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Background: Short and rare episodes of atrial fibrillation (AF) are commonly detected using implanted devices (device-detected AF) in patients with prior stroke or transient ischemic attack (TIA). The effectiveness and safety of oral anticoagulation in patients with prior stroke or TIA and device-detected AF but with no ECG-documented AF is unclear., Methods and Results: This prespecified analysis of the NOAH-AFNET 6 (Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) trial with post hoc elements assessed the effect of oral anticoagulation in patients with device-detected AF with and without a prior stroke or TIA in the randomized, double-blind, double-dummy NOAH-AFNET 6 trial. Outcomes were stroke, systemic embolism, and cardiovascular death (primary outcome) and major bleeding and death (safety outcome). A prior stroke or TIA was found in 253 patients with device-detected AF randomized in the NOAH-AFNET 6 (mean age, 78 years; 36.4% women). There was no treatment interaction with prior stroke or TIA for any of the primary and secondary time-to-event outcomes. In patients with a prior stroke or TIA, 14 out of 122 patients experienced a primary outcome event with anticoagulation (5.7% per patient-year). Without anticoagulation, there were 16 out of 131 patients with an event (6.3% per patient-year). The rate of stroke was lower than expected (anticoagulation: 4 out of 122 [1.6% per patient-year]; no anticoagulation: 6 out of 131 [2.3% per patient-year]). Numerically, there were more major bleeding events with anticoagulation in patients with prior stroke or TIA (8 out of 122 patients) than without anticoagulation (2 out of 131 patients)., Conclusions: Anticoagulation appears to have ambiguous effects in patients with device-detected AF and a prior stroke or TIA in this hypothesis-generating analysis of the NOAH-AFNET 6 in the absence of ECG-documented AF, partially due to a low rate of stroke without anticoagulation.

Background: Pulsed-field ablation (PFA) is a nonthermal energy source for ablation of cardiac arrhythmias. This study investigated the prospective outcomes of a novel PFA generator in conjunction with a commercially available, contact force-sensing, focal ablation catheter., Objective: The purpose of this study was to assess the feasibility, safety, and lesion characteristics of point-by-point PFA in consecutive patients undergoing repeat ablation of atrial fibrillation (AF)., Methods: The study involved reisolation of pulmonary veins (PVs) with electrical reconnection and the creation of an anterior line (AL) in patients with anterior substrate or durable pulmonary vein isolation (PVI)., Results: In 24 patients (46% female; mean age 67 ± 10 years; 67% persistent AF), successful reisolation of 27 of 27 reconnected PVs (100%) was performed. In 19 patients, AL ablation was performed, with bidirectional block in 16 (84%), median ablation time 26 [21, 33] minutes, and first-pass bidirectional block in 13 patients (68%). Acute AL reconduction occurred in 8 of 19 patients (42%). Among these 8 patients, a subsequent sustained block of the AL was achieved in 5 (63%). Ultra-high-density electroanatomic mapping revealed homogeneous but relatively large low-voltage areas in the ablated regions. Median procedural, left atrial dwell, and fluoroscopy times were 100 [90, 109] minutes, 83 [75, 98] minutes, and 10 [8, 13] minutes, respectively. No major or minor complications occurred., Conclusion: This study demonstrated feasibility, acute efficacy, and safety of point-by-point PFA for repeat PVI and AL ablation. Further studies are warranted to assess the long-term durability and comparison with established ablation methods., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Arterial hypertension is considered a risk factor for the development of heart failure. Here we investigate cross-sectional associations of systolic and diastolic blood pressure with subtle functional and morphological changes of left ventricular echocardiographic parameters representing early dysfunction in three representative German population-based studies. We assessed 26,719 individuals without symptomatic heart failure from the Hamburg City Health Study (HCHS, n = 7396, derivation cohort), the Gutenberg Health Study (GHS, 14,715, validation cohort) and the Study of Health in Pomerania (SHIP, 4608, validation cohort). Multivariable linear regression analyses with systolic and diastolic blood pressure as continuous exposure variables were adjusted for common cardiovascular risk factors and antihypertensive medication. Both systolic and diastolic blood pressure were consistently associated with measures of left ventricular hypertrophy (β per standard deviation (SD) for LV mass (g) and systolic blood pressure: 5.09 (p < 0.001); diastolic blood pressure: 2.29 (p < 0.001) in HCHS). Systolic blood pressure correlated with declining diastolic function (β per SD for E/e': 0.29, p < 0.001 in HCHS) and diastolic blood pressure with declining systolic function (β per SD for LVEF, in %: - 0.15; p = 0.041 in HCHS) in all cohorts. Pending further validation, our results from three independent German population samples suggest differential effects of systolic versus diastolic blood pressure on left ventricular structure and function., (© 2023. Springer Nature Limited.)

Competing Interests: Disclosures Dr Wenzel received funding from the German Foundation of Heart Research (F/29/19) and travel grants from Boston Scientific in each case unrelated to this project. Dr Lemoine received a research grant from Farapulse and was supported by the Research Promotion Fund of the Faculty of Medicine unrelated to this project. Dr Metzner received speaker’s honoraria and travel grants from Medtronic, Biosense Webster, Boston Scientific, and EPD Solutions/Philips and a research grant from Farapulse. Dr Rillig received travel grants, speaker fees, and consultant fees from Biosense Webster, Medtronic, Cardiofocus, Ablamap, and EPD Solutions/Philips (KODEX-EPD). Dr Reissmann received speaker’s honoraria and travel grants from Medtronic. The other authors report no conflicts.

Coffee, next to water the most widespread beverage, is attributed both harmful and protective characteristics concerning cardiovascular health. This study aimed to evaluate associations of coffee consumption with cardiac biomarkers, echocardiographic, electrocardiographic parameters and major cardiovascular diseases. We performed a cross-sectional analysis of 9009 participants of the population-based Hamburg City Health Study (HCHS), enrolled between 2016 and 2018 median age 63 [IQR: 55; 69] years. Coffee consumption was classified into three groups: < 3 cups/day (low), 3-4 cups/day (moderate), > 4 cups/day (high). In linear regression analyses adjusted for age, sex, body mass index, diabetes, hypertension, smoking, and additives, high coffee consumption correlated with higher LDL-cholesterol (β = 5.92; 95% CI 2.95, 8.89; p < 0.001). Moderate and high coffee consumption correlated with lower systolic (β = - 1.91; 95% CI - 3.04, - 0.78; p = 0.001; high: β = - 3.06; 95% CI - 4.69, - 1.44; p < 0.001) and diastolic blood pressure (β = - 1.05; 95% CI - 1.67, - 0.43; p = 0.001; high: β = - 1.85; 95% CI - 2.74, - 0.96; p < 0.001). Different levels of coffee consumption did neither correlate with any investigated electrocardiographic or echocardiographic parameter nor with prevalent major cardiovascular diseases, including prior myocardial infarction and heart failure. In this cross-sectional analysis, high coffee consumption correlated with raised LDL-cholesterol levels and lower systolic and diastolic blood pressure. However, major cardiovascular diseases including heart failure and its diagnostic precursors were not associated with coffee consumption, connoting a neutral role of coffee in the context of cardiovascular health., (© 2023. The Author(s).)

Aims: Three Tesla (T) magnetic resonance imaging (MRI) provides critical imaging information for many conditions. Owing to potential interactions of the magnetic field, it is largely withheld from patients with cardiac implantable electronic devices (CIEDs). Therefore, we assessed the safety of 3T MRI in patients with '3T MRI-conditional' and 'non-3T MRI-conditional' CIEDs., Methods and Results: We performed a retrospective single-centre analysis of clinically indicated 3T MRI examinations in patients with conventional pacemakers, cardiac resynchronization devices, and implanted defibrillators from April 2020 to May 2022. All CIEDs were interrogated and programmed before and after scanning. Adverse events included all-cause death, arrhythmias, loss of capture, inappropriate anti-tachycardia therapies, electrical reset, and lead or generator failure during or shortly after MRI. Changes in signal amplitude and lead impedance were systematically assessed. Statistics included median and interquartile range. A total of 132 MRI examinations were performed on a 3T scanner in 97 patients. Thirty-five examinations were performed in patients with 'non-3T MRI-conditional' CIEDs. Twenty-six scans were performed in pacemaker-dependent patients. No adverse events occurred during or shortly after MRI. P-wave or R-wave reductions ≥ 50 and ≥ 25%, respectively, were noted after three (2.3%) scans, all in patients with '3T MRI-conditional' CIEDs. Pacing and shock impedance changed by ± 30% in one case (0.7%). Battery voltage and stimulation thresholds did not relevantly change after MRI., Conclusion: Pending verification in independent series, our data suggest that clinically indicated MRI scans at 3T field strength should not be withheld from patients with cardiac pacemakers or defibrillators., Competing Interests: Conflict of interest: Dr Fluschnik received a grant from Biotronik, all outside this submitted work. Dr Tahir has no disclosures to declare. Dr Erley has no disclosures to declare. Dr Müllerleile has no disclosures to declare. Dr Metzner received consultant fees from Medtronic, Biosense Webster and Lecture honoraria from Medtronic, Biosense Webster, Boston Scientific, Cardiofocus, Bayer. Dr Wenzel has no disclosures to declare. Dr Guerreiro has no disclosures to declare. Dr Adam has no disclosures to declare. Dr Blankenberg has received speakers fee from Medtronic, Pfizer, Roche, Novartis, SiemensDiagnostics (unrelated to the submitted work). Dr Kirchhof receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past, but not in the last three years (unrelated to the submitted work). Dr Kirchhof is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Dr Tönnis has no disclosures to declare. Dr Nikorowitsch has no disclosures to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Despite associations of regular coffee consumption with fewer neurodegenerative disorders, its association with microstructural brain alterations is unclear. To address this, we examined the association of coffee consumption with brain MRI parameters representing vascular brain damage, neurodegeneration, and microstructural integrity in 2316 participants in the population-based Hamburg City Health Study. Cortical thickness and white matter hyperintensity (WMH) load were measured on FLAIR and T1-weighted images. Microstructural white matter integrity was quantified as peak width of skeletonized mean diffusivity (PSMD) on diffusion-weighted MRI. Daily coffee consumption was assessed in five groups (<1 cup, 1-2 cups, 3-4 cups, 5-6 cups, >6 cups). In multiple linear regressions, we examined the association between brain MRI parameters and coffee consumption (reference group <1 cup). After adjustment for covariates, 3-4 cups of daily coffee were associated with lower PSMD ( p = 0.028) and higher cortical thickness ( p = 0.015) compared to <1 cup. Moreover, 1-2 cups per day was also associated with lower PSMD ( p = 0.022). Associations with WMH load or other groups of coffee consumption were not significant ( p > 0.05). The findings indicate that regular coffee consumption is positively associated with microstructural white matter integrity and cortical thickness. Further research is necessary to determine longitudinal effects of coffee on brain microstructure.

Aims: Data on the association between periodontitis and preclinical cardiac alterations remain scarce. The aim of the current study is to determine if periodontitis is associated with morphological and functional cardiac changes measured by transthoracic echocardiography as well as different heart failure (HF) phenotypes., Methods: Participants from the population-based Hamburg City Health Study [ClinicalTrial.gov (NCT03934957)], who underwent transthoracic echocardiography and periodontal screening were included. Periodontitis was classified according to Eke and Page (none/mild, moderate, severe). The 2021 ESC HF guidelines were applied and HF was classified into HF with preserved ejection fraction (HFpEF, ejection fraction ≥50%), HF with mid-range and reduced ejection fraction [HF(m)rEF, ejection fraction <50%], and HF in general [HFpEF and HF(m)rEF]. Due to limited size, all subjects with LVEF <50% and symptoms or signs of HF were classified as HF with reduced and mildly reduced ejection fraction [HF(m)rEF]., Results: Within 6209 participants with full periodontal examination, we identified an overlap of n = 167 participants with periodontitis and HF. Participants with severe periodontitis showed a higher burden of cardiovascular risk factors (men at advanced age, diabetes mellitus, hypertension) when compared with participants with none/mild periodontitis. After adjustment for age, sex, body mass index, smoking, diabetes, hypertension, atrial fibrillation, and coronary artery disease, severe periodontitis was significantly associated with HF(m)rEF (odds ratio: 3.16; 95% CI: 1.21, 8.22; P = 0.019), although no association was found for HFpEF and HF in general., Conclusions: The current study demonstrated that severe periodontitis was significantly associated with HF(m)rEF, although no relevant associations were found with HFpEF and HF in general as well as echocardiographic variables. The results implicate a potential target group, who need special attention from cooperating physicians and dentists. Future studies are warranted to verify whether systemic inflammation could be the link between the two diseases., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Transthoracic echocardiography (TTE) and cine cardiac magnetic resonance imaging (CMR) are established imaging methods of the aortic root. We aimed to evaluate the comparability of measurements in TTE and standard cine CMR sequences of the aortic root. Our study included 741 subjects (mean age 63.5 ± 8 years, 43.7% female) from the Hamburg City Health Study (HCHS). Subjects underwent CMR and TTE. Aortic root measurements were performed at the level of the aortic annulus (AoAn), sinus of Valsalva (SoV), and sinotubular junction (STJ) by standard cine CMR in left ventricular long axis and left ventricular outflow tract view. Measurements were performed applying the leading-edge to leading-edge (LL) convention and inner-edge to inner-edge (II) convention in TTE and the II convention in CMR. Inter correlation coefficients (ICCs) demonstrated high inter- and intraobserver reproducibility for CMR and TTE measurements of SoV and STJ (ICCs 0.9-0.98) and moderate reproducibility for AoAn (ICCs 0.68-0.91). CMR measurements of SoV and STJ showed strong agreement with TTE: while correlations were comparable (r = 0.75-0.85) bias was lower with TTE II (bias - 0.1 to - 0.74) versus TTE LL measurements (mean bias - 1.49 to - 2.58 mm). The agreement for AoAn was fair (r = 0.51-0.57) with variable bias (mean bias 0.39-3.9). Standard cine CMR and TTE derived aortic root measurements are reproducible and comparable with higher agreement for TTE II instead of LL measurements. These results support an interchangeable application of TTE and standard CMR for screening of aortic root diseases thereby possibly reducing redundant multimodality imaging., (© 2022. The Author(s).)

Aim: The diagnosis of heart failure (HF) has been refined in several steps in recent years, reflecting evolving diagnostic and therapeutic approaches. The European Society of Cardiology (ESC) recently published a modified definition of HF in the 2021 heart failure (HF) guidelines. The impact of this new diagnostic algorithm on the prevalence of HF is not known. The aim of this study was to describe the contemporary prevalence of HF in a representative, completely phenotyped sample from the general population., Methods and Results: This analysis was conducted among 7074 participants (aged 45-78 years, 51.5% women) from the population-based Hamburg City Health Study. Compared with the 2016 version, HF prevalence increased with the 2021 HF guidelines from 4.31% to 4.83% (12% increase). This increase was driven by a higher number of subjects with HF with reduced/mildly-reduced ejection fraction (0.47% to 0.52%; 1.37% to 2.12%), while the number of subjects with HF with preserved ejection fraction decreased from 2.46% to 2.19%. Importantly, this did not impact the known risk factor profiles of the phenotypes. Although four drugs are recommended for all subjects with HFrEF in the new guidelines, several adjunctive therapies are recommended for dedicated cases/scenarios (e.g. <1% eligibility for ivabradine/vericiguat/devices)., Conclusion: Heart failure remains common in a contemporary general population sample. The number of patients with HF will increase when the current diagnostic criteria are applied. This offers opportunities to initiate preventive therapies, especially in patients with HFmrEF and HFrEF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: Left ventricular diastolic dysfunction (DD), a common finding in the general population, is considered to be associated with heart failure with preserved ejection faction (HFpEF). Here we evaluate the prevalence and correlates of DD in subjects with and without HFpEF in a middle-aged sample of the general population., Methods and Results: From the first 10,000 participants of the population-based Hamburg City Health Study (HCHS), 5913 subjects (mean age 64.4 ± 8.3 years, 51.3% females), qualified for the current analysis. Diastolic dysfunction (DD) was identified in 753 (12.7%) participants. Of those, 11.2% showed DD without HFpEF (ALVDD) while 1.3% suffered from DD with HFpEF (DDwHFpEF). In multivariable regression analysis adjusted for major cardiovascular risk factors, ALVDD was associated with arterial hypertension (OR 2.0, p < 0.001) and HbA1c (OR 1.2, p = 0.007). Associations of both ALVDD and DDwHFpEF were: age (OR 1.7, p < 0.001; OR 2.7, p < 0.001), BMI (OR 1.2, p < 0.001; OR 1.6, p = 0.001), and left ventricular mass index (LVMI). In contrast, female sex (OR 2.5, p = 0.006), atrial fibrillation (OR 2.6, p = 0.024), CAD (OR 7.2, p < 0.001) COPD (OR 3.9, p < 0.001), and QRS duration (OR 1.4, p = 0.005) were strongly associated with DDwHFpEF but not with ALVDD., Conclusion: The prevalence of DD in a sample from the first 10,000 participants of the population-based HCHS was 12.7% of whom 1.3% suffered from HFpEF. DD with and without HFpEF showed significant associations with different major cardiovascular risk factors and comorbidities warranting further research for their possible role in the formation of both ALVDD and DDwHFpEF., (© 2021. The Author(s).)

Background: Positive and negative influences on oral health are attributed to coffee consumption. The aim of the current study is to evaluate the association between coffee consumption and periodontitis in the general population of Hamburg., Methods: A total of 6,209 participants from the Hamburg City Health Study were included in this cross-sectional study. Information on coffee consumption was collected using a food frequency questionnaire. Periodontal examination included assessment of dental care ability via Plaque Index, measurement of pocket depth, gingival recession, and bleeding on probing. Classification was based on the criteria of Eke and Page. Ordinal logistic regression models were performed unadjusted and adjusted for confounding variables., Results: Periodontal cohort consists of 6,209 participants, presenting either none/mild (n = 1,453, 39.6% men, 2.4% strong coffee drinkers), moderate (n = 3,580, 49.3% men, 3.3% strong coffee drinkers), or severe (n = 1,176, 60.9% men, 5.0% strong coffee drinkers) periodontitis. There was a significant association between strong coffee consumption (≥ 7or more cups/day) and periodontitis (OR: 1.51; CI: 1.07, 2.12; p > 0.001), compared with low coffee consumption. Conversely, moderate coffee consumption was not associated with periodontitis, compared with low coffee consumption., Conclusion: and clinical relevance. In this cross-sectional study of a northern German population, strong coffee consumption was significantly associated with periodontitis. Influence of changes in coffee consumption on periodontal disease etiology/progression should be investigated in future prospective study designs, in order to identify strong coffee consumption as a potential risk factor of periodontitis., (© 2021. The Author(s).)

To evaluate the prevalence of aortic regurgitation (AR) and associations between the individual aortic root components and AR severity in the general population. The study included the first 10,000 participants of the population-based Hamburg City Health Study (HCHS) of whom 8259 subjects, aged 62.23 ± 8.46 years (51.3% females), enrolled 2016-2018, provided echocardiographic data. 69 subjects with bicuspid valves and 23 subjects with moderate/severe aortic stenosis were excluded. Aortic root dimensions were measured using state-of-the-art cardiac ultrasound, including the aortic annulus, sinus of Valsalva, sinotubular junction (STJ), and ascending aorta, in diastole and systole. The distribution of AR was: 932 (11.4%) mild, 208 (2.5%) moderate, and 20 (0.24%) severe. Patients with moderate or severe AR were predominantly male at advanced age who had hypertension, coronary artery disease, atrial fibrillation, and renal dysfunction. Increasing AR severity correlated with higher absolute and indexed aortic root diameters (e.g., end-diastolic sinus of Valsalva for no-mild-moderate-severe AR in mm ± standard deviation: 34.06 ± 3.81; 35.65 ± 4.13; 36.13 ± 4.74; 39.67 ± 4.61; p < 0.001). In binary logistic regression analysis, all aortic root components showed significant associations with moderate/severe AR. Mid-systolic STJ showed the strongest association with moderate/severe AR (OR 1.33, 95% confidence interval 1.25-1.43, p < 0.001). AR was prevalent in 14.2%, of whom 2.8% showed moderate/severe AR. All assessed aortic root diameters correlated with the prevalence and severity of AR. STJ diameter had the strongest association with moderate/severe AR possibly reflecting the pathophysiological impact of an increasingly dilated STJ in the context of an ageing aorta., (© 2021. The Author(s).)

Objectives: This study aimed to assess the clinical outcome of the bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary obstruction (BASILICA) technique in a single-center patient cohort considered at high or prohibitive risk of transcatheter aortic valve implantation (TAVI)-induced coronary obstruction., Methods: Between October 2019 and January 2021, a total of 15 consecutive patients (age 81.0 [78.1, 84.4] years; 53.3% female; EuroSCORE II 10.6 [6.3, 14.8] %) underwent BASILICA procedure prior to TAVI at our institution. Indications for TAVI were degeneration of stented (n = 12, 80.0%) or stentless (n = 1, 6.7%) bioprosthetic aortic valves, or calcific stenosis of native aortic valves (n = 2, 13.3%), respectively. Individual risk of TAVI-induced coronary obstruction was assessed by pre-procedural computed tomography analysis. Procedural and 30-day outcomes were documented in accordance with Valve Academic Research Consortium (VARC)-2 criteria., Results: BASILICA was attempted for single left coronary cusp in 12 patients (80.0%), for single right coronary cusp in 2 patients (13.3%), and for both cusps in 1 patient (6.7%), respectively. The procedure was feasible in 13 patients (86.7%) resulting in effective prevention of coronary obstruction, whilst TAVI was performed without prior successful bioprosthetic leaflet laceration in two patients (13.3%). In one of these patients (6.7%), additional chimney stenting immediately after TAVI was performed. No all-cause deaths or strokes were documented after 30 days., Conclusion: The BASILICA technique appears to be a feasible, safe and effective concept to avoid iatrogenic coronary artery obstruction during TAVI in both native and bioprosthetic valves of patients at high or prohibitive risk. ClinicalTrials.gov Identifier: NCT04227002 (Hamburg AoRtic Valve cOhoRt)., (© 2021. The Author(s).)

Here we generate up-to-date reference values of transthoracic echocardiographic aortic root dimensions matched by sex, age, and body surface area (BSA) derived from the population-based Hamburg City Health Study (HCHS) cohort. In 1687 healthy subjects (mean age 57.1 ± 7.7, 681 male and 1006 female), derived from the first prospectively-recruited 10,000 HCHS participants, dimensions of the aortic root were measured in systole and diastole using state-of-the-art 2-dimensional transthoracic echocardiography. Diameters were assessed at four levels: aortic annulus, Sinus of Valsalva, sinotubular junction, and ascending aorta. Female sex was associated with significantly smaller absolute aortic root dimensions, while indexing for BSA resulted in a reverse effect at all levels. There was a strong age dependency of all aortic root diameters as well as aortic annulus/sinotubular junction ratio for both sexes. Multivariate analysis revealed age, sex, weight, height, and BSA to be significant determinants of aortic root size. Finally, formulas were generated for the calculation of individual aortic root reference values considering age, sex, weight, and height. We provide population-based reference values of aortic root diameters based on a standardized transthoracic echocardiographic protocol of the population-based HCHS which may support the diagnosis, monitoring, and treatment of aortic root disease., (© 2021. The Author(s).)

Aims: Heart failure with preserved ejection fraction (HFpEF) is common in patients presenting with dyspnoea. Recently, clinical tools were developed to facilitate the diagnosis of HFpEF. Here, we apply the European Society of Cardiology (ESC) 2016 heart failure guidelines and the H 2 FPEF and HFA-PEFF scores to a middle-aged sample of the general population and compared the different groups with each other., Methods and Results: This study included the first 10 000 participants of the population-based Hamburg City Health Study. A total of 5613 subjects, aged 62 ± 8.7 years (51.1% women), qualified for the analysis. Unexplained dyspnoea was present in 407 (7.3%) subjects. In those, the estimated prevalence of HFpEF was 20.4% (ESC 2016), 12.3% (H 2 FPEF), and 7.6% (HFA-PEFF). The majority of subjects was classified as HFpEF not excludable according to the HFA-PEFF (57.7%) and H 2 FPEF (59.2%) scores. For all algorithms, subjects diagnosed with HFpEF showed elevated age and body mass index as well as a higher prevalence of atrial fibrillation, diabetes, and arterial hypertension compared with those without HFpEF or HFpEF not excludable. The distribution of those co-morbidities and risk factors varied between the differently diagnosed HFpEF groups with the highest burden in the HFpEF group defined by the H 2 FPEF score. The overlap of subjects diagnosed with HFpEF according to the different algorithms was very limited., Conclusions: Unexplained dyspnoea is common in the middle-aged general population. The ESC 2016 algorithm and the H 2 FPEF and HFA-PEFF scores detect different, discordant subpopulations of probands with breathlessness. Further classification of the HFpEF syndrome is desirable., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background Risk stratification among patients with coronary artery disease (CAD) is of considerable interest due to the potential to guide secondary preventive therapies. Thus, we evaluated the predictive value of soluble urokinase-type plasminogen activator receptor (suPAR) levels for cardiovascular mortality and nonfatal myocardial infarction in patients with CAD. Methods and Results Plasma levels of suPAR were measured in a cohort of 1703 patients with documented CAD as evidenced by coronary angiography-including 626 patients with acute coronary syndrome and 1077 patients with stable angina pectoris. Cardiovascular death and/or nonfatal myocardial infarction were defined as main outcome measures. During a median follow-up of 3.5 years, suPAR levels reliably predicted cardiovascular death or myocardial infarction in CAD, evidenced by survival curves stratified for tertiles of suPAR levels. In Cox regression analyses, the hazard ratio for the prediction of cardiovascular death and/or myocardial infarction was 2.19 ( P <0.001) in the overall cohort and 2.56 in the acute coronary syndrome cohort ( P <0.001). Even after adjustment for common cardiovascular risk factors, renal function and the biomarkers C-reactive protein, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I suPAR still enabled a reliable prediction of cardiovascular death or myocardial infarction with a hazard ratio of 1.61 ( P =0.022) in the overall cohort and 2.22 ( P =0.005) in the acute coronary syndrome cohort. Conclusions SuPAR has a strong and independent prognostic value in secondary prevention settings, and thereby might represent a valuable biomarker for risk estimation in CAD.

Risk stratification among patients with coronary artery disease (CAD) is of considerable interest to potentially guide secondary preventive therapies. Cardiac troponins as well as C-reactive protein (hsCRP) and natriuretic peptides have emerged as biomarkers for risk stratification. The question remains if one of these biomarkers is superior in predicting adverse outcomes. Thus, we perform a head-to-head comparison between high-sensitivity troponin I (hsTnI), hsCRP, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with CAD. Plasma levels were measured in a cohort of 2193 patients with documented CAD. The main outcome measures were cardiovascular (CV) death and/or nonfatal myocardial infarction (MI). During a median follow-up of 3.8 years, all three biomarkers were associated with cardiovascular death and/or MI. After adjustments for conventional cardiovascular risk factors, the hazard ratio (HR) per standard deviation (SD) for the prediction of CV death and/or nonfatal MI was 1.39 [95% CI: 1.24-1.57, p < 0.001] for hsTnI, 1.41 [95% CI: 1.24-1.60, p < 0.001] for hsCRP, and 1.64 [95% CI: 1.39-1.92, p < 0.001] for NT-proBNP. However, upon further adjustments for the other two biomarkers, only NT-proBNP was still associated with the combined endpoint with an HR of 1.47 [95% CI: 1.19-1.82, p < 0.001]. Conclusively, NT-proBNP is reliably linked to CV death and MI in patients with CAD and provides incremental value beyond hsCRP and hsTnI.

Background: Early risk stratification of patients with suspected acute myocardial infarction (AMI) constitutes an unmet need in current daily clinical practice. We aimed to evaluate the predictive value of soluble urokinase-type plasminogen activator receptor (suPAR) levels for 1-year mortality in patients with suspected AMI., Methods and Results: suPAR levels were determined in 1314 patients presenting to the emergency department with suspected AMI. Patients were followed up for 12 months to assess all-cause mortality. Of 1314 patients included, 308 were diagnosed with AMI. Median suPAR levels did not differ between subjects with AMI compared to non-AMI (3.5 ng/ml vs. 3.2 ng/ml, p = 0.066). suPAR levels reliably predicted all-cause mortality after 1 year. Hazard ratio for 1-year mortality was 12.6 (p < 0.001) in the quartile with the highest suPAR levels compared to the first quartile. The prognostic value for 6-month mortality was comparable to an established risk prediction model, the Global Registry of Acute Coronary Events (GRACE) score, with an AUC of 0.79 (95% CI 0.72-0.86) for the GRACE score and 0.77 (95% CI 0.69-0.84) for suPAR. Addition of suPAR improved the GRACE score, as shown by integrated discrimination improvement statistics of 0.036 (p = 0.03) suggesting a further discrimination of events from non-events by the addition of suPAR., Conclusions: suPAR levels reliably predicted mortality in patients with suspected AMI., Study Registration: http://www.clinicaltrials.gov (NCT02355457).

The soluble urokinase-type plasminogen activator receptor (suPAR) is a new marker for immune activation and inflammation and may provide diagnostic value on top of established biomarkers in patients with suspected acute myocardial infarction (AMI). Here, we evaluate the diagnostic potential of suPAR levels on top of high-sensitivity troponin I (hs-TnI) in a cohort of patients with suspected AMI. A total of 1220 patients presenting to the emergency department with suspected AMI were included, of whom 245 were diagnosed with AMI. Median suPAR levels at admission were elevated in subjects with AMI compared to non-AMI (3.8 ng/mL vs 3.3 ng/mL, p = 0.001). In C-statistics, the area under the curve (AUC) regarding the diagnosis of AMI was low (0.57 at an optimized cut-off of 3.7 ng/mL). Moreover, baseline suPAR levels on top of troponin values at admission and hour 1 reduced the number of patients who were correctly ruled-out as non-AMI, and who were correctly ruled-in as AMI. Our study shows that circulating levels of suPAR on top of high-sensitivity troponin I do not improve the early diagnosis of AMI., Competing Interests: Neumann received honoraria from Siemens and Abbott Diagnostics. Blankenberg received honoraria from Abbott Diagnostics, Siemens, Thermo Fisher, and Roche Diagnostics and is a consultant for Thermo Fisher. Westermann reports personal fees from Bayer, Boehringer-Ingelheim, Berlin Chemie, Astra Zeneca, Biotronik and Novartis. Karakas received consultancy fees outside of the scope of this manuscript from Vifor Pharma, Amgen, Sanofi, and Astra-Zeneca, and furthermore, grant support from Abbott Diagnostics, Adrenomed AG and Vifor Pharma.

Unlabelled: Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras(G12D)-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in Kras(G12D) mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials., Significance: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies., (©2014 American Association for Cancer Research.)