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This study investigates the value of influencer endorsement within brand-owned social media posts in terms of engagement and online store performance. Specifically, it focuses on how endorser-caused engagement translates to online store performance. The authors examine metrics that capture short-term performance (online shop visits and immediate sales) by tracking immediate responses to social media posts. They conduct an empirical analysis based on real Facebook posts published over 1.5 years by a leading European online fashion retailer that targets young adults. To confirm results and shed light on the underlying mechanisms, the authors further conduct a randomized online experiment (N = 305) that mimics the field study. They find that influencer endorsements are associated with increased engagement and that engagement is associated with higher online store performance. The results show that endorsement negatively moderates the effect of engagement because it distracts from the products (i.e., the “vampire effect”). The authors conclude that consumers’ underlying intentions of engaging with social media posts vary, which implies that engagement caused by an endorser has less economic value than engagement motivated by other (e.g., product-related) reasons. From a practical perspective, social media brand post endorsement should be considered a tool for brand marketing rather than for performance marketing, and social media metrics should be interpreted with care, because not all engagement may help online store performance.

The association between aortic stiffness, cardiovascular risk factors and prognosis in patients with recent ST-elevation myocardial infarction (STEMI) is poorly understood. We analyzed the relationship between cardiovascular risk factors and arterial stiffening and assessed its prognostic significance in patients with recent STEMI. We prospectively enrolled 408 consecutive patients who sustained a first STEMI and underwent primary percutaneous coronary intervention (PPCI). Aortic pulse wave velocity (PWV), the most widely used measure of aortic stiffness, was determined by the transit-time method using velocity-encoded, phase-contrast cardiac magnetic resonance imaging. Patient characteristics were acquired at baseline and major adverse cardiac and cerebrovascular events (MACCE) were assessed at 13 [interquartile range (IQR) 12–31] months. Cox regression- and logistic regression analysis were performed to explore predictors of aortic stiffness and MACCE. Median aortic PWV was 6.6 m/s (IQR 5.6–8.3 m/s). In multivariable analysis, age [odds ratio (OR) 1.10, 95% confidence interval (CI), 1.08–1.14, p 0.05). High PWV significantly and independently predicted occurrence of MACCE in adjusted analysis [hazard ratio (HR) 2.45, 95% CI 1.19–5.04, p = 0.014]. In patients with recent STEMI, the impact of classical cardiovascular risk factors on aortic stiffness is mainly dependent on age and increased blood pressure. Increased aortic stiffness is associated with adverse clinical outcome post-STEMI, suggesting it as a relevant therapeutic target in this population. Trial (NCT04113356).

BACKGROUND The role of C-reactive protein velocity (CRPv) as an early and sensitive marker of an excessive inflammatory response in the setting of acute ST-elevation myocardial infarction (STEMI) is only poorly understood. The aim of this study was to investigate, in patients with STEMI treated with primary percutaneous coronary intervention (PCI), the association of CRPv with microvascular infarct pathology. METHODS AND RESULTS This prospective cohort study included a total of 316 patients with STEMI undergoing PCI. CRPv was defined as the difference between CRP 24 ± 8 h and CRP at hospital admission, divided by the time (in h) that have passed during the two examinations. The association of biomarker levels with cardiac magnetic resonance (CMR)-determined microvascular obstruction (MVO) was evaluated. CMR was performed at a median of 3 [interquartile range 2-4] days after PCI. After adjustment for cardiac troponin T (cTnT), anterior infarction and TIMI flow pre and post-PCI, CRPv (odds ratio 2.70, 95% confidence interval (CI) 1.54-4.73; p = 0.001) remained significantly associated with the occurrence of MVO. CRPv (area under the curve [AUC] 0.76, 95% CI 0.71-0.81; p < 0.001) was a better predictor for MVO compared to 24 h CRP (AUC difference: 0.03, p = 0.002). The addition of CRPv to peak cTnT resulted in a higher AUC for MVO prediction than peak cTnT alone (AUC 0.86, 95% CI 0.82-0.90; p < 0.001 vs. AUC 0.84, 95% CI 0.79-0.88; p < 0.001. AUC difference: 0.02, p = 0.042). CONCLUSIONS In patients with STEMI treated with primary PCI, CRPv was associated with microvascular infarct pathology with a predictive value incremental to cTnT, suggesting CRPv as an early and sensitive biomarker for more severe infarct pathology and outcome.

C-reactive protein velocity (CRPv) has been proposed as a very early and sensitive risk predictor in patients with ST-elevation myocardial infarction (STEMI). However, the association of CRPv with early left ventricular (LV) dysfunction after STEMI is unknown. The aim of this study was to investigate the relationship between CRPv and early LV dysfunction, either before or at hospital discharge, in patients with first STEMI. This analysis evaluated 432 STEMI patients that were included in the prospective MARINA-STEMI (Magnetic Resonance Imaging In Acute ST-elevation Myocardial Infarction. ClinicalTrials.gov Identifier: NCT04113356) cohort study. The difference of CRP 24 ± 8 h and CRP at hospital admission divided by the time (in h) that elapsed during the two examinations was defined as CRPv. Cardiac magnetic resonance (CMR) imaging was conducted at a median of 3 (IQR 2–4) days after primary percutaneous coronary intervention (PCI) for the determination of LV function and myocardial infarct characteristics. The association of CRPv with the CMR-derived LV ejection fraction (LVEF) was investigated. The median CRPv was 0.42 (IQR 0.21–0.76) mg/l/h and was correlated with LVEF (rS = −0.397, p < 0.001). In multivariable linear as well as binary logistic regression analysis (adjustment for biomarkers and clinical and angiographical parameters), CRPv was independently associated with LVEF (β: 0.161, p = 0.004) and LVEF ≤ 40% (OR: 1.71, 95% CI: 1.19–2.45; p = 0.004), respectively. The combined predictive value of peak cardiac troponin T (cTnT) and CRPv for LVEF ≤ 40% (AUC: 0.81, 95% CI 0.77–0.85, p < 0.001) was higher than it was for peak cTnT alone (AUC difference: 0.04, p = 0.009). CRPv was independently associated with early LV dysfunction, as measured by the CMR-determined LVEF, revealing an additive predictive value over cTnT after acute STEMI treated with primary PCI.

Aims To evaluate the prognostic validity of clinical risk factors as well as infarct characterization and myocardial deformation by cardiac magnetic resonance (CMR) in ST-elevation myocardial infarction (STEMI) patients with preserved left ventricular ejection fraction (LVEF) following primary percutaneous coronary intervention (PCI). Methods and results This multicentre, individual patient-data analysis from two large CMR trials included 1247 STEMI patients. Cardiac magnetic resonance examinations were conducted 3 [interquartile range (IQR) 2–4] days after PCI. LVEF, infarct size, microvascular obstruction (MVO), and myocardial strain values were measured. Primary endpoint was defined as composite of major adverse cardiovascular events (MACE) including death, re-infarction, and congestive heart failure. A preserved LVEF (defined as LVEF ≥50%) was observed in 724 patients (=58%). In the overall cohort, 97 patients experienced a MACE event [follow-up time 12 (IQR 12–13) months], and 34 MACE events occurred in the group with preserved LVEF (5% vs. 12% incidence rate in patients with LVEF < 50%). TIMI risk score [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.02–1.59; P = 0.03] and female gender (HR 2.24, 95% CI 1.10–4.57; P = 0.03) emerged as independent clinical determinants of MACE in the patient group with preserved LVEF. Among CMR parameters, the presence of MVO (HR 2.39, 95% CI 1.05–5.46; P = 0.04) and reduced global longitudinal strain (GLS; HR 1.12, 95% CI 1.02–1.23; P = 0.02) independently predicted MACE in the LVEF-preserved population. The addition of MVO and GLS to the clinical prognostic markers (TIMI risk score, female gender) increased (P = 0.02) the prognostic validity [AUC 0.76 (95% CI 0.73–0.79)] compared to the clinical markers alone [AUC 0.65 (0.62–0.69)]. Conclusion In contemporary treated STEMI patients showing preserved LVEF, a CMR-based risk prediction approach assessing MVO and GLS provided strong prognostic value that was incremental to clinical outcome parameters.

Background Implantation of occluders in the left atrial appendage (LAA) has been established to prevent patients with atrial fibrillation (AF) from stroke and embolisation. Currently, the individual occluder sizing will be done intraprocedurally using fluoroscopy and/or transesophageal echo (TEE) imaging. Purpose Development of a new approach allowing preprocedural occluder sizing and its validation by conventional intraprocedural methods. Methods The CARTO electro-anatomical mapping system was used in 62 consecutive patients (40 m, 22 f, age: 69.8±8.4 years) to preprocedurally predict the size of Watchman (n=34) or Amplatzer Amulet (n=28) devices. During device implantation, 23 of the patients (37.1%) were in AF. LAA morphologies were Chicken Wing (40.0%), Cauliflower (31.7%), Windsock (20.0%) and Cactus (8.3%). CHA2DS2-VASc Score was 3.7±1.9 and HAS-BLED-Score was 3.6±1.3. Preprocedurally, routine cardiac CT scans were imported into the CARTO segmentation tool for segmentation of the left atrium. The resulting volume images (VI) and slice images (SI) were adjusted in their 3-dimensional orientation to fit the manufacturer's sizing recommendations. Subsequently, the match between pre- and intraprocedural sizing was compared with the actually implanted device size. Results In the Watchman group, preprocedural VI corresponded with 38.1% (8/21) and SI with 42.3% (11/26), while intraprocedural fluoroscopy corresponded with 29.6% (8/27) and TEE with 40.0% (12/30) of all actually implanted devices. According to clinical routine an aberration of one size is common practice. After including one additional size to the estimation, VI corresponded with 81.0% (17/21), SI with 84.6% (22/26), while fluoroscopy corresponded with 85.2% (23/27) and TEE with 80.0% (24/30) of all actually implanted occluders. In the Amplatzer Amulet group, VI corresponded with 37.0% (10/27), SI with 57.1% (16/28) and fluoroscopy with 71.4% (20/28) of all actually implanted devices. After including one additional size to the estimation, VI corresponded with 66.7% (18/27), SI with 85.7% (24/28) and fluoroscopy with 100% (28/28) of all actually implanted occluders. The remaining were selected empirically. Conclusion In this study cohort of 62 patients, feasibility of a preprocedural sizing using the CARTO segmentation tool was demonstrated for Watchman occluders providing results comparable with conventional intraprocedural fluoroscopy and/or TEE based intraprocedural sizing. Possibly due to the different manufacturer measuring recommendation, 10 to 12 mm away from the LAA ostium, results for the Amplatzer Amulet system were found to be less accurate. Nevertheless, the proposed approach offers the advantage of preoperative visualisation of the individual LAA anatomy and morphology. Funding Acknowledgement Type of funding sources: None.

Background The association between aortic stiffness, cardiovascular risk factors and prognosis in patients with recent ST-elevation myocardial infarction (STEMI) is poorly understood. We analyzed the relationship between cardiovascular risk factors and arterial stiffening and assessed its prognostic significance in patients with recent STEMI. Methods We prospectively enrolled 408 consecutive patients who sustained a first STEMI and underwent primary percutaneous coronary intervention (PPCI). Aortic pulse wave velocity (PWV), a direct measure of aortic stiffness, was determined by the transit-time method using velocity-encoded, phase-contrast cardiac magnetic resonance imaging. Patient characteristics were acquired at baseline and major adverse cardiac and cerebrovascular events (MACCE) were assessed at 13 (interquartile range [IQR] 12–31) months. Cox regressionand logistic regression analysis were performed to explore predictors of PWV and MACCE. Results Median aortic PWV was 6.6 m/s (IQR 5.6–8.3m/s). In multivariable analysis, age (odds ratio [OR] 1.10, 95% confidence interval [CI], 1.08–1.14, p0.05). High PWV significantly and independently predicted occurrence of MACCE in adjusted analysis (hazard ratio [HR] 2.45, 95% CI 1.19–5.04, p=0.014). Conclusion In patients with recent STEMI, the impact of classical cardiovascular risk factors on aortic stiffness is mainly dependent on age and increased blood pressure. Increased aortic stiffness is associated with adverse clinical outcome post-STEMI, suggesting it as a relevant therapeutic target in this population. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Austrian Science Fund (FWF)Austrian Society of Cardiology Figure 1. Biorender.com

Background The role of C-reactive protein velocity (CRPv) as an early and sensitive marker of an excessive inflammatory response in the setting of acute ST-elevation myocardial infarction (STEMI) is only poorly understood. Purpose The aim of this study was to investigate, in patients with STEMI treated with primary percutaneous coronary intervention (PCI), the association of CRPv with microvascular infarct pathology. Methods This prospective cohort study included a total of 316 patients with STEMI undergoing PCI. CRPv was defined as the difference between CRP 24±8h and CRP at hospital admission, divided by the time (in h) that have passed during the two examinations. The association of biomarker levels with cardiac magnetic resonance (CMR)-determined microvascular obstruction (MVO) was evaluated. CMR was performed at a median of 3 [interquartile range 2–4] days after PCI. Results After adjustment for cardiac troponin T (cTnT), culprit lesion location and TIMI-flow post-PCI, CRPv (odds ratio 3.36, 95% confidence interval (CI) 1.72–6.57; p Conclusions In patients with STEMI treated with primary PCI, CRPv was associated with microvascular infarct pathology with a predictive value incremental to cTnT, suggesting CRPv as an early and sensitive biomarker for more severe infarct pathology and outcome. Funding Acknowledgement Type of funding sources: None. ROC analysis for the prediction of MVO.CRPv (median) and clinical outcome.

Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) represents the optimal modality for the diagnosis of left ventricular (LV) thrombus ([1][1]), which is associated with worse outcomes following ST-segment elevation myocardial infarction (STEMI) ([2][2]). However, CMR imaging is

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Aims Little is known about the clinical relevance of interleukin (IL)-6 in patients with acute ST-elevation myocardial infarction (STEMI). This study examined the possible associations of plasma IL-6 concentrations with infarct size (IS), reperfusion injury and adverse left ventricular remodelling (LVR), in STEMI patients treated with primary percutaneous coronary intervention (PCI). Methods and results We prospectively included 170 consecutive STEMI patients (median age 57 years, 14% women) treated with primary PCI between 2017 and 2019. Blood samples for biomarker analyses including IL-6 were collected on Day 2. Left ventricular ejection fraction (LVEF), IS, and reperfusion injury [microvascular obstruction (MVO) and intramyocardial haemorrhage (IMH)] were determined using cardiac magnetic resonance (CMR) imaging on Day 4. Left ventricular remodelling was defined as ≥10% increase in left ventricular end-diastolic volume from baseline to 4 months CMR follow-up. Patients with IL-6 concentrations ≥median (17 ng/L) showed a significantly lower LVEF (43% vs. 52%, P Conclusions High concentrations of circulating plasma IL-6 on Day 2 after STEMI were independently associated with worse myocardial function, larger infarct extent, more severe reperfusion injury, and a higher likelihood for LVR, suggesting IL-6 as a useful biomarker of more serious outcome and potential therapeutic target. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT04113356;NCT04113356.

BackgroundRecently, a simple ECG score (DETERMINE score) has been proposed for estimating myocardial scar in patients with ischaemic cardiomyopathy. We sought to evaluate the usefulness of the DETERMINE score for the assessment of myocardial infarct size (IS) as well as microvascular obstruction (MVO), in the setting of ST-elevation myocardial infarction (STEMI).MethodsThis observational study enrolled 423 patients with STEMI (median age 56, 17% women), revascularised by primary percutaneous coronary intervention (PCI). For evaluation of the DETERMINE and Selvester scoring system (an established but complex ECG score for IS estimation), ECG was conducted before discharge (median: 4 (IQR 2–6) days). Cardiac magnetic resonance (CMR) was conducted within a week after infarction for determination of IS and MVO.ResultsMedian DETERMINE score of the overall cohort was 8 points (IQR 5–11). A higher DETERMINE score was significantly associated with a larger IS (21% vs 11% of left ventricular myocardial mass (LVMM), pConclusionsIn patients undergoing PCI for STEMI, the DETERMINE score provides an easy and inexpensive tool for appropriate estimation of infarct severity as determined by CMR.

Summary Background SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin–angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. Methods ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. Findings Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66–80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00–2·00) vs 1·00 (0·00–3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00–9·25] vs 3·50 [0·00–23·50]; p=0·040), mean SOFA score (0·00 [0·00–0·31] vs 0·12 [0·00–0·78]; p=0·040), and 30-day SOFA score (0·00 [10–90th percentile, 0·00–1·20] vs 0·00 [0·00–24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. Interpretation Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. Funding Austrian Science Fund and German Center for Cardiovascular Research.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund Background The magnitude of myocardial damage after acute ST-elevation myocardial infarction (STEMI) is a crucial prognostic determinant. Cardiac magnetic resonance (CMR) imaging offers a precise infarct severity assessment after STEMI; however, limited to restricted availability in daily clinical routine. Recently, a simple ECG score (DETERMINE score) was developed for infarct size (IS) estimation in STEMI patients with prior infarction. We sought to validate this score in patients with first-time STEMI for the assessment of myocardial injury visualized by CMR. Methods In this validation study, 423 revascularized first-time STEMI patients (median age 56, 17% women) were included. ECG was conducted at discharge for evaluation of the DETERMINE and Selvester score. CMR imaging was performed at a median of 3 days for the assessment of infarct characteristics (IS and microvascular obstruction [MVO]). Results Median DETERMINE score of the overall cohort was 8 points (interquartile range: 5-11). Patients presenting with a score > 8 points had more often anterior infarct localization (64% vs. 29%, p Conclusions In survivors of first-time STEMI, the DETERMINE score provides an easy and inexpensive tool for suitable IS estimation. Moreover, the DETERMINE score showed significant and independent association with MVO. Thus, this simple ECG score might help identify patients at high risk of large infarct burden who might benefit from more aggressive treatment strategies.

Background Cardiac magnetic resonance (CMR) is the reference standard for left ventricular (LV) thrombus detection in patients with acute ST-elevation myocardial infarction (STEMI). However, routine CMR imaging is currently not recommended post-STEMI. Objective This observational study sought to develop a practical risk score for the prediction of early LV thrombus formation after STEMI to identify patients in whom routine CMR might be appropriate. Methods and results Five hundred and fifty-six consecutive patients underwent transthoracic echocardiography (TTE) and CMR at 3 [IQR: 2–4] days after primary percutaneous coronary intervention (PCI) for acute STEMI. A LV thrombus was visualized in 12 patients (2.2%) using TTE and in 22 patients (4%) using CMR. A weighted risk score including multivariable associates of LV thrombus formation (LV ejection fraction by TTE, peak high-sensitivity cardiac troponin T and peak high-sensitivity C-reactive protein) and left anterior descending coronary artery as culprit vessel, with a range of 0 to 7 points (median risk score: 2 points) showed a strong and significantly higher area under the curve (0.93 (95% CI 0.88–0.97; p Conclusions The proposed risk score provides incremental value for the prediction of early LV thrombus and could be useful to identify STEMI patients in whom routine CMR for LV thrombus evaluation could be most meaningful. Additional investigation is warranted to validate the clinical application of the score. Funding Acknowledgement Type of funding source: None

Key Points Question Does an association exist between myocardial injury and systemic release of serum procalcitonin in acute ST-elevation myocardial infarction that is treated with primary percutaneous coronary intervention? Findings In this cohort study of 141 patients with ST-elevation myocardial infarction, there were no significant correlations between concentration of procalcitonin 24 or 48 hours after intervention and myocardial or microvascular injury as assessed by cardiac magnetic resonance imaging. Meaning These data highlight the clinical potential of procalcitonin to identify concomitant infection and to guide antibiotic treatments for patients with ST-elevation myocardial infarction; however, randomized trials are needed to evaluate the clinical benefit of a procalcitonin-guided strategy., Importance Myocardial tissue injury due to acute ST-elevation myocardial infarction (STEMI) initiates an inflammatory response that leads to a release of systemic inflammatory biomarkers, including C-reactive protein (CRP) and white blood cells, consequently reducing the usefulness of these routine biomarkers for identifying concomitant infections. The clinical role of procalcitonin (PCT), a promising marker of bacterial infection, to detect concomitant infection in acute STEMI is unknown, mainly because it is unclear whether myocardial injury per se induces systemic PCT release. Objective To investigate the release of serum PCT in the acute setting of STEMI (24 and 48 hours after primary percutaneous coronary intervention) and to elucidate any associations with myocardial injury markers through a comprehensive assessment by cardiac magnetic resonance (CMR) imaging. Design, Setting, and Participants This prospective cohort study conducted between 2016 and 2018 included 141 consecutive patients with STEMI treated with primary percutaneous coronary intervention. Concentrations of PCT, high-sensitivity CRP (hs-CRP), and high-sensitivity cardiac troponin T (hs-cTnT) and white blood cell counts were measured serially 24 and 48 hours after infarct. Exposures Acute STEMI and primary percutaneous coronary intervention. Main Outcomes and Measures The association of PCT and typical inflammatory marker levels with CMR-determined myocardial damage was assessed. Infarct size, extent of microvascular obstruction, and occurrence of intramyocardial hemorrhage as determined by CMR within the first week following STEMI were also evaluated. Results In total, 141 patients with STEMI (117 men [83%]) having a median age of 56 years (interquartile range, 50-66 years) were included. The median PCT concentration was 0.07 μg/L (interquartile range, This cohort study evaluates whether an association exists between myocardial injury assessed with cardiac magnetic resonance imaging and the release of serum procalcitonin in patients with acute ST-elevation myocardial infarction who are treated with primary percutaneous coronary intervention.

Background: Adverse left ventricular remodeling is one of the major determinants of heart failure and mortality in patients surviving ST-segment elevation myocardial infarction (STEMI). The hypothalamic–pituitary–thyroid axis is a key cardiovascular regulator; however, the relationship between hypothalamic–pituitary–thyroid status and post-STEMI left ventricular remodeling is unclear. We aimed to investigate the association between thyroid-stimulating hormone concentrations and the development of left ventricular remodeling following reperfused STEMI. Methods: In this prospective observational study of 102 consecutive STEMI patients, thyroid-stimulating hormone levels were measured at the first day after infarction and 4 months thereafter. Cardiac magnetic resonance scans were performed within the first week as well as at 4 months follow-up to determine infarct characteristics, myocardial function and as primary endpoint left ventricular remodeling, defined as a 20% or greater increase in left ventricular end-diastolic volume. Results: Patients with left ventricular remodeling ( n=15, 15%) showed significantly lower concentrations of baseline (1.20 [0.92–1.91] vs. 1.73 [1.30–2.60] mU/l; P=0.02) and follow-up (1.11 [0.86–1.28] vs. 1.51 [1.15–2.02] mU/l; P=0.002) thyroid-stimulating hormone. The association between baseline thyroid-stimulating hormone and left ventricular remodeling remained significant after adjustment for major clinical (peak high-sensitivity cardiac troponin T and C-reactive protein, heart rate; odds ratio (OR) 5.33, 95% confidence interval (CI) 1.52–18.63; P=0.01) and cardiac magnetic resonance predictors of left ventricular remodeling (infarct size, microvascular obstruction, ejection fraction; OR 4.59, 95% CI 1.36–15.55; P=0.01). Furthermore, chronic thyroid-stimulating hormone was related to left ventricular remodeling independently of chronic left ventricular remodeling correlates (infarct size, ejection fraction, left ventricular end-diastolic volume, left ventricular end-systolic volume; OR 9.22, 95% CI 1.69–50.22; P=0.01). Conclusions: Baseline and chronic thyroid-stimulating hormone concentrations following STEMI were independently associated with left ventricular remodeling, proposing a novel pathophysiological axis in the development of post-STEMI left ventricular remodeling.

Objectives/background To assess brake reaction time (BRT; key factor in driving ability) in patients receiving transfemoral coronary angiography (CAG). We assumed that patients would have a significantly impaired BRT after the procedure. Methods A prospective, observational study design was applied. Consecutive patients undergoing right-sided transfemoral CAG as part of the clinical routine were included. An experimental driving simulator was used to determine BRT after receiving a visual stimulus. The subjects applied the brake with their right foot as quickly as possible when a red-light signal appeared. The time interval between stimulus and brake application was taken as BRT. In addition to the total BRT, also its components were determined: neurologic reaction time, foot transfer time and brake travel time. BRT was determined before and 1 day after CAG (pre-post comparison). Results 71 patients were included in the analysis (58 male, age 61 ± 9 years). Total BRT was 594 ± 188 and 591 ± 198 ms before and after the CAG procedure, respectively (p = 0.270). Similarly, also the BRT components ‘foot transfer time’ and ‘brake travel time’ did not show significant differences between the two test occasions. However, neurologic reaction time decreased from 269 ± 67 to 255 ± 64 ms (p = 0.036). Conclusions We found no impairment of BRT on the first day after puncture of the right-sided femoral artery in patients undergoing CAG. Therefore, with regard to BRT, it is regarded safe to resume driving from day 1 after CAG. Other factors of driving safety beyond BRT must also be considered.

Although guideline recommendations have shifted towards a transradial route, femoral puncture is still an established vascular access, especially for complex coronary interventions. The FemoSeal™ vascular closure device (FVCD) helps to reduce femoral compression time and access site complications after removal of the catheter sheath. To ensure safe use, an angiography of the femoral artery prior to FVCD deployment is recommended by the manufacturer. We postulate that omitting this angiography does not relevantly increase the risk for vascular complications. In this retrospective analysis of an all-comers population (n = 1923) including patients receiving a percutaneous coronary intervention (PCI), we could show that combined vascular complication rates without femoral angiography were low (primary endpoint 4.6%) and comparable to a randomized clinical trial that did perform angiography of the vascular access site in a cohort of patients receiving diagnostic coronary angiography only. In addition to this analysis, we could demonstrate that patients with an acute coronary syndrome, receiving periprocedural anticoagulation or anti-platelet therapy had an increased risk for the formation of arterial pseudoaneurysms; however, we did not observe any ischemic vascular event after FVCD deployment. Closure of the femoral access site after coronary angiography using the FVCD can be safely performed without femoral angiography; however, due to an increased risk for the formation of pseudoaneurysms we recommend the transradial access in situations with increased bleeding risk.

Background Optimal strut coverage and early vascular healing are important factors to reduce the risk of stent thrombosis. Data on early vascular healing with the new bioresorbable vascular scaffolds (BVS) are lacking. Further, healing response after BVS implantation in different clinical presentation has not been fully investigated. Methods and Results We assessed with optical coherence tomography (OCT) the early vascular response to BVS implantation in 26 consecutive patients presenting with acute coronary syndrome (ACS) or stable angina (SA). Images from 16 BVSs (17,166 struts) in ACS patients and 17 BVSs (23,045 struts) in SA patients were analyzed. The mean implanted BVS diameter and length was 3.1 ± 0.4 mm and 20.4 ± 5.8 mm. At mean 47.6 ± 6.3 days, overall 99% of BVS struts were covered. There were no differences between ACS and SA on the amount of tissue coverage per strut (0.09 ± 0.02 mm vs. 0.09 ± 0.01 mm; P = 0.86, respectively) and lumen area stenosis (24.2 ± 19.3% vs. 22.3 ± 22.0%; P = 0.78, respectively). However, a numerically higher proportion of protruding (ACS 1.2 ± 2.7%; SA 4.2 ± 6.5%; P = 0.11) and malapposed (ACS 0.4 ± 0.5%; SA 2.4 ± 5.8%; P = 0.18) struts were observed in SA compared to ACS, with trendy better healing score in ACS (1.87 ± 1.67 vs. 5.28 ± 7.28, P = 0.08). Conclusion Early after BVS implantation almost complete scaffold strut coverage without any thrombi was observed by OCT, independent by the clinical presentation at index coronary intervention. However, BVS in ACS lesions were associated with easier strut penetration and a trendy better healing score compared with SA.

Background Autologous progenitor cell therapy comprising granulocyte-colony stimulating factor (G-CSF) for mobilization of bone-marrow derived progenitor cells (BMPCs) into peripheral blood and inhibition of dipeptidylpeptidase-IV by sitagliptin for enhanced myocardial recruitment of circulating BMPCs has been shown to improve survival after acute myocardial infarction (MI) in preclinical studies. In the SITAGRAMI trial we found that during short-term follow-up G-CSF plus sitagliptin (GS) failed to show a beneficial effect on cardiac function and clinical events in patients with acute MI that underwent successful PCI. The objective of the present analysis was to assess the impact of GS versus placebo treatment on long-term clinical outcomes of the SITAGRAMI trial patient population. Methods In the randomized, prospective, double-blind, placebo-controlled SITAGRAMI trial, 174 patients with acute MI were assigned to GS or placebo in a 1:1 ratio. The primary outcome for the present long-term analysis was the composite of death, MI or stroke on long-term follow-up. Results The median [IQR] follow-up duration was 4.50 [3.56–5.95] years. The primary outcome occurred in 12.8% of patients assigned to placebo and 9.2% assigned to GS (HR 0.69, 95% CI 0.28–1.69; p=0.42). The incidence of the combined cardiovascular outcome was 47.7% in the placebo- and 41.4% in the GS-group (HR 0.75, 95% CI 0.48–1.18; p=0.21). Overall, there was no significant difference in MACCE rates between both treatment groups (p=0.41). Conclusion These long-term follow-up data indicate that GS therapy does not improve clinical outcomes of patients with acute MI.

Background Outcome data of patients with acute myocardial infarction (AMI)–induced cardiogenic shock (CS) receiving extracorporeal life support (ECLS) are sparse. Methods A consecutive series of 106 patients with AMI-induced CS receiving ECLS was evaluated regarding ECLS weaning success, hospital mortality, and long-term outcome. The Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) risk score was applied, and multivariable Cox regression analysis was performed. Results Mean patient age was 58.2 ± 11.2 years, and 78.3% were men. In 34 patients (32.1%), ECLS was implemented during ongoing cardiopulmonary resuscitation. De novo AMI was present in 58 patients (54.7%), and percutaneous coronary intervention complications were causative among 48 patients (45.3%). Multivessel coronary artery disease was diagnosed among 73.6% with mean Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) scores of 30.8 ± 4.8. Actuarial survival was 54.4% at 30 days, 42.2% at 1 year, and 38.0% at 5 years and was significantly higher among patients with low and intermediate IABP-SHOCK II risk scores at ECLS onset (log-rank P = .017). ECLS weaning with curative intention after a mean perfusion time of 6.6 ± 5.1 days was feasible in 51 patients (48.1%) and more likely among patients with complete revascularization (P = .026). Multivariable Cox regression analysis identified complete revascularization (hazard ratio, 2.38; 95% confidence interval, 1.1 to 5.1; P = .028) and absence of relevant mitral regurgitation at ECLS discontinuation (hazard ratio, 2.71; 95% confidence interval, 1.2 to 6.0; P = .014) to be associated with beneficial long-term survival after ECLS discontinuation. Conclusions Emergency ECLS is a valuable option among patients with AMI-induced CS with low and intermediate IABP-SHOCK II risk scores. ECLS weaning is manageable, but additional revascularization of all nonculprit lesions is mandatory after ECLS implementation.

Objective Glipitins are widely used for the treatment of type 2 diabetic patients. In addition to their improvement of glycemic control, animal studies have suggested an independent anti-atherosclerotic effect of gliptins. Nevertheless, recent clinical trials regarding long-term effects of gliptin therapy on vascular events have been disappointing. This discrepancy led us to better dissect the functional role of SDF-1/CXCR4 signaling as a potential mechanism underlying gliptin action. The study should give improved understanding of the potential of gliptin therapy in the prevention and treatment of atherosclerosis. Methods and results In an ApoE−/− mouse model on high cholesterol diet, long-term treatment with the DPP-4 inhibitor Sitagliptin significantly reduced atherosclerosic plaque load in the aorta. Flow cytometry analyses showed an enrichment of M2 macrophages in the aortic wall under gliptin therapy. Importantly, the number of recruited CD206+ macrophages was inversely correlated with total plaque area while no correlation was found for the overall macrophage population or M1 macrophages. Blockade of CXCR4/SDF-1 signaling by AMD3100 inhibited aortic M2 accumulation and the therapeutic effect of Sitagliptin. Correspondingly, Sitagliptin shifted the polarization profile of macrophages towards a M2-like phenotype. Conclusion Sitagliptin-mediated inhibition of early atherosclerosis is based on M2-polarization during monocyte differentiation via the SDF-1/CXCR4 signaling. In contrast to earlier assumptions gliptin treatment might be especially effective in prevention of atherosclerosis.

Aims Dual therapy comprising G-CSF for mobilization of bone marrow-derived progenitor cells (BMPCs), with simultaneous pharmacological inhibition of dipeptidylpeptidase-IV for enhanced myocardial recruitment of circulating BMPC via the SDF-1α/CXCR4-axis, has been shown to improve survival after acute myocardial infarction (AMI). Using an innovative method to provide non-invasive serial in vivo measurements and information on metabolic processes, we aimed to substantiate the possible effects of this therapeutic concept on cardiac remodelling after AMI using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET). Methods and results AMI was induced in C57BL/6 mice by performing surgical ligation of the left anterior descending artery in these mice. Animals were then treated with granulocyte-colony stimulating factor + Sitagliptin (GS) or placebo for a duration of 5 days following AMI. From serial PET scans, we verified that the infarct size in GS-treated mice ( n = 13) was significantly reduced at Day 30 after AMI when compared with the mice receiving placebo ( n = 10). Analyses showed a normalized FDG uptake on Day 6 in GS-treated mice, indicating an attenuation of the cardiac inflammatory response to AMI in treated animals. Furthermore, flow cytometry showed a significant increase in the anti-inflammatory M2-macrophages subpopulation in GS-treated animals. In comparing GS treated with placebo animals, those receiving GS-therapy showed a reduction in myocardial hypertrophy and left ventricular dilatation, which indicates the beneficial effect of GS treatment on cardiac remodelling. Remarkably, flow cytometry and immunohistochemistry showed an increase of myocardial c-kit positive cells in treated mice ( n = 12 in both groups). Conclusion Using the innovative method of micro-PET for non-invasive serial in vivo measurements of metabolic myocardial processes in mice, we were able to provide mechanistic evidence that GS therapy improves cardiac regeneration and reduces adverse remodelling after AMI.

Introduction. DPP4 inhibitors (gliptins) are commonly used antidiabetic drugs for the treatment of type 2 diabetes. Gliptins also act in a glucose-independent manner and show vasoregenerative effects. We have shown that gliptins can remarkably accelerate vascular healing after vascular injury. However, the underlying mechanisms remain unclear. Here, we examined potential signaling pathways linking gliptins to enhanced endothelial regeneration. Methods and Results. We used wild-type and GLP1 receptor knockout (Glp1r−/−) mice to investigate the underlying mechanisms of gliptin-induced reendothelialization. The prototype DPP4 inhibitor sitagliptin accelerated endothelial healing in both animal models. Improved endothelial growth was associated with gliptin-mediated progenitor cell recruitment into the diseased vascular wall via the SDF1-CXCR4 axis independent of GLP1R-dependent signaling pathways. Furthermore, SDF1 showed direct proproliferative effects on endothelial cells. Excessive neointimal formation was not observed in gliptin- or placebo-treated Glp1r−/− mice. Conclusion. We identified the SDF1-CXCR4 axis as a crucial signaling pathway for endothelial regeneration after acute vascular injury. Furthermore, SDF1 can directly increase endothelial cell proliferation. Gliptin-mediated potentiation of endothelial regeneration was preserved in Glp1r−/− animals. Thus, gliptin-mediated endothelial regeneration proceeds through SDF-1/CXCR4 in a GLP1R-independent manner after acute vascular injury.

Background MicroRNAs (miRs) have shown to exert fibrotic and anti-fibrotic effects in preclinical models of acute myocardial infarction (AMI). The aim of this study was to evaluate miR-1, miR-21, miR-29b and miR-92a as circulating biomarkers for adverse ventricular remodeling (AVR) in post-AMI patients. Methods Plasma levels of miR-1, miR-21, miR-29b and miR-92a were measured in 44 patients of the SITAGRAMI trial population at day 4, day 9 and 6month after AMI and in 18 matched controls (CTL). MiR expression patterns were correlated with magnetic resonance imaging (MRI) parameters for AVR (absolute change (Δ) in infarct volume (IV), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) between day 4 and 6months after AMI) and a combined cardiovascular endpoint. Results Expression of miR-1, miR-21 and miR-29b but not miR-92a was increased in AMI vs. CTL cohort showing highest miR levels at d9. However, only miR-1 and miR-29b levels significantly correlated with ΔIV and showed a trend for correlation with ΔLVEF. Only miR-29b levels at day 9 correlated with ΔLVEDV at 6-month follow-up. There was no correlation of miR levels with an adverse outcome. Conclusion Mir-1 and miR-29b plasma levels post-AMI correlate with IV changes. In addition, miR-29b levels are associated with changes of LVEDV over time. These results provide insights into the role of miRs as diagnostic AVR surrogate markers. Further large scale clinical trials will be needed to evaluate the real prognostic relevance of these miRs with respect to a clinical implication in the future.

Background Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available. We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury. Methods and Results Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin+AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4+ progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4+ progenitor cells (CD133+, Flk1+), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia. Conclusion Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4+ progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.

Background Medical stimulation of endogenous progenitor cell circulation may serve as a new therapeutic tool for treatment of acute myocardial infarction. We analyzed the effects of antidiabetic gliptins plus GCSF (granulocyte colony stimulating factor) on myocardial regeneration after myocardial infarction in a mouse model. Methods and results After surgical LAD-ligation (left anterior descending artery), Sitagliptin/Vildagliptin was applied yielding sufficient blood levels verified by mass spectrometry and significantly reducing activity of dipeptidyl peptidase (DPP) IV. GCSF or saline was administered intraperitoneally for 6days. We assessed stem cell mobilization and homing (flow cytometry), infarct size (histology), neovascularization and cellular proliferation (immunohistology), heart function (Millar tip catheterization) and survival (Kaplan–Meier-curves). Gliptins±GCSF administration increased mobilization and cardiac homing of bone-marrow derived stem cells by stabilization of cardiac SDF1 (stromal cell-derived factor). For Sitagliptin, it could be shown that resident cardiac stem cells were stimulated, neovascularization was enhanced and cardiac remodeling was reduced. These effects finally improved myocardial function and increased survival for both gliptins. Although gliptins as a mono therapy lead to remarkable effects in a dose dependent manner and were superior to G-CSF mono-therapy, dual application of GCSF and gliptins revealed the best results. Since both gliptins yielded comparable effects concerning stem cell homing, cardiac function and survival, we suggest a class-effect of DPP-IV-inhibitors. Conclusions Thus, gliptins+GCSF and in high concentrations even as mono therapy have beneficial effects on cardiac regeneration after myocardial infarction beyond its anti-diabetic potential.

Optimal strut coverage and early vascular healing are important factors to reduce the risk of stent thrombosis. Data on early vascular healing with the new bioresorbable vascular scaffolds (BVS) are lacking. Further, healing response after BVS implantation in different clinical presentation has not been fully investigated.We assessed with optical coherence tomography (OCT) the early vascular response to BVS implantation in 26 consecutive patients presenting with acute coronary syndrome (ACS) or stable angina (SA). Images from 16 BVSs (17,166 struts) in ACS patients and 17 BVSs (23,045 struts) in SA patients were analyzed. The mean implanted BVS diameter and length was 3.1 ± 0.4 mm and 20.4 ± 5.8 mm. At mean 47.6 ± 6.3 days, overall 99% of BVS struts were covered. There were no differences between ACS and SA on the amount of tissue coverage per strut (0.09 ± 0.02 mm vs. 0.09 ± 0.01 mm; P = 0.86, respectively) and lumen area stenosis (24.2 ± 19.3% vs. 22.3 ± 22.0%; P = 0.78, respectively). However, a numerically higher proportion of protruding (ACS 1.2 ± 2.7%; SA 4.2 ± 6.5%; P = 0.11) and malapposed (ACS 0.4 ± 0.5%; SA 2.4 ± 5.8%; P = 0.18) struts were observed in SA compared to ACS, with trendy better healing score in ACS (1.87 ± 1.67 vs. 5.28 ± 7.28, P = 0.08).Early after BVS implantation almost complete scaffold strut coverage without any thrombi was observed by OCT, independent by the clinical presentation at index coronary intervention. However, BVS in ACS lesions were associated with easier strut penetration and a trendy better healing score compared with SA.

Ischemic disorders are the main cause of death in the Western world. With more patients surviving their acute myocardial infarction and an aging population, congestive heart failure is the rising health problem. At present, heart transplantation remains the only curative treatment for end stage heart failure. The discrepancy between demand and supply of donor organs does not fill the clinical need. This explains the huge efforts made in the field of stem cell research trying to establish alternative methods for endogenous tissue regeneration and to find sources for tissue replacement. In contrast to adult stem cells mainly acting in a paracrine fashion pluripotent stem cells have the potential to generate transplantable myocardial and vascular tissue.

ES-cell-based cardiovascular repair requires an in-depth understanding of the molecular mechanisms underlying the differentiation of cardiovascular ES cells. A candidate cardiovascular-fate inducer is the bHLH transcription factor MesP1. As one of the earliest markers, it is expressed specifically in almost all cardiovascular precursors and is required for cardiac morphogenesis. Here we show that MesP1 is a key factor sufficient to induce the formation of ectopic heart tissue in vertebrates and increase cardiovasculogenesis by ES cells. Electrophysiological analysis showed all subtypes of cardiac ES-cell differentiation. MesP1 overexpression and knockdown experiments revealed a prominent function of MesP1 in a gene regulatory cascade, causing Dkk-1-mediated blockade of canonical Wnt-signalling. Independent evidence from ChIP and in vitro DNA-binding studies, expression analysis in wild-type and MesP knockout mice, and reporter assays confirm that Dkk-1 is a direct target of MesP1. Further analysis of the regulatory networks involving MesP1 will be required to preprogramme ES cells towards a cardiovascular fate for cell therapy and cardiovascular tissue engineering. This may also provide a tool to elicit cardiac transdifferentiation in native human adult stem cells.

Objective In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI). Research design and methods After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6months of follow-up (Δ LVEF , Δ RVEF ), as determined by cardiac MRI. Results At follow-up Δ LVEF as well as Δ RVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12months of follow-up as compared to patients under GS. Conclusion Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12months. (EudraCT: 2007–003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation).

BACKGROUND: Recent studies suggest that stem cells may represent a putative source for the generation of beta cells. However, the identity and characteristics of stem cells from adult pancreas and conditions for their large scale expansion are still poorly defined. METHODS: DPC were isolated from adult pancreatic ducts of C57BI/6 mice. Expression profile was investigated by PCR, FAGS and immunohistochemistry. RESULTS: DPC express a panel of stem cell associated markers such as Pdx-1, cytokeratin-19 (CK19), nestin, Sox9 together with the transcription factor MafA and hepatic nuclear factors HNF1 beta, HNF3 beta, HNF4 alpha and HNF6. This gene expression profile is suggesting that DPC might be a promising tool for endocrine diMrentiation. Atter stimulation with picolinic acid and hypoxia, DPC expressed the endocrine differentiation marker Ngn3. Nevertheless, insulin production was not observed. CONCLUSIONS: We here describe a protocol for the isolation end expansion of murine pancreatic ductal progenitor cells (DPC) displaying high self-renewal, spheroid-and colony-forming capacity. Further studies are required to elucidate the conditions for differentiation into mature pancreatic endocrine cell lineages.

Gliptins are accepted as a standard therapy for diabetes mellitus today. By inhibition of the enzyme dipeptidyl peptidase 4 (DPP4), gliptins prolong the GLP1-dependent insulin secretion in the pancreatic β-cells and thus support physiological blood glucose control. Various studies have now raised hope for an additional protective effect of pharmacological DPP4 inhibition in vascular diseases. Besides GLP1, especially, the inhibition of SDF1 cleavage has been shown to depict a relevant mechanism to enhance endothelial regeneration and reduce atherosclerosis progression via the SDF1-CXCR4 axis. Furthermore, several clinical trials have now shown an excellent safety profile of gliptin therapy in cardiovascular risk patients. In this review, we give a comprehensive overview on DPP4-dependent vascular functions and pathophysiological mechanisms with a detailed discussion of the underlying molecular mechanisms. We further analyse the role of pharmacological DPP4 inhibitors and their potential therapeutic impact on endothelial function and regeneration besides their effect during atherosclerosis development. Finally, we discuss presently available data from in vitro and in vivo studies with respect to the results of the recent clinical trials in diabetic and non-diabetic patients.

The epicardium supports cardiomyocyte proliferation early in development and provides fibroblasts and vascular smooth muscle cells to the developing heart. The epicardium has been shown to play an important role during tissue remodeling after cardiac injury, making access to this cell lineage necessary for the study of regenerative medicine. Here we describe the generation of epicardial lineage cells from human pluripotent stem cells by stage-specific activation of the BMP and WNT signaling pathways. These cells display morphological characteristics and express markers of the epicardial lineage, including the transcription factors WT1 and TBX18 and the retinoic acid–producing enzyme ALDH1A2. When induced to undergo epicardial-tomesenchymal transition, the cells give rise to populations that display characteristics of the fibroblast and vascular smooth muscle lineages. These findings identify BMP and WNT as key regulators of the epicardial lineage in vitro and provide a model for investigating epicardial function in human development and disease.

Introduction: Major parts of the population in the western world are suffering from atherosclerotic diseases like coronary and peripheral artery disease or stroke. Interventional and pharmacological therapies at present focus on the treatment of vascular stenoses, secondary prophylaxis or reduction of cardiovascular risk factors. Hypothesis: In this project, we want to establish the pharmacological inhibition of DPP4 as a new therapeutic concept focussing on macrophage polarization during development of atherosclerosis. Methods: Non-diabetic ApoE-/- mice were treated with normal diet or high fat diet for three months to induce arterial atherosclerotic lesion formation. The descending aorta was stained using Oil-Red-O to quantify atherosclerotic lesions. In parallel mice were treated with Sitagliptin or placebo. Macrophage subtype content (M1, M2) in the aortic wall was quantified using FACS. Results: Mice on high fat diet treated with Sitagliptin showed a dramatic reduction in atherosclerotic lesion formation in contrast to placebo treated animals. Regarding total macrophage content in the vascular wall we could not detect a difference between the treatment groups. However, the number of protective M2 macrophages was more than tripled in the gliptin-treated animals. Moreover, the number of mural M2 macrophages inversely correlated with the aortic plaque burden. In further analyses we could demonstrate that Sitagliptin favoured macrophage polarization to alternatively activated M2 macrophages via the CXCR4-signaling pathway. Conclusions: We demonstrated that long-term Sitagliptin treatment in ApoE-/- animals on high fat diet can successfully inhibit atherosclerotic lesion formation via induction of macrophage polarization to the protective M2 phenotype. Due to the promising results of this study we are currently planning to transfer the underlying therapeutical concept into a randomized clinical trial.

It is well established that an interplay between natural killer (NK) cells and dendritic cells (DCs) gives rise to their reciprocal activation and provides a Th1-biased cytokine milieu that fosters antitumor T-cell responses. Ex vivo-differentiated DCs transferred into mice strongly stimulate endogenous NK cells to produce interferon (IFN)-γ and initiate a cascade that eventually leads to cytotoxic T-lymphocyte responses. We show that the ability of exogenous DCs to trigger this pathway obviates CD40 signaling and CD4(+) T-cell help and depends on a preceding maturation step. Importantly, this mechanism was also effective in endogenously arising tumors where IFN-γ production is compromised in contrast to transplantable tumors. In c-myc-transgenic mice developing spontaneous lymphomas, injection of unpulsed DCs caused NK-cell activation and induced CD8(+) T cells capable of recognizing the lymphoma cells. Animals treated with unpulsed DCs showed a survival benefit compared to untreated myc mice. Hence, tumor immunity induced by DC-based vaccines not only depends on specific antigens loaded on the DCs. Rather, DC vaccines generate broader immune responses, because endogenous DCs presenting tumor antigens may also become stimulated by NK cells that were activated by exogenous DCs. Thus, the DC/NK-cell/cytotoxic T lymphocyte axis may commonly have relevance for DC-based vaccination protocols in clinical settings.

Aims Our pre-clinical studies demonstrated that G-CSF based stem cell mobilization in combination with genetic or pharmaceutical CD26/DPP-IV inhibition after acute myocardial infarction leads to improved cardiac homing of stem cells, enhanced heart function and increased survival. Thereupon, we initiated a phase III, multi-centre, randomised, placebo-controlled efficacy and safety study ( n =100) analyzing the effect of combined application of G-CSF and Sitagliptin, which is a clinically admitted, anti-diabetic DPP-IV-inhibitor, after acute myocardial infarction ("SITAGRAMI-Trial"; EudraCT Number: 2007-003941-34). Methods The primary objective of the study is to assess myocardial regeneration by improved myocardial homing of mobilized stem cells, as measured by cardiac function using MRI analysis. In this paper, we report on the study design and a planned first interim-analysis on safety issues without unblinding. Results During the first 6weeks of follow-up, only two major adverse cardiac events occurred (one de novo stenosis and one instent-restenosis) in the first 36 patients. Presumably, they were not related to any study medication. No other side effects like headache, bone pain, hypoglycaemias etc. were observed. Furthermore, no myocardial infarction or death occurred in any patient. Thus, the rate of serious adverse events lay within the expected range. Conclusions Our data demonstrate that the combined application of Sitagliptin and G-CSF seems to be safe on the short term and feasible after acute myocardial infarction and may represent a new therapeutic option in future.

231 Absence of PI3Kg leads to increased reendothelialization in mice through modulation of IP-10 secretion. {#article-title-2} The main way of treating symptomatic atherosclerosis is angioplasty with stent placement. This intervention injures the vascular wall, causing endothelial loss, inflammation and intimal hyperplasia (IH), which frequently cause restenosis, a de novo obstruction of the lumen. To prevent this complication, Drug Eluting Stents have been coated with antiproliferative agents. Although they have proven their efficiency, their use is associated with increased early neoatherosclerosis and, although rare long term thrombosis leading to fatal issue. This side effect is in correlation with an impaired endothelial healing due to the lack of specificity of the antiproliferative drugs. So it is of major importance to find new therapeutic targets to prevent restenosis without interfering with a correct reendothelialization. We have previously shown that the invalidation of the kinase activity of phosphoinositide 3-kinase gamma efficiently prevented intimal hyperplasia in mice after arterial injury. Interestingly, immunohistochemical staining strongly suggested that endothelial coverage was increased in mice lacking PI3Kg activity (PI3KgKD, kinase dead) compared to WT controls. PI3Kg is especially known for its inflammatory and immune roles. Yet, no causal link between endothelial healing and immuno-inflammatory processes has been previously reported. We aimed to study the mechanisms by which PI3Kg is involved in endothelial healing. For this purpose, mice were subjected to an endovascular mechanical injury of the carotid artery. Intravenous injection of Evans Blue, allowing the staining of the deendothelialized area, showed a 2 fold increase in reendothelialization rates in PI3Kg KD mice compared with WT, demonstrating a deleterious role of PI3Kg activity upon endothelial healing. Bone marrow transfer experiment showed that this role was attributable to PI3Kg activity in the medullar compartment. A screen at genetic and protein levels showed a PI3Kg dependant increase in the expression and secretion of IP-10 , (IFNg-induced protein 10) in injured carotid arteries, a chemokine previously identified as a possible regulator of endothelial cell proliferation . Moreover, injection of IP-10 neutralizing antibodies accelerates reendothelialization as the same level than observed in absence of PI3Kg activity. Our results demonstrate that PI3Kg invalidation improves endothelial healing through an indirect mechanism involving IP-10 secretion. When added to our previous results, the inhibition of PI3Kg represents a way of preventing complication of arterial angioplasty such as neoatherosclerosis and late stent thrombosis. # 232 DPP4 inhibition mediates vascular protection in acute and chronic vascular injury {#article-title-3} Background/Purpose: Available therapies for vascular diseases at present focus on the treatment of vascular stenoses and reduction of cardiovascular risk factors only. In this project, we want to establish the pharmacological inhibition of DPP4 as a new therapeutic concept focusing on inhibition of atherosclerosis development and improvement of endothelial healing. Methods: ApoE-/- mice were treated with a DPP4 inhibitor ± AMD3100 (in alzet osmotic pumps) or placebo starting before initiation of high-cholesterol-diet(HD)-induced atherosclerosis. Aortic plaque development was quantified after 12 weeks of treatment using the Oil-Red-O staining. Mechanistic analyses comprised FACS analyses for macrophage subtypes isolated from the diseased aortic wall and detailed in-vitro monocyte/macrophage differentiation assays. To evaluate endothelial healing under treatment with different DPP4 inhibitors the common carotid artery of wildtype mice was denuded at a length of 4 mm using an electric injury model. Evans blue staining was used to quantify endothelial recovery after 3 and 6 days of treatment. Further mechanistic analyses were performed using FACS, ultrasound and enzymatic assays. Results: We could demonstrate that DPP4 inhibition tremendously reduced HD-induced neo-atherosclerosis in the ApoE-ko mice. Gliptin-mediated protective effects were reversed by addition of the CXCR4 blocker AMD3100, which clearly proved the SDF-1α/CXCR4-signaling as the therapeutic relevant gliptin-mediated pathway. We could further show that CXCR4 is highly expressed on the surface of cholesterol-exporting M2 macrophages and that the number of M2 macrophages in the aortic wall of Sitagliptin-treated animals was significantly higher than in placebo-treated animals on HD. While the number of M2 macrophages inversely correlated to total plaque area, AMD3100 inhibited the mural enrichment of these cells. Additional in vitro analyses showed that gliptin-mediated enrichment of mural M2 macrophages occurred due to induction of monocyte differentiation rather than induction of cell recruitment. Regarding endothelial recovery, we were able to show that an accelerated reendothelialization of denuded arterial blood vessels via inhibition of DPP4 is mediated by the enhanced recruitment of circulating progenitor cells. Interestingly, reendothelialization occurred only from the borders of the injured area, which supports the notion that local proliferating endothelial cells may exclusively have formed the regenerated endothelial coverage. Conclusion: Different gliptins show a protective effect on arterial blood vessels. Depending on the mechanism of injury (acute endothelial vs. chronic atherosclerotic damage) different cellular mechanisms appear to be responsible for the DPP4-dependent vascular protection. Thus, pharmacological inhibition of DPP4 may depict a future option for the prevention of ischemic cardiomyopathy in diabetic and non-diabetic patients. # 233 Effects of transforming growth factor beta signalling on smooth muscle cell phenotype in the angiotensin II-induced abdominal aortic aneurysm model {#article-title-4} Introduction: Abdominal aortic aneurysm (AAA) is a leading cause of sudden death in aged people. Vascular smooth muscle cells (VSMC) experience phenotypic adaptations to a variety of pathophysiological conditions of alterations underlie progressive aortic dilation. TGFβ modulates the transition between VSMC contractile and synthetic phenotypes. Increased TGFβ signalling results in thoracic aortic aneurysm. In contrast, ies based in the development of AAA report this growth factor as a protective cytokine in the development of AAA. Purpose: To study the role of TGF-beta in phenotypic alteration of VSMC in angiotensin II (Ang II) AAA model Methods: C57BL6 mice received AngII (1.8 µg/hour, 2 wk) infused with osmotic pumps. A neutralizing Anti-TGFβ antibody was injected intraperitoneally (24 mg/kg/wk). AA diameter was measured by echography. Aortic tissue was processed for gene quantification (qPCR) and transmission electron microscopy (TEM). VSMC isolated from human AA were treated with recombinant TGFβ1 and AngII for 24h and processed for gene quantification (qPCR) and immunofluorescence. The morphological phenotype and contractile, synthetic and proliferation markers were determined. Results: AngII infusion to mice induced suprarenal aortic dilatation (48±6%). Treatment with TGFβ-Ab plus AngII potentiated the dilation (83±13%) and the mortality due to AAA rupture. mRNA levels of collagens and fibronectin, as well as α-SMA were increased by TGFβ-Ab plus AngII when compared with AngII alone. TEM of the aortic wall confirmed higher synthetic and contractile VSMC phenotypes, ECM accumulation and elastic disarray in the latter group. In cultured human VSMC, treatment with either AngII or TGFβ1 induced a contractile phenotype (α-SMA: 2±0.2). Conversely, the combined treatment with AngII plus rTGFβ1 reduced the expression of contractile markers (calponin1: 0.3±0.09; α-SMA: 0.6±0.2; connective tissue growth factor: 0.5±0.12), and increased the proliferation marker, cyclin D1. Conclusion: Neutralization of TGF-β potentiates AAA dilation, ECM deposition and contractile phenotype in AngII-infused mice. On the contrary, association of rTGFβ1 to AngII in cultured VSMC downregulates genes encoding contractile markers and collagens. We suggest that TGFβ protects against AAA by decreasing intracellular and extracellular matrix contributors to aortic wall stiffness.

Yang et al. have broadly summarized potential DPP4-dependentmolecular mechanisms for the development of atherosclerosis [1]. In our hands, vascular protective effects based on pharmacological inhibition of DPP4 can be seen in acute vascular injury as well as during initiation of atherosclerosis [2,3]. These effects are based on progenitor cell recruitment or priming of macrophage differentiation, respectively. Thus, our experiments confirm the variety of DPP4-related protective effects on the arterial vasculature. Besides these molecular effects, future translational approaches should now focus on vascular outcomes in gliptin-treated patients. Large-scale randomized trials have investigated clinically relevant vascular events in gliptin-treated diabetic patients. In line with our in vitro results, safety analyses within these studies have already shown some hints for a potential reduction of (urgent) coronary revascularizations in gliptin-treated patients after an acute coronary syndrome [4,5]. Furthermore, we will shortly publish the effects of Sitagliptin treatment