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Was ist neu? Neuer medikamentöser Therapie-Algorithmus für Herzinsuffizienz mit LVEF ≤ 40 % Für Herzinsuffizienz mit reduzierter Pumpfunktion ≤ 40 % (HFrEF) empfehlen die neuen Herzinsuffizienz-Leitlinien 2021 der ESC einen grundlegend neuen Behandlungsalgorithmus. Dieser sieht vor, dass alle 4 letalitätssenkenden Substanzen (ARNI oder ACE-Hemmer, Betablocker, MRA und SGLT-2-Inhibitoren) so früh wie möglich gegeben werden. Das konventionelle Stufenschema mit schrittweiser Erhöhung wird nicht mehr empfohlen. Empfehlungen für HfpEF Vereinfacht wurde der Diagnose-Algorithmus für die HFpEF, der nun neben Symptomen und Zeichen einer Herzinsuffizienz, einer LVEF ≥ 50 % zusätzlich objektive Kriterien für eine strukturelle und/oder funktionelle Auffälligkeit mit diastolischer Dysfunktion und erhöhten Füllungsdrücken fordert sowie erhöhte natriuretische Peptide. Für die Behandlung der HFpEF gibt es keine Veränderungen im Vergleich zu 2016, jedoch ist hier eine kurzfristige Überarbeitung der Leitlinie zu erwarten. Bedeutung ausgewählter Begleit-Erkrankungen Die primäre Empfehlung bei Vorhofflimmern ist die Antikoagulation mittels NOAK. Der Stellenwert der PVI ist aufgewertet worden. Die Entscheidung zur Transkatheter-Therapie einer sekundären Mitralklappen-Insuffizienz sollte bei Vorliegen entsprechender Kriterien im Heartteam getroffen werden. Fortgeschrittene Herzinsuffizienz Für die Diagnose einer fortgeschrittenen Herzinsuffizienz wurden 4 Kriterien definiert. Diese umfassen schwere und persistierende Symptome NYHA III oder IV, den Nachweis einer schweren kardialen Dysfunktion, Episoden von Stauung, die mittels i. v. Diuretika und/oder Inotropika behandelt werden müssen, maligne Arrhythmien und eine schwere Einschränkung der Belastungskapazität. Für diese Patienten gibt es einen neuen Behandlungsalgorithmus, in welchem der Stellenwert der mechanischen Kreislaufunterstützung aufgewertet wurde. Akute Herzinsuffizienz Für Patienten mit akuter Herzinsuffizienz wird nach der Entlassung aus der stationären Behandlung eine Einbindung in ein „Disease Management Program“ und in ein multimodales, multiprofessionelles Therapiekonzept empfohlen.

Aims: Control of pulmonary pressures monitored remotely reduced heart failure hospitalizations mainly by lowering filling pressures through the use of loop diuretics. Sacubitril/valsartan improves heart failure outcomes and increases the kidney sensitivity for diuretics. We explored whether sacubitril/valsartan is associated with less utilization of loop diuretics in patients guided with haemodynamic monitoring in the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF). Methods and results: The MEMS-HF population (n = 239) was separated by the use of sacubitril/valsartan (n = 68) or no use of it (n = 164). Utilization of diuretics and their doses was prespecified in the protocol and was monitored in both groups. Multivariable regression, ANCOVA, and a generalized linear model were used to fit baseline covariates with furosemide equivalents and changes for 12 months. MEMS-HF participants (n = 239) were grouped in sacubitril/valsartan users [n = 68, 64 ± 11 years, left ventricular ejection fraction (LVEF) 25 ± 9%, cardiac index (CI) 1.89 ± 0.4 L/min/m2] vs. non-users (n = 164, 70 ± 10 years, LVEF 36 ± 16%, CI 2.11 ± 0.58 L/min/m2, P = 0.0002, P Conclusions: In patients whose treatment was guided by remote PAP monitoring, concomitant use of sacubitril/valsartan was associated with reduced utilization of loop diuretics, which could potentially be relevant for outcomes.

ZusammenfassungWeltweit sind bei Frauen kardiovaskuläre Erkrankungen die Haupttodesursache. Bei Ätiologie, Epidemiologie, Pathophysiologie, Symptomatik und Komorbiditäten der Herzinsuffizienz (HI) sowie bei Wirkungen und Nebenwirkungen von Therapiemaßnahmen und der Prognose gibt es relevante Geschlechtsunterschiede. Trotzdem sind in klinischen Studien Frauen als Teilnehmerinnen bzw. in der Studienleitung unterrepräsentiert. Sekundäre Analysen aus Therapiestudien legen Geschlechtsunterschiede bei Wirksamkeit, Nebenwirkungsprofil und optimaler Dosierung von Medikamenten und beim Nutzen von Device-Therapien nahe. Prospektive Studiendesigns mit dem Ziel, Geschlechtsunterschiede zu herauszuarbeiten, gibt es kaum, und Leitlinienempfehlungen sind meist geschlechtsneutral. Dieser Übersichtsartikel beschreibt Unterschiede bei Behandlungseffekten, Verfügbarkeit von Therapien und Krankheitsprognose, beleuchtet Wissenslücken und zeigt, wo Handlungsbedarf besteht, um die Situation von Frauen mit HI zu verbessern.

ZusammenfassungHerzinsuffizienz betrifft etwa 4 Millionen Menschen in Deutschland, stellt die häufigste Ursache für Hospitalisierungen dar und trägt wesentlich zur Morbidität und Letalität einer älter werdenden Gesellschaft bei. Bei der Herzinsuffizienz gibt es ausgeprägte geschlechtsspezifische Unterschiede, sowohl bezüglich Epidemiologie, Pathophysiologie und Risikofaktoren als auch in der bildgebenden Diagnostik. Daher ist die Kenntnis der Unterschiede zwischen Männern und Frauen mit Herzinsuffizienz in Hinblick auf die genannten Faktoren essenziell sowohl für das Erkennen der Erkrankung als auch für Interpretation der Diagnostik. Mit dem aktuellen Artikel wollen wir einen kurzen Überblick zu geschlechtsspezifischen Unterschieden der Herzinsuffizienz-Entwicklung geben und zum Weiterlesen inspirieren.

NEW DRUG THERAPY ALGORITHM FOR HEART FAILURE WITH LVEF ≤ 40 %: The new Heart Failure Guidelines 2021 recommend a fundamentally new treatment algorithm for heart failure (HF) with reduced ejection fraction ≤ 40 % (HFrEF). This involves, that all four mortality reducing substances (ARNI or ACE-Inhibitor, Betablocker, MRA und SGLT-2-Inhibitor) are given as fast as possible. The conventional sequence with stepwise uptitration is no longer recommended. The diagnostic algorithm has been simplified for HFpEF, which requires not only signs and symptoms of HF, but also a LVEF ≥ 50 % and additionally objective criteria for a structural and/or functional abnormalities with diastolic dysfunction, elevated filling pressures and elevated natriuretic peptides. Etiology of HFpEF should be evaluated. There is no change in the treatment recommendations of HFpEF in contrast to 2016, but a short-term revision of the guidelines can be expected. The primary recommendation for atrial fibrillation is anticoagulation with NOAKs. The value of PVI has been upgraded. The decision for transcatheter therapy of secondary mitral regurgitation should be made in the heart team if appropriate criteria are present. For the diagnosis of advanced heart failure four key criteria were defined, including severe and persistent symptoms (NYHA III or IV), a severe cardiac dysfunction, episodes of congestion treated with i. v. diuretics and/or inotropes, malignant arrhythmias and a severe impairment of exercise capacity. There is a new treatment algorithm for these patients, in which the importance of mechanical support was upgraded. For patients with acute heart failure, integration into a disease management program and a multimodal, multiprofessional therapy concept is recommended after discharge from inpatient treatment.NEUER MEDIKAMENTöSER THERAPIE-ALGORITHMUS FüR HERZINSUFFIZIENZ MIT LVEF ≤ 40 %: Für Herzinsuffizienz mit reduzierter Pumpfunktion ≤ 40 % (HFrEF) empfehlen die neuen Herzinsuffizienz-Leitlinien 2021 der ESC einen grundlegend neuen Behandlungsalgorithmus. Dieser sieht vor, dass alle 4 letalitätssenkenden Substanzen (ARNI oder ACE-Hemmer, Betablocker, MRA und SGLT-2-Inhibitoren) so früh wie möglich gegeben werden. Das konventionelle Stufenschema mit schrittweiser Erhöhung wird nicht mehr empfohlen. EMPFEHLUNGEN FüR HFPEF: Vereinfacht wurde der Diagnose-Algorithmus für die HFpEF, der nun neben Symptomen und Zeichen einer Herzinsuffizienz, einer LVEF ≥ 50 % zusätzlich objektive Kriterien für eine strukturelle und/oder funktionelle Auffälligkeit mit diastolischer Dysfunktion und erhöhten Füllungsdrücken fordert sowie erhöhte natriuretische Peptide. Für die Behandlung der HFpEF gibt es keine Veränderungen im Vergleich zu 2016, jedoch ist hier eine kurzfristige Überarbeitung der Leitlinie zu erwarten. BEDEUTUNG AUSGEWäHLTER BEGLEIT-ERKRANKUNGEN: Die primäre Empfehlung bei Vorhofflimmern ist die Antikoagulation mittels NOAK. Der Stellenwert der PVI ist aufgewertet worden. Die Entscheidung zur Transkatheter-Therapie einer sekundären Mitralklappen-Insuffizienz sollte bei Vorliegen entsprechender Kriterien im Heartteam getroffen werden. FORTGESCHRITTENE HERZINSUFFIZIENZ: Für die Diagnose einer fortgeschrittenen Herzinsuffizienz wurden 4 Kriterien definiert. Diese umfassen schwere und persistierende Symptome NYHA III oder IV, den Nachweis einer schweren kardialen Dysfunktion, Episoden von Stauung, die mittels i. v. Diuretika und/oder Inotropika behandelt werden müssen, maligne Arrhythmien und eine schwere Einschränkung der Belastungskapazität. Für diese Patienten gibt es einen neuen Behandlungsalgorithmus, in welchem der Stellenwert der mechanischen Kreislaufunterstützung aufgewertet wurde. AKUTE HERZINSUFFIZIENZ: Für Patienten mit akuter Herzinsuffizienz wird nach der Entlassung aus der stationären Behandlung eine Einbindung in ein „Disease Management Program“ und in ein multimodales, multiprofessionelles Therapiekonzept empfohlen.

textabstractAims: Heart failure (HF) leads to repeat hospitalisations and reduces the duration and quality of life. Pulmonary artery pressure (PAP)-guided HF management using the CardioMEMS™ HF system was shown to be safe and reduce HF hospitalisation (HFH) rates in New York Heart Association (NYHA) class III patients. However, these findings have not been replicated in health systems outside the United States. Therefore, the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) evaluated the safety, feasibility, and performance of this device in Germany, The Netherlands, and Ireland. Methods and results: A total of 234 NYHA class III patients (68 ± 11 years, 22% female, ≥1 HFH in the preceding year) from 31 centres were implanted with a CardioMEMS sensor and underwent PAP-guided HF management. One-year rates of freedom from device- or system-related complications and from sensor failure (co-primary outcomes) were 98.3% [95% confidence interval (CI) 95.8–100.0] and 99.6% (95% CI 97.6–100.0), respectively. Survival rate was 86.2%. For the 12 months post- vs. pre-implant, HFHs decreased by 62% (0.60 vs. 1.55 events/patient-year; hazard ratio 0.38, 95% CI 0.31–0.48; P < 0.0001). After 12 months, mean PAP decreased by 5.1 ± 7.4 mmHg, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall/clinical summary scores increased from 47.0 ± 24.0/51.2 ± 24.8 to 60.5 ± 24.3/62.4 ± 24.1 (P < 0.0001), and the 9-item Patient Health Questionnaire sum score improved from 8.7 ± 5.9 to 6.3 ± 5.1 (P < 0.0001). Conclusion: Haemodynamic-guided HF management proved feasible and safe in the health systems of Germany, The Netherlands, and Ireland. Physician-directed treatment modifications based on remotely obtained PAP values were associated with fewer HFH, sustainable PAP decreases, marked KCCQ improvements, and remission of depressive symptoms.

Was ist neu? Klinische Manifestation Die kardiale Transthyretin-Amyloidose (ATTR) ist als seltene Ursache einer Kardiomyopathie Teil einer unterdiagnostizierten Systemerkrankung. Für die kardiale Transthyretin-Amyloidose, bei der es zur Ablagerung von fehlgefaltetem Transthyretin kommt, entweder als Wildtyp (wtATTR) oder mutierte (mATTR) Form, sind seit kurzem evidenzbasierte Therapiemöglichkeiten mit Verlangsamung der Kardiomyopathie-Progression und deutlicher Reduktion der Hospitalisierungsraten verfügbar. Daher ist es wichtig, diese schwerwiegende Erkrankung frühzeitig zu diagnostizieren. Diagnostik Mittels Bildgebung (kardiale MRT oder szintigrafische Verfahren) sowie Immunfixation mit Bestimmung der freien Leichtketten ist ein klinisches Screening einfach möglich, bevor mittels Biopsie und/oder Genetik die definitive Diagnose gestellt wird. Eine interdisziplinäre Aufarbeitung bei Verdacht auf kardiale Amylodiose unter Einbezug von Hämatoonkologie, Nephrologie, Neurologie und weiteren Disziplinen ist hierbei unabdingbar. Therapie Bei Patienten mit einer kardialen Amyloidose kann eine Herzinsuffizienz-Therapie mit Betablocker, Renin-Angiotensin-Aldosteron-Inhibitoren und Diuretika erfolgen, sollte allerdings aufgrund unerwünschter Nebenwirkungen vorsichtig erfolgen. Studien haben in den letzten Jahren die Wirksamkeit eines Tetramer-Stabilisators sowie von TTR-mRNA-interferierenden Therapeutika zur medikamentösen Therapie der ATTR-Amyloidose gezeigt – 9 10. Eine spezifische Zulassung zur Therapie der kardialen ATTR-Amyloidose existiert seit neuestem für den Tetramer-Stabilisator Tafamidis 11 12.

Background Heightened risk of cardiac arrest following physical exertion has been reported. Among patients with an implantable defibrillator, an appropriate shock for sustained ventricular arrhythmia was preceded by a retrospective self-report of engaging in mild-to-moderate physical activity. Previous studies evaluating the relationship between activity and sudden cardiac arrest lacked an objective measure of physical activity and women were often underrepresented. Objective To determine the relationship between physical activity, recorded by accelerometer in a wearable cardioverter-defibrillator (WCD), and sustained ventricular arrhythmia among female patients. Methods A dataset of female adult patients prescribed a WCD for a diagnosis of myocardial infarction or dilated cardiomyopathy was compiled from a commercial database. Curve estimation, to include linear and nonlinear interpolation, was applied to physical activity as a function of time (days before arrhythmia). Results Among women who received an appropriate WCD shock for sustained ventricular arrhythmia (N = 120), a quadratic relationship between time and activity was present prior to shock. Physical activity increased starting at the beginning of the 30-day period up until day -16 (16 days before the ventricular arrhythmia) when activity begins to decline. Conclusion For patients who received treatment for sustained ventricular arrhythmia, a decline in physical activity was found during the 2 weeks preceding the arrhythmic event. Device monitoring for a sustained decline in physical activity may be useful to identify patients at near-term risk of a cardiac arrest.

Aims Implantable pulmonary artery pressure (PAP) sensors have been shown to reduce heart failure hospitalizations (HFH) in selected patients. The goal of this study was to evaluate the safety and efficacy of a novel wireless PAP monitoring system in patients with heart failure (HF). Methods and results This is a prospective, multi-centre, open-label, single-arm trial evaluating the safety and efficacy of the Cordella (TM) PA Sensor System including the comprehensive Cordella (TM) Heart Failure System (CHFS) in patients with New York Heart Association (NYHA) Class III heart failure with a heart failure hospitalization and/or increase of N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) within 12 months of enrolment. The primary efficacy endpoint was the accuracy of PA sensor mean PAP measurements, compared with fluid-filled catheter mean PAP measurements obtained by standard right heart catheterization (RHC) at 90 days post-implant, assessed in all patients with a successful implant. The primary safety endpoint was freedom from adverse events associated with use of the Cordella PA Sensor System through 30 days post-implant, assessed in all patients who entered the cath lab for PA sensor implant. The PA sensor was successfully implanted in 70 patients. Equivalence between the PA sensor and RHC for mean pulmonary artery pressures was excellent with measurements confined within the equivalence bounds of -4.0 to 4.0 mmHg (mean PAP: 0.0 to 2.9 mmHg, P = 0.003). The device safety profile was excellent with 98.6% freedom from Device System Related Complications, defined as invasive treatment, device explant or death. There were no pressure sensor failures. Patients' adherence to daily measurement transmissions of PAP and vital signs was 94%. Conclusions This trial supports the safety and efficacy of the Cordella PA Sensor System and in conjunction with the CHFS enables comprehensive HF management in NYHA class III heart failure patients.

Background Remote monitoring of patients with New York Heart Association (NYHA) functional class III heart failure (HF) using daily transmission of pulmonary artery (PA) pressure values has shown a reduction in HF-related hospitalizations and improved quality of life in patients. Objectives PASSPORT-HF is a prospective, randomized, open, multicenter trial evaluating the effects of a hemodynamic-guided, HF nurse-led care approach using the CardioMEMS™ HF-System on clinical end points. Methods and results The PASSPORT-HF trial has been commissioned by the German Federal Joint Committee (G-BA) to ascertain the efficacy of PA pressure-guided remote care in the German health-care system. PASSPORT-HF includes adult HF patients in NYHA functional class III, who experienced an HF-related hospitalization within the last 12 months. Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy. Patients will be randomized centrally 1:1 to implantation of a CardioMEMS™ sensor or control. All patients will receive post-discharge support facilitated by trained HF nurses providing structured telephone-based care. The trial will enroll 554 patients at about 50 study sites. The primary end point is a composite of the number of unplanned HF-related rehospitalizations or all-cause death after 12 months of follow-up, and all events will be adjudicated centrally. Secondary end points include device/system-related complications, components of the primary end point, days alive and out of hospital, disease-specific and generic health-related quality of life including their sub-scales, and laboratory parameters of organ damage and disease progression. Conclusions PASSPORT-HF will define the efficacy of implementing hemodynamic monitoring as a novel disease management tool in routine outpatient care. Trial registration ClinicalTrials.gov; NCT04398654, 13-MAY-2020. Graphical abstract

Right ventricular (RV) function is the main determinant of the outcome of patients with pulmonary hypertension (PH). RV dysfunction develops gradually and worsens progressively over the course of PH, resulting in RV failure and premature death. Currently, approved therapies for the treatment of left ventricular failure are not established for the RV. Furthermore, the direct effects of specific vasoactive drugs for treatment of pulmonary arterial hypertension (PAH, Group 1 of PH) on RV are not fully investigated. Pulmonary artery banding (PAB) allows to study the pathogenesis of RV failure solely, thereby testing potential therapies independently of pulmonary vascular changes. This review aims to discuss recent studies of the mechanisms of RV remodeling and RV-directed therapies based on the PAB model.

Aims Fibroblast growth factor 23 (FGF‐23) is known to be elevated in patients with congestive heart failure (CHF). As FGF‐23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF‐23 in CHF remains unclear. It is also unclear if FGF‐23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF‐23 levels measured in bone marrow plasma (FGF‐23‐BM) and in peripheral blood (FGF‐23‐P) in CHF patients to gain further insights into the heart–bone axis of FGF‐23 expression. We also investigated possible associations between FGF‐23‐BM as well as FGF‐23‐P and outcome in CHF patients. Methods and results We determined FGF‐23‐P and FGF‐23‐BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF‐23‐BM and FGF‐23‐P with all‐cause mortality in CHF patients, 32 events, median follow‐up 1673 days, interquartile range [923, 1828]. FGF‐23‐P (median 60.3 vs. 22.0 RU/mL, P

Aims Somatic mutations in haematopoietic stem cells can lead to the clonal expansion of mutated blood cells, known as clonal haematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF) ≥ 2% have been associated with atherosclerosis and chronic heart failure of ischemic origin (CHF). However, the effects of mutations in other driver genes for CH with low VAF (

Introduction The interface between heart and bone emerges as a key trigger of post-infarction inflammation and progression of chronic heart failure (CHF). However, our knowledge on the underlying mechanisms of this interaction is incomplete. Bone vasculature, specifically so-called H-type (Endomucinhigh) endothelial cells (EC), plays a crucial role in maintenance of the bone integrity and regulation of hematopoietic stem cells (HSC). While previous studies in mice showed the reduction of H-type vessels by aging, the impact of ischemic heart disease is unclear. Therefore, we aimed to investigate the effects of myocardial infarction (MI) and chronic heart failure on the vascular bone cell composition in mice and humans. Methods and results Flow cytometric analysis of harvested bones at the different timepoints after MI induction in mice revealed a gradual loss of H-type endothelial cells in the time-course of developing chronic heart failure (P Conclusions Our data show for the first time an impact of myocardial infarction and chronic heart failure on the bone marrow vasculature. These changes seem to be strongly associated with inflammatory response in H-type vessels, which precedes its loss after MI. Specifically, the induction of the inflammatory cytokine IL1b may contribute to the disturbed phenotype. This suggest that inhibition of IL1b (e.g. by canakinumab) be used as a novel strategy to prevent or reverse the deterioration of the vascular bone function in ischemic heart disease. Funding Acknowledgement Type of funding source: None

Background Recurrent somatic mutations in blood stem cells cause the emergence of mutated blood cell clones, known as clonal hematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF)≥2% have been associated with atherosclerosis and chronic heart failure (CHF). However, the effects of mutations in other driver genes for CH with low VAF ( Purpose To assess the potential prognostic significance of mutations in distinct genes other than DNMT3A and TET2 causing CH at low VAF in patients with CHF due to post-ischemic origin. Methods We analyzed mononuclear bone marrow and peripheral blood cells from 400 CHF patients by deep error-corrected targeted amplicon sequencing allowing for the detection of very low VAF of ≥0.5% in 56 CH driver genes and associated such with the long-term mortality in these patients. Results Median age of the patients was 63 and median follow-up time was 4.8 years. We detected 1116 mutations with a VAF≥0.5% in 348 of 400 patients (87%). 21% of the patients carried 1 mutation, whereas 66% showed 2 and more mutations. Only 52 (13%) patients had no detectable mutation at all. Despite a high prevalence of mutations in the most frequently mutated driver genes DNMT3A (165 patients) and TET2 (107 pts), mutations in the genes CBL (8 pts), CEBPA (10 pts), PHF6 (22 pts), SMC1A (18 pts) and SRSF2 (14 pts) were associated with increased death compared to the average death rate of all patients (18.8%). To avoid confounding effects caused by the presence of DNMT3A and TET2 CHIP mutations, we excluded patients with DNMT3A-, TET2- and other CHIP-related mutations with a VAF≥2% for further analyses. Kaplan-Meier survival curve analyses revealed a significantly higher mortality in patients with mutations in either of the five genes, combined as the CH risk gene set for CHF (Fig. 1). Patients with mutations in the risk gene set (44 pts) did not differ from patients with mutations in other CH driver genes or without mutations with respect to age, cardiovascular risk factors, disease severity or CH clone size. By multivariate Cox proportional regression analysis, including the Seattle heart failure model (SHFM) score (as tertiles), death remained independently associated with the presence of mutations in the risk gene set (HR, 2.57; 95% CI, 1.30–5.10; p=0.007), in addition to SHFM score tertiles (tertile 2, HR, 2.36; 95% CI, 0.73–7.65 and tertile 3, HR, 7.96; 95% CI, 2.77–22.90). Conclusions Somatic mutations with low VAF in a distinct set of genes, namely in CBL, CEBPA, PHF6, SMC1A and SRSF2, are significantly associated with mortality in CHF, independently of the classical CHIP-driver mutations DNMT3A and TET2. Mutations in the CH risk gene set are prevalent in young CHF patients and comprise an independent risk factor for the outcome of CHF, potentially providing a novel tool for cardiovascular risk assessment and precision medicine in CHF. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG)

Background Cell therapy has emerged as a promising additional therapy after myocardial infarction (MI). We have previously shown that interactions between risk factors and cell therapy influence efficacy, suggesting that only certain patient populations benefit from cell therapy after MI. Purpose We aim to generate and validate a prediction model for cell therapy after MI for both functional outcome and clinical endpoints. Methods Data from the REPAIR-AMI and REGENERATE-AMI trial were used to model the effect of autologous bone marrow-derived mononuclear cell transplantation after acute MI. First, a prediction model was generated based on the REPAIR-AMI trial. The outcome measure for the model was difference in ejection fraction (EF) over time. Prespecified variables of interest were age, sex, weight, hypertension, hyperlipidaemia, diabetes, history of smoking and baseline EF, taking into account their interaction per therapy (placebo vs cells). This model resembles the gain in function over time after cell therapy, compared to the placebo group. Validation of this model was performed in the REGENERATE-AMI trial dataset, to test whether interactions that influence the therapy are similar across trials. Finally, the model was tested for its ability to predict clinical outcome (i.e. MACE) in REPAIR-AMI. Results The generated prediction model on REPAIR-AMI data included multiple interactions with therapy. Internally, the model functioned appropriately to predict the difference in EF (n=186, R2=0.17, p=9x10–9). In the validation step, our model showed similar predictive capacity in REGENERATE-AMI (n=94, R2=0.19, p=1.4x10–5) specifically in the cell therapy group (R2=0.31, p=1.9x10–5) (see Figure). A multivariable analysis on the combined datasets revealed that patients with a smoking history or low baseline EF were more likely to have an increased functional response after cell therapy. Applying this prediction model to clinical endpoint data showed that a generated benefit score (based on cardiac function) translates to differences in event rate. The high benefit group yielded a significantly different event rate between groups (45% in placebo vs 15% in cell therapy group, p=0.001). Conclusion Based on real life clinical data of two autologous cell therapy trials we have generated a clinically useful prediction model for the response to cell therapy after MI. Particular factors (smoking, baseline EF) showed relevant interactions. Not only functional outcome, but also clinical endpoints are adequately predicted by a model-derived benefit score, indicating that specific patient groups might benefit more from cell therapy. Ideally, this will be validated prospectively in large trials, like the BAMI trial (NCT01569178) and ultimately implemented in future clinical trial design to identify these patient groups upfront. A future analysis of the BAMI trial data will follow after its primary publication, using our generated prediction model. Figure 1. Validation in REGENERATE-AMI Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): CVON HUSTCARE, Alexandre Suerman stipend UMC Utrecht

Cardiac amyloidosis is a rare cause of cardiomyopathy, however, it is part of an underdiagnosed underlying systemic disease. For transthyretin (ATTR) amyloidosis, which is caused by the deposition of incorrectly folded transthyretin, either as the wild-type (wtATTR) or mutated (mATTR) form, novel evidence-based treatment options were recently shown to reduce disease progression as well as hospitalisation rates for heart failure. Thus, it is important to establish early and reliable diagnosis of cardiac involvement with ATTR amyloidosis.Modern non-invasive imaging (cardio magnetic resonance (CMR) and scintigraphic methods) together with immune fixation with determination of free light chains allow fast and reliable clinical screening for cardiac amyloidosis, whereas endomyocardial biopsy and genetics are used for confirmation of the underlying diagnosis. Interdisciplinary teams including hemato-oncology, neurology, nephrology in addition to cardiology are essential to enable personalized targeted treatment strategies.Die kardiale Transthyretin-Amyloidose (ATTR) ist als seltene Ursache einer Kardiomyopathie Teil einer unterdiagnostizierten Systemerkrankung. Für die kardiale Transthyretin-Amyloidose, bei der es zur Ablagerung von fehlgefaltetem Transthyretin kommt, entweder als Wildtyp (wtATTR) oder mutierte (mATTR) Form, sind seit kurzem evidenzbasierte Therapiemöglichkeiten mit Verlangsamung der Kardiomyopathie-Progression und deutlicher Reduktion der Hospitalisierungsraten verfügbar. Daher ist es wichtig, diese schwerwiegende Erkrankung frühzeitig zu diagnostizieren.Mittels Bildgebung (kardiale MRT oder szintigrafische Verfahren) sowie Immunfixation mit Bestimmung der freien Leichtketten ist ein klinisches Screening einfach möglich, bevor mittels Biopsie und/oder Genetik die definitive Diagnose gestellt wird. Eine interdisziplinäre Aufarbeitung bei Verdacht auf kardiale Amylodiose unter Einbezug von Hämatoonkologie, Nephrologie, Neurologie und weiteren Disziplinen ist hierbei unabdingbar.Bei Patienten mit einer kardialen Amyloidose kann eine Herzinsuffizienz-Therapie mit Betablocker, Renin-Angiotensin-Aldosteron-Inhibitoren und Diuretika erfolgen, sollte allerdings aufgrund unerwünschter Nebenwirkungen vorsichtig erfolgen. Studien haben in den letzten Jahren die Wirksamkeit eines Tetramer-Stabilisators sowie von TTR-mRNA-interferierenden Therapeutika zur medikamentösen Therapie der ATTR-Amyloidose gezeigt – 9 10. Eine spezifische Zulassung zur Therapie der kardialen ATTR-Amyloidose existiert seit neuestem für den Tetramer-Stabilisator Tafamidis 11 12.

Background Data on the arrhythmic burden of women at risk for sudden cardiac death are limited, especially in patients using the wearable cardioverter-defibrillator (WCD). Objective We aimed to characterize WCD compliance, atrial and ventricular arrhythmic burden, and WCD outcomes by sex in patients enrolled in the Prospective Registry of Patients Using the Wearable Cardioverter Defibrillator (WEARIT-II U.S. Registry). Methods In the WEARIT-II Registry, we stratified 2000 patients by sex into women (n = 598) and men (n = 1402). WCD wear time, ventricular and atrial arrhythmic events during WCD use, and implantable cardioverter-defibrillator (ICD) implantation rates at the end of WCD use were evaluated. Results The mean WCD wear time was similar in women and men (94 days vs 90 days; P = .145), with longer daily use in women (21.4 h/d vs 20.7 h/d; P = .001). Burden of ventricular tachycardia or ventricular fibrillation was higher in women, with 30 events per 100 patient-years compared with 18 events per 100 patient-years in men (P = .017), with similar findings for treated and non-treated ventricular tachycardia/ventricular fibrillation. Recurrent atrial arrhythmias/sustained ventricular tachycardia was also more frequent in women than in men (167 events per 100 patient-years vs 73 events per 100 patient-years; P = .042). However, ICD implantation rate at the end of WCD use was similar in both women and men (41% vs 39%; P = .448). Conclusion In the WEARIT-II Registry, we have shown a higher burden of ventricular and atrial arrhythmic events in women than in men. ICD implantation rates at the end of WCD use were similar. Our findings warrant monitoring women at risk for sudden cardiac death who have a high burden of atrial and ventricular arrhythmias while using the WCD.

SummaryBone vasculature provides protection and signals necessary to control stem cell quiescence and renewal1. Specifically, type H capillaries, which highly express Endomucin, constitute the endothelial niche supporting a microenvironment of osteoprogenitors and long-term hematopoietic stem cells2–4. The age-dependent decline in type H endothelial cells was shown to be associated with bone dysregulation and accumulation of hematopoietic stem cells, which display cell-intrinsic alterations and reduced functionality3. The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the vascular bone cell composition. We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Inhibition of NLRP3-dependent IL-1β production partially prevents the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of vascular bone function in ischemic heart disease.

IntroductionCurrent studies suggest improved survival in patients with severe functional mitral regurgitation (FMR) treated successfully with the MitraClip (MC) compared to medical treatment alone, in addition to a significant reduction of FMR severity. Recently, the Carillon system (CS) has also been shown to significantly reduce FMR. However, whether this beneficial effect of CS also translates into a survival benefit comparable to the MC system has not been investigated so far. The aim of the study was to compare the course of FMR grade and mortality after MC or CS in a retrospective, non-randomized, single-center analysis.Material and methodsA hundred and fifty-four patients with symptomatic FMR 2+ were included in this study (MC: n = 117, CS: n = 37). Baseline characteristics did not differ significantly between groups.ResultsInitially, the degree of FMR was reduced in the MC group from 2.9 ±0.3 to 1.7 ±0.7 and from 2.7 ±0.5 to 2.1 ±0.7 in the CS group, p within and between groups < 0.01. Within 6 months, FMR remained reduced in the MC group (1.83 ±0.6) and CS group (2.1 ±0.7). One-year survival was 34.8% in the MC group and 54.8% in the CS group (p = 0.663). Median long-term survival was 1.66 years in the MC group and 3.92 years in the CS group, log rank p = 0.001.

Aims Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF. Methods and results We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF >0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF Conclusion The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF.

Heart failure (HF) leads to repeat hospitalisations and reduces the duration and quality of life. Pulmonary artery pressure (PAP)-guided HF management using the CardioMEMS™ HF system was shown to be safe and reduce HF hospitalisation (HFH) rates in New York Heart Association (NYHA) class III patients. However, these findings have not been replicated in health systems outside the United States. Therefore, the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) evaluated the safety, feasibility, and performance of this device in Germany, The Netherlands, and Ireland.A total of 234 NYHA class III patients (68 ± 11 years, 22% female, ≥1 HFH in the preceding year) from 31 centres were implanted with a CardioMEMS sensor and underwent PAP-guided HF management. One-year rates of freedom from device- or system-related complications and from sensor failure (co-primary outcomes) were 98.3% [95% confidence interval (CI) 95.8-100.0] and 99.6% (95% CI 97.6-100.0), respectively. Survival rate was 86.2%. For the 12 months post- vs. pre-implant, HFHs decreased by 62% (0.60 vs. 1.55 events/patient-year; hazard ratio 0.38, 95% CI 0.31-0.48; P 0.0001). After 12 months, mean PAP decreased by 5.1 ± 7.4 mmHg, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall/clinical summary scores increased from 47.0 ± 24.0/51.2 ± 24.8 to 60.5 ± 24.3/62.4 ± 24.1 (P 0.0001), and the 9-item Patient Health Questionnaire sum score improved from 8.7 ± 5.9 to 6.3 ± 5.1 (P 0.0001).Haemodynamic-guided HF management proved feasible and safe in the health systems of Germany, The Netherlands, and Ireland. Physician-directed treatment modifications based on remotely obtained PAP values were associated with fewer HFH, sustainable PAP decreases, marked KCCQ improvements, and remission of depressive symptoms.

Aims Identification of signatures of immune cells at single-cell level may provide novel insights into changes of immune-related disorders. Therefore, we used single-cell RNA-sequencing to determine the impact of heart failure on circulating immune cells. Methods and results We demonstrate a significant change in monocyte to T-cell ratio in patients with heart failure, compared to healthy subjects, which were validated by flow cytometry analysis. Subclustering of monocytes and stratification of the clusters according to relative CD14 and FCGR3A (CD16) expression allowed annotation of classical, intermediate, and non-classical monocytes. Heart failure had a specific impact on the gene expression patterns in these subpopulations. Metabolically active genes such as FABP5 were highly enriched in classical monocytes of heart failure patients, whereas β-catenin expression was significantly higher in intermediate monocytes. The selective regulation of signatures in the monocyte subpopulations was validated by classical and multifactor dimensionality reduction flow cytometry analyses. Conclusion Together this study shows that circulating cells derived from patients with heart failure have altered phenotypes. These data provide a rich source for identification of signatures of immune cells in heart failure compared to healthy subjects. The observed increase in FABP5 and signatures of Wnt signalling may contribute to enhanced monocyte activation.

Patienten mit fortgeschrittener Herzinsuffizienz leiden unter wiederholten Hospitalisierungen. Nichtinvasives hamodynamisches Telemonitoring zur Bestimmung des pulmonalvaskularen Fullungsdrucks kann Hospitalisierungen reduzieren. In diesem Beitrag wird uber mogliche Kontrollintervalle und Standardisierung in der Nachsorge des hamodynamischen Telemonitorings berichtet. Eine Literaturrecherche sowie eigene Erfahrungswerte in der Nachsorge bezuglich des implantierbaren pulmonalarteriellen Drucksensors zum nichtinvasiven hamodynamischen Telemonitoring bei Patienten mit fortgeschrittener Herzinsuffizienz werden prasentiert. Eine standardisierte Nachsorge fur Patienten mit hamodynamischem Monitoring erfordert ein spezialisiertes Team aus Heart Failure Nurse und Herzinsuffizienzarzt. Dieses Team arbeitet idealerweise nach einer einheitlichen SOP („standard operating procedure“), um fur alle Patienten sowohl identische Kontrollintervalle als auch standardisierte Therapien bei klassischen hamodynamischen Veranderungen umzusetzen. Grundsatzlich mussen alle Therapiemodifikationen arztlich angeordnet und bei Bedarf individuell modifiziert werden. Die optimierte Nachsorge bei hamodynamisch gefuhrtem Herzinsuffizienzmanagement erfordert neue Strukturen im deutschen Gesundheitssystem, damit der in Studien nachweisbare klinische Nutzen auch in der klinischen Routine umgesetzt werden kann.

AIM Patients with advanced systolic chronic heart failure frequently suffer from progressive functional mitral regurgitation. We report our initial experience in patients with an implanted pulmonary artery pressure (PAP) sensor, who developed severe mitral regurgitation, which was treated with the MitraClip system. We non-invasively compared changes in PAP values in patients after MitraClip with PAP changes in patients without MitraClip. METHODS AND RESULTS Among 28 patients with New York Heart Association III heart failure with implanted PAP sensor for haemodynamic telemonitoring from a single centre, four patients (age 66 ± 6 years, left ventricular ejection fraction 21 ± 3%, and cardiac index 1.8 ± 0.3) received a MitraClip procedure and were compared with 24 patients (age 72 ± 8 years, left ventricular ejection fraction 26 ± 9.9%, and cardiac index 2.0 ± 1.0) without MitraClip procedure in a descriptive manner. Ambulatory PAP values were followed for 90 days in both groups. In comparison with the PAP values 4 weeks before MitraClip procedure, PAP was profoundly reduced in all four patients after 30 days (ΔPAPmean -11 ± 5, ΔPAPdiast -7 ± 3 mmHg, P

Wireless monitoring of pulmonary artery (PA) pressures with the CardioMEMS HF™ system is indicated in patients with New York Heart Association (NYHA) class III heart failure (HF). Randomized and observational trials have shown a reduction in HF-related hospitalizations and improved quality of life in patients using this device in the United States. MEMS-HF is a prospective, non-randomized, open-label, multicenter study to characterize safety and feasibility of using remote PA pressure monitoring in a real-world setting in Germany, The Netherlands and Ireland. After informed consent, adult patients with NYHA class III HF and a recent HF-related hospitalization are evaluated for suitability for permanent implantation of a CardioMEMS™ sensor. Participation in MEMS-HF is open to qualifying subjects regardless of left ventricular ejection fraction (LVEF). Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy as tolerated. The study will enroll 230 patients in approximately 35 centers. Expected duration is 36 months (24-month enrolment plus ≥ 12-month follow-up). Primary endpoints are freedom from device/system-related complications and freedom from pressure sensor failure at 12-month post-implant. Secondary endpoints include the annualized rate of HF-related hospitalization at 12 months versus the rate over the 12 months preceding implant, and health-related quality of life. Endpoints will be evaluated using data obtained after each subject’s 12-month visit. The MEMS-HF study will provide robust evidence on the clinical safety and feasibility of implementing haemodynamic monitoring as a novel disease management tool in routine out-patient care in selected European healthcare systems. ClinicalTrials.gov; NCT02693691.

Nowadays permanent mechanical circulatory support is a common treatment option for end-stage heart failure. Due to a shortage of donor heart transplantation not always being available for the patient in need to get life-saving treatment, a left ventricular assist devices (LVAD) is a suitable treatment option to overcome long waiting times on the transplant waiting list (1). Despite the technical evolution and better understanding of LVAD, there are still drawbacks in treating patients with an LVAD. Typical complications are bleeding complications, infections, right heart failure, and the risk of thrombus formation, which can lead to a device failure with a hemodynamic instability of the patient (2).