRF) on heart's plasticity and function in a population-based setting.

Methods: We used data from 1165 participants (539 women; 46.3%) aged 21-81 years from two independent cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analyzed the cross-sectional associations of peak oxygen uptake (VO), determined by symptom-limited cardiopulmonary exercise testing, with structural and functional left ventricular (LV) and left atrial (LA) parameters determined by magnetic resonance imaging (MRI) using multivariable- adjusted linear regression models.

Results: A 1 L/min lower VO was associated with a 10.5 g (95% confidence interval: 8.00 to 12.9; p < 0.001) lower LV mass, a 14.8 mL (10.9 to 18.6; p < 0.001) lower LV end-diastolic volume, a 0.29 mm (0.19 to 0.40; p < 0.001) lower LV wall-thickness, a 8.85 mL/beat (6.53 to 11.2; p < 0.001) lower LV stroke volume, a 0.42 L/min (0.25 to 0.60; p < 0.001) lower LV cardiac output and a 7.51 mL (3.88 to 11.1; p < 0.001) lower LA end-diastolic volume. Moreover, there were no associations with a concentric or eccentric remodeling and LV and LA ejection fraction.

Conclusions: Lower CRF was associated with a smaller heart, LV wall-thickness and mass, LV and LA stroke volume and cardiac output. Conversely, there was no association with LA and LV ejection fraction. Our cross-sectional observations are consistent with cardiac adaptations reflecting reduced volume loading demands of a sedentary lifestyle - "the sedentary's heart".
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http://dx.doi.org/10.1016/j.pcad.2021.09.003DOI 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

Safety and efficacy of minimalist transcatheter aortic valve implantation using a new-generation balloon-expandable transcatheter heart valve in bicuspid and tricuspid aortic valves.

Clin Res Cardiol 2021 Sep 9. Epub 2021 Sep 9.

German Heart Centre Munich, Technical University Munich, Munich, Germany.

Background: Bicuspid aortic valve may be associated with increased complications during transcatheter aortic valve implantation (TAVI).

Aims: Compare balloon-expandable transcatheter heart valve (THV) safety and efficacy in severe tricuspid (TAV) and bicuspid (BAV) aortic stenosis.

Methods: Transfemoral TAVI was performed in 743 patients (Jan 2014-June 2019) using the SAPIEN 3 THV. Aortic valve morphology was determined using computed tomography. Valve Academic Research Consortium-2 (VARC-2) derived safety and efficacy endpoints at 1 year were evaluated.

Results: BAV patients (n = 78), were younger (77 [72, 81] vs. 81 [78, 85] years, p < 0.001) with lower surgical risk (EuroSCORE II 2.96% vs. 4.51% p < 0.001). Bicuspid valves were more calcified (BAV 1308mm, TAV 848mm p < 0.001) with more asymmetric calcification (BAV 63/78 (81%), TAV 239/665 (36%), p < 0.001). Device success (BAV 94%, TAV 90%, p = 0.45) and major vascular complications (BAV 6%, TAV 9%, p = 0.66) were comparable. At 1 year, there was a trend toward lower combined all-cause mortality and rehospitalization for congestive heart failure in BAV patients (BAV 7%, TAV 13%, p = 0.08) with significantly lower all-cause mortality in this cohort (BAV 1%, TAV 9%, p = 0.020). VARC-2 time-related valve safety (BAV 22%, TAV 20%, p = 0.60) was comparable; however, bioprosthetic valve thrombosis remained more common in BAV patients (BAV 7%, TAV 2%, p = 0.010, Hazard ratio 3.57 [95% confidence interval 1.26, 10.10]). After propensity score matching, only bioprosthetic valve thrombosis remained significantly different.

Conclusions: Safety and efficacy of the SAPIEN 3 balloon-expandable THV in BAV is comparable with TAV. Higher rates of bioprosthetic valve thrombosis require further investigation.
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http://dx.doi.org/10.1007/s00392-021-01935-7DOI 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

Identification of a Functional Variant at the Chromosome 4q27 Coronary Artery Disease Locus in an Extended Myocardial Infarction Family.

Circulation 2021 Aug 23;144(8):662-665. Epub 2021 Aug 23.

Department of Cardiology, German Heart Centre Munich (T.A.D., T.K., J.W., H.B.S., H.S.), Technical University of Munich, Germany.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052975DOI Listing
August 2021

Coronary Artery Disease Genetics Enlightened by Genome-Wide Association Studies.

JACC Basic Transl Sci 2021 Jul 26;6(7):610-623. Epub 2021 Jul 26.

German Heart Centre Munich, Department of Cardiology, Technical University of Munich, Munich, Germany.

Many cardiovascular diseases are facilitated by strong inheritance. For example, large-scale genetic studies identified hundreds of genomic loci that affect the risk of coronary artery disease. At each of these loci, common variants are associated with disease risk with robust statistical evidence but individually small effect sizes. Only a minority of candidate genes found at these loci are involved in the pathophysiology of traditional risk factors, but experimental research is making progress in identifying novel, and, in part, unexpected mechanisms. Targets identified by genome-wide association studies have already led to the development of novel treatments, specifically in lipid metabolism. This review summarizes recent genetic and experimental findings in this field. In addition, the development and possible clinical usefulness of polygenic risk scores in risk prediction and individualization of treatment, particularly in lipid metabolism, are discussed.
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http://dx.doi.org/10.1016/j.jacbts.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326228PMC
July 2021

Impact of Atrial Fibrillation on Outcome in Takotsubo Syndrome: Data From the International Takotsubo Registry.

J Am Heart Assoc 2021 08 28;10(15):e014059. Epub 2021 Jul 28.

Department of Cardiology Intensive Care Medicine and Angiology Vincentius-Diakonissen-Hospital Karlsruhe Germany.

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher (<0.001), and there were fewer women (=0.046) in the AF than in the non-AF group. Left ventricular ejection fraction was significantly lower (=0.001), and cardiogenic shock was more often observed (<0.001) in the AF group. Both in-hospital (<0.001) and long-term mortality (<0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long-term mortality (hazard ratio, 2.31; 95% CI, 1.50-3.55; <0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in-hospital and long-term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in-hospital and long-term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01947621.
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http://dx.doi.org/10.1161/JAHA.119.014059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475688PMC
August 2021

Impact of Acute and Chronic Psychosocial Stress on Vascular Inflammation.

Antioxid Redox Signal 2021 Sep 14. Epub 2021 Sep 14.

Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.

Atherosclerosis and its complications, such as acute coronary syndromes, are the leading causes of death worldwide. A wide range of inflammatory processes substantially contribute to the initiation and progression of cardiovascular disease (CVD). In addition, epidemiological studies strongly associate both chronic stress and acute psychosocial stress with the occurrence of CVDs. Extensive research during recent decades has not only identified major pathways in cardiovascular inflammation but also revealed a link between psychosocial factors and the immune system in the context of atherosclerosis. Both chronic and acute psychosocial stress drive systemic inflammation neuroimmune interactions and promote atherosclerosis progression. The associations human epidemiological studies found between psychosocial stress and cardiovascular inflammation have been substantiated by additional experimental studies in mice and humans. However, we do not yet fully understand the mechanisms through which psychosocial stress drives cardiovascular inflammation; consequently, specific treatment, although urgently needed, is lacking. Psychosocial factors are increasingly acknowledged as risk factors for CVD and are currently treated behavioral interventions. Additional mechanistic insights might provide novel pharmacological treatment options to reduce stress-related morbidity and mortality.
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http://dx.doi.org/10.1089/ars.2021.0153DOI Listing
September 2021

Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis.

Eur Heart J 2021 10;42(39):4077-4088

Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.

Aims: Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear.

Methods And Results: Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques.

Conclusion: Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability.
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http://dx.doi.org/10.1093/eurheartj/ehab371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516477PMC
October 2021

Meta-Analysis of Short vs. Prolonged Dual Antiplatelet Therapy after Drug-Eluting Stent Implantation and Role of Continuation with either Aspirin or a P2Y Inhibitor Thereafter.

J Atheroscler Thromb 2021 Jul 10. Epub 2021 Jul 10.

Klinik fuer Herz- und Kreislauferkrankungen, Deutsches Herzzentrum Munich.

Aim: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is an ongoing debate and novel data has emerged. The aim of this meta-analysis was to assess outcomes of short vs. control DAPT duration. In addition, the role of single antiplatelet therapy (SAPT) after DAPT with either aspirin or P2Y monotherapy was analyzed.

Methods: The authors searched MEDLINE and Cochrane databases and proceedings of international meetings for randomized controlled trials (RCT) comparing ≤ 3 months with ≥ 6 months DAPT after DES implantation. The primary and co-primary outcomes of interest were definite or probable stent thrombosis (ST) and bleeding. In addition, we performed an analysis on studies who continued with either aspirin or P2Y monotherapy after DAPT.

Results: 9 RCTs comprising 41,864 patients were included and we analyzed a short DAPT duration of median 1.5 months vs. 12.1 months in the control group. The risk for ST was similar with short vs. control DAPT duration (0.5 vs. 0.5%; hazard ratio 1.17[95% CI 0.89-1.54]; p=0.26). Bleeding was significantly reduced with short vs. control DAPT duration (1.9 vs. 3.0%; 0.65[0.54-0.77]; p<0.0001). ST was not different between short vs. control DAPT duration in the analysis of the 4 RCTs who continued with aspirin after DAPT and the 5 P2Y RCTs, respectively, and no heterogeneity was detected (p=0.861). Bleeding was also reduced with short vs. control DAPT in both the aspirin (1.2 vs. 1.7%; 0.71[0.51-0.99]; p=0.04) and P2Y inhibitor studies (2.1 vs. 3.4%; 0.62[0.47-0.80]; p=0.0003) and no heterogeneity was detected (p=0.515).

Conclusions: Our meta-analysis shows that short DAPT ≤ 3 months followed by SAPT reduces bleeding and is not associated with an increase in ST. The results were consistent within the aspirin and P2Y SAPT studies.
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http://dx.doi.org/10.5551/jat.63000DOI Listing
July 2021

Genetics of coronary artery disease in the post-GWAS era.

J Intern Med 2021 Nov 23;290(5):980-992. Epub 2021 Aug 23.

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

During the past decade, genome-wide association studies (GWAS) have transformed our understanding of many heritable traits. Three recent large-scale GWAS meta-analyses now further markedly expand the knowledge on coronary artery disease (CAD) genetics in doubling the number of loci with genome-wide significant signals. Here, we review the unprecedented discoveries of CAD GWAS on low-frequency variants, underrepresented populations, sex differences and integrated polygenic risk. We present the milestones of CAD GWAS and post-GWAS studies from 2007 to 2021, and the trend in identification of variants with smaller odds ratio by year due to the increasing sample size. We compile the 321 CAD loci discovered thus far and classify candidate genes as well as distinct functional pathways on the road to indepth biological investigation and identification of novel treatment targets. We draw attention to systems genetics in integrating these loci into gene regulatory networks within and across tissues. We review the traits, biomarkers and diseases scrutinized by Mendelian randomization studies for CAD. Finally, we discuss the potentials and concerns of polygenic scores in predicting CAD risk in patient care as well as future directions of GWAS and post-GWAS studies in the field of precision medicine.
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http://dx.doi.org/10.1111/joim.13362DOI Listing
November 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

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

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

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry.

Clin Res Cardiol 2021 May 19. Epub 2021 May 19.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.

Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.

Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.

Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.

Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621.
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http://dx.doi.org/10.1007/s00392-021-01857-4DOI Listing
May 2021

Developing an App for Cardiovascular Prevention and Scientific Data Collection.

Stud Health Technol Inform 2021 May;279:103-104

Technical University of Munich, Munich, Germany.

Background: Mobile apps may encourage a lifestyle that avoids unhealthy behaviors, such as smoking or poor nutrition, which promotes cardiovascular diseases (CVD). Yet, little data is available on the utilization, perception, and long-term effects of such apps to prevent CVD.

Objectives: To develop a mobile app concept to reduce the individual CVD risk and collect information addressing research questions on CVD prevention while preserving data privacy and security.

Methods: To validate the concept, a prototype will be built, and usability studies will be performed.

Results: We expect to determine whether it is possible to reach a broad user base and to collect scientific information while protecting user data sufficiently.

Conclusion: To address CVD prevention, we propose a mobile coaching app. We expect high acceptance rates in validation studies.
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http://dx.doi.org/10.3233/SHTI210095DOI Listing
May 2021

[Banks, archives or libraries? Models for the ethical foundation of biobanks].

Dtsch Med Wochenschr 2021 04 27;146(9):623-626. Epub 2021 Apr 27.

Institut für Technik, Theologie und Naturwissenschaften, Evangelisch-Theologische Fakultät, Ludwig-Maximilians-Universität München.

At present, when it comes to research with biomedical data, research interests and data protection seem to be irreconcilable. Such differences are best mediated by an institution. The presuppositions of biobanking can be productively questioned with respect to public libraries. These represent a successful combination of knowledge and power, security and freedom.
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http://dx.doi.org/10.1055/a-1294-1291DOI Listing
April 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

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

A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy.

Eur Heart J 2021 05;42(18):1773-1785

Department of Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany.

Aims: In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.

Methods And Results: Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of about 5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences between injured and non-injured vessels. We observed major changes in the composition of the extracellular matrix and cell migration processes. Among the latter, we identified the classical transient receptor potential channel 6 (TRPC6) to drive neointima formation. While Trpc6-/- mice presented reduced neointima formation compared to wild-type mice (1.44 ± 0.39 vs. 2.16 ± 0.48, P = 0.01), activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased [vehicle 156.9 ± 15.8 vs. 1-oleoyl-2-acetyl-sn-glycerol 179.1 ± 8.07 (103 pixels), P = 0.01] or decreased migratory capacity [vehicle 130.0 ± 26.1 vs. SAR7334 111.4 ± 38.0 (103 pixels), P = 0.04], respectively. In a cohort of individuals with angiographic follow-up (n = 3068, males: 69.9%, age: 59 ± 11 years, follow-up 217.1 ± 156.4 days), homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49, 95% confidence interval 1.08-2.05; P = 0.01).

Conclusions: Our study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. We present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation.
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http://dx.doi.org/10.1093/eurheartj/ehab140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104955PMC
May 2021
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