Charakterisierung eines transgenen Mausmodells zur Kooperation zwischen NFATc1 und KrasG12D in der Pankreaskarzinogenese

Der Nuclear Factor of Activated T-Cells (NFAT) c1 ist ein onkogener Transkriptionsfaktor, der im humanen Pankreaskarzinom überexprimiert wird. In Kooperation mit unterschiedlichen Partnerproteinen beeinflusst NFATc1 die Expression von Genen der Zellzyklus-Regulation und fördert so das Tumorwachstum. Im transgenen Mausmodell konnte zwar eine wachstumsregulierende Funktion von NFATc1 bestätigt werden, allerdings führte die Pankreas-spezifische Expression von konstitutiv nukleärem NFATc1 (c.n.NFATc1) weder zur Ausbildung prämaligner PanIN-Läsionen noch zur Entwicklung invasiver Karzinome. Als entscheidender Faktor für die Initiation der Pankreaskarzinogenese gilt eine aktivierende Mutation des Proto-Onkogens Kras, die in mehr als 90% der humanen Pankreaskarzinome vorliegt und dessen Expression in transgenen Mausmodellen zur Ausbildung von Vorläuferläsionen führt. Eine alleinige Mutation von Kras führt allerdings nur sporadisch zur Entwicklung invasiver Pankreaskarzinome. Daher wurde postuliert, dass für die weitere Progression zum invasiven Karzinom weitere genetische oder epigenetische Ereignisse essentiell sind. Ziel dieser Arbeit war es, die potentielle onkogene Kooperation von NFATc1 und KrasG12D in vivo zu überprüfen, zu charakterisieren und die zugrunde liegenden Mechanismen zu entschlüsseln. Dazu wurde eine im humanen Pankreaskarzinom häufig vorkommende Situation (ca.70%) – eine NFATc1-Überexpression und Kras-Mutation - im Mausmodell genetisch induziert. Es zeigte sich, dass die gemeinsame Aktivierung beider Onkogene (c.n.NFATc1;KrasG12D;P48/PDX1-Cre) in einer massiven Akzeleration der Karzinogenese mit Entstehung duktaler Adenokarzinome des Pankreas mündet. Auf histologischer Ebene rekapitulieren die Karzinome die humane Pankreaskarzinogenese mit Ausbildung früher azinär-duktaler Metaplasien, benigner Zwischenstadien (PanIN1-3 Läsionen) und der Entwicklung duktaler Adenokarzinome. In Analogie zur humanen Karzinogenese zeigten die Tumore eine hohe Proliferationsrate und eine Aktivierung zentraler onkogener Signalwege wie z.B. dem Notch-Signalweg. Hierbei scheint die NFATc1-abhängige Überwindung der KrasG12D-induzierten Seneszenz durch Inaktivierung des Tumorsuppressors p16INK4A eine Progression der Karzinogenese zu begünstigen. Zusammenfassend konnte eine onkogene Kooperation zwischen Kras und NFATc1 in der Karzinogenese des Pankreas aufgezeigt werden. Eine gezielte Intervention des NFATc1 Signalweges könnte ein neue Strategie in der Behandlung des Pankreaskarzinoms darstellen

Charakterisierung eines transgenen Mausmodells zur Kooperation zwischen NFATc1 und KrasG12D in der Pankreaskarzinogenese

Der Nuclear Factor of Activated T-Cells (NFAT) c1 ist ein onkogener Transkriptionsfaktor, der im humanen Pankreaskarzinom überexprimiert wird. In Kooperation mit unterschiedlichen Partnerproteinen beeinflusst NFATc1 die Expression von Genen der Zellzyklus-Regulation und fördert so das Tumorwachstum. Im transgenen Mausmodell konnte zwar eine wachstumsregulierende Funktion von NFATc1 bestätigt werden, allerdings führte die Pankreas-spezifische Expression von konstitutiv nukleärem NFATc1 (c.n.NFATc1) weder zur Ausbildung prämaligner PanIN-Läsionen noch zur Entwicklung invasiver Karzinome. Als entscheidender Faktor für die Initiation der Pankreaskarzinogenese gilt eine aktivierende Mutation des Proto-Onkogens Kras, die in mehr als 90% der humanen Pankreaskarzinome vorliegt und dessen Expression in transgenen Mausmodellen zur Ausbildung von Vorläuferläsionen führt. Eine alleinige Mutation von Kras führt allerdings nur sporadisch zur Entwicklung invasiver Pankreaskarzinome. Daher wurde postuliert, dass für die weitere Progression zum invasiven Karzinom weitere genetische oder epigenetische Ereignisse essentiell sind. Ziel dieser Arbeit war es, die potentielle onkogene Kooperation von NFATc1 und KrasG12D in vivo zu überprüfen, zu charakterisieren und die zugrunde liegenden Mechanismen zu entschlüsseln. Dazu wurde eine im humanen Pankreaskarzinom häufig vorkommende Situation (ca.70%) – eine NFATc1-Überexpression und Kras-Mutation - im Mausmodell genetisch induziert. Es zeigte sich, dass die gemeinsame Aktivierung beider Onkogene (c.n.NFATc1;KrasG12D;P48/PDX1-Cre) in einer massiven Akzeleration der Karzinogenese mit Entstehung duktaler Adenokarzinome des Pankreas mündet. Auf histologischer Ebene rekapitulieren die Karzinome die humane Pankreaskarzinogenese mit Ausbildung früher azinär-duktaler Metaplasien, benigner Zwischenstadien (PanIN1-3 Läsionen) und der Entwicklung duktaler Adenokarzinome. In Analogie zur humanen Karzinogenese zeigten die Tumore eine hohe Proliferationsrate und eine Aktivierung zentraler onkogener Signalwege wie z.B. dem Notch-Signalweg. Hierbei scheint die NFATc1-abhängige Überwindung der KrasG12D-induzierten Seneszenz durch Inaktivierung des Tumorsuppressors p16INK4A eine Progression der Karzinogenese zu begünstigen. Zusammenfassend konnte eine onkogene Kooperation zwischen Kras und NFATc1 in der Karzinogenese des Pankreas aufgezeigt werden. Eine gezielte Intervention des NFATc1 Signalweges könnte ein neue Strategie in der Behandlung des Pankreaskarzinoms darstellen

Head-to-Head Comparison of the Incremental Predictive Value of The Three Established Risk Markers, Hs-troponin I, C-Reactive Protein, and NT-proBNP, in Coronary Artery Disease

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

Diastolic dysfunction in individuals with and without heart failure with preserved ejection fraction

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

Aortic root dimensions as a correlate for aortic regurgitation’s severity

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

Transthoracic echocardiographic reference values of the aortic root: results from the Hamburg City Health Study

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

Diagnostic Value of Soluble Urokinase-Type Plasminogen Activator Receptor in Addition to High-Sensitivity Troponin I in Early Diagnosis of Acute Myocardial Infarction

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

Heart failure in the general population and impact of the 2021 European Society of Cardiology Heart Failure Guidelines

Abstract 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

Repeat pulmonary vein isolation and anterior line ablation using a novel point-by-point pulsed-field ablation system

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

The association between coffee consumption and periodontitis: a cross-sectional study of a northern German population

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 &amp;gt; 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