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Senescent endothelial cells (EC) are key players in the pathophysiology of cardiovascular diseases and are characterized by a reduced angiogenic and regenerative potential. Therefore, targeting these cells has been suggested as an effective therapeutic strategy to reduce vascular disease burden and potentially improve health and lifespan of humans. Here, we aimed to establish a pharmacological, partial reprogramming strategy to improve replicative senescent endothelial cell function in the context of angiogenesis. We demonstrate that our treatment improves tube formation and sprouting capacity but also increases proliferation and migration capacity in vitro. Further, inflammation and DNA damage were reduced in the replicative senescent cells. These processes were initiated by a short and timely-restricted overexpression of the Yamanaka-factors induced by our pharmacological strategy. The advantage of these compounds is that they are FDA approved in their respective concentrations which could pave the way for use in a clinical setting. [ABSTRACT FROM AUTHOR] more...

Purpose: We investigated the protection offered by vaccinations and previous infections for the household transmission of Omicron variant of SARS-CoV-2. Methods: 34,666 participants of the German DigiHero cohort study with two or more household members were invited to a prospective household transmission study between June and December 2022. In case of a positive SARS-CoV-2 test in a household, symptom diaries were completed for at least 14 days. Dry blood spots (DBS) were taken from all household members at the beginning and six to eight weeks later. DBS were analyzed for SARS-CoV-2 antibodies. Results: 1191 individuals from 457 households participated. The risk of acquiring a SARS-CoV-2 infection decreased with higher S-titer levels at the time of exposure (from 80% at titer of 0 binding antibody units (BAU)/ml to 20% at titer of 3000 BAU/ml) and increased linearly with the time since vaccination/previous infection (20% for less than one month to 80% at one year). Transmission probability was also reduced when the symptoms of the primary case were mild and if preventive measures were implemented. Conclusion: Vaccinations/previous infections offer a high protection against infection with the Omicron variant for a few months only, supporting the notion of seasonal circulation of the virus. [ABSTRACT FROM AUTHOR] more...

Background: Heart rate variability (HRV), an important marker of autonomic nervous system activity, is usually determined from electrocardiogram (ECG) recordings corrected for extrasystoles and artifacts. Especially in large population-based studies, computer-based algorithms are used to determine RR intervals. The Modular ECG Analysis System MEANS is a widely used tool, especially in large studies. The aim of this study was therefore to evaluate MEANS for its ability to detect non-sinus ECG beats and artifacts and to compare HRV parameters in relation to ECG processing. Additionally, we analyzed how ECG processing affects the statistical association of HRV with cardiovascular disease (CVD) risk factors. Methods: 20-min ECGs from 1,674 subjects of the population-based CARLA study were available for HRV analysis. All ECGs were processed with the ECG computer program MEANS. A reference standard was established by experienced clinicians who visually inspected the MEANS-processed ECGs and reclassified beats if necessary. HRV parameters were calculated for 5-minute segments selected from the original 20-minute ECG. The effects of misclassified typified normal beats on i) HRV calculation and ii) the associations of CVD risk factors (sex, age, diabetes, myocardial infarction) with HRV were modeled using linear regression. Results: Compared to the reference standard, MEANS correctly classified 99% of all beats. The averaged sensitivity of MEANS across all ECGs to detect non-sinus beats was 76% [95% CI: 74.1;78.5], but for supraventricular extrasystoles detection sensitivity dropped to 38% [95% CI: 36.8;38.5]. Time-domain parameters were less affected by false sinus beats than frequency parameters. Compared to the reference standard, MEANS resulted in a higher SDNN on average (mean absolute difference 1.4ms [95% CI: 1.0;1.7], relative 4.9%). Other HRV parameters were also overestimated as well (between 6.5 and 29%). The effect estimates for the association of CVD risk factors with HRV did not differ between the editing methods. Conclusion: We have shown that the use of the automated MEANS algorithm may lead to an overestimation of HRV due to the misclassification of non-sinus beats, especially in frequency domain parameters. However, in population-based studies, this has no effect on the observed associations of HRV with risk factors, and therefore an automated ECG analyzing algorithm as MEANS can be recommended here for the determination of HRV parameters. [ABSTRACT FROM AUTHOR] more...

65 million people worldwide are estimated to suffer from long-term symptoms after their SARS-CoV-2 infection (Long COVID). However, there is still little information about the early recovery among those who initially developed Long COVID, i.e. had symptoms 4–12 weeks after infection but no symptoms after 12 weeks. We aimed to identify associated factors with this early recovery. We used data from SARS-CoV-2-infected individuals from the DigiHero study. Participants provided information about their SARS-CoV-2 infections and symptoms at the time of infection, 4–12 weeks, and more than 12 weeks post-infection. We performed multivariable logistic regression to identify factors associated with early recovery from Long COVID and principal component analysis (PCA) to identify groups among symptoms. 5098 participants reported symptoms at 4–12 weeks after their SARS-CoV-2 infection, of which 2441 (48%) reported no symptoms after 12 weeks. Men, younger participants, individuals with mild course of acute infection, individuals infected with the Omicron variant, and individuals who did not seek medical care in the 4–12 week period after infection had a higher chance of early recovery. In the PCA, we identified four distinct symptom groups. Our results indicate differential risk of continuing symptoms among individuals who developed Long COVID. The identified risk factors are similar to those for the development of Long COVID, so people with these characteristics are at higher risk not only for developing Long COVID, but also for longer persistence of symptoms. Those who sought medical help were also more likely to have persistent symptoms. [ABSTRACT FROM AUTHOR] more...

Circulating endothelial cells (CEC) are arising as biomarkers for vascular diseases. However, whether they can be utilized as markers of endothelial cell (EC) senescence in vivo remains unknown. Here, we present a protocol to isolate circulating endothelial cells for a characterization of their senescent signature. Further, we characterize different models of EC senescence induction in vitro and show similar patterns of senescence being upregulated in CECs of aged patients as compared to young volunteers. Replication-(ageing), etoposide-(DNA damage) and angiotensin II-(ROS) induced senescence models showed the expected cell morphology and proliferation-reduction effects. Expression of senescence-associated secretory phenotype markers was specifically upregulated in replication-induced EC senescence. All models showed reduced telomere lengths and induction of the INK4a/ARF locus. Additional p14ARF-p21 pathway activation was observed in replication- and etoposide-induced EC senescence. Next, we established a combined magnetic activated- and fluorescence activated cell sorting (MACS-FACS) based protocol for CEC isolation. Interestingly, CECs isolated from aged volunteers showed similar senescence marker patterns as replication- and etoposide-induced senescence models. Here, we provide first proof of senescence in human blood derived circulating endothelial cells. These results hint towards an exciting future of using CECs as mirror cells for in vivo endothelial cell senescence, of particular interest in the context of endothelial dysfunction and cardiovascular diseases. [ABSTRACT FROM AUTHOR] more...

Circulating endothelial cells (CEC) are arising as biomarkers for vascular diseases. However, whether they can be utilized as markers of endothelial cell (EC) senescence in vivo remains unknown. Here, we present a protocol to isolate circulating endothelial cells for a characterization of their senescent signature. Further, we characterize different models of EC senescence induction in vitro and show similar patterns of senescence being upregulated in CECs of aged patients as compared to young volunteers. Replication-(ageing), etoposide-(DNA damage) and angiotensin II-(ROS) induced senescence models showed the expected cell morphology and proliferation-reduction effects. Expression of senescence-associated secretory phenotype markers was specifically upregulated in replication-induced EC senescence. All models showed reduced telomere lengths and induction of the INK4a/ARF locus. Additional p14ARF-p21 pathway activation was observed in replication- and etoposide-induced EC senescence. Next, we established a combined magnetic activated- and fluorescence activated cell sorting (MACS-FACS) based protocol for CEC isolation. Interestingly, CECs isolated from aged volunteers showed similar senescence marker patterns as replication- and etoposide-induced senescence models. Here, we provide first proof of senescence in human blood derived circulating endothelial cells. These results hint towards an exciting future of using CECs as mirror cells for in vivo endothelial cell senescence, of particular interest in the context of endothelial dysfunction and cardiovascular diseases. [ABSTRACT FROM AUTHOR] more...

The rapid development of safe and effective vaccines helped to prevent severe disease courses after SARS-CoV-2 infection and to mitigate the progression of the COVID-19 pandemic. While there is evidence that vaccination may reduce the risk of developing post-COVID-19 conditions (PCC), this effect may depend on the viral variant. Therapeutic effects of post-infection vaccination have been discussed but the data for individuals with PCC remains inconclusive. In addition, extremely rare side effects after SARS-CoV-2 vaccination may resemble the heterogeneous PCC phenotype. Here, we analyze the plasma levels of 25 cytokines and SARS-CoV-2 directed antibodies in 540 individuals with or without PCC relative to one or two mRNA-based COVID-19 vaccinations as well as in 20 uninfected individuals one month after their initial mRNA-based COVID-19 vaccination. While none of the SARS-CoV-2 naïve individuals reported any persisting sequelae or exhibited PCC-like dysregulation of plasma cytokines, we detected lower levels of IL-1β and IL-18 in patients with ongoing PCC who received one or two vaccinations at a median of six months after infection as compared to unvaccinated PCC patients. This reduction correlated with less frequent reporting of persisting gastrointestinal symptoms. These data suggest that post-infection vaccination in patients with PCC might be beneficial in a subgroup of individuals displaying gastrointestinal symptoms. [ABSTRACT FROM AUTHOR] more...

Background: To potentially improve impaired vasomotion of patients with multiple organ dysfunction syndrome (MODS), we tested whether an electromagnetic field of low flux density coupled with a biorhythmically defined impulse configuration (Physical Vascular Therapy BEMER®, PVT), in addition to standard care, is safe and feasible and might improve disturbed microcirculatory blood flow and thereby improve global haemodynamics. Methods: In a prospective, monocentric, one-arm pilot study, 10 MODS patients (APACHE II score 20–35) were included. Patients were treated, in addition to standard care, for 4 days with PVT (3 treatment periods of 8 min each day; day 1: field intensity 10.5 μT; day 2:14 μT, day 3:17.5 μT; day 4:21.0 μT). Primary endpoint was the effect of PVT on sublingual microcirculatory perfusion, documented by microvascular flow index (MFI). Patient safety, adverse events, and outcomes were documented. Results: An increase in MFI by approximately 25% paralleled 4-day PVT, with the increase starting immediately after the first PVT and lasting over the total 4-day treatment period. Concerning global haemodynamics (secondary endpoints), halving vasopressor use within 24 h, and haemodynamic stabilisation paralleled 4-day PVT with an increase in cardiac index, stroke volume index, and cardiac power index by 30%–50%. No adverse events (AEs) or serious adverse events (SAEs) were classified as causally related to the medical product (PVT) or study. Three patients died within 28 days and one patient between 28 and 180 days. Conclusion: PVT treatment was feasible and safe and could be performed without obstruction of standard patient care. An increase in microcirculatory blood flow, a rapid reduction in vasopressor use, and an improvement in global haemodynamics paralleled PVT treatment. Findings of this pilot study allowed forming a concept for a randomized trial for further proof. [ABSTRACT FROM AUTHOR] more...

Introduction: Cardiac resynchronization therapy (CRT) with biventricular pacing (BiV‐CRT) is ineffective in approximately one‐third of patients. CRT with Conduction system pacing (CSP‐CRT) may achieve greater synchronization. We aimed to assess the effectiveness of CRT with His pacing (His‐CRT) or left bundle branch pacing (LBB‐CRT) in lieu of biventricular CRT. Methods and Results: The PubMed, Embase, Web of Science, Scopus, and the Cochrane Library were systematically searched until August 19, 2023, for original studies including patients with reduced left ventricular ejection fraction (LVEF) who received His‐ or LBB‐CRT, that reported either CSP‐CRT success, LVEF, QRS duration (QRSd), or New York Heart Association (NYHA) classification. Effect measures were compared with frequentist network meta‐analysis. Thirty‐seven publications, including 20 comparative studies, were included. Success rates were 73.5% (95% CI: 61.2–83.0) for His‐CRT and 91.5% (95% CI: 88.0–94.1) for LBB‐CRT. Compared to BiV‐CRT, greater improvements were observed for LVEF (mean difference [MD] for His‐CRT +3.4%; 95% CI [1.0; 5.7], and LBB‐CRT: +4.4%; [2.5; 6.2]), LV end‐systolic volume (His‐CRT:17.2mL [29.7; 4.8]; LBB‐CRT:15.3mL [28.3; 2.2]), QRSd (His‐CRT: –17.1ms [–25.0; –9.2]; LBB‐CRT: –17.4ms [–23.2; –11.6]), and NYHA (Standardized MD [SMD]: His‐CRT:0.4 [0.8; 0.1]; LBB‐CRT:0.4 [–0.7; –0.2]). Pacing thresholds at baseline and follow‐up were significantly lower with LBB‐CRT versus both His‐CRT and BiV‐CRT. CSP‐CRT was associated with reduced mortality (R = 0.75 [0.61–0.91]) and hospitalizations risk (RR = 0.63 [0.42–0.96]). Conclusion: This study found that CSP‐CRT is associated with greater improvements in QRSd, echocardiographic, and clinical response. LBB‐CRT was associated with lower pacing thresholds. Future randomized trials are needed to determine CSP‐CRT efficacy. [ABSTRACT FROM AUTHOR] more...

During the COVID-19 pandemic in Germany, vaccination uptake exhibited considerable regional disparities. To assess the factors contributing to this variation, we examined the association of sociodemographic variables with COVID-19, COVID-19 booster, and influenza vaccination status within a cohort of 37,078 participants from 13 German federal states in the digital health cohort study commonly known as DigiHero. Our findings revealed variations in vaccination rates based on sociodemographic factors. However, these factors had limited explanatory power regarding regional differences in vaccine uptake. In contrast, we found substantial correlations between regional support of specific parties during the last local elections and the vaccination uptake at the level of each administrative district. In conclusion, sociodemographic factors alone did not suffice to explain the regional disparities in vaccine uptake. Political stances can play a major role, although the current investigation did not assess individual political orientations but rather used only an ecological approach. [ABSTRACT FROM AUTHOR] more...

Introduction: The Russian invasion of Ukraine and the resulting consequences are in the center of political discussions, media, and likely individual thinking of the population in Germany. Yet, the impact of this prolonged exposure on mental health is not known hitherto. Methods: Using the population based cohort study DigiHero from three federal states (Saxony-Anhalt, Saxony, and Bavaria), we assessed anxiety levels (GAD-7), depressive symptoms (PHQ-9), and distress (modified PDI) in the first weeks of war and 6 months later. Results: Of those 19,432, who responded in the first weeks of war, 13,934 (71.1%) responded also 6 months later. While anxiety and emotional distress decreased during the 6 months, their average scores were still elevated, and a substantial fraction of respondents displayed clinically relevant sequelae. Persons from lowincome households were especially affected, specifically by fears related to the personal financial situation. Those who reacted with a particularly strong fear in the beginning of war were more likely to have persistent clinically relevant symptoms of depression and anxiety also 6 months later. Discussion: The Russian invasion of Ukraine is accompanied by continuing impairment of mental health in the German population. Fears surrounding the personal financial situation are a strong determinant. [ABSTRACT FROM AUTHOR] more...

Post‐acute sequelae of COVID‐19 (PASC) are long‐term consequences of SARS‐CoV‐2 infection that can substantially impair the quality of life. Underlying mechanisms ranging from persistent viruses to innate and adaptive immune dysregulation have been discussed. Here, we profiled the plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero), including individuals after mild to moderate COVID‐19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS‐CoV‐2 spike (S1) protein as a potential biomarker for persistent viral reservoirs. At a median time of 8 months after infection, we found pronounced dysregulation in almost all tested soluble factors, including both pro‐inflammatory and pro‐fibrotic cytokines. These immunological perturbations were remarkably independent of ongoing PASC symptoms per se, but further correlation and regression analyses suggested PASC‐specific patterns involving CCL2/MCP‐1 and IL‐8 that either correlated with sCD162, sCD206/MMR, IFN‐α2, IL‐17A and IL‐33, or IL‐18 and IL‐23. None of the analyzed factors correlated with the detectability or levels of circulating S1, indicating that this represents an independent subset of patients with PASC. These data confirm prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrate its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes. [ABSTRACT FROM AUTHOR] more...

The COVID-19 pandemic shows that vaccination strategies building on an ancestral viral strain need to be optimized for the control of potentially emerging viral variants. Therefore, aiming at strong B cell somatic hypermutation to increase antibody affinity to the ancestral strain - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants since high affinity may offer some flexibility to compensate for strain-individual mutations. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529. [ABSTRACT FROM AUTHOR] more...

The COVID-19 pandemic shows that vaccination strategies building on an ancestral viral strain need to be optimized for the control of potentially emerging viral variants. Therefore, aiming at strong B cell somatic hypermutation to increase antibody affinity to the ancestral strain - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants since high affinity may offer some flexibility to compensate for strain-individual mutations. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529. [ABSTRACT FROM AUTHOR] more...

Different devices for mechanical circulatory support (MCS) have been developed for the treatment of refractory cardiogenic shock. However, all of them are associated with direct blood contact, the need for anticoagulation and bleeding complications. To overcome these limitations the pericardial sac got into the focus as a promising implantation site for MCS. For this purpose, further knowledge about the mechanical properties of human pericardium is required. In this prospective, monocentric, experimental pilot study 56 samples of human pericardium were extracted postmortem from 13 critically ill patients. After preparation of test specimens uniaxial tensile tests were performed. The primary end points were load at fracture per sample width and strain at fracture. Acute inflammation was assessed by blood levels of C-reactive protein, white blood count and procalcitonin measured at several times during hospital stay. Inflammatory load was estimated by area under the inflammatory curves. Correlation and regression analysis were used to assess the relationship of primary end points to inflammation, comorbidities and postmortem time to preparation. Human pericardium showed a load at fracture per sample width of 1.95 [1.38–2.94] N/mm (median [inter quartile range]) and a strain at fracture of 89.29 [73.84–135.23] %. Markers of acute inflammation and cardiac hypertrophy did not correlate to load or strain at fracture. However, strain at fracture increased with higher body mass index and an increasing number of postmortem days. In contrast, higher patient age was associated with a lower strain at fracture. Inflammation and cardiac hypertrophy did not influence mechanical properties of human pericardium. [ABSTRACT FROM AUTHOR] more...

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The CARLA study (Cardiovascular Disease, Living and Ageing in Halle) is a longitudinal population-based cohort study of the general population of the city of Halle (Saale), Germany. The primary aim of the cohort was to investigate risk factors for cardiovascular diseases based on comprehensive cardiological phenotyping of study participants and was extended to study factors associated with healthy ageing. In total, 1779 probands (812 women and 967 men, aged 45–83 years) were examined at baseline (2002–2005), with a first and second follow-up performed 4 and 8 years later. The response proportion at baseline was 64.1% and the reparticipation proportion for the first and second follow-up was 86% and 77% respectively. Sixty-four percent of the study participants were in retirement while 25% were full- or partially-employed and 11% were unemployed at the time of the baseline examination. The currently running third follow-up focuses on the assessment of physical and mental health, with an intensive 4 h examination program, including measurement of cardiovascular, neurocognitive, balance and gait parameters. The data collected in the CARLA Study resulted in answering various research questions in over 80 publications, of which two thirds were pooled analyses with other similar population-based studies. Due to the extensiveness of information on risk factors, subclinical conditions and evident diseases, the biobanking concept for the biosamples, the cohort representativeness of an elderly population, and the high level of quality assurance, the CARLA cohort offers a unique platform for further research on important indicators for healthy ageing. [ABSTRACT FROM AUTHOR] more...

Objective: Rare disease Background: Allopurinol is the first-line therapy for the treatment of symptomatic hyperuricemia (gout). In clinical practice, there is a tendency to overmedicate asymptomatic patients who have elevated serum urate. Because of this practice, serious and life-threatening reactions such as Stevens-Johnson syndrome (SJS) or the more dramatic toxic epidermal necrolysis (TEN), both frequently caused by uricostatics, may occur. To increase awareness of these complications, we present a case with fulminant TEN caused by allopurinol. Case Report: A 75-year-old woman noticed a mildly itching skin rash accompanied by fever, shivering, and weakness approximately 3 weeks after taking newly prescribed allopurinol. The initial clinical examination revealed a generalized maculopapular exanthema. An adverse drug reaction was recognized, and allopurinol was discontinued. Ambulatory supportive therapy using prednisolone and cetirizine was started but failed. The patient developed a progressive exanthema with painful widespread blistering, skin peeling, and mucosal and conjunctival lesions. After recurrent presentations to the Emergency Department, the patient was transferred to our Intensive Care Unit (ICU). The clinical picture confirmed the suspected diagnosis of TEN. Massive fluid replacement, prednisolone, and cyclosporine were used as anti-inflammatory therapy. Polyhexanide and octenidine were applied for local treatment. All treatment measures were guided daily by a multidisciplinary team. After 7 days in the ICU, the patient was transferred to the Dermatology Department and was discharged from the hospital 42 days later. Conclusions: With the prescription of allopurinol, there should be awareness of potentially life-threatening complications such as SJS or TEN. Patients with SJS or TEN should be immediately transferred to an ICU with dermatological expertise and multidisciplinary therapy. [ABSTRACT FROM AUTHOR] more...

Objectives: T cells have an essential role in the antiviral defence. Public T‐cell receptor (TCR) clonotypes are expanded in a substantial proportion of COVID‐19 patients. We set out to exploit their potential use as read‐out for COVID‐19 T‐cell immune responses. Methods: We searched for COVID‐19‐associated T‐cell clones with public TCRs, as defined by identical complementarity‐determining region 3 (CDR3) beta chain amino acid sequence that can be reproducibly detected in the blood of COVID‐19 patients. Of the different clonotype identification algorithms used in this study, deep sequencing of brain tissue of five patients with fatal COVID‐19 delivered 68 TCR clonotypes with superior representation across 140 immune repertoires of unrelated COVID‐19 patients. Results: Mining of immune repertoires from subjects not previously exposed to the virus showed that these clonotypes can be found in almost 20% of pre‐pandemic immune repertoires of healthy subjects, with lower representation in repertoires from risk groups like individuals above the age of 60 years or patients with cancer. Conclusion: Together, our data show that at least a proportion of the SARS‐CoV‐2 T‐cell response is mediated by public TCRs that are present in repertoires of unexposed individuals. The lower representation of these clones in repertoires of risk groups or failure to expand such clones may contribute to more unfavorable clinical COVID‐19 courses. [ABSTRACT FROM AUTHOR] more...

Background: Clinical ethics case consultations (CECCs) provide a structured approach in situations of ethical uncertainty or conflicts. There have been increasing calls in recent years to assess the quality of CECCs by means of empirical research. This study provides detailed data of a descriptive quantitative and qualitative evaluation of a CECC service in a department of cardiology and intensive care at a German university hospital.Methods: Semi-structured document analysis of CECCs was conducted in the period of November 1, 2018, to May 31, 2020. All documents were analysed by two researchers independently.Results: Twenty-four CECCs were requested within the study period, of which most (n = 22; 92%) had been initiated by physicians of the department. The patients were an average of 79 years old (R: 43-96), and 14 (58%) patients were female. The median length of stay prior to request was 12.5 days (R: 1-65 days). The most frequent diagnoses (several diagnoses possible) were cardiology-related (n = 29), followed by sepsis (n = 11) and cancer (n = 6). Twenty patients lacked decisional capacity. The main reason for a CECC request was uncertainty about the balancing of potential benefit and harm related to the medically indicated treatment (n = 18). Further reasons included differing views regarding the best individual treatment option between health professionals and patients (n = 3) or between different team members (n = 3). Consensus between participants could be reached in 18 (75%) consultations. The implementation of a disease specific treatment intervention was recommended in five cases. Palliative care and limitation of further disease specific interventions was recommended in 12 cases.Conclusions: To the best of our knowledge, this is the first in-depth evaluation of a CECC service set up for an academic department of cardiology and intensive medical care. Patient characteristics and the issues deliberated during CECC provide a starting point for the development and testing of more tailored clinical ethics support services and research on CECC outcomes. [ABSTRACT FROM AUTHOR] more...

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1−/− mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo. In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4. As more intersection points between platelets and the immune system are found, the role of platelets for vessel growth in the adult organism remains unclear. The authors demonstrate that platelets negatively modulate revascularization through CXCL4 secretion induced by activation C5aR1 on their surface. [ABSTRACT FROM AUTHOR] more...

Aims Recent studies revealed that the bromodomain and extra-terminal (BET) epigenetic reader proteins resemble key regulators in the underlying pathophysiology of cancer, diabetes, or cardiovascular disease. However, whether they also regulate vascular remodelling processes by direct effects on vascular cells is unknown. In this study, we investigated the effects of the BET proteins on human smooth muscle cell (SMC) function in vitro and neointima formation in response to vascular injury in vivo. Methods and results Selective inhibition of BETs by the small molecule (+)-JQ1 dose-dependently reduced proliferation and migration of SMCs without apoptotic or toxic effects. Flow cytometric analysis revealed a cell cycle arrest in the G0/G1 phase in the presence of (+)-JQ1. Microarray- and pathway analyses revealed a substantial transcriptional regulation of gene sets controlled by the Forkhead box O (FOXO1)1-transcription factor. Silencing of the most significantly regulated FOXO1-dependent gene, CDKN1A , abolished the antiproliferative effects. Immunohistochemical colocalization, co-immunoprecipitation, and promoter-binding ELISA assay data confirmed that the BET protein BRD4 directly binds to FOXO1 and regulates FOXO1 transactivational capacity. In vivo , local application of (+)-JQ1 significantly attenuated SMC proliferation and neointimal lesion formation following wire-induced injury of the femoral artery in C57BL/6 mice. Conclusion Inhibition of the BET-containing protein BRD4 after vascular injury by (+)-JQ1 restores FOXO1 transactivational activity, subsequent CDKN1A expression, cell cycle arrest and thus prevents SMC proliferation in vitro and neointima formation in vivo. Inhibition of BET epigenetic reader proteins might thus represent a promising therapeutic strategy to prevent adverse vascular remodelling. [ABSTRACT FROM AUTHOR] more...

Objective: Management of emergency care Background: Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for inhospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. Case Report: We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. Conclusions: Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment. [ABSTRACT FROM AUTHOR] more...

Takotsubo syndrome (TTS) is an acute and mostly reversible cardiomyopathy that mimics an acute coronary syndrome with left ventricular (LV) systolic dysfunction without relevant obstructive coronary artery disease. Its prevalence is probably underestimated and reaches 1.2-2% in patients with acute coronary syndrome undergoing coronary catheterization. Although supraphysiological epinephrine levels have been associated with TTS, the detailed pathophysiology is incompletely understood. Chest pain is the most common clinical presentation; however, cardiac decompensation, cardiogenic shock, and sudden cardiac death due to ventricular fibrillation may also be the first clinical manifestations. Patients are mostly postmenopausal women, in whom the condition is commonly associated with emotional triggers; however, men have a higher prevalence of TTS being associated with physical triggers, which has a worse prognosis compared with TTS associated with emotional triggers. As a diagnosis of exclusion, TTS has no single definitive diagnostic test. According to the distribution of LV wall motion abnormalities, various morphological subtypes have been identified. The final diagnosis depends on cardiac imaging with left ventricular angiography during acute heart catheterization, as well as on echocardiography and cardiac magnetic resonance. Most patients recover completely, albeit several factors have been associated with worse prognosis. Management is based on observational data, while randomized multicenter studies are still lacking. This review provides a general overview of TTS and focuses on the hypothesized pathophysiology, and especially on current practices in diagnosis, prognosis, and treatment. [ABSTRACT FROM AUTHOR] more...

Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR] more...

OBJECTIVES There is an ongoing discussion about how to treat coronary stents during bypass surgery: Should patent stents be left alone and the stented vessels be ungrafted, or should every stented coronary artery receive a bypass graft? This study aims to determine the relevance of perioperative stent stenosis or occlusion on postoperative outcomes up to 3 years postoperatively. METHODS Patients undergoing coronary artery bypass grafting surgery (CABG) (±concomitant procedures) with previous percutaneous coronary intervention from 4 centres were prospectively included in this observatory study between April 2015 and June 2017. A coronary angiography was conducted between the fifth and seventh postoperative days. The preoperative and postoperative angiograms were assessed in a core laboratory, assessing the patencies of coronary stents and bypass grafts. The core lab investigators were blinded to the patients' characteristics and perioperative course. RESULTS A total of 107 patients were included in the study. In the postoperative coronary angiography, 265 bypass grafts and 189 coronary stents were examined angiographically. Ninety-seven percent of preoperatively patent stents remained patent. New coronary stent stenoses were observed in 5 patients (4.7%). All 5 patients were asymptomatic and managed conservatively. Bypass stenoses were observed in 12 patients (11%), of whom were managed conservatively, 4 underwent percutaneous coronary intervention and 1 underwent redo-CABG. Two years postoperatively, 97% of patients were alive. Patients with new stent stenosis tended to have a better survival compared with patients with bypass stenosis (100% vs 73%; P  = 0.09) up to 3 years postoperatively. CONCLUSIONS Perioperative coronary stent stenosis occurs rarely. It is safe to leave a patently stented coronary vessel without bypass grafting. [ABSTRACT FROM AUTHOR] more...

The senescence of vascular smooth muscle cells (VSMCs) has been implicated as a causal pro-inflammatory mechanism for cardiovascular disease development and progression of atherosclerosis, the instigator of ischemic heart disease. Contemporary limitations related to studying this cellular population and senescence-related therapeutics are caused by a lack of specific markers enabling their detection. Therefore, we aimed to profile a phenotypical and molecular signature of senescent VSMCs to allow reliable identification. To achieve this goal, we have compared non-senescent and senescent VSMCs from two in vitro models of senescence, replicative senescence (RS) and DNA-damage induced senescence (DS), by analyzing the expressions of established senescence markers: cell cycle inhibitors- p16 INK4a, p14 ARF, p21 and p53; pro-inflammatory factors-Interleukin 1β (IL-1β), IL-6 and high mobility group box-1 (HMGB-1); contractile proteins-smooth muscle heavy chain- (MYH11), smoothelin and transgelin (TAGLN), as well as structural features (nuclear morphology and LMNB1 (Lamin B1) expression). The different senescence-inducing modalities resulted in a lack of the proliferative activity. Nucleomegaly was seen in senescent VSMC as compared to freshly isolated VSMC Phenotypically, senescent VSMC appeared with a significantly larger cell size and polygonal, non-spindle-shaped cell morphology. In line with the supposed switch to a pro-inflammatory phenotype known as the senescence associated secretory phenotype (SASP), we found that both RS and DS upregulated IL-1β and released HMGB-1 from the nucleus, while RS also showed IL-6 upregulation. In regard to cell cycle-regulating molecules, we detected modestly increased p16 levels in both RS and DS, but largely inconsistent p21, p14ARF, and p53 expressions in senescent VSMCs. Since these classical markers of senescence showed insufficient deregulation to warrant senescent VSMC detection, we have conducted a non-biased proteomics and in silico analysis of RS VSMC demonstrating altered RNA biology as the central molecular feature of senescence in this cell type. Therefore, key proteins involved with RNA functionality, HMGB-1 release, LMNB-1 downregulation, in junction with nuclear enlargement, can be used as markers of VSMC senescence, enabling the detection of these pathogenic pro-inflammatory cells in future therapeutic studies in ischemic heart disease and atherosclerosis. [ABSTRACT FROM AUTHOR] more...

Meta-analysis on immunohistological (IHC) concepts for the detection of inflammatory cardiomyopathy (InfCM) in endomyocardial biopsies (EMB). We included 61 publications, with 10,491 patients (mean age 47.1 years; men 66%) who underwent EMB and IHC evaluation. The 460 control patients were devoid of IHC proof of InfCM. The mean IHC detection rate of InfCM was 50.8% (95% CI 47.7-53.8%; range 18.4-91.7%). A publication bias was excluded (Funnel Plot p = 0.4264). This IHC detection rate was significantly (p < 0.0001) higher compared to the histological detection of myocarditis according to the Dallas criteria (mean 8.04%; 95% CI 5.08-12.5%; subset of 3274 patients in 30 publications). However, 13 different diagnostic IHC criteria were described in the publications, with various thresholds of diverse phenotypes of quantified infiltrates, and endothelial expression of diverse cell adhesion molecules (CAM), quantified either visually or by digital image analysis (DIA). The comparison of IHC with cardiac magnetic resonance (CMR) data available in a subset of 13 publications with 1185 patients revealed a sensitivity for CMR of 69% (95% CI 58-79%), a specificity of 73% (95% CI 59-84%), and a ROC-AUC of 0.77 (95% CI 0.73-0.81). This meta-analysis encompassing 10,491 patients confirms a mean detection rate of InfCM in 50.8% of EMB, being significantly more sensitive compared to the histological Dallas criteria. IHC cannot be fully substituted by CMR. However, standardization of the diverse IHC markers and protocols seems pertinent, especially considering the published adverse prognostic impact of IHC-confirmed InfCM and its published suitability for the selection of candidates responding favorably to immunosuppression. [ABSTRACT FROM AUTHOR] more...

Background: Percutaneous closure (LAAC) of the left atrial appendage (LAA) is an efficacious preventive procedure for patients with non-valvular atrial fibrillation (NVAF) and considerable bleeding risk. We sought to systematically review the available LAAC data on the novel occluder device LAmbre™.Methods: For this systematic review, a search of the literature was conducted by 3 independent reviewers, reporting the safety and therapeutic success of LAAC in patients being treated with a LAmbre™. Publications reporting the safety and therapeutic success of LAAC using LAmbre™ in n > 5 patients were included.Results: The literature search retrieved n = 10 publications, encompassing n = 403 NVAF patients treated with a LAmbre™ LAAC, with relevant data regarding safety and therapeutic success of the procedure. The mean CHA2DS2-VASc Score was 4.0 + 0.9, and the mean HAS-BLED score was 3.4 + 0.5. The implantation success was 99.7%, with a mean procedure time of 45.4 ± 18.7 min, and a fluoroscopy time of 9.6 ± 5.9 min, and a contrast agent volume of 96.7 ± 0.7 ml. The anticoagulation regimen was switched to DAPT post procedure in the majority of the patients (96.8%). Partial and full recapture were done in 45.5% and in 25.6%, respectively. Major complications were reported in 2.9%, with 0.3% mortality, 1.7% pericardial tamponade, 0.3% stroke, and 0.6% major bleeding complications; no device embolization was observed. During follow up at 6 or 12 months, major adverse cardiovascular events were reported in 3.3%: Stroke or TIA in 1.7%, thrombus formation on the device in 0.7%, and residual flow > 5 mm in 1.0%. In some publications, the favorable implantion properties of the LAmbre™ for difficult anatomies such as shallow or multilobular LAA anatomies were described.Conclusions: This systematic review on the LAmbre™ LAA-occluder including n = 403 NVAF patients demonstrates an excellent implantion success rate, promising follow-up clinical data, and favorable properties for also challenging LAA anatomies,. While its design seems to be helpful in preventing device embolization, pericardial tamponade may not be substantially reduced by the LAmbre™ as compared with other established LAAC devices. Further larger prospective multicenter registries and randomized trials are needed to scrutinize the value of the LAmbre™ compared with established LAAC devices. [ABSTRACT FROM AUTHOR] more...

Background: Colchicine has been used as anti-inflammatory agent in pericardial effusion (PE). We sought to perform a meta-analysis of randomized trials assessing the efficacy and safety of colchicine in patients with pericarditis or postpericardiotomy syndrome (PPS).Methods: In the systematic literature search following the PRISMA statement, 10 prospective randomized controlled studies with 1981 patients with an average follow-up duration of 13.6 months were identified.Results: Colchicine reduced the recurrence rate of pericarditis in patients with acute and recurrent pericarditis and reduced the incidence of PPS (RR: 0.57, 95% CI: 0.44-0.74). Additionally, the rate of rehospitalizations as well as the symptom duration after 72 h was significantly decreased in pericarditis (RR 0.33; 95% CI 0.18-0.60; and RR 0.43; 95% CI 0.34-0.54; respectively), but not in PPS. Treatment with colchicine was associated with significantly higher adverse event (AE) rates (RR 1.42; 95% CI 1.05-1.92), with gastrointestinal intolerance being the leading AE. The reported number needed to treat (NNT) for the prevention of recurrent pericarditis ranged between 3 and 5. The reported NNT for PPS prevention was 10, and the number needed to harm (NNH) was 12, respectively. Late colchicine administration > 7 days after heart surgery did not reduce postoperative PE.Conclusions: Our meta-analysis confirms that colchicine is efficacious and safe for prevention of recurrent pericarditis and PPS, while it reduces rehospitalizations and symptom duration in pericarditis. The clinical use of colchicine for the setting of PPS and postoperative PE after heart surgery should be investigated in further multicenter RCT. [ABSTRACT FROM AUTHOR] more...

Purpose: The chemokine receptor CXCR4 is a promising target for molecular imaging of CXCR4+ cell types, e.g. inflammatory cells, in cardiovascular diseases. We speculated that a specific CXCR4 ligand, [68Ga]pentixafor, along with novel techniques for motion correction, would facilitate the in vivo characterization of CXCR4 expression in small culprit and nonculprit coronary atherosclerotic lesions after acute myocardial infarction by motion-corrected targeted PET/CT.Methods: CXCR4 expression was analysed ex vivo in separately obtained arterial wall specimens. [68Ga]Pentixafor PET/CT was performed in 37 patients after stent-based reperfusion for a first acute ST-segment elevation myocardial infarction. List-mode PET data were reconstructed to five different datasets using cardiac and/or respiratory gating. Guided by CT for localization, the PET signals of culprit and various groups of nonculprit coronary lesions were analysed and compared.Results: Ex vivo, CXCR4 was upregulated in atherosclerotic lesions, and mainly colocalized with CD68+ inflammatory cells. In vivo, elevated CXCR4 expression was detected in culprit and nonculprit lesions, and the strongest CXCR4 PET signal (median SUVmax 1.96; interquartile range, IQR, 1.55-2.31) was observed in culprit coronary artery lesions. Stented nonculprit lesions (median SUVmax 1.45, IQR 1.23-1.88; P = 0.048) and hot spots in naive remote coronary segments (median SUVmax 1.34, IQR 1.23-1.74; P = 0.0005) showed significantly lower levels of CXCR4 expression. Dual cardiac/respiratory gating provided the strongest CXCR4 PET signal and the highest lesion detectability.Conclusion: We demonstrated the basic feasibility of motion-corrected targeted PET/CT imaging of CXCR4 expression in coronary artery lesions, which was triggered by vessel wall inflammation but also by stent-induced injury. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of coronary atherosclerotic plaque. [ABSTRACT FROM AUTHOR] more...

Plaque microvascularization and increased endothelial permeability are key players in the development of atherosclerosis, from the initial stages of plaque formation to the occurrence of acute cardiovascular events. First, endothelial dysfunction and increased permeability facilitate the entry of diverse inflammation-triggering molecules and particles such as low-density lipoproteins into the artery wall from the arterial lumen and vasa vasorum (VV). Recognition of entering particles by resident phagocytes in the vessel wall triggers a maladaptive inflammatory response that initiates the process of local plaque formation. The recruitment and accumulation of inflammatory cells and the subsequent release of several cytokines, especially from resident macrophages, stimulate the expansion of existing VV and the formation of new highly permeable microvessels. This, in turn, exacerbates the deposition of pro-inflammatory particles and results in the recruitment of even more inflammatory cells. The progressive accumulation of leukocytes in the intima, which trigger proliferation of smooth muscle cells in the media, results in vessel wall thickening and hypoxia, which further stimulates neoangiogenesis of VV. Ultimately, this highly inflammatory environment damages the fragile plaque microvasculature leading to intraplaque hemorrhage, plaque instability, and eventually, acute cardiovascular events. This review will focus on the pivotal roles of endothelial permeability, neoangiogenesis, and plaque microvascularization by VV during plaque initiation, progression, and rupture. Special emphasis will be given to the underlying molecular mechanisms and potential therapeutic strategies to selectively target these processes. [ABSTRACT FROM AUTHOR] more...

Aims Adventitial cells have been suggested to contribute to neointima formation, but the functional relevance and the responsible signalling pathways are largely unknown. Sonic hedgehog (Shh) is a regulator of vasculogenesis and promotes angiogenesis in the adult. Methods and results Here we show that proliferation of vascular smooth muscle cells (SMC) after wire-induced injury in C57BL/6 mice is preceded by proliferation of adventitial fibroblasts. Simultaneously, the expression of Shh and its downstream signalling protein smoothened (SMO) were robustly increased within injured arteries. In vitro, combined stimulation with Shh and platelet-derived growth factor (PDGF)-BB strongly induced proliferation and migration of human adventitial fibroblasts. The supernatant of these activated fibroblasts contained high levels of interleukin-6 and 8 and strongly induced proliferation and migration of SMC. Inhibition of SMO selectively prevented fibroblast proliferation, cytokine release and paracrine SMC activation. Mechanistically, we found that PDGF-BB activates protein kinase A in fibroblasts and thereby induces trafficking of SMO to the plasma membrane, where it can be activated by Shh. In vivo, SMO-inhibition significantly prevented the proliferation of adventitial fibroblasts and neointima formation following wire-induced injury. Conclusions The initial activation of adventitial fibroblasts is essential for the subsequent proliferation of SMC and neointima formation. We identified SMO-dependent Shh signalling as a specific process for the activation of adventitial fibroblasts. [ABSTRACT FROM AUTHOR] more...

Background: The novel nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone holds promise to be safe and efficient in the treatment of patients with heart failure and/or chronic kidney disease. However, its effects on vascular function remain elusive. Purpose: The aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells in vitro and the effect on vascular remodeling following acute vascular injury in vivo. Methods and results: In vitro, finerenone dose-dependently reduced aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC) apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay. In vivo, oral application of finerenone resulted in an accelerated re-endothelialization 3 days following electric injury of the murine carotid artery. Furthermore, finerenone treatment inhibited intimal and medial cell proliferation following wire-induced injury of the murine femoral artery 10 days following injury and attenuated neointimal lesion formation 21 days following injury. Conclusion: Finerenone significantly reduces apoptosis of ECs and simultaneously attenuates SMC proliferation, resulting in accelerated endothelial healing and reduced neointima formation of the injured vessels. Thus, finerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling. [ABSTRACT FROM AUTHOR] more...

Platelet P2Y12 is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y12 but not P2Y¹ receptors and antagonises 10 μM ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of ~250 μM. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 μM. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 μMwas 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptor was verified by P2Y12 receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2-and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that may be useful for therapeutic intervention. [ABSTRACT FROM AUTHOR] more...

Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists is the mainstay of treatment for metastatic prostate cancer (mCaP). However, ADT is associated with serious cardiovascular events. Only a few studies that directly compare the cardiovascular risk of LHRH agonists versus GnRH antagonists have been published.Objectives: This review aims to compare the cardiovascular risk of LHRH agonists versus GnRH antagonists based on the literature.Methods: A literature search that considered full publications and abstracts published before December 10, 2014 was performed. Due to their high evidence quality, only meta-analyses and pooled studies were included in this review.Results: Four studies were included. These investigated the cardiovascular risk of patients receiving an ADT with LHRH agonists and/or GnRH antagonists. However, only one of these directly compared the cardiovascular risk of ADT with LHRH agonists versus GnRH antagonists. This meta-analysis showed a significant reduction in cardiovascular risk for patients receiving a GnRH antagonist compared to those patients receiving a LHRH agonist (HR: 0.597; 95 % CI: 0.380-0.938; P = 0.0253). Subgroup analyses showed that, in particular, patients with pre-existing cardiovascular diseases who were treated with a GnRH antagonist have a significantly lower risk of experiencing a cardiovascular event when compared with patients receiving a GnRH agonist (HR: 0.44; 95 % CI: 0.26-0.74; P = 0.002).Conclusion: In conclusion, GnRH antagonists are associated with a lower risk of cardiovascular events, compared with LHRH agonists, when administered as ADT in CaP patients, and particularly in patients with a history of cardiovascular disease. Thus, patients with a history of cardiovascular disease may benefit from ADT with a GnRH antagonist. [ABSTRACT FROM AUTHOR] more...