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Aims Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce. Methods and results Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40–80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6–37.4%], 13.3% [12.6–13.9%], and 40.8% [39.9–41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19–1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11–2.05), P = 0.009]. Conclusion Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.

We estimated the association between outdoor light at night at the residence and risk of coronary heart disease (CHD) within a prospective cohort of older adults in Hong Kong.Over a median of 11 years of follow-up, we identified 3772 incident CHD hospitalizations and 1695 CHD deaths. Annual levels of outdoor light at night at participants' residential addresses were estimated using time-varying satellite data for a composite of persistent night-time illumination at ∼1 km2 scale. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between outdoor light at night at the residence and risk of CHD. The association between light at night and incident CHD hospitalization and mortality exhibited a monotonic exposure-response function. An interquartile range (IQR) (60.0 nW/cm2/sr) increase in outdoor light at night was associated with an HR of 1.11 (95% CI: 1.03, 1.18) for CHD hospitalizations and 1.10 (95% CI: 1.00, 1.22) for CHD deaths after adjusting for both individual and area-level risk factors. The association did not vary across strata of hypothesized risk factors.Among older adults, outdoor light at night at the residence was associated with a higher risk of CHD hospitalizations and deaths. We caution against causal interpretation of these novel findings. Future studies with more detailed information on exposure, individual adaptive behaviours, and potential mediators are warranted to further examine the relationship between light at night and CHD risk.

Introduction Diabetes mellitus (DM) represents a notable risk factor after surgical and interventional procedures but data on the influence of DM on long-term survival after Transcatheter Edge-to-edge Repair (TEER) for Mitral valve Regurgitation (MR) are sparse. Purpose To compare the outcome of patients with and without DM after TEER. Methods Retrospective monocentric assessment of patients after successful treatment of MR by TEER (exclusion of combined forms of transcatheter repair) between 06/2010 and 03/2018. Patients were stratified for DM at baseline and observed regarding mortality during follow-up. Cox regression analyses were performed for survival analyses. Results 627 patients (47.0% females, 88.2% aged ≥70 years) and among these 174 subjects with DM (27.3%) were included with a median follow-up period of 486 days [IQR 157–916 days]). Within the investigation period, 20 patients (3.2%) were lost to follow-up. Patients with DM more often presented severe comorbidities like obesity (27.3% vs. 9.2%, p Conclusions Even though DM-patients presented with a more vulnerable clinical profile, no relevant differences in short- and long-term mortality after TEER for MR were found. Although being factored in most common risk scores, DM could not be associated with an adverse prognosis after transcatheter therapy of MR. Funding Acknowledgement Type of funding sources: None.

Background Venous thromboembolism (VTE) is common and associated with high morbidity and mortality. Although chronic inflammation was not categorized as a traditional risk factor for VTE, chronic inflammation might increase the risk to develop VTE events. While studies confirmed an increased cardiovascular morbidity and mortality in psoriatic patients, data regarding the influence of psoriasis on patients' cardiovascular profile and on prognosis of patients with pulmonary embolism (PE) are sparse. Purpose We aimed to investigate the impact of psoriasis on prognosis of PE patients. Methods Hospitalized PE patients were stratified for psoriasis and the impact of psoriasis on outcome was investigated in the German nationwide inpatient sample of the years 2005–2017 (source: Research Data Center (RDC) of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2005–2017, own calculations). Results Overall, 1,076,384 hospitalizations of PE patients (53.7% females, median age 72.0 [60.0–80.0] years) were recorded in Germany 2005–2017. Among these, 3,145 patients were additionally coded with psoriasis (0.3%). Psoriatic PE patients were younger (68.0 [57.0–76.0] vs. 72.0 [60.0–80.0] years, P Psoriatic PE patients showed a lower in-hospital case-fatality rate (11.1% vs. 16.0%, P Conclusions Overall, only a minority (0.3%) of all PE cases were coded additionally with psoriasis. PE patients with psoriasis were hospitalized in median four years earlier than those without. Although psoriasis was associated with an unfavorable cardiovascular-risk and VTE-risk profile in PE patients, our data demonstrate a lower in-hospital mortality rate in psoriatic PE, which might be mainly driven by younger age. Our findings may improve the clinical management of these patients and contribute evidence for relevant systemic manifestation of psoriasis. Funding Acknowledgement Type of funding sources: None.

Objectives In patients with acute pulmonary embolism (PE), right atrial pressure is elevated, which increases risk for right-to-left shunt when patent foramen ovale (PFO) is present and thus potentially increases risk for paradoxical embolism. Little is known about the clinical outcome of patients with PE and concomitant PFO. Methods We analysed data on patient characteristics, treatments and in-hospital outcomes for all PE patients (ICD-code I26) with concomitant presence of PFO in Germany 2005–2018 (source: Research Data Center (RDC) of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2005–2018, and own calculations). Results Between January 2005 and December 2018, 1,174,235 patients with acute PE (53.5% females) were included in this analysis; of those, 5,486 (0.5%) had a concomitant diagnosis of PFO. Trends analysis demonstrating an increasing frequency of diagnosed PE with additional PFO from 2005 (n=299) to 2018 (n=556; p Conclusion Patients with acute PE and the concomitant presence of PFO are associated with a high risk for paradox arterial emboli and intracranial bleeding events. Especially in normotensive patients, the use of systemic thrombolysis should be considered with cautious. Thus, our findings may improve the clinical management of patients with PE and PFO. Funding Acknowledgement Type of funding sources: None.

Background A symptomatic and prognostic benefit by Transcatheter edge-to-edge repair (TEER) for mitral regurgitation (MR) has been proven. A variety of individual factors including female sex has been suggested to be associated with adverse outcome in cardio-surgical procedures. Purpose While gender is factored in common risk factor models for adverse outcome, evidence on sex-specific differences in long-term outcome after TEER for MR is limited. We aimed to investigate the impact of gender on prognosis in a large monocentric cohort with long-term follow-up. Methods We analyzed survival stratified for gender after successful isolated edge-to-edge repair of MR in the period between 06/2010 and 03/2018 (exclusion of combined forms of TMVR) in a monocentric retrospective cohort by performing survival analyses and cox regression analyses. Results Consecutively, 627 patients (47.0% females, 57.4% functional MR; survival status was available in 96.7%) entered the study and were followed for a median follow-up period of 462 days [IQR 142–945 days]. Survival rates were 97.6% at discharge, 75.7% after 1, 54.5% after 3, 37.6% after 5 and 21.7% after 7 years. Risk score as calculated by the Logistic Euroscore I did not differ significantly between females and males (at baseline: 25.0 [IQR 18.0/34.8] vs. 27.0 [18.4/40.1]%, p=0.093) and no relevant differences were found for in-hospital (2.0 vs. 2.7%, p=0.613), 30 days (4.8 vs. 6.5%, p=0.473) and 1-year mortality (27.0 vs. 25.3%, p=0.675). At the time of procedure, women were older (79.9 [IQR 75.6/84.4] vs. 78.3 [72.9/83.4] years, p Conclusion In our cohort of patients undergoing TEER for MR, we found no evidence for an impaired short- and mid-term prognosis for female patients. In contrary and not as indicated by Logistic Euroscore, female sex was associated with better long-term survival in comparison to men despite higher median age, which might be partly explained by a slightly more favorable cardiovascular risk profile. Funding Acknowledgement Type of funding sources: None. Figure 1

It is unclear whether night-time noise events, including from aeroplanes, could trigger a cardiovascular death. In this study, we investigate the potential acute effects of aircraft noise on mortality and the specific role of different night-time exposure windows by means of a case-crossover study design.We selected 24 886 cases of death from cardiovascular disease (CVD) from the Swiss National Cohort around Zürich Airport between 2000 and 2015. For night-time deaths, exposure levels 2 h preceding death were significantly associated with mortality for all causes of CVD [OR = 1.44 (1.03-2.04) for the highest exposure group (LAeq50 dB vs.20 dB)]. Most consistent associations were observed for ischaemic heart diseases, myocardial infarction, heart failure, and arrhythmia. Association were more pronounced for females (P = 0.02) and for people living in areas with low road and railway background noise (P = 0.01) and in buildings constructed before 1970 (P = 0.36). We calculated a population attributable fraction of 3% in our study population.Our findings suggest that night-time aircraft noise can trigger acute cardiovascular mortality. The association was similar to that previously observed for long-term aircraft noise exposure.

Aims In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. Methods and results The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P Conclusion As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting. EUDRACT-No 2011-005305-73

Aims Electronic (e)-cigarettes have been marketed as a ‘healthy’ alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms. Methods and results Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation. Conclusions E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks.

Aims Ambient air pollution is a major health risk, leading to respiratory and cardiovascular mortality. A recent Global Exposure Mortality Model, based on an unmatched number of cohort studies in many countries, provides new hazard ratio functions, calling for re-evaluation of the disease burden. Accordingly, we estimated excess cardiovascular mortality attributed to air pollution in Europe. Methods and results The new hazard ratio functions have been combined with ambient air pollution exposure data to estimate the impacts in Europe and the 28 countries of the European Union (EU-28). The annual excess mortality rate from ambient air pollution in Europe is 790 000 [95% confidence interval (95% CI) 645 000–934 000], and 659 000 (95% CI 537 000–775 000) in the EU-28. Between 40% and 80% are due to cardiovascular events, which dominate health outcomes. The upper limit includes events attributed to other non-communicable diseases, which are currently not specified. These estimates exceed recent analyses, such as the Global Burden of Disease for 2015, by more than a factor of two. We estimate that air pollution reduces the mean life expectancy in Europe by about 2.2 years with an annual, attributable per capita mortality rate in Europe of 133/100 000 per year. Conclusion We provide new data based on novel hazard ratio functions suggesting that the health impacts attributable to ambient air pollution in Europe are substantially higher than previously assumed, though subject to considerable uncertainty. Our results imply that replacing fossil fuels by clean, renewable energy sources could substantially reduce the loss of life expectancy from air pollution.

Background Transcatheter Aortic Valve Implantation (TAVI) is today the first option for older patients with aortic valve stenosis (AS) at intermediate or high risk for surgery. Constant development of bioprosthetic valves and delivery systems have reduced complications and improved outcomes over the years. The 3rd generation Edwards Sapien 3 Valve (S3) and the 2nd generation Medtronic Evolut R Valve (ER) are currently the most frequently used worldwide. There is a paucity of published data regarding long term outcomes in these new generation TAVI patients. Methods and results In our retrospective, single-center analysis we included patients with severe Aortic Stenosis who underwent transfemoral TAVI with a new generation prosthesis between 2014 and 2016. Peri- and postprocedural outcomes of these patients were analyzed according to the VARC-2 criteria. The study population consisted of 359 patients (mean patient age 82±7 years, 47% male, mean EuroSCORE II 8.0±8). The S3 group included 215 patients, the ER group 144 patients. Median follow-up period was 3.8 years (IQR 3.3 to 4.4 years, maximum follow-up in living patients 5.1 years). Device Success rates where equal in both groups (93.0% vs. 92.4%, p=0.812). We report a 30-day mortality of 2.8% in the S3 group, 2.1% in the ER group, respectively (p=0.674). There was no difference in stroke rate, conversion to open heart surgery, major vascular complications, life-threatening or disabling bleeding or myocardial infarction. Implantation of a new permanent pacemaker was lower in the S3 group (S3: 27.4% vs. ER: 44.5%, p=0.002). While prosthesis mean gradients where higher in the S3 group (12.0 mmHg vs. 8.2 mmHg, p All-Cause Mortality up to 5 years did not show a difference between both patient groups (mean survival S3 3.5 years, ER 3.3 years, p=0.895). Independent predictors of death where impaired left ventricular function (HR 1.61, p=0.007), chronic kidney injury (HR 1.55, p=0.032), peripheral artery disease (HR 2.10, p=0.003), malignant tumor (HR 2.40, p Discussion We present a comparison of the new-generation aortic valve prostheses Edwards Sapien 3 and Medtronic Evolut R concerning long-term as well as periprocedural outcomes. The analyzed cohort consisted of patients at intermediate to high surgical risk. Yet, 30-day mortality was very low both in S3 and ER patients. Device success and periprocedural outcomes in both groups were comparable and are in line with previous studies using VARC-2 definitions. Conclusion New generation TAVI valves offer an excellent implant and outcome success rate compared to early transcatheter Aortic valve replacement. Long-term survival was independent of prostheses choice and mainly attributed to pre- and intraprocedural comorbidities and complications. All-Cause Mortality (Kaplan-Meier) Funding Acknowledgement Type of funding source: None

Background Diabetes mellitus (DM) represents a major cardiovascular risk factor for coronary artery disease and myocardial infarction (MI). Purpose We aimed to assess in-hospital events and time trends in MI patients with and without DM between 2005 and 2016 in Germany. Methods The nationwide German inpatient sample 2005–2016 was used for statistical analysis (source: Research Data Center (RDC) of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2005–2016, own calculations). Hospitalized MI patients were stratified for the presence of DM and the impact of DM on in-hospital events was investigated. Results A total of 3,307,703 patients with acute MI (37.6% females, 56.8% aged ≥70 years) were included in the present analysis. Of these, 1,007,326 (30.5%) patients were coded for additional DM. More MI patients with DM were female (41.2% vs. 36.0%, P Conclusions While the proportion of MI patients with DM increased only slightly from 2005 to 2016, the in-hospital mortality decreased substantially in MI patients with DM. DM was associated with an aggravated cardiovascular risk profile, higher prevalence of comorbidities and increased in-hospital mortality during hospitalization. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1503); institutional grant for the Center for Thrombosis and Hemostasis.

Background Venous thromboembolism (VTE) is a frequent acute cardiovascular disease, leading to significant morbidity and mortality worldwide. Major trauma, surgery, immobilisation and joint replacements are major provoking factors for VTE. In particular, patients undergoing knee and hip joint replacement surgery are at high risk of developing VTE perioperatively, even in the era of established pharmacological thromboprophylaxis. Without thromboprophylaxis, as many as 20–60% of patients may develop perioperative VTE. Purpose As recent studies indicate an increasing number of total knee and hip replacement surgeries in European countries and the United States, aims of our study were to investigate a) total burden and temporal trends of VTE complications following knee (KJR) and hip joint replacement (HJR) in Germany 2005–2016 and to identify b) predictors of VTE during hospitalization. Methods In an analysis of the nationwide German inpatient sample, we included all hospitalized patients with elective primary KJR and HJR in Germany between 2005 and 2016 (source: Research Data Center (RDC) of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2005–2016, own calculations). We analyzed temporal trends of surgical procedure, mortality, and VTE, and identified predictors of VTE. Results A total of 1,804,496 hospitalized patients underwent KJR (65.1% women, 53.4% aged ≥70 years) and 1,885,839 received HJR (59.1% women, 51.4% ≥70 years). VTE was documented in 23,297 (1.3% of total) KJR patients and in 11,554 HJR patients (0.6%). The number of primary KJR (129,832 in 2005 to 167,881 in 2016 [β-(slope)-estimate 1978 per year; 95% CI 1951 to 2004, P In-hospital VTE decreased from 1.9% to 0.9% (β-estimate −0.77 [95% CI: −0.81 to −0.72], P Infections during hospitalization were associated with a higher VTE risk. VTE events were associated with in-hospital death in KJR (OR 20.86 [95% CI: 18.78–23.15], P Conclusions While total numbers of KJR and HJR interventions increased in Germany between 2005 and 2016, the rate of VTE decreased substantially. VTE complications were associated with 15-to 21-fold increase of in-hospital case-fatality rate. Perioperative infections increased the risk for VTE substantially. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1503), institutional grant for the Center for Thrombosis and Hemostasis. The authors are responsible for the contents of this publication.

Background Prediabetes and type 2 diabetes mellitus (T2DM) have been demonstrated to alter left ventricular geometry and promote left ventricular (LV) hypertrophy (LVH). However, the impact of impaired glucose metabolism on cardiac structure is still not completely understood and controversially discussed. Purpose To investigate the impact of prediabetes and T2DM on left ventricular geometry and their potential interaction with LVH in the prediction of survival. Methods Data from the Gutenberg Health Study (N=15,010) – a population-based study with highly standardized phenotyping – were analysed. Information was obtained from computer-assisted personal interviews, medical-technical examinations, laboratory measurements in fasting state and echocardiography according to standard operating procedures with detailed quality control. Individuals with other types of diabetes or hyperinsulinemia were excluded from analysis. Study participants aged 35 to 74 years were categorized according to long-term glucose state (HbA1c) into euglycemia, prediabetes and T2DM. LV geometry was assessed according to current guideline recommendations. Multivariable regression analyses were performed to evaluate the association between glucose state and measures of left ventricular geometry. Survival analyses were carried out to assess the prognostic impact dependent on the presence of LVH. Results The analysis sample comprised 14,852 individuals aged 55.0±11.1 years (49.5% females). The prevalence of LVH was 10.2% (n=1,227) in euglycaemia, 17.2% in prediabetes and 23.8% in T2DM. Similarly, concentric and eccentric hypertrophy had the highest prevalence in T2DM (13.1% and 10.8%, respectively), followed by prediabetes (9.6% and 8.2%) and euglycaemia (5.7% and 4.5%). In multivariable regression analysis with adjustment for age, sex, traditional cardiovascular risk factors (CVRF), C-reactive protein and LV function, T2DM had a higher impact on relative wall thickness (β: 0.0135 [0.0087; 0.0182]; P Conclusions Although cardiac geometry is altered both in presence of prediabetes and T2DM, only T2DM is a strong predictor of premature mortality in the general population. This merits consideration for future preventive strategies to decrease the burden of cardiovascular disease. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The study was supported by the Federal Ministry of Education and Research (BMBF), the government of Rheinland-Pfalz and the Center for Translational Vascular Biology (CTVB) of the Johannes Gutenberg-University of Mainz, Germany.

Background Transcatheter tricuspid valve repair (TTVR) using edge-to-edge leaflet therapy (E2E) has evolved as a feasible therapy to treating severe tricuspid regurgitation (TR). The TRILUMINATE trial using the new TriClip NT has shown promising clinical and functional improvements. However, the 3rd generation MitraClip XTr (Abbott Structural Heart, Santa Clara, CA, USA) has a broad off-label experience in the European Union to address tricuspid TR with wider gaps. There is insufficient data on the secondary effects of E2E on tricuspid annular geometry. The aim of this study was to address this lack of knowledge by evaluating the acute effects of E2E using the MitraClip XTr. Methods We retrospectively analyzed the imaging data of procedures using the MitraClip XTr to treat severe symptomatic TR at our Institution in 2018. Tricuspid annular geometry was assessed before and immediately after clip implantation by 3D TEE analysis of biplane and manual and automated volume data. Results During 2018, 69 patients were treated for severe TR using a transcatheter approach. In 61 patients, E2E was used, in 58 patients the MitraClip XTr was utilized (Pascal: n=3, Edwards Lifesciences, Irvine, CA, USA). Mean age was 79.0 years ± 6.4. Percutaneous TTVR using the MitraClip XTr significantly decreased the diastolic septal-lateral diameter (S/L: 4.1±0.7cm vs. 3.6±0.7cm; p Conclusions Percutaneous TTVR using MitraClip XTr showed significant changes in TV annulus geometry by focal perimeter and area reduction. This highlights a new mechanism of E2E therapy through indirectly adressing the dilated annulus in patients with severe TR. Annulus geometry by TOE, 3D- and autoMPR Funding Acknowledgement Type of funding source: None

Background and purpose Catheter-directed treatment of acute pulmonary embolism (PE) is technically advancing. Recent guidelines acknowledge this treatment option for patients with overt or imminent haemodynamic decompensation, particularly when systemic thrombolysis is contraindicated or has failed. We investigated baseline characteristics and in-hospital outcomes of patients with PE who underwent catheter-directed thrombolysis (CDT) in the German nationwide inpatient cohort. Methods Data from hospitalizations with PE between 2005 and 2016 were collected by the Federal Office of Statistics (Statistisches Bundesamt) in Germany and included in this analysis. Patients with PE who underwent CDT were compared with patients receiving systemic thrombolysis, and those without thromboytic or other reperfusion treatment. Results We analyzed data from 978,094 hospitalized patients with PE. Of these, 41,903 (4.3%) patients received thrombolytic treatment (systemic thrombolysis in 4.2%, CDT in 0.1%). Among PE patients with shock, CDT was associated with lower in-hospital mortality compared to systemic thrombolysis (OR, 0.29, 95% CI 0.13–0.66, P=0.003). No intracranial bleeding occurred among PE patients with shock who received CDT. Among haemodynamically stable PE patients with right ventricular (RV) dysfunction (intermediate-risk PE), CDT also was associated with a lower risk of in-hospital mortality compared to systemic thrombolysis (OR, 0.52 [95% CI 0.38–0.70]; P Conclusion In the German nationwide inpatient cohort, CDT was associated with lower in-hospital mortality rates compared to systemic thrombolysis. Prospective controlled data are urgently needed to determine the true value of this treatment option in acute PE. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1503).

Background Mitral valve regurgitation (MR) is a frequent heart valve disorder affecting 1–2% of the humans in the general population and over 10% of the individuals older than 75 years. While a symptomatic and prognostic benefit of transcatheter edge-to-edge repair for MR (TMVR) was reported, data regarding long-term outcome as well as influence of concomitant tricuspid regurgitation (TR) are sparse. Purpose We aimed to investigate the impact of periinterventional development of TR on survival of patients undergoing interventional edge-to-edge repair for MR in a large retrospective monocentric study. Methods We retrospectively analyzed survival of patients successfully treated with isolated edge-to-edge repair for MR from 06/2010–03/2018 (exclusion of combined forms of TMVR) in our center. Baseline, periprocedural as well as follow-up data were gathered. Concomitant TR was evaluated at baseline and after 30 days and categorized from grades 0 (no TR) to grade III (severe TR). We analyzed the influence of severe vs. non-severe TR on 30-day, 1-year and long-term survival. Results Overall, 627 consecutive patients (47.0% female, 57.4% functional MR) were enrolled. Median follow-up time was 462 days [IQR 142–945]. Survival status was available in 96.7%. Survival rates were 97.6% at discharge, 75.7% after 1, 54.5% after 3, 37.6% after 5 and 21.7% after 7 years. TR at baseline (examination results were available in 92.3%) was categorized as severe TR in 25.6%, medium TR in 33.3%, mild TR in 35.1% and no TR in 6.0%. TR at 1 month (examination results were available in 81.1%) was severe in 16.7%, medium in 30.2%, mild in 45.6% and no TR was found in 7.4%; improvement by at least 1 TR-grade was documented in 33.6% of the patients. While a severe (compared to non-severe) TR at baseline did not affect the 30-day mortality (7.4% vs. 5.2%, p=0.354), 1-year survival was substantially impaired in those patients (36.5% vs. 23.0%, p=0.012). Accordingly, severe TR was not associated with 30d-mortality (as evaluated by univariate Cox regression, p=0.340), but with 1-year survival (HR 1.78, 95% CI 1.19–2.65, p=0.005) and showed a trend towards impaired long-term survival (HR 1.30, 95% CI 0.96–1.76, p=0.089). While residual severe TR at one month did not influence 1-year-mortality significantly (p=0.478), improvement of TR demonstrated a trend to better survival after the first year (86.9 vs. 81.0%, p=0.208) confirmed in the Cox regression analysis (HR 0.66, 95% CI 0.36–1.22, p=0.188). Conclusions In this large retrospective monocentric study with a long-term follow-up-period of >7 years after edge-to-edge therapy for MR, we demonstrated that severe TR at the time of the intervention had an impact on 1-year-survival. Furthermore, a missing periinterventional improvement of TR was shown to be unfavorable regarding the long-term survival of these patients. Funding Acknowledgement Type of funding source: None

Aims Assessment of endothelial function in humans by measuring flow-mediated dilation (FMD) risk-stratifies individuals with established cardiovascular disease, whereas its predictive value is limited in primary prevention. We therefore aimed to establish and evaluate novel markers of FMD at the population level. Methods and results In order to identify novel targets that were negatively correlated with FMD and investigate their contribution to vascular function, we performed a genome-wide association study (GWAS) of 4175 participants of the population based Gutenberg Health Study. Subsequently, conditional knockout mouse models deleting the gene of interest were generated and characterized. GWAS analysis revealed that single-nucleotide polymorphisms (SNPs) in the tubulin-folding cofactor E (TBCE) gene were negatively correlated with endothelial function and TBCE expression. Vascular smooth muscle cell (VSMC)-targeted TBCE deficiency was associated with endothelial dysfunction, aortic wall hypertrophy, and endoplasmic reticulum (ER) stress-mediated VSMC hyperproliferation in mice, paralleled by calnexin up-regulation and exacerbated by the blood pressure hormone angiotensin II. Treating SMMHC-ERT2-Cre+/−TBCEfl/fl mice with the ER stress modulator tauroursodeoxycholic acid amplified Raptor/Beclin-1-dependent autophagy and reversed vascular dysfunction. Conclusion TBCE and tubulin homeostasis seem to be novel predictors of vascular function and offer a new drug target to ameliorate ER stress-dependent vascular dysfunction.

Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving smokers or generating new addicts. Here, we provide an updated overview of the impact of tobacco/waterpipe (shisha) smoking and e-cigarette vaping on endothelial function, a biomarker for early, subclinical, atherosclerosis from human and animal studies. Also their emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and the circadian clock are summarized. We briefly discuss heat-not-burn tobacco products and their cardiovascular health effects. We discuss the impact of the toxic constituents of these products on endothelial function and subsequent CVD and we also provide an update on current recommendations, regulation and advertising with focus on the USA and Europe. As outlined by the WHO, tobacco cigarette, waterpipe, and e-cigarette smoking/vaping may contribute to an increased burden of symptoms due to coronavirus disease 2019 (COVID-19) and to severe health consequences., Graphical Abstract Graphical Abstract

Ambient air pollution is a leading cause of non-communicable disease globally. The largest proportion of deaths and morbidity due to air pollution is now known to be due to cardiovascular disorders. Several particulate and gaseous air pollutants can trigger acute events (e.g. myocardial infarction, stroke, heart failure). While the mechanisms by which air pollutants cause cardiovascular events is undergoing continual refinement, the preponderant evidence support rapid effects of a diversity of pollutants including all particulate pollutants (e.g. course, fine, ultrafine particles) and gaseous pollutants such as ozone, on vascular function. Indeed alterations in endothelial function seem to be critically important in transducing signals and eventually promoting cardiovascular disorders such as hypertension, diabetes, and atherosclerosis. Here, we provide an updated overview of the impact of particulate and gaseous pollutants on endothelial function from human and animal studies. The evidence for causal mechanistic pathways from both animal and human studies that support various hypothesized general pathways and their individual and collective impact on vascular function is highlighted. We also discuss current gaps in knowledge and evidence from trials evaluating the impact of personal-level strategies to reduce exposure to fine particulate matter (PM2.5) and impact on vascular function, given the current lack of definitive randomized evidence using hard endpoints. We conclude by an exhortation for formal inclusion of air pollution as a major risk factor in societal guidelines and provision of formal recommendations to prevent adverse cardiovascular effects attributable to air pollution.

Background Ischemic heart disease (IHD) is the most common cause of death with an increasing frequency worldwide. It accounts for approximately 20% of all deaths in Europe and the United States of America. Approximately 1/3 of the IHD patients present with sudden cardiac death. The acute presentation of IHD myocardial infarction (MI) is a life-threatening, serious health problem, which causes substantially morbidity and mortality. It is well established that the onset of MI follows a circadian and seasonal periodicity. Seasonal variation regarding the incidence and the short-term mortality of acute MI was frequently reported, but data about sex-specific differences are sparse. Purpose Thus, our objectives were to investigate seasonal variations of myocardial infarction. Methods We analyzed the impact of seasons on incidence and in-hospital mortality of patients with acute MI in Germany from 2005 to 2015. We included all MI patients (ICD code I21) with an acute MI (, but not those MI patients with a recurrent event in the first 28 days after a previous MI (ICD code I22)), who were hospitalized in Germany between 2005 and 2015, in this analysis (source: RDC of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2005–2015, own calculations). Results The nationwide sample comprised 3,008,188 hospitalizations of patients with MI (2005–2015). The annual incidence was 334.7 per 100.000 population. Incidence inclined from 316.3 to 341.6 per 100.000 population per year (β 0.17 [0.10 to 0.24], P Seasonal variation of both incidence and in-hospital mortality were of substantial magnitude. Seasonal incidence (86.1 vs. 79.0 per 100.000 population per year, P We observed sex-specific differences regarding the seasonal variation of in-hospital mortality: males showed lowest mortality in summer, while females during fall. Low temperature dependency of mortality seems more pronounced in males. Conclusions Incidence of acute MI increased 2005–2015, while in-hospital mortality rate decreased. Seasonal variations of incidence and in-hospital mortality were of substantial magnitude with lowest incidence and lowest mortality in the summer season. Additionally, we observed sex-specific differences regarding the seasonal variation of the in-hospital mortality. Acknowledgement/Funding This study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1503)

Background Environmental noise pollution has been identified as a cardiovascular risk and is characterized by moderate hypertension, endothelial dysfunction, increased oxidative stress, and inflammation. We have gained insights into the mechanism by which these consequences occur by exposing mice lacking the critical NADPH oxidase subunit gp91phox to aircraft noise. Mice were protected from the effects of aircraft noise exposure. NADPH oxidase is believed to be the mediator by which angiotensin II increases oxidative stress, making investigation into the additive effect of noise and hypertension an important subject in modern cardiovascular health research. Methods and results C57Bl/6J mice were implanted with subcutaneous osmotic mini-pumps, delivering a moderate dose of 0.5mg/kg/d of angiotensin II for 7 days. Immediately following the implantation, half the mice were exposed to aircraft noise for 7 days at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A), a level at which hearing loss does not occur*. Non-invasive blood pressure measurements revealed an additive increase in blood pressure in noise-exposed hypertensive mice. Following sacrifice, endothelial dysfunction was evaluated through isometric tension recordings of 3mm aortic ring segments. These recordings support the blood pressure measurements and indicate a more serious impairment in acetylcholine-induced vasorelaxation in hypertensive mice exposed to noise than the hypertensive or noise only controls. Whole blood stimulated with phorbol 12,13-dibutyrate (PDBu) or zymosan A showed an additive increase in oxidative burst in in noise-exposed hypertensive mice. Dihydroethidium (DHE) staining was used to assess the presence of vascular and cerebral oxidative stress, showing similar additive effects in mice with hypertension plus noise exposure. High performance liquid chromatography (HPLC) measurement of 2-hydroxyethidium further confirmed additive increase of oxidative stress in the aorta and brain. Western blot analysis of aortic tissue revealed highest levels of gp91phox in mice with hypertension plus noise exposure and indicated a decrease in the ratio of P-eNOSSer1177:eNOS as well as a decrease in the ratio of eNOS dimer:monomer, exposing eNOS uncoupling as a potential pathomechanism for endothelial dysfunction and gp91phox as a source for the oxidative stress.Ongoing immunohistochemical and flow cytometric investigations will characterize the role of immune cells in these adverse effects. Conclusion Herein, we present novel data demonstrating additive noise-induced cardiovascular consequences on developing hypertension. Noise has previously been established as a cardiovascular risk factor, but the effects have not been determined in pre-existing or developing cardiovascular disease. Our results show a cumulative effect between noise exposure and hypertension and forge an important link between environmental stressors and cardiovascular health. Acknowledgement/Funding Boehringer Ingelheim Foundation

Objective The LEADER trial demonstrated that glucagon-like peptide-1 (GLP-1) analogs like Liraglutide (Lira) reduce the risk of cardiovascular events in T2DM, an effect beyond glycemic control. A detailed evaluation of the precise mechanisms underlying the cardiovascular protective effects of GLP-1 has been hampered by the fact that the GLP-1 receptor is expressed on different cell types in the vasculature including platelets, neuronal, endothelial and inflammatory cells. We used endothelial and myeloid cell-specific knockout mice of the GLP-1 receptor (GLP-1r) in an angiotensin-II (ATII)-induced model of hypertension. The aim of the recent study was to investigate the cardioprotective effects of GLP-1 in ATII-induced arterial hypertension and to characterize the cell-specific contribution of GLP-1r signaling. Methods Arterial hypertension was induced by s.c. ATII administration (0.5mg/kg/d; 7 days) in WT (C57/BL6J) as well as endothelial and myeloid cell-specific GLP-1r knockout mice (Cdh5crexGLP-1rfl/fl and LysMcrexGLP-1rfl/fl mice). Animals were treated with Lira (2x30μg/d; 7 days). Blood pressure was measured by tail-cuff. Vascular function was tested by isometric tension recording. Aortic and cardiac tissue was used for Western blotting, qRT-PCR, FACS, IHC and HPLC to determine the extent of inflammation, oxidative stress and fibrosis. ELISA was used to determine GLP-1 and insulin levels in plasma. Results Endogenous GLP-1 (7–36 and 9–36) was reduced in hypertensive animals. Lira ameliorated blood pressure and improved endothelial dysfunction, vascular oxidative stress and inflammation caused by ATII, in both WT and myeloid cell-specific GLP-1r knockout mice. Hypertension led to infiltration of inflammatory monocytes (Ly6G-Ly6Chigh) and neutrophils (Ly6G+Ly6C+) into the vascular wall, which was prevented by Lira. In accordance, Lira suppressed vascular oxidative stress and mRNA expression of iNOS, CD11b and Nox2. Endothelial NO synthase (eNOS) was S-glutathionylated with ATII treatment indicating uncoupled eNOS. Thus, aortic NO levels were reduced, all of which was restored by Lira. Furthermore, vascular fibrosis and cardiac hypertrophy were tremendously reduced by GLP-1. Interestingly, all of these beneficial cardiovascular effects of GLP-1 were abolished in endothelial cell-specific GLP-1r knockout mice. Conclusion We show that Lira reduces blood pressure and improves vascular function, fibrosis and cardiac hypertrophy in experimental arterial hypertension in mice. Mechanistically, Lira prevents the infiltration of inflammatory cells to the vascular wall, leading to reduced oxidative stress and improved NO bioavailability. Beneficial effects of GLP-1 are mediated by the GLP-1r expressed on endothelial and not myeloid cells. With the present study we provide a mechanistic approach to explain the cardioprotective effects of GLP-1 analogs like Lira, for which the endothelial GLP-1 receptor is indispensable. Acknowledgement/Funding Deutsche Forschungsgesellschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF)

Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.

Copyright © 2020 European Society of Cardiology, Aims: Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS. Methods and results: Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort. Conclusions: Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.

Environmental factors can act as facilitators of chronic non-communicable diseases. Ambient noise and air pollution collectively outrank all other environmental risk factors in importance, contributing to over 75% of the disease and disability burden associated with known environmental risk factors. In the first part of this review, we discussed the global burden and epidemiologic evidence supporting the importance of these novel risk factors as facilitators of cardiometabolic disease. In this part, we will discuss pathophysiological mechanisms responsible for noise and air pollution-mediated effects. Akin to traditional cardiovascular risk factors, a considerable body of evidence suggests that these environmental agents induce low-grade inflammation, oxidative stress, vascular dysfunction, and autonomic nervous system imbalance, thereby facilitating the development of diseases such as hypertension and diabetes. Through their impact on traditional risk factors and via additional novel mechanisms, environmental risk factors may have much larger impact on cardiovascular events than currently appreciated. In the second part of this review, we discuss deficiencies and gaps in knowledge and opportunities for new research.

Aims Left-ventricular (LV) remodelling impacts on the LV end-diastolic pressure–volume relationship (EDPVR), which is different in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In a large-scale, population-based cohort (Gutenberg Health Study), we aimed to investigate alterations of the EDPVR in HF patients and their association to risk factors and all-cause mortality in non-HF individuals. Methods and results Based on clinical and echocardiographic data, participants were divided into ‘No HF’ ( n = 14487), HFrEF ( n = 215), and HFpEF ( n = 79). We estimated the position of the EDPVR and its stiffness-coefficient β from echocardiographic data using a single-beat method. The EDPVR was shifted rightward in HFrEF and leftward in HFpEF compared with ‘No HF’, while the stiffness-coefficient β was increased in both HFrEF and HFpEF. In ‘No HF’, a higher stiffness-coefficient β was associated with age, female gender, hypertension, diabetes, and obesity, while age and female gender were associated with a leftward shift of the EDPVR, whereas dyslipidaemia, obesity, smoking, and impaired renal function were associated with a rightward shift of the EDPVR. Both changes of the EDPVR were associated with increased all-cause mortality. Conclusion In a large-scale, population-based cohort, we show distinct alterations of the EDPVR in HFrEF and HFpEF. Already in non-HF individuals, the presence of risk factors for HF is linked alterations of the EDPVR, which are associated with increased mortality.

Aims Pulmonary embolism (PE) is the third most common cardiovascular cause of death; systemic thrombolysis is potentially lifesaving treatment in patients presenting with haemodynamic instability. We investigated trends in the use of systemic thrombolysis and the outcome of patients with acute PE. Methods and results We analysed data on the characteristics, comorbidities, treatment, and in-hospital outcome of 885 806 PE patients in Germany between 2005 and 2015. Incidence of acute PE was 99/100 000 population/year and increased from 85/100 000 in 2005 to 109/100 000 in 2015 [β 0.32 (0.26–0.38), P Conclusion Although the proportion of PE patients treated with systemic thrombolysis increased slightly in Germany between 2005 and 2015, only the minority of haemodynamically unstable patients currently receive this treatment. In the nationwide inpatient cohort, thrombolytic therapy was associated with reduced in-hospital mortality rates in PE patients with shock, and also in those who underwent CPR.

Background Peri-stent coronary evaginations may disturb flow and have been proposed as possible risk factor for late stent thrombosis. We describe incidence, predictors, and possible mechanisms of coronary evaginations 12 months after implantation of bioresorbable vascular scaffolds (BVS).Methods and results One hundred and two BVS implanted in 90 patients (age 63 ± 13 years, 71 males, 14 diabetics) were analysed with angiography and optical coherence tomography (OCT) 12 months after implantation. Evaginations were identified as any hollow in the luminal vessel contour between well-apposed struts and were classified as major when extending ≥3 mm with a depth ≥10% of the BVS diameter. Fifty-five (54%) of the BVS (50(56%) of the patients) had at least one evagination (6.1 ± 6.2 evaginations per BVS), with a mean volume of 1.9 ± 1.9 mm³. Major evaginations were only found in one patient, and in-BVS aneurysms in three patients (4BVS). The presence of evaginations was strongly associated with that of malapposition (P = 0.003) and strut fractures (P = 0.01). No association could be shown between the presence and volume of the evaginations and any clinical variable or the presence of uncovered struts (P > 0.5). Peri-strut low- intensity areas (PSLIA) were present in 29 (53%) of the BVS with evaginations and 12 (26%) of those without (P = 0.0049); their presence was independently associated with the presence, the number (P < 0.003) and volume of the evaginations (P = 0.004) and with that of strut fracture. Conclusions Optical coherence tomography-detected evaginations are relatively common after BVS implantation, but, as for modern drug-eluting metallic stents, major evaginations are very rare. Optical coherence tomography evidence of immature neointima and strut fractures were associated with more severe development of evaginations.