Telomerlängenanalysen bei Patienten mit Vorhofflimmern

Vorhofflimmern stellt die häufigste Herzrhythmusstörung der westlichen Welt dar und führt unbehandelt durch die Verursachung von Schlaganfällen zu erheblichen Gesundheitskosten. Neben kardiovaskulären Erkrankungen spielt das Lebensalter bei der Entwicklung von Vorhofflimmern eine entscheidende Rolle. Telomere sind neben dem numerischen Lebensalter ein anerkannter Biomarker für das Fortschreiten biologischer Seneszenzprozesse. Die Telomerdynamik und -länge ist bei Individuen mit Vorhofflimmern jedoch nur unzureichend in kleineren epidemiologischen Studien untersucht worden und die Ergebnisse bezüglich einer pathogenetischen Bedeutung der altersassoziierten Telomerverkürzung oder die Nutzung von Telomerlängen als Biomarker sind inkongruent. In einer großen epidemiologischen Arbeit, analysierten wir Telomerlängen mittels quantitativer Real-Time PCR bei Patienten mit Vorhofflimmern (AFLMU, n = 2475) im Vergleich zu einer Bevölkerungs-basierten Referenzkohorte (KORA F4, n = 3077). Wir fanden kürzere Telomere bei Rauchern, bei Patienten mit arterieller Hypertonie oder nach Myokardinfarkt und bei Individuen mit männlichem Geschlecht. Patienten mit Vorhofflimmern wiesen signifikant kürzere Telomere auf als Vorhofflimmer-freie Kontrollprobanden (Telomerlänge KORA F4: 13,27 [11,94, 13,69] versus Telomerlänge AFLMU: 9,81 [5,98, 13,10], p < 0,001). Eine multivariabel adjustierte, logistische Regressionsanalyse identifizierte neben arterieller Hypertonie, männlichem Geschlecht, Body-Mass-Index und Diabetes mellitus eine signifikante Interaktion zwischen Telomerlänge und Vorhofflimmern (Odds Ratio pro Einheit höhere Telomerlänge: 0.77 [95% Konfidenzintervall 0,74 - 0,77], p < 0,001). Dieses Ergebnis war robust im Rahmen einer zusätzlichen Propensity Score - gematchten Analyse der AFLMU und KORA F4 Kohorten (Odds Ratio 0,75 [0,73, 0,60], p < 0,001). Unsere Daten demonstrieren somit, dass kürzere Telomere, hypothesen-gemäß also ein höheres biologisches Alter, mit einer erhöhten Inzidenz von Vorhofflimmern einhergehen. Wir postulieren daher, dass die Telomerlänge einen Risikomarker für Vorhofflimmern darstellt, dessen Bestimmung möglicherweise zu einer verbesserten diagnostischen und therapeutischen Stratifizierbarkeit betroffener Patienten führen kann

Telomerlängenanalysen bei Patienten mit Vorhofflimmern

Vorhofflimmern stellt die häufigste Herzrhythmusstörung der westlichen Welt dar und führt unbehandelt durch die Verursachung von Schlaganfällen zu erheblichen Gesundheitskosten. Neben kardiovaskulären Erkrankungen spielt das Lebensalter bei der Entwicklung von Vorhofflimmern eine entscheidende Rolle. Telomere sind neben dem numerischen Lebensalter ein anerkannter Biomarker für das Fortschreiten biologischer Seneszenzprozesse. Die Telomerdynamik und -länge ist bei Individuen mit Vorhofflimmern jedoch nur unzureichend in kleineren epidemiologischen Studien untersucht worden und die Ergebnisse bezüglich einer pathogenetischen Bedeutung der altersassoziierten Telomerverkürzung oder die Nutzung von Telomerlängen als Biomarker sind inkongruent. In einer großen epidemiologischen Arbeit, analysierten wir Telomerlängen mittels quantitativer Real-Time PCR bei Patienten mit Vorhofflimmern (AFLMU, n = 2475) im Vergleich zu einer Bevölkerungs-basierten Referenzkohorte (KORA F4, n = 3077). Wir fanden kürzere Telomere bei Rauchern, bei Patienten mit arterieller Hypertonie oder nach Myokardinfarkt und bei Individuen mit männlichem Geschlecht. Patienten mit Vorhofflimmern wiesen signifikant kürzere Telomere auf als Vorhofflimmer-freie Kontrollprobanden (Telomerlänge KORA F4: 13,27 [11,94, 13,69] versus Telomerlänge AFLMU: 9,81 [5,98, 13,10], p < 0,001). Eine multivariabel adjustierte, logistische Regressionsanalyse identifizierte neben arterieller Hypertonie, männlichem Geschlecht, Body-Mass-Index und Diabetes mellitus eine signifikante Interaktion zwischen Telomerlänge und Vorhofflimmern (Odds Ratio pro Einheit höhere Telomerlänge: 0.77 [95% Konfidenzintervall 0,74 - 0,77], p < 0,001). Dieses Ergebnis war robust im Rahmen einer zusätzlichen Propensity Score - gematchten Analyse der AFLMU und KORA F4 Kohorten (Odds Ratio 0,75 [0,73, 0,60], p < 0,001). Unsere Daten demonstrieren somit, dass kürzere Telomere, hypothesen-gemäß also ein höheres biologisches Alter, mit einer erhöhten Inzidenz von Vorhofflimmern einhergehen. Wir postulieren daher, dass die Telomerlänge einen Risikomarker für Vorhofflimmern darstellt, dessen Bestimmung möglicherweise zu einer verbesserten diagnostischen und therapeutischen Stratifizierbarkeit betroffener Patienten führen kann

De-Escalation of P2Y(12) Receptor Inhibitor Therapy after Acute Coronary Syndromes in Patients Undergoing Percutaneous Coronary Intervention

Dual antiplatelet therapy (DAPT) - a combination of a P2Y(12) receptor inhibitor and aspirin - has revolutionized antithrombotic treatment. Potent P2Y(12) inhibitors such as prasugrel and ticagrelor exhibit a strong and more consistent platelet inhibition when compared to clopidogrel. Therefore, ticagrelor and prasugrel significantly reduce ischemic events, but at an expense of an increased bleeding risk in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). These observations have engaged intensive clinical research in alternative DAPT regimens to achieve sufficient platelet inhibition with an acceptable bleeding risk. Our review focusses on P2Y(12) receptor therapy de-escalation defined as a switch from a potent antiplatelet agent (ticagrelor or prasugrel) to clopidogrel. Recently, both unguided (platelet function testing independent) and guided (platelet function testing dependent) DAPT de-escalation strategies have been investigated in different clinical studies and both switching strategies could be possible options to prevent bleeding complications without increasing ischemic risk. In light of the still limited data currently available, future large-scale trials should accumulate more data on various DAPT de-escalation regimens with both ticagrelor and prasugrel in unguided and guided de-escalation approaches. In the current review we aim at summarizing and discussing the current evidence on this still emerging topic in the field of antiplatelet treatment

Clec12a Is an Inhibitory Receptor for Uric Acid Crystals that Regulates Inflammation in Response to Cell Death

SummaryRecognition of cell death by the innate immune system triggers inflammatory responses. However, how these reactions are regulated is not well understood. Here, we identify the inhibitory C-type lectin receptor Clec12a as a specific receptor for dead cells. Both human and mouse Clec12a could physically sense uric acid crystals (monosodium urate, MSU), which are key danger signals for cell-death-induced immunity. Clec12a inhibited inflammatory responses to MSU in vitro, and Clec12a-deficient mice exhibited hyperinflammatory responses after being challenged with MSU or necrotic cells and after radiation-induced thymocyte killing in vivo. Thus, we identified a negative regulatory MSU receptor that controls noninfectious inflammation in response to cell death that has implications for autoimmunity and inflammatory disease

Suture-based vs. pure plug-based vascular closure devices for VA-ECMO decannulation–A retrospective observational study

BackgroundVeno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a valuable treatment option for patients in cardiogenic shock, but complications during decannulation may worsen the overall outcome. Therefore, the aim of this study was to compare the efficacy and safety of suture-based to pure plug-based vascular closure devices for VA-ECMO decannulation.MethodsIn this retrospective study, the procedural outcome of 33 patients with suture-based Perclose ProGlide closure devices was compared to 38 patients with MANTA plug-based closure devices.ResultsRate of technically correct placement of closure devices was 88% in the suture-based group and 97% in the plug-based group (p = 0.27). There was a significant reduction of severe bleeding events during VA-ECMO decannulation in plug-based versus suture-based systems (3% vs. 21%, p = 0.04). Ischemic complications occurred in 6% with suture-based and 5% with plug-based device (p = 1.00). Pseudoaneurysm formation was detected in 3% in both groups (p = 1.00). No switch to vascular surgery due to bleeding after decannulation was necessary in both groups.ConclusionBased on our retrospective analysis, we propose that plug-based vascular closure should be the preferred option for VA-ECMO decannulation. This hypothesis should be further tested in a randomized trial

Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease: The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial

Importance The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant. Objective To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI. Design, Setting, and Participants A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI). Interventions Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy. Main Outcomes and Measures The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days. Results Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5'-diphosphate-induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36). Conclusions and Relevance Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms. Trial Registration ClinicalTrials.gov Identifier: NCT03312855

Treatment of acute cardiac tamponade: A retrospective analysis of classical intermittent versus continuous pericardial drainage

Background Acute cardiac tamponade is a life-threatening pathology in modern cardiology as catheter-based interventions become increasingly relevant. Pericardiocentesis is usually the primary treatment of choice. However, protocols for handling of draining pigtail catheters are very variable due to limit data and require further investigation. Methods We retrospectively analyzed 52 patients with acute cardiac tamponade requiring immediate pericardiocentesis from January 2017 to August 2020. Patients were treated with a classical approach of intermittent manual aspiration or continuous pericardial drainage using a redon drainage system. Results Mean age of patients was 74 years in both groups. Most common causes for cardiac tamponade were percutaneous coronary interventions in about 50% and transaortic valve implantations in 25% of all cases. 28 patients were treated with classic intermittent drainage from 2017 to 2020. 24 patients were treated with continuous drainage from December 2018-2020. Compared to classical intermittent drainage treatment, continuous drainage was associated with a lower rate of a surgical intervention or cardiac re-tamponade and a lower mortality at 5 days (HR 0.2, 95% CI 0.1-0.9, log-rank p = 0.03). Despite a longer total drainage time under continuous suction, drainage volumes were comparable in both groups. Conclusion Acute cardiac tamponade can be efficiently treated by pericardiocentesis with subsequent continuous negative pressure drainage via a pigtail catheter. Our retrospective analysis shows a significantly lower mortality, a decreased rate of interventions and lower rates of cardiac re-tamponade without any relevant side effects when compared to classical intermittent manual drainage. These findings require further investigations in larger, randomized trials

Adrenoceptor expression during intervertebral disc degeneration

Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and spine sections of wildtype mice (WT) and of a mouse line that develops spontaneous IVD degeneration (IVDD, in SM/J mice) were stained for ARs and extracellular matrix (ECM) components. In IVD homogenates and cells α1a-, α1b-, α2a-, α2b-, α2c-, β1-, and β2-AR genes were expressed. In human sections, β2-AR was detectable, and its localization parallels with ECM alterations. Similarly, in IVDs of WT mice, only β2-AR was expressed, and in IVDs of SM/J mice, β2AR expression was stronger accompanied by increased collagen II, collagen XII, decorin as well as decreased cartilage oligomeric matrix protein expression. In addition, norepinephrine stimulation of isolated human IVD cells induced intracellular signaling via ERK1/2 and PKA. For the first time, the existence and functionality of ARs were demonstrated in IVD tissue samples, suggesting that the sympathicus might play a role in IVDD. Further studies will address relevant cellular mechanisms and thereby help to develop novel therapeutic options for IVDD

Comparison of balanced and unbalanced crystalloids as resuscitation fluid in patients treated for cardiogenic shock

Abstract Background The efficacy and safety of saline versus balanced crystalloid solutions in ICU-patients remains complicated by exceptionally heterogenous study population in past comparative studies. This study sought to compare saline and balanced crystalloids for fluid resuscitation in patients with cardiogenic shock with or without out-of-hospital cardiac arrest (OHCA). Methods We retrospectively analyzed 1032 propensity score matched patients with cardiogenic shock from the Munich University Hospital from 2010 to 2022. In 2018, default resuscitation fluid was changed from 0.9% saline to balanced crystalloids. The primary endpoint was defined as 30-day mortality rate. Results Patients in the saline group (n = 516) had a similar 30-day mortality rate as patients treated with balanced crystalloids (n = 516) (43.1% vs. 43.0%, p = 0.833), but a higher incidence of new onset renal replacement therapy (30.2% vs 22.7%, p = 0.007) and significantly higher doses of catecholamines. However, OHCA-patients with a lactate level higher than 7.4 mmol/L had a significantly lower 30-day mortality rate when treated with saline (58.6% vs. 79.3%, p = 0.013). In addition, use of balanced crystalloids was independently associated with a higher mortality in the multivariate cox regression analysis after OHCA (hazard ratio 1.43, confidence interval: 1.05–1.96, p = 0.024). Conclusions In patients with cardiogenic shock, use of balanced crystalloids was associated with a similar all-cause mortality at 30 days but a lower rate of new onset of renal replacement therapy. In the subgroup of patients after OHCA with severe shock, use of balanced crystalloids was associated with a higher mortality than saline. Trial registration: LMUshock registry (WHO International Clinical Trials Registry Platform Number DRKS00015860)

Incidence and Outcome of Patients with Cardiogenic Shock and Detection of Herpes Simplex Virus in the Lower Respiratory Tract

(1) Herpes simplex virus (HSV) reactivation in critically ill patients can cause infection in the lower respiratory tract, prolonging mechanical ventilation. However, the association of HSV reactivation with cardiogenic shock (CS) is unclear. As CS is often accompanied by pulmonary congestion and reduced immune system activity, the aim of our study was to determine the incidence and outcome of HSV reactivation in these patients. (2) In this retrospective, single-center study, bronchial lavage (BL) was performed on 181 out of 837 CS patients with mechanical ventilation. (3) In 44 of those patients, HSV was detected with a median time interval of 11 days since intubation. The occurrence of HSV was associated with an increase in C-reactive protein and the fraction of inspired oxygen at the time of HSV detection. Arterial hypertension, bilirubin on ICU admission, the duration of mechanical ventilation and out-of-hospital cardiac arrest were associated with HSV reactivation. (4) HSV reactivation could be detected in 24.3% of patients with CS on whom BL was performed, and its occurrence should be considered in patients with prolonged mechanical ventilation. Due to the limited current evidence, the initiation of treatment for these patients remains an individual choice. Dedicated randomized studies are necessary to investigate the efficacy of antiviral therapy