Publications by authors named "Malte Kelm"

535 Publications

Sphingosine-1-phosphate: A mediator of the ARB-MI paradox?

Int J Cardiol 2021 Mar 3. Epub 2021 Mar 3.

Institute of Molecular Medicine III, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), Jena University Hospital, Jena, Germany. Electronic address:

Background: Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are important in the prevention of cardiovascular disease. The "ARB-MI paradox" implies that no risk reduction of myocardial infarction (MI) was found in ARB-treated patients despite target blood pressure control. Sphingosine-1-phosphate (S1P) is a cardioprotective sphingolipid which is released by platelets during activation. In this study we aimed to investigate differences of S1P homeostasis mediated by bradykinin and sphingosine kinases during ACEI/ARB treatment.

Methods: In this hypothesis generating pilot study, we investigated S1P plasma concentrations in 34 patients before and 3 months after ARB/ACEI medication. S1P levels were measured via liquid chromatography-tandem mass spectrometry. Bradykinin levels were measured by an enzyme-linked immunosorbent assay.

Results: Patient characteristics were not different between the ACEI and ARB group. Baseline S1P plasma concentrations were similar before ARB and ACEI treatment (0.74 SD 0.19 pmol vs. 0.78 SD 0.27 pmol, p = 0.54). After 3 months, S1P plasma levels were significantly higher in ACEI (0.93 SD 0.22 pmol) as compared to ARB treated patients (0.74 SD 0.24 pmol, p = 0.0015). Pearson correlation showed no significant association between bradykinin and S1P levels before (r = -0.219; 95% CI [-0.54-0.15]; p = 0.245) or after three months of treatment with ACEI or ARB (r = -0.015; 95% CI [-0.48-0.45]; p = 0.95).

Conclusions: S1P plasma concentrations are higher in ACE treated patients as compared to ARB treatment. This leads to the hypothesis, that differences in S1P metabolism might partially explain the ARB-MI paradox. This needs to be tested in clinical trials.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.082DOI Listing
March 2021

Propensity-Adjusted Comparison of Mortality of Elderly Versus Very Elderly Ventilated Patients.

Respir Care 2021 Mar 2. Epub 2021 Mar 2.

Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.

Background: The growing proportion of elderly intensive care patients constitutes a public health challenge. The benefit of critical care in these patients remains unclear. We compared outcomes in elderly versus very elderly subjects receiving mechanical ventilation.

Methods: In total, 5,557 mechanically ventilated subjects were included in our post hoc retrospective analysis, a subgroup of the VENTILA study. We divided the cohort into 2 subgroups on the basis of age: very elderly subjects (age ≥ 80 y; = 1,430), and elderly subjects (age 65-79 y; = 4,127). A propensity score on being very elderly was calculated. Evaluation of associations with 28-d mortality was done with logistic regression analysis.

Results: Very elderly subjects were clinically sicker as expressed by higher SAPS II scores (53 ± 18 vs 50 ± 18, < .001), and their rates of plateau pressure < 30 cm HO were higher, whereas other parameters did not differ. The 28-d mortality was higher in very elderly subjects (42% vs 34%, < .001) and remained unchanged after propensity score adjustment (adjusted odds ratio 1.31 [95% CI 1.16-1.49], < .001).

Conclusions: Age was an independent and unchangeable risk factor for death in mechanically ventilated subjects. However, survival rates of very elderly subjects were > 50%. Denial of critical care based solely on age is not justified. (ClinicalTrials.gov registration NCT02731898.).
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http://dx.doi.org/10.4187/respcare.08547DOI Listing
March 2021

Fate of Tricuspid Regurgitation in Patients Undergoing Transcatheter Edge-to-Edge Mitral Valve Repair.

EuroIntervention 2021 Mar 2. Epub 2021 Mar 2.

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

Background: Mitral valve repair may lead to alterations of tricuspid regurgitation (TR).

Aims: We investigated alterations, predictors and prognostic relevance of TR evolution in a large-scale multicentre population of patients undergoing transcatheter mitral valve repair (TMVR) via MitraClip.

Methods: In total, we included 531 TMVR-patients with at least one available follow-up echocardiography. TR-improvement was defined as a TR ≥II at baseline, which showed a decline of at least one TR-categorization.

Results: Distribution of pre-procedural TR severity was TR0/I 41% (220/531), TRII 39% (209/531) and TR≥III 19% (102/531), respectively. Follow-up echocardiography was at 308±187days. TR severity improved to TR0/I 49% (259/531), TRII 35% (183/531) and TRIII 17% (89/531), p=0.003. Out of 311 patients with TR≥II at baseline, 41% (127/311) showed TR-improvement. Atrial fibrillation (AF), residual mitral regurgitation ≥II (rMR) and tricuspid annular diameter (TAD) remained variables which prevented TR-improvement [odds ratio 0.49(0.29-0.84), 0.47(0.27-0.81) & 0.97(0.93-0.997), respectively]. TR-improvement was associated with better event-free survival regarding post-procedural heart-failure hospitalization (HHF) [hazard ratio 0.6(0.38-0.94)]. The main changes of TR-severity occurred within 3-month post TMVR (p=0.006), while there were only minor TR-changes between 3 and 12-month of follow-up (p=0.813).

Conclusions: TR-improvement was frequent after TMVR. Predictors preventing TR-improvement were AF, post-procedural rMR, and TAD. Furthermore, TR-improvement was an early phenomenon primarily occurring within the first three months post TMVR and served as a suitable marker of reduced HHF.
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http://dx.doi.org/10.4244/EIJ-D-20-01094DOI Listing
March 2021

Fine particulate matter: An underestimated cardiovascular risk factor?

Eur J Prev Cardiol 2020 Jan 22. Epub 2020 Jan 22.

Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf, Germany.

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http://dx.doi.org/10.1177/2047487319899122DOI Listing
January 2020

Impella versus extracorporal life support in cardiogenic shock: a propensity score adjusted analysis.

ESC Heart Fail 2021 Feb 9. Epub 2021 Feb 9.

Department of Medicine, Division of Cardiology, Pulmonary Diseases and Vascular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany.

Aims: The mortality in cardiogenic shock (CS) is high. The role of specific mechanical circulatory support (MCS) systems is unclear. We aimed to compare patients receiving Impella versus ECLS (extracorporal life support) with regard to baseline characteristics, feasibility, and outcomes in CS.

Methods And Results: This is a retrospective cohort study including CS patients over 18 years with a complete follow-up of the primary endpoint and available baseline lactate level, receiving haemodynamic support either by Impella 2.5 or ECLS from two European registries. The decision for device implementation was made at the discretion of the treating physician. The primary endpoint of this study was all-cause mortality at 30 days. A propensity score for the use of Impella was calculated, and multivariable logistic regression was used to obtain adjusted odds ratios (aOR). In total, 149 patients were included, receiving either Impella (n = 73) or ECLS (n = 76) for CS. The feasibility of device implantation was high (87%) and similar (aOR: 3.14; 95% CI: 0.18-56.50; P = 0.41) with both systems. The rates of vascular injuries (aOR: 0.95; 95% CI: 0.10-3.50; P = 0.56) and bleedings requiring transfusions (aOR: 0.44; 95% CI: 0.09-2.10; P = 0.29) were similar in ECLS patients and Impella patients. The use of Impella or ECLS was not associated with increased odds of mortality (aOR: 4.19; 95% CI: 0.53-33.25; P = 0.17), after correction for propensity score and baseline lactate level. Baseline lactate level was independently associated with increased odds of 30 day mortality (per mmol/L increase; OR: 1.29; 95% CI: 1.14-1.45; P < 0.001).

Conclusions: In CS patients, the adjusted mortality rates of both ECLS and Impella were high and similar. The baseline lactate level was a potent predictor of mortality and could play a role in patient selection for therapy in future studies. In patients with profound CS, the type of device is likely to be less important compared with other parameters including non-cardiac and neurological factors.
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http://dx.doi.org/10.1002/ehf2.13200DOI Listing
February 2021

"Get with the Guidelines Heart Failure Risk Score" for mortality prediction in patients undergoing MitraClip.

Clin Res Cardiol 2021 Jan 31. Epub 2021 Jan 31.

Department of Cardiology, Angiology, Pneumology and Medical Intensive Care, Heart Center of the University of Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

Background: Reliable risk scores in patients undergoing transcatheter edge-to-edge mitral valve repair (TMVR) are lacking. Heart failure is common in these patients, and risk scores derived from heart failure populations might help stratify TMVR patients.

Methods: Consecutive patients from three Heart Centers undergoing TMVR were enrolled to investigate the association of the "Get with the Guidelines Heart Failure Risk Score" (comprising the variables systolic blood pressure, urea nitrogen, blood sodium, age, heart rate, race, history of chronic obstructive lung disease) with all-cause mortality.

Results: Among 815 patients with available data 177 patients died during a median follow-up time of 365 days. Estimated 1-year mortality by quartiles of the score (0-37; 38-42, 43-46 and more than 46 points) was 6%, 10%, 23% and 30%, respectively (p < 0.001), with good concordance between observed and predicted mortality rates (goodness of fit test p = 0.46). Every increase of one score point was associated with a 9% increase in the hazard of mortality (95% CI 1.06-1.11%, p < 0.001). The score was associated with long-term mortality independently of left ventricular ejection fraction, NYHA class and NTproBNP, and was equally predictive in primary and secondary mitral regurgitation.

Conclusion: The "Get with the Guidelines Heart Failure Risk Score" showed a strong association with mortality in patients undergoing TMVR with additive information beyond traditional risk factors. Given the routinely available variables included in this score, application is easy and broadly possible.
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http://dx.doi.org/10.1007/s00392-021-01804-3DOI Listing
January 2021

Right ventricular dysfunction assessed by cardiovascular magnetic resonance is associated with poor outcome in patients undergoing transcatheter mitral valve repair.

PLoS One 2021 29;16(1):e0245637. Epub 2021 Jan 29.

Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Duesseldorf, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.

Aims: To evaluate whether CMR-derived RV assessment can facilitate risk stratification among patients undergoing transcatheter mitral valve repair (TMVR).

Background: In patients undergoing TMVR, only limited data exist regarding the role of RV function. Previous studies assessed the impact of pre-procedural RV dysfunction stating that RV failure may be associated with increased cardiovascular mortality after the procedure.

Methods: Sixty-one patients underwent CMR, echocardiography and right heart catheterization prior TMVR. All-cause mortality and heart failure hospitalizations were assessed during 2-year follow-up.

Results: According to RV ejection fraction (RVEF) <46%, 23 patients (38%) had pre-existing RV dysfunction. By measures of RV end-diastolic volume index (RVEDVi), 16 patients (26%) revealed RV dilatation. Nine patients (15%) revealed both. RV dysfunction was associated with increased right and left ventricular volumes as well as reduced left ventricular (LV) ejection fraction (all p<0.05). During follow-up, 15 patients (25%) died and additional 14 patients (23%) were admitted to hospital due to heart failure symptoms. RV dysfunction predicted all-cause mortality even after adjustment for LV function. Similarly, RVEDVi was a predictor of all-cause mortality even after adjustment for LVEDVi. Kaplan-Meier survival analysis unraveled that, among patients presenting with CMR indicative of both, RV dysfunction and dilatation, the majority (78%) experienced an adverse event during follow-up (p<0.001).

Conclusion: In patients undergoing TMVR, pre-existing RV dysfunction and RV dilatation are associated with reduced survival, in progressive additive fashion. The assessment of RV volumes and function by CMR may aid in risk stratification prior TMVR in these high-risk patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245637PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846001PMC
January 2021

Endothelium-dependent remote signaling in ischemia and reperfusion: Alterations in the cardiometabolic continuum.

Free Radic Biol Med 2021 Jan 23;165:265-281. Epub 2021 Jan 23.

Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany. Electronic address:

Intact endothelial function plays a fundamental role for the maintenance of cardiovascular (CV) health. The endothelium is also involved in remote signaling pathway-mediated protection against ischemia/reperfusion (I/R) injury. However, the transfer of these protective signals into clinical practice has been hampered by the complex metabolic alterations frequently observed in the cardiometabolic continuum, which affect redox balance and inflammatory pathways. Despite recent advances in determining the distinct roles of hyperglycemia, insulin resistance (InR), hyperinsulinemia, and ultimately diabetes mellitus (DM), which define the cardiometabolic continuum, our understanding of how these conditions modulate endothelial signaling remains challenging. It is widely accepted that endothelial cells (ECs) undergo functional changes within the cardiometabolic continuum. Beyond vascular tone and platelet-endothelium interaction, endothelial dysfunction may have profound negative effects on outcome during I/R. In this review, we summarize the current knowledge of the influence of hyperglycemia, InR, hyperinsulinemia, and DM on endothelial function and redox balance, their influence on remote protective signaling pathways, and their impact on potential therapeutic strategies to optimize protective heterocellular signaling.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.040DOI Listing
January 2021

Endothelial β1 Integrin-Mediated Adaptation to Myocardial Ischemia.

Thromb Haemost 2021 Jan 14. Epub 2021 Jan 14.

Institute of Metabolic Physiology, Department of Biology, Heinrich-Heine-University, Düsseldorf, Germany.

Background:  Short episodes of myocardial ischemia can protect from myocardial infarction. However, the role of endothelial β1 integrin in these cardioprotective ischemic events is largely unknown.

Objective:  In this study we investigated whether endothelial β1 integrin is required for cardiac adaptation to ischemia and protection from myocardial infarction.

Methods:  Here we introduced transient and permanent left anterior descending artery (LAD) occlusions in mice. We inhibited β1 integrin by intravenous injection of function-blocking antibodies and tamoxifen-induced endothelial cell (EC)-specific deletion of . Furthermore, human was silenced in primary human coronary artery ECs using small interfering RNA. We analyzed the numbers of proliferating ECs and arterioles by immunohistochemistry, determined infarct size by magnetic resonance imaging (MRI) and triphenyl tetrazolium chloride staining, and analyzed cardiac function by MRI and echocardiography.

Results:  Transient LAD occlusions were found to increase EC proliferation and arteriole formation in the entire myocardium. These effects required β1 integrin on ECs, except for arteriole formation in the ischemic part of the myocardium. Furthermore, this integrin subunit was also relevant for basal and mechanically induced proliferation of human coronary artery ECs. Notably, β1 integrin was needed for cardioprotection induced by transient LAD occlusions, and the absence of endothelial β1 integrin resulted in impaired growth of blood vessels into the infarcted myocardium and reduced cardiac function after permanent LAD occlusion.

Conclusion:  We showed that endothelial β1 integrin is required for adaptation of the heart to cardiac ischemia and protection from myocardial infarction.
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http://dx.doi.org/10.1055/s-0040-1721505DOI Listing
January 2021

Real-time echocardiography-fluoroscopy fusion imaging for left atrial appendage closure: prime time for fusion imaging?

Acta Cardiol 2021 Jan 13:1-9. Epub 2021 Jan 13.

Division of Cardiology, Pulmonology and Vascular Medicine, University Medical Center Düsseldorf, Düsseldorf, Germany.

Background: Real-time echocardiography-fluoroscopy fusion imaging (FI) merges real-time echocardiographic imaging with fluoroscopic images allowing intuitive anatomical spatial orientation during structural heart disease interventions. We aimed to assess the safety and efficacy of FI during percutaneous left atrial appendage closure (LAAC)

Methods: 34 consecutive patients before (-FI) and 121 patients after (+FI) the introduction of FI for LAAC were included in a single-centre study. In-hospital safety parameters were analysed according to adverse event (AE) definition of the Munich consensus document and procedure-related parameters were assessed for efficacy. An ANCOVA was performed to investigate the influence of a learning curve.

Results: Time until successful transseptal puncture was significantly reduced as well as total procedure time and the amount of contrast agent used (+FI/-FI:17 ± 6.35 min vs. 22 ± 8.33 min,  = 0.001; +FI/-FI: 50 min IQR 43 min - 60 min vs. 57 min IQR 45 min -70 min;  = 0.013; +FI/-FI: 70 mL, IQR 55 ml-90 mL vs. 152 mL, IQR 107 mL - 205 mL;  < 0.001). However, fluoroscopy time and dose-area product did not differ between both groups. There was no significant difference in the occurrence of in-hospital adverse events (+FI/-FI: 2.5% vs. 0%;  = 0.596). The ANCOVA revealed that the learning curve does not affect procedural efficacy parameters such as procedure time, time to transseptal puncture, amount of contrast agent and dose-area product.

Conclusions: FI for LAAC reduces the total procedure time, the time to successful transseptal puncture and periprocedural amount of contrast agent.
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http://dx.doi.org/10.1080/00015385.2020.1870193DOI Listing
January 2021

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

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

Institut für Herzinfarktforschung, Ludwigshafen, Germany.

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

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

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

Modern NCDR and ACTION risk models outperform the GRACE model for prediction of in-hospital mortality in acute coronary syndrome in a German cohort.

Int J Cardiol 2021 Jan 4. Epub 2021 Jan 4.

Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.

Background And Purpose: Risk prediction with the Global Registry of Acute Coronary Events (GRACE) risk model is guideline-recommended in acute coronary syndrome (ACS) patients. However, the performance of more contemporary scores derived from ACTION (Acute Coronary Treatment and Intervention Outcomes Network) and National Cardiovascular Data (NCDR) registries remains incompletely understood. We aimed to compare these models in German ACS patients.

Methods And Results: A total of 1567 patients with (Non-)ST-segment elevation myocardial infarction (NSTEMI: 1002 patients, STEMI: 565 patients) undergoing invasive management at University Hospital Düsseldorf (Germany) from 2014 to 2018 were included. Overall in-hospital mortality was 7.5% (NSTEMI 3.7%, STEMI 14.5%). Parameters for calculation of GRACE 1.0, GRACE 2.0, ACTION and NCDR risk models and in-hospital mortality were assessed and risk model performance was compared. The GRACE 1.0 risk model for prediction of in-hospital mortality discriminated risk superior (c-index 0.84) to its successor GRACE 2.0 (c-index 0.79, p = 0.0008). The NCDR model performed best in discrimination of risk in ACS overall (c-index 0.89; p < 0.0001; p < 0.0001) and showed superior performance compared to GRACE in NSTEMI and STEMI subgroups (p both < 0.02). ACTION and GRACE risk models performed comparable to each other (both c-index 0.84, p = 0.68), with advantages for ACTION in NSTEMI patients (c-index 0.87 vs. 0.84 (GRACE); p = 0.02). ACTION and GRACE 2.0 showed the most accurate calibration of all models.

Conclusions: In a contemporary German patient population with ACS, modern NCDR and ACTION risk models showed superior performance in prediction of in-hospital mortality compared to the gold-standard GRACE model.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.085DOI Listing
January 2021

New insights on potential permanent pacemaker predictors in TAVR using the largest self-expandable device.

Cardiovasc Diagn Ther 2020 Dec;10(6):1816-1826

Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.

Background: Post-procedural conduction disorders following transcatheter aortic valve replacement (TAVR) still remain frequent, especially using the largest self-expandable device (Medtronic Corevalve Evolut R, 34 mm, STHV-34). We, therefore, assessed previously described, predictive factors of permanent pacemaker (PPM) implantation in the context of the STHV-34, including calcification distribution, implantation depth and membranous septum length (MSL).

Methods: We performed a dual centre analysis of 130 of 182 consecutive patients treated with STHV-34, further stratified into subjects without post-procedural PPM (-PPM n=100, 76.9%) and those requiring post-procedural PPM (+PPM n=30, 23.1%). These events were further analyzed by univariate and multivariate analysis according to several underlying conditions.

Results: Multivariate analysis only depicted previous right bundle branch block [RBBB; OR: 11.52 (2.63-50.44), P=0.001] and eccentricity index of the left ventricular outflow tract (LVOT-EI) >0.3 [OR: 3.07 (1.22-7.77), P=0.018] as highly predictive for PPM-need, being also confirmed by c-statistics [area under the curve (AUC) =0.68; 95% confidence interval (CI): 0.57-0.80; P=0.0025]. There was only moderate correlation of implantation depth over the MSL in terms of PPM prediction (r=0.23; P<0.0001).

Conclusions: This study offers new insights into potential PPM predictors using the STHV-34: previous RBBB and a pronounced LVOT-EI were independent predictors of PPM, while most of the previously reported determinants failed to predict PPM-need including MSL and implantation depth.
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http://dx.doi.org/10.21037/cdt-20-680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758768PMC
December 2020

Impact of Combined "CHADS-BLED" Score to Predict Short-Term Outcomes in Transfemoral and Transapical Aortic Valve Replacement.

J Interv Cardiol 2020 18;2020:9414397. Epub 2020 Dec 18.

Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Medical Faculty, Moorenstr. 5, Düsseldorf 40225, Germany.

Background: High CHADS-VASC and HAS-BLED scores are linked to increased mortality in structural and nonstructural cardiovascular interventions irrespective of the presence of atrial fibrillation (AF) or oral anticoagulation. We aimed to use the aforementioned scores to quantify the risk of 30-day mortality, major vascular and bleeding events (MVASC/BARC), and cerebrovascular insults (CVI) in patients undergoing different access routes in transcatheter aortic valve replacement (TAVR).

Methods: Out of 1329 patients, 980 transfemoral (TF) TAVR (73.7%) and 349 transapical (TA) TAVR (26.3%) were included. CHADS-VASC, HAS-BLED, and combined "CHADS-BLED" scores were calculated and compared to the predictive value of the established EuroSCORE and STS score.

Results: In all-comers TF TAVR patients, the applied risk models showed only poor association with 30-day mortality while, in patients with concomitant AF, a strong association was observed using the combined CHADS-BLED score (c-index: 0.83; 95% CI: 0.76-0.91;  < 0.0001). Concerning 30-day mortality, only the STS score for TF TAVR (c-index: 0.68; 95% CI: 0.59-0.76;  = 0.001) and EuroSCORE for TA TAVR (c-index: 0.66; 95% CI: 0.56-0.76;  = 0.005) could show some predictive value. High CHADS-BLED was associated with enhanced CVI (3.0% vs. 7.2%;=0.0039 ) and more frequent MVASC/BARC (3.2% vs. 6.3%;  = 0.0362) in the all-comers TAVR cohort. All risk models failed in the prediction of CVI and MVASC/BARC for TA TAVR patients.

Conclusion: The combined CHADS-BLED score was a strong predictor for 30-day mortality in TF TAVR patients with AF. A high CHADS-BLED score showed a good predictive value for major vascular and bleeding events as well as CVI in TF TAVR patients. This study is registered at clinical trials (NCT01805739).
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http://dx.doi.org/10.1155/2020/9414397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762668PMC
December 2020

Improving the Assessment of Flow-Mediated Dilation Through Detection of Peak Time in Healthy Subjects and Subjects With Type 2 Diabetes.

Angiology 2020 Dec 30:3319720984884. Epub 2020 Dec 30.

Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany.

The assessment of flow-mediated dilation (FMD) is widely used to quantify endothelial function. Historically, FMD was determined at 60 seconds post-cuff deflation. We investigated whether FMD would be more accurate if determined at maximum dilatory peak (MDP) than at 60 seconds in healthy subjects and subjects with type 2 diabetes mellitus (T2DM). We studied 95 healthy and 72 subjects with T2DM and assessed FMD at MDP, 60 and 90 seconds. Twenty-four healthy and 12 subjects with T2DM underwent a repeat FMD after 28 days. In healthy subjects, FMD at MDP was higher than at 60 and 90 seconds, with mean difference MDP versus 60 seconds 1.14% (95% CI: 0.6-1.7); < .0001 and MDP versus 90 seconds 1.9% (95% CI: 1.3-2.5) with similar results in T2DM, that is, 1.0% (95% CI: 0.1-1.9) and 2.3% (95% CI: 1.3-3.2), respectively. Intraindividual variability was lowest with MDP compared with 60 and 90 seconds, that is, 15.0 versus 23.2% and 40.0%, respectively, resulting in a more than 2-fold reduction in necessary sample size. In healthy subjects and subjects with T2DM, assessment of FMD using MDP results in a more accurate and precise assessment leading to a substantial reduction in sample size.
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http://dx.doi.org/10.1177/0003319720984884DOI Listing
December 2020

Frailty as a Prognostic Indicator in Intensive Care.

Dtsch Arztebl Int 2020 Oct;117(40):668-673

Department of Cardiology, Pulmonary Diseases and Vascular Medicine, Faculty of Medicine, Düsseldorf University Hospital; Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Intensive Care Medicine, Hadassah-Hebrew University Hospital, Jerusalem, Israel; Cardiovascular Research Institute Düsseldorf (CARID).

Background: The percentage of patients in intensive care who are 80 years old or older is continually increasing. Such patients already made up more than 20% of all patients in intensive care in Germany in the years 2007-2011. Meanwhile, effective treatments that support the organs of the body and keep severely ill patients alive are also being continually developed and refined. Frailty is a key prognostic parameter. The scientifically based assessment of frailty can be highly useful in intensive care medicine with regard to consented decision-making, individualized prognostication, treatment planning, and aftercare.

Methods: Pertinent publications were retrieved by a selective search in the PubMed database. On the basis of the literature assessment, a variety of screening instruments were used to assess frailty and its significance for very old, critically ill patients in German intensive care units.

Results: Only a small number of screening instruments are suitable for routine use in German intensive care units. The scores vary in diagnostic precision. The Clinical Frailty Scale (CFS) enables highly accurate prognostication; it considers the patient in relation to his or her social environment, and to the reference population. Categorization is achieved by means of pictograms that are supplemented with brief written descriptions. The CFS can be used prospectively and is easy to learn. Its interrater reliability is high (weighted Cohen's κ: 0.85 [0.84; 0.87]), and it has been validated for routine use in intensive care units in Germany.

Conclusion: None of the available scores enable perfect prognostication. In Germany, frailty in intensive-care patients is currently best assessed on a simple visual scale (CFS).
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http://dx.doi.org/10.3238/arztebl.2020.0668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838379PMC
October 2020

Failure of Lactate Clearance Predicts the Outcome of Critically Ill Septic Patients.

Diagnostics (Basel) 2020 Dec 18;10(12). Epub 2020 Dec 18.

Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.

Purpose: Early lactate clearance is an important parameter for prognosis assessment and therapy control in sepsis. Patients with a lactate clearance >0% might differ from patients with an inferior clearance in terms of intensive care management and outcomes. This study analyzes a large collective with regards to baseline risk distribution and outcomes.

Methods: In total, 3299 patients were included in this analysis, consisting of 1528 (46%) ≤0% and 1771 (54%) >0% patients. The primary endpoint was intensive care unit (ICU) mortality. Multilevel logistic regression analyses were used to compare both groups: A baseline model (model 1) with lactate clearance as a fixed effect and ICU as a random effect was installed. For model 2, patient characteristics (model 2) were included. For model 3, intensive care treatment (mechanical ventilation and vasopressors) was added to the model. Models 1 and 2 were used to evaluate the primary and secondary outcomes, respectively. Model 3 was only used to evaluate the primary outcomes. Adjusted odds ratios (aORs) with respective 95% confidence intervals (CI) were calculated.

Results: The cohorts had no relevant differences regarding the gender, BMI, age, heart rate, body temperature, and baseline lactate. Neither the primary infection focuses nor the ethnic background differed between both groups. In both groups, the most common infection sites were of pulmonary origin, the urinary tract, and the gastrointestinal tract. Patients with lactate clearance >0% evidenced lower sepsis-related organ failure assessment (SOFA) scores (7 ± 6 versus 9 ± 6; < 0.001) and creatinine (1.53 ± 1.49 versus 1.80 ± 1.67; < 0.001). The ICU mortality differed significantly (14% versus 32%), and remained this way after multivariable adjustment for patient characteristics and intensive care treatment (aOR 0.43 95% CI 0.36-0.53; < 0.001). In the additional sensitivity analysis, the lack of lactate clearance was associated with a worse prognosis in each subgroup.

Conclusion: In this large collective of septic patients, the 6 h lactate clearance is an independent method for outcome prediction.
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http://dx.doi.org/10.3390/diagnostics10121105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767189PMC
December 2020

Thromboembolic Events in Patients With Left Ventricular Assist Devices Are Related to Microparticle-Induced Coagulation.

ASAIO J 2021 01;67(1):59-66

From the Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Thromboembolic events (TEs) are a feared complication in patients supported by a continuous-flow left ventricular assist device (LVAD). The aim of the study was to analyze the role of circulating microparticles (MPs) in activating the coagulation system in LVAD patients, which might contribute to the occurrence of TEs. First, we analyzed the effect of LVAD support on endothelial function, on the levels of endothelial MPs (EMPs) and platelet MPs (PMPs), and on the procoagulative activity of circulating MPs (measured as MP-induced thrombin formation) before LVAD implantation, post-implantation, and at a 3 month follow-up (n = 15). Second, these parameters were analyzed in 43 patients with ongoing LVAD support who were followed up for the occurrence of TEs in the following 12 months. In patients undergoing LVAD implantation, the levels of PMPs and MP-induced thrombin formation increased post-LVAD implantation. The flow-mediated vasodilation (FMD) decreased, while the levels of EMPs increased post-LVAD implantation. TEs occurred in eight patients with ongoing LVAD support despite adequate coagulation. The levels of PMPs and MP-induced thrombin formation were higher in LVAD patients with TEs than in LVAD patients without TEs and were independent predictors for the risk of TEs under LVAD support. As conclusion, implantation of LVAD enhanced MP-induced coagulation, which was independently associated with the occurrence of TEs. These parameters may serve in risk stratification for early transplantation and individualized modification of standard LVAD therapy.
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http://dx.doi.org/10.1097/MAT.0000000000001200DOI Listing
January 2021

German Multicenter Experience With a New Leaflet-Based Transcatheter Mitral Valve Repair System for Mitral Regurgitation.

JACC Cardiovasc Interv 2020 Dec;13(23):2769-2778

Department of Cardiology, Heart Centre, Faculty of Medicine, University of Cologne, Cologne, Germany. Electronic address:

Objectives: The aim of this study was to investigate the procedural and short-term safety and efficacy of a new leaflet-based transcatheter mitral valve repair system.

Background: The PASCAL repair system has been recently approved for percutaneous treatment of mitral regurgitation (MR). Novel characteristics are broad paddles positioned around a central spacer and the ability for independent leaflet capture.

Methods: Procedural and 30-day outcomes were investigated in the first 309 patients with symptomatic MR 3+/4+ treated with the PASCAL repair system at 10 sites. Primary efficacy endpoints were technical success and degree of residual MR at discharge. The primary safety endpoint was the rate of major adverse events (MAE).

Results: Among the 309 patients (mean age 77 ± 10 years, 42% women, mean European System for Cardiac Operative Risk Evaluation II score 5.8 ± 4.5%) included in this study, MR etiology was degenerative in 33%, functional in 52%, and mixed in 16%. Eighty-six percent of patients were in New York Heart Association functional class III or IV. The technical success rate was 96%. Of 308 patients discharged alive, MR was ≤2+ in 93.5%. At 30 days, the MAE rate was 4.1%, with an estimated all-cause mortality rate of 2.0%, and 72% of patients were in New York Heart Association functional class ≤II (p < 0.001). Rates of device success and CLASP (Edwards PASCAL Transcatheter Mitral Valve Repair System Study) trial-defined clinical success were 81.9% and 86.9%, respectively. Single-leaflet device attachment occurred in 7 patients (2.3%).

Conclusions: Mitral valve repair with the PASCAL system in the early post-approval phase was effective and safe, with high procedural success rates and low rates of MAE. MR was significantly reduced, accompanied by significant improvement in functional status.
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http://dx.doi.org/10.1016/j.jcin.2020.08.025DOI Listing
December 2020

Next-generation sequencing analysis of circulating micro-RNA expression in response to parabolic flight as a spaceflight analogue.

NPJ Microgravity 2020 Nov 2;6(1):31. Epub 2020 Nov 2.

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf, Germany.

Understanding physiologic reactions to weightlessness is an indispensable requirement for safe human space missions. This study aims to analyse changes in the expression of circulating miRNAs following exposure to gravitational changes. Eight healthy volunteers (age: 24.5 years, male: 4, female: 4) were included. Each subject underwent 31 short-term phases of weightlessness and hypergravity induced by parabolic flight as a spaceflight analogue. At baseline, 1 and 24 h after parabolic flight, venous blood was withdrawn. Analysis of circulating miRNAs in serum was conducted by means of next generation sequencing. In total, 213 miRNAs were robustly detected (TPM > 5) by small RNA sequencing in all 24 samples. Four miRNAs evidenced a significant change in expression after adjusting for multiple testing. Only miR-223-3p showed a consistent significant decrease 24 h after parabolic flight compared to baseline values and values at 1 h after parabolic flight. miR-941 and miR-24-3p showed a significant decrease 24 h after parabolic flight compared to 1 h after parabolic flight but not to baseline values. miR-486-5p showed a significant increase 24 h after parabolic flight compared to 1 h after parabolic flight but not to baseline values. A target network analysis identified genes of the p53 signaling pathway and the cell cycle highly enriched among the targets of the four microRNAs. Our findings suggest cellular adaption to gravitational changes at the post-transcriptional level. Based on our results, we suggest a change in cell cycle regulation as potential explanation for adaptational changes observed in space missions.
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http://dx.doi.org/10.1038/s41526-020-00121-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606465PMC
November 2020

Two year outcome in nonagenarians undergoing percutaneous mitral valve repair.

ESC Heart Fail 2021 Feb 6;8(1):577-585. Epub 2020 Dec 6.

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Aims: Percutaneous mitral valve repair (PMVR) has emerged as standard treatment in selected patients with clinically relevant mitral regurgitation (MR) and increased surgical risk. We aimed to evaluate the safety and clinical outcomes in nonagenarians undergoing PMVR.

Methods And Results: Altogether, 493 patients with severe MR who were treated with PMVR were included in this open-label prospective study and followed up for 2 years. We treated 25 patients with PMVR aged 90 years or above, 185 patients aged 80-89 years, and 283 patients aged <80 years. PMVR in nonagenarians was safe and did not differ from PMVR in younger patients in terms of safety endpoints. Device success did not differ among the groups (100% in nonagenarians, 95.7% in octogenarians, and 95.1% in septuagenarians, P = 0.100). Unadjusted 2 year mortality was 28% in nonagenarians, 32.4% in octogenarians, and 19.8% in septuagenarians (P = 0.008). Kaplan-Meier curves confirmed similar 2 year survival in the nonagenarian and octogenarian groups (P = 0.657). In the multivariate analysis, age [hazard ratio (HR) 1.031, 95% confidence interval (CI) 1.002-1.060, P = 0.034], higher post-procedural transmitral valve gradients (HR 1.187, 95% CI 1.104-1.277, P = 0.001), and post-procedural acute kidney injury (HR 2.360, 95% CI 1.431-3.893, P = 0.001) were independent predictors of 2 year mortality. Altogether, 89.4% of the nonagenarians, 85.9% of the octogenarians, and 86.4% of the septuagenarians had MR grade of 2+ or less at 1 year after PMVR (P = 0.910). New York Heart Association functional class improved in the vast majority of patients, irrespective of age (P = 0.129). After 1 year, 9.5% of the nonagenarians, 22.3% of the octogenarians, and 25.2% of the septuagenarians (each P = 0.001 compared with baseline) suffered from New York Heart Association Functional Class III or IV. The rate of heart failure rehospitalization in the first 12 months after PMVR did not differ among the groups (16% in the nonagenarians, 16.7% in the octogenarians, and 17.7% in the septuagenarians) (P = 0.954). Quality of life assessed by the Minnesota Living with Heart Failure Questionnaire before and at 1 year after PMVR improved in all age groups (P = 0.001).

Conclusions: Percutaneous mitral valve repair in carefully selected nonagenarians is feasible and safe with intermediate-term beneficial effects comparable with those in younger patients.
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http://dx.doi.org/10.1002/ehf2.13127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835616PMC
February 2021

Exposure to acute normobaric hypoxia results in adaptions of both the macro- and microcirculatory system.

Sci Rep 2020 12 1;10(1):20938. Epub 2020 Dec 1.

Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.

Although acute hypoxia is of utmost pathophysiologic relevance in health and disease, studies on its effects on both the macro- and microcirculation are scarce. Herein, we provide a comprehensive analysis of the effects of acute normobaric hypoxia on human macro- and microcirculation. 20 healthy participants were enrolled in this study. Hypoxia was induced in a normobaric hypoxia chamber by decreasing the partial pressure of oxygen in inhaled air stepwisely (pO; 21.25 kPa (0 k), 16.42 kPa (2 k), 12.63 kPa (4 k) and 9.64 kPa (6 k)). Macrocirculatory effects were assessed by cardiac output measurements, microcirculatory changes were investigated by sidestream dark-field imaging in the sublingual capillary bed and videocapillaroscopy at the nailfold. Exposure to hypoxia resulted in a decrease of systemic vascular resistance (p < 0.0001) and diastolic blood pressure (p = 0.014). Concomitantly, we observed an increase in heart rate (p < 0.0001) and an increase of cardiac output (p < 0.0001). In the sublingual microcirculation, exposure to hypoxia resulted in an increase of total vessel density, proportion of perfused vessels and perfused vessel density. Furthermore, we observed an increase in peripheral capillary density. Exposure to acute hypoxia results in vasodilatation of resistance arteries, as well as recruitment of microvessels of the central and peripheral microcirculation. The observed macro- and microcirculatory effects are most likely a result from compensatory mechanisms to ensure adequate tissue oxygenation.
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http://dx.doi.org/10.1038/s41598-020-77724-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708486PMC
December 2020

MTX Treatment Does Not Improve Outcome in Mice with AMI.

Pharmacology 2020 Nov 20:1-7. Epub 2020 Nov 20.

Department of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany,

Background: Targeting inflammation in patients with coronary artery disease and/or acute myocardial infarction (AMI) is a matter of debate. Methotrexate (MTX) is one of the most widely used immunosuppressants. Cardiovascular Inflammation Reduction Trial (CIRT) recently failed to demonstrate reduced cardiovascular events in MTX-treated patients. However, it is not known if long-term MTX treatment improves cardiac outcome in AMI. Therefore, in this study, we investigated the postischemic phase in MTX-treated mice undergoing AMI.

Methods: Wild-type mice received MTX medication intraperitoneally for 2 weeks. Afterward, AMI was induced by transient left anterior ascending artery ligation. Postischemic cardiac damage after 24 h was assessed.

Results: MTX treatment did not affect infarct size as compared to control (IS/AAR: Con 76.20% ± 12.37%/AAR vs. MTX 73.51 ± 11.72%/AAR, p = 0.64). Moreover, systolic function and structural parameters did not differ between groups (24hejection fraction: Con 36.49 ± 3.23% vs. MTX 32.77 ± 2.29%, p = 0.41; 24hLVID; d: Con 3.57 ± 0.17 mm vs. MTX 3.19 ± 0.13 mm, p = 0.14). Platelets were increased by MTX (Con 1,442 ± 69.20 × 103/mm3 vs. MTX 1,920 ± 68.68 × 103/mm3, p < 0.0001). White blood cell and RBC as well as rate of monocytes, granulocytes, lymphocytes, and serum amyloid P levels were equal.

Conclusion: MTX medication did not improve postischemic cardiac damage in a murine model of AMI. Future trials are needed to identify and investigate other anti-inflammatory targets to improve cardiovascular outcome.
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http://dx.doi.org/10.1159/000511279DOI Listing
November 2020

Outcomes in CME/CPD - Special Collection: How to make the "pyramid" a perpetuum mobile.

J Eur CME 2020 Oct 27;9(1):1832750. Epub 2020 Oct 27.

European Board for Accreditation in Cardiology (EBAC), Cologne, Germany.

Continuing medical education (CME) should not be an end in itself, but as expressed in Moore's pyramid, help to improve both individual patient and ultimately community, health. However, there are numerous barriers to translation of physician competence into improvements in community health. To enhance the effect CME may achieve in improving community health the authors suggest a kick-off/keep-on continuum of medical competence, and integration of aspects of public health at all levels from planning to delivery and outcomes measurement in CME.
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http://dx.doi.org/10.1080/21614083.2020.1832750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599014PMC
October 2020

Percutaneous left ventricular assist support is associated with less pulmonary congestion and lower rate of pneumonia in patients with cardiogenic shock.

Open Heart 2020 11;7(2)

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany

Objectives: The aim of this study was to investigate the impact of acute left ventricular unloading by percutaneous left ventricular assist device on pulmonary congestion and pneumonia in patients with cardiogenic shock (CS).

Methods: In this retrospective study, we analysed patients with CS who received the Impella percutaneous left ventricular assist device (n=50) compared with those who received intra-aortic balloon pump (IABP) support (n=50). Pulmonary congestion was longitudinally assessed while on support by calculating characteristic findings on the chest X-ray using the Halperin score. The rate of pneumonia and early mortality were assessed as a secondary endpoint.

Results: The groups (Impella vs IABP) did not differ in terms of age, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology, Chronic Health Evaluation (APACHE) II score or serum lactate levels. Pulmonary congestion decreased in patient treated with Impella at each time point postimplantation. No change in congestion status was observed in patients supported with IABP. Multivariate analysis indicated Impella support as an independent predictor for pulmonary decongestion (OR 4.06, 95% CI 1.15 to 14.35, p=0.030). The rate of early pneumonia was lower in the Impella group compared with the IABP group (54% vs 74%, p=0.037). Failure of pulmonary decongestion during mechanical circulatory support independently predicted early pneumonia (OR 0.28, 95% CI 0.12 to 0.70, p=0.006).

Conclusion: Pulmonary decongestion may facilitate treatment of pneumonia in patients with CS. Left ventricular unloading by Impella device might support pulmonary decongestion, although a larger prospective trial in this patient population is required.
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http://dx.doi.org/10.1136/openhrt-2020-001385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607612PMC
November 2020

Sex-specific outcome disparities in very old patients admitted to intensive care medicine: a propensity matched analysis.

Sci Rep 2020 10 29;10(1):18671. Epub 2020 Oct 29.

Department of Cardiology, Pulmonology and Angiology, University Hospital, Moorenstraße 5, 40225, Duesseldorf, Germany.

Female and male very elderly intensive patients (VIPs) might differ in characteristics and outcomes. We aimed to compare female versus male VIPs in a large, multinational collective of VIPs with regards to outcome and predictors of mortality. In total, 7555 patients were included in this analysis, 3973 (53%) male and 3582 (47%) female patients. The primary endpoint was 30-day-mortality. Baseline characteristics, data on management and geriatric scores including frailty assessed by Clinical Frailty Scale (CFS) were documented. Two propensity scores (for being male) were obtained for consecutive matching, score 1 for baseline characteristics and score 2 for baseline characteristics and ICU management. Male VIPs were younger (83 ± 5 vs. 84 ± 5; p < 0.001), less often frail (CFS > 4; 38% versus 49%; p < 0.001) but evidenced higher SOFA (7 ± 6 versus 6 ± 6 points; p < 0.001) scores. After propensity score matching, no differences in baseline characteristics could be observed. In the paired analysis, the mortality in male VIPs was higher (mean difference 3.34% 95%CI 0.92-5.76%; p = 0.007) compared to females. In both multivariable logistic regression models correcting for propensity score 1 (aOR 1.15 95%CI 1.03-1.27; p = 0.007) and propensity score 2 (aOR 1.15 95%CI 1.04-1.27; p = 0.007) male sex was independently associated with higher odds for 30-day-mortality. Of note, male gender was not associated with ICU mortality (OR 1.08 95%CI 0.98-1.19; p = 0.14). Outcomes of elderly intensive care patients evidenced independent sex differences. Male sex was associated with adverse 30-day-mortality but not ICU-mortality. Further research to identify potential sex-specific risk factors after ICU discharge is warranted.Trial registration: NCT03134807 and NCT03370692; Registered on May 1, 2017 https://clinicaltrials.gov/ct2/show/NCT03370692 .
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http://dx.doi.org/10.1038/s41598-020-74910-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596065PMC
October 2020

Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking.

Pflugers Arch 2020 12 23;472(12):1733-1742. Epub 2020 Oct 23.

Institute of Neurophysiology, Medical Faculty, University of Düsseldorf, Universitätsstr 1, 40225, Düsseldorf, Germany.

The hyperpolarization-activated cation current I is a key determinant for cardiac pacemaker activity. It is conducted by subunits of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel family, of which HCN4 is predominant in mammalian heart. Both loss-of-function and gain-of-function mutations of the HCN4 gene are associated with sinus node dysfunction in humans; however, their functional impact is not fully understood yet. Here, we sought to characterize a HCN4 V759I variant detected in a patient with a family history of sick sinus syndrome. The genomic analysis yielded a mono-allelic HCN4 V759I variant in a 49-year-old woman presenting with a family history of sick sinus syndrome. This HCN4 variant was previously classified as putatively pathogenic because genetically linked to sudden infant death syndrome and malignant epilepsy. However, detailed electrophysiological and cell biological characterization of HCN4 V759I in Xenopus laevis oocytes and embryonic rat cardiomyocytes, respectively, did not reveal any obvious abnormality. Voltage dependence and kinetics of mutant channel activation, modulation of cAMP-gating by the neuronal HCN channel auxiliary subunit PEX5R, and cell surface expression were indistinguishable from wild-type HCN4. In good agreement, the clinically likewise affected mother of the patient does not exhibit the reported HCN4 variance. HCN4 V759I resembles an innocuous genetic HCN channel variant, which is not sufficient to disturb cardiac pacemaking. Once more, our work emphasizes the importance of careful functional interpretation of genetic findings not only in the context of hereditary cardiac arrhythmias.
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http://dx.doi.org/10.1007/s00424-020-02481-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691308PMC
December 2020

Cardiac magnetic resonance T2 mapping and feature tracking in athlete's heart and HCM.

Eur Radiol 2020 Oct 15. Epub 2020 Oct 15.

Department of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University Düsseldorf, Moorenstraße 5, Düsseldorf, 40225, Germany.

Objectives: Distinguishing hypertrophic cardiomyopathy (HCM) from left ventricular hypertrophy (LVH) due to systematic training (athlete's heart, AH) from morphologic assessment remains challenging. The purpose of this study was to examine the role of T2 mapping and deformation imaging obtained by cardiovascular magnetic resonance (CMR) to discriminate AH from HCM with (HOCM) or without outflow tract obstruction (HNCM).

Methods: Thirty-three patients with HOCM, 9 with HNCM, 13 strength-trained athletes as well as individual age- and gender-matched controls received CMR. For T2 mapping, GRASE-derived multi-echo images were obtained and analyzed using dedicated software. Besides T2 mapping analyses, left ventricular (LV) dimensional and functional parameters were obtained including LV mass per body surface area (LVMi), interventricular septum thickness (IVS), and global longitudinal strain (GLS).

Results: While LVMi was not significantly different, IVS was thickened in HOCM patients compared to athlete's. Absolute values of GLS were significantly increased in patients with HOCM/HNCM compared to AH. Median T2 values were elevated compared to controls except in athlete's heart. ROC analysis revealed T2 values (AUC 0.78) and GLS (AUC 0.91) as good parameters to discriminate AH from overall HNCM/HOCM.

Conclusion: Discrimination of pathologic from non-pathologic LVH has implications for risk assessment of competitive sports in athletes. Multiparametric CMR with parametric T2 mapping and deformation imaging may add information to distinguish AH from LVH due to HCM.

Key Points: • Structural analyses using T2 mapping cardiovascular magnetic resonance imaging (CMR) may help to further distinguish myocardial diseases. • To differentiate pathologic from non-pathologic left ventricular hypertrophy, CMR including T2 mapping was obtained in patients with hypertrophic obstructive/non-obstructive cardiomyopathy (HOCM/HNCM) as well as in strength-trained athletes. • Elevated median T2 values in HOCM/HNCM compared with athlete's may add information to distinguish athlete's heart from pathologic left ventricular hypertrophy.
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http://dx.doi.org/10.1007/s00330-020-07289-4DOI Listing
October 2020

Risk of mortality following transcatheter aortic valve replacement for low-flow low-gradient aortic stenosis.

Clin Res Cardiol 2021 Mar 14;110(3):391-398. Epub 2020 Oct 14.

Heart Center Bonn, Department of Medicine II, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Background: Low-flow low-gradient (LF-LG) aortic stenosis (AS) is associated with high mortality, even after transcatheter aortic valve replacement (TAVR). Further knowledge of risk indicators is needed and a clinical risk score would be desirable for optimizing patient selection and therapeutic strategy.

Methods: The study cohort comprised of 219 consecutive LF-LG AS patients undergoing TAVR from 2008 to 2018 in two high-volume German centers. Predictive factors for one-year all-cause mortality were defined according to a Cox proportional hazard model.

Results: At one-year follow-up after TAVR, 28% of patients had died. A multivariate model revealed six independent predictors of one-year mortality: history of myocardial infarction (HR 2.05, 95%CI 1.13-3.72), eGFR < 30 ml/min/1.73m (HR 2.75, 95%CI 1.48-5.11), tricuspid regurgitation moderate or more (HR 2.06, 95%CI 1.14-3.72), stroke volume index < 25 mL/m (HR 2.03, 95%CI 1.14-3.62), self-expandable device (HR 2.72, 95%CI 1.17-6.27), and non-transfemoral approach (HR 3.42, 95%CI 1.28-9.14). The Rhineland Risk Score (RRS) consisting of these variables (c statistic 0.75, 95%CI 0.68-0.82, p < 0.001) was superior to the EuroSCORE II (c statistic 0.63) and STS-PROM score (c statistic 0.69) at predicting one-year mortality. Patients with a RRS ≥ 8 had a prohibitive risk of one-year mortality of 67.6% (95%CI 52.0-82.4%).

Conclusion: In patients with LF-LG AS, history of myocardial infarction, renal dysfunction, tricuspid regurgitation, a low stroke volume index, self-expandable device, and non-femoral approach were associated with increased 1-year mortality after TAVR. The RRS might serve as a helpful tool for risk prediction and patient selection for TAVR in patients with LF-LG AS.
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http://dx.doi.org/10.1007/s00392-020-01752-4DOI Listing
March 2021