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Background: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. Methods: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance Results: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P =0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P =0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P =0.004). Conclusions: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

We present a patient with acute heart failure and new onset atrial fibrillation secondary to giant cell myocarditis with lone atrial involvement. The diagnosis was managed with cardiac magnetic resonance and confirmed by interventionally guided biopsy. In the future, diagnosis could be managed noninvasively for this rare entity as the gold standard. (Level of Difficulty: Advanced.), Graphical abstract

Aims:\ud \ud Impaired left ventricular diastolic function leading to elevated left atrial pressures, particularly during exertion, is a key driver of symptoms and outcomes in heart failure with preserved ejection fraction (HFpEF). Insertion of an interatrial shunt device (IASD) to reduce left atrial pressure in HFpEF has been shown to be associated with short‐term haemodynamic and symptomatic benefit. We aimed to investigate the potential effects of IASD placement on HFpEF survival and heart failure hospitalization (HFH).\ud Methods and results:\ud \ud Heart failure with preserved ejection fraction patients participating in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure study (Corvia Medical) of an IASD were followed for a median duration of 739 days. The theoretical impact of IASD implantation on HFpEF mortality was investigated by comparing the observed survival of the study cohort with the survival predicted from baseline data using the Meta‐analysis Global Group in Chronic Heart Failure heart failure risk survival score. Baseline and post‐IASD implant parameters associated with HFH were also investigated. Based upon the individual baseline demographic and cardiovascular profile of the study cohort, the Meta‐analysis Global Group in Chronic Heart Failure score‐predicted mortality was 10.2/100 pt years. The observed mortality rate of the IASD‐treated cohort was 3.4/100 pt years, representing a 33% lower rate (P = 0.02). By Kaplan–Meier analysis, the observed survival in IASD patients was greater than predicted (P = 0.014). Baseline parameters were not predictive of future HFH events; however, poorer exercise tolerance and a higher workload‐corrected exercise pulmonary capillary wedge pressure at the 6 months post‐IASD study were associated with HFH.\ud Conclusions:\ud \ud The current study suggests IASD implantation may be associated with a reduction in mortality in HFpEF. Large‐scale ongoing randomized studies are required to confirm the potential benefit of this therapy.

BACKGROUND: Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS. METHODS: Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality. RESULTS: In total, 237 patients treated with an Impella could be matched to 237 patients from the IABP-SHOCK II trial. Baseline parameters were similarly distributed after matching. There was no significant difference in 30-day all-cause mortality (48.5% versus 46.4%, P=0.64). Severe or life-threatening bleeding (8.5% versus 3.0%, P

Aims Left atrial appendage closure is a non-pharmacological alternative for stroke prevention in high-risk patients with non-valvular atrial fibrillation. The objective of the multicentre EWOLUTION registry was to obtain clinical data on procedural success and complications, and long-term patient outcomes, including bleeding and incidence of stroke/transient ischaemic attack (TIA). Here, we report on the peri-procedural outcomes of up to 30 days. Methods and results Baseline/implant data are available for 1021 subjects. Subjects in the study were at high risk of stroke (average CHADS 2 score: 2.8 ± 1.3, CHA 2 DS 2 -VASc: 4.5 ± 1.6) and moderate-to-high risk of bleeding (average HAS-BLED score: 2.3 ± 1.2). Almost half of the subjects (45.4%) had a history of TIA, ischaemic stroke, or haemorrhagic stroke; 62% of patients were deemed unsuitable for novel oral anticoagulant by their physician. The device was successfully deployed in 98.5% of patients with no flow or minimal residual flow achieved in 99.3% of implanted patients. Twenty-eight subjects experienced 31 serious adverse events (SAEs) within 1 day of the procedure. The overall 30-day mortality rate was 0.7%. The most common SAE occurring within 30 days of the procedure was major bleeding requiring transfusion. Incidence of SAEs within 30 days was significantly lower for subjects deemed to be ineligible for oral anticoagulation therapy (OAT) compared with those eligible for OAT (6.5 vs. 10.2%, P = 0.042). Conclusion Left atrial appendage closure with the WATCHMAN device has a high success rate in complete LAAC with low peri-procedural risk, even in a population with a higher risk of stroke and bleeding, and multiple co-morbidities. Improvement in implantation techniques has led to a reduction of peri-procedural complications previously limiting the net clinical benefit of the procedure.

Titelblatt, Inhaltsverzeichnis, Curriculum vitae I. Einleitung II. Eigene Originalarbeiten A. Spezifische Transkriptionsfaktoren bei entzündlichen Lungenerkrankungen 1\. Signaltransduktionswege der Zytokin-induzierten NF-κB Aktivierung 2\. Inhibition der GM-CSF Freisetzung durch Glukokortikoide B. Spezifische Transkriptionsfaktoren bei Herzinsuffizienz 1\. NF-κB als Überlebensfaktor bei der TNF-α induzierten Apoptose von Kardiomyozyten 2\. Statine als Überlebensfaktoren bei der Apoptose von Kardiomyozyten 3\. Signalpfade der Hypertrophie von Kardiomyozyten nach Hypoxie/Reoxygenierung III. Diskussion IV. Zusammenfassung V. Terminologie VI. Abkürzungsverzeichnis VII. Danksagung Literaturverzeichnis, Die hier vorgestellten molekularen Arbeiten lassen sich vor dem klinischen Hintergrund des Asthma bronchiale und der Herzinsuffizienz unter zwei Leitgedanken subsumieren: 1) Pathophysiologisch bedeutsame Signaltransduktionswege münden in die Aktivierung spezifischer Transkriptionsfaktoren, deren pharmakologische Inhibition eine neue therapeutische Option darstellen könnte. 2) Die Untersuchung der molekularen Wirkmechanismen etablierter pharmakologischer Therapieansätze im Hinblick auf die beeinflussten Transkriptionsfaktoren kann dazu beitragen, bisher unberücksichtigte klinische Effekte zu identifizieren. Das Asthma bronchiale ist eine chronisch entzündliche Erkrankung des Bronchialepithels. Der Transkriptionsfaktor NF-kB steuert die Aktivierung einer Vielzahl von pro- inflammatorischen Zytokinen, Wachstumsfaktoren und Adhäsionsmolekülen. Die Untersuchung der NF-kB Aktivierungswege identifizierte die Faktoren PC-PLC, PKC und MAPK p38 als entscheidende Signalmoleküle, die die NF-kB abhängige Transkription steuern. Der durch eine NF-kB Bindungsstelle in seinem Promotor regulierte Wachstumsfaktor GM-CSF wurde im folgenden verwendet, um den Mechanismus der hochpotenten anti-inflammatorischen Wirkung von Glukokortikoiden auf molekularer Ebene zu klären. Es konnte kein Effekt von Dexamethason auf die NF-kB Aktivierung in T-Zellen gefunden werden. Der klinisch manifesten Herzinsuffizienz geht auf molekularer Ebene häufig ein einheitlicher Kompensationsmechanismus voraus: die gemeinsame Endstrecke einer chronischen Druck- oder Volumenbelastung sowie einer ischämischen Herzerkrankung ist die myokardiale Hypertrophie. Die Vermehrung der kontraktilen Elemente einer einzelnen Herzmuskelzelle kann jedoch nur vorübergehend das Defizit an Herzmuskelkraft ausgleichen. Parallel kommt es zum apoptotischen Untergang von Herzmuskelzellen. Eigene Arbeiten zeigen, dass die Aktivierung des Transkriptionsfaktors NF-kB nach TNF-a Stimulation ein Überlebenssignal darstellt. Die Inkubation von Kardiomyozyten mit Statinen, einer Medikamentenklasse zur Sekundärprophylaxe arteriosklerotischer Gefäßveränderungen, verminderte die durch Hypoxie induzierte Apoptose von Herzmuskelzellen in vitro. Eine vorübergehende Hypoxie, gefolgt von einer Phase der Reoxygenierung, induzierte direkt die Hypertrophie von Kardiomyozyten. Dieser Effekt war mit der Freisetzung von Sauerstoffradikalen (ROS) verknüpft. Die CREB-Aktivierung über diesen Signalpfad ist essentiell für die Hypoxie-induzierte Hypertrophie in diesem Modell. Die vorgelegten Daten fügen die Transkriptionsfaktoren NF-kB, CREB und b-catenin in die Modelle der Signaltransduktionswege bei Apoptose und Hypertrophie von Kardiomyozyten ein. Die mögliche klinische Relevanz muss in weiteren genetischen Untersuchungen bzw. klinischen Studien geklärt werden., The work presented below was performed on the clinical background of chronic asthma and heart failure. The different projects were based on two ideas, how molecular medicine may generate new concepts concerning treatment of these common diseases: ÿ Signaling pathways important for disease progression are integrated by specific transcription factors, whose pharmaceutical inhibition may prove to be a new treatment option. ÿ The investigation of known pharmaceutical principles concerning effects on transcription factor activation can identify new indications and molecular mechanisms. Asthma is a chronic inflammatory disease of the bronchial wall. The transcription factor NF-kB drives the expression of numerous cytokines, growth factors and adhesion molecules important for disease progression. The studies identified the factors PC-PLC, PKC and MAPK p38 as important for NF-kB activation specifically at the transactivating level. Inhibition of these factors had no effect on DNA binding, which is mainly regulated by IkBa degradation. Further studies utilizing the GM-CSF promoter as a model for NF-kB dependent transcription studied the molecular mechanism of the inhibitory effects of glucocorticoids on inflammatory cytokine release. Surprisingly, no effect of dexamethasone on GM-CSF promoter activity was found. Instead, post- transcriptional processing was affected resulting in significantly reduced GM- CSF levels released from isolated, primary T-cells and primary blood mononuclear cells after stimulation. Chronic heart failure is commonly preceded by a uniform stress response of the heart, namely cardiomyocyte hypertrophy. While this compensatory response to chronic pressure overload or ischemic cardiac disease is of benefit on the short term, hypertrophied cardiomyocyte are more susceptible to apoptosis and generally precede the development of heart failure. The studies showed that the transcription factor NF-kB is a survival factor for cardiomyocytes after TNFa stimulation. Furthermore, treatment of cardiomyocytes with statins (a commonly used cholesterol lowering drug class) was able to inhibit cardiomyocyte apoptosis induced by hypoxia/ reoxygenation. This effect was associated with stabilization of the transcription factor b-catenin. Interestingly, hypoxia/reoxygenation also induced hypertrophy of isolated cardiomyocytes in vitro. This effect involved activation of reactive oxygen species coupled to Gi receptor activation. Downstream of these events, activation of the PI3-kinase/AKT/GSK3b signaling cascade was essential upstream of the transcription factor CREB. CREB activity was necessary for hypoxia/reoxygenation induced hypertrophy. In summary, the data show involvement of transcription factor NF-kB, CREB and b-catenin in adult heart remodeling involving apoptosis and hypertrophy of cardiomyocytes. The clinical significance of these findings must be evaluated in further studies involving mouse models.

Background: Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS. Methods: Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality. Results: In total, 237 patients treated with an Impella could be matched to 237 patients from the IABP-SHOCK II trial. Baseline parameters were similarly distributed after matching. There was no significant difference in 30-day all-cause mortality (48.5% versus 46.4%, P =0.64). Severe or life-threatening bleeding (8.5% versus 3.0%, P P =0.01) occurred significantly more often in the Impella group. Limiting the analysis to IABP-treated patients as a control group did not change the results. Conclusions: In this retrospective analysis of patients with AMI-CS, the use of an Impella device was not associated with lower 30-day mortality compared with matched patients from the IABP-SHOCK II trial treated with an IABP or medical therapy. To further evaluate this, a large randomized trial is warranted to determine the effect of the Impella device on outcome in patients with AMI-CS. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03313687.