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Aims: We aim to assess the theoretical impact of the atrial flow regulator (AFR) on survival in heart failure. Methods and results: The prospective, multicentre, open‐label, non‐randomised PRELIEVE study (NCT 03030274) assessed the safety and efficacy of the Occlutech AFR device in patients with symptomatic heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction (LVEF) ≥ 15% and <40%) or heart failure with preserved ejection fraction (HFpEF) (LVEF ≥40% and <70%) and elevated PCWP (≥15 mmHg at rest or ≥25 mmHg during exercise). In this analysis, after the first 60 patients completed 12 months of follow‐up, the theoretical impact of AFR implantation on survival was assessed by comparing the observed mortality rate with the median predicted probability for one‐year mortality. Each subject's risk of mortality was predicted from individual baseline data using the Meta‐Analysis Global Group in Chronic HF (MAGGIC) prognostic model. A total of 87 patients (46% female, median age 69 years [IQR 62–74]) had undergone successful device implantation for the treatment of HFrEF (53%) and HFpEF (47%). Sixty patients had a complete 12 month follow‐up. The median follow‐up was 351 days (interquartile range [IQR] 202–370). Six (7%) patients died during follow‐up (8.6 deaths per 100 patient‐years; 95% confidence interval [CI] 2.7 to 15.5), all of which had HFrEF. The median predicted mortality rate for the overall study population was 12.2 deaths per 100 patient‐years (95% CI 10.2 to 14.7). While the observed mortality rate (0 deaths per 100 patient‐years) was significantly lower than the median predicted mortality rate (9.3 deaths per 100 patient‐years; 95% CI 8.4 to 11.1) in patients with HFpEF (−9.3 deaths per 100 patient‐years; 95% CI −11.1 to −8.4), there was no difference in patients with HFrEF (−3.6 deaths per 100 patient‐years; 95% CI −9.5 to 3.0). Four deaths were HF‐related deaths (5.7 HF‐related deaths per 100 patient‐years; 95% CI 1.4 to 11.9; 10.8 HF‐related deaths per 100 patient‐years; 95% CI 2.5 to 23.1 in the HFrEF subgroup). Conclusions: In patients with HFpEF, the mortality rate following AFR implantation was lower than the predicted mortality rate. Dedicated randomised, controlled trials are needed – and currently ongoing – to investigate whether the AFR improves mortality. [ABSTRACT FROM AUTHOR]

Aims: The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue‐derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF). Methods and results: The study was a European multicentre, double‐blind, placebo‐controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II–III, left ventricular ejection fraction (LVEF) <45%, and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end‐systolic volume (LVESV) at 6‐month follow‐up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug‐related severe adverse events or difference in cardiac‐related adverse events during a 3‐year follow‐up period. There were no significant differences between groups during follow‐up in LVESV (0.3 ± 5.0 ml, p = 0.945), nor in secondary endpoints of left ventricular end‐diastolic volume (−2.0 ± 6.0 ml, p = 0.736) and LVEF (−1.6 ± 1.0%, p = 0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6‐min walk test, NT‐proBNP, C‐reactive protein or quality of life the first year in any groups. Conclusion: The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre‐defined endpoints and induce restoration of cardiac function or clinical symptoms. [ABSTRACT FROM AUTHOR]

Aims: Attenuating exercise‐induced elevated left atrial pressure with an atrial shunt device is under clinical investigation for treatment of symptomatic heart failure (HF). Methods and results: PRELIEVE was a prospective, non‐randomised, multicentre, first‐in‐man study in symptomatic HF patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction and pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg during exercise. Here, we provide follow‐up data up to 1 year after implantation of the Atrial Flow Regulator (AFR) device. The AFR was successfully implanted in 53 patients (HFrEF n = 24 and HFpEF n = 29). Two patients were not enrolled due to an unsuccessful transseptal puncture. There was one device embolisation into the left atrium, which required surgical removal. One patient experienced a serious procedure‐related adverse event (post‐procedural bleeding and syncope). All patients with sufficient echocardiography readout confirmed device patency with left–right shunt both at 3 (n = 47/51, 92%) and 12 (n = 45/49, 92%) months. At 3 months, rest PCWP decreased by 5 (−12, 0) mmHg (P = 0.0003, median Q1, Q3). No patient developed a stroke, worsening of right heart function or significant increase of pulmonary artery pressure. Six (6/53, 11%) patients were hospitalised for worsening of HF and three (3/53, 6%) patients died. We observed improvements in New York Heart Association functional class, 6‐min walking distance and quality of life (Kansas City Cardiomyopathy Questionnaire) in certain patients. Conclusions: Implantation of the AFR device in HF patients was feasible. No shunt occlusion, stroke or new right HF was observed during the 1‐year follow‐up, with clinical improvements in certain patients. [ABSTRACT FROM AUTHOR]

Aims: Ischaemic heart failure (IHF) patients have a poor prognosis even with current guideline-derived therapy. Intramyocardial injections of autologous or allogeneic mesenchymal stromal cells might improve cardiac function leading to better clinical outcome.Methods: The SCIENCE (Stem Cell therapy in IschEmic Non-treatable Cardiac diseasE) consortium has initiated a Horizon 2020 funded multicentre phase II study in six European countries. It is a double-blind, placebo-controlled trial testing the safety and efficacy of allogeneic Cardiology Stem Cell Centre Adipose-derived Stromal Cells (CSCC_ASC) from healthy donors or placebo in 138 symptomatic IHF patients. Main inclusion criteria are New York Heart Association class II-III, left ventricular ejection fraction < 45% and N-terminal pro-B-type natriuretic peptide levels > 300 pg/mL. Patients are randomized in a 2:1 pattern to receive intramyocardial injections of either CSCC_ASC or placebo. CSCC_ASC and placebo treatments are prepared centralized at Rigshospitalet in 5 mL vials as an off-the-shelf product. Vials are distributed to all clinical partners and stored in nitrogen vapour tanks ready to be used directly after thawing. A total of 100 × 106 CSCC_ASC or placebo are injected directly into viable myocardium in the infarct border zone using the NOGA XP system (BDS, Cordis, Johnson & Johnson, USA). Primary endpoint is a centralized core-laboratory assessed change in left ventricular end-systolic volume at 6-month follow-up measured by echocardiography. The trial started in January 2017, 58 patients were included and treated until July 2018.Conclusion: The SCIENCE trial will provide clinical data on efficacy and safety of intramyocardial cell therapy of allogeneic adipose-derived stromal cells from healthy donors in patients with IHF. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome (TTS) is a reversible form of heart failure with incompletely understood pathophysiology. This study analyzed altered cardiac hemodynamics during TTS to elucidate underlying disease mechanisms. Left ventricular (LV) pressure–volume loops were recorded in 24 consecutive patients with TTS and a control population of 20 participants without cardiovascular diseases. TTS was associated with impaired LV contractility (end-systolic elastance 1.74 mm Hg/mL vs 2.35 mm Hg/mL [ P = 0.024]; maximal rate of change in systolic pressure over time 1,533 mm Hg/s vs 1,763 mm Hg/s [ P = 0.031]; end-systolic volume at a pressure of 150 mm Hg, 77.3 mL vs 46.4 mL [ P = 0.002]); and a shortened systolic period (286 ms vs 343 ms [ P < 0.001]). In response, the pressure–volume diagram was shifted rightward with significantly increased LV end-diastolic (P = 0.031) and end-systolic (P < 0.001) volumes, which preserved LV stroke volume (P = 0.370) despite a lower LV ejection fraction (P < 0.001). Diastolic function was characterized by prolonged active relaxation (relaxation constant 69.5 ms vs 45.9 ms [ P < 0.001]; minimal rate of change in diastolic pressure –1,457 mm Hg/s vs –2,192 mm Hg/s [ P < 0.001]), whereas diastolic stiffness (1/compliance) was not affected during TTS (end-diastolic volume at a pressure of 15 mm Hg, 96.7 mL vs 109.0 mL [ P = 0.942]). Mechanical efficiency was significantly reduced in TTS (P < 0.001) considering reduced stroke work (P = 0.001), increased potential energy (P = 0.036), and a similar total pressure–volume area compared with that of control subjects (P = 0.357). TTS is characterized by reduced cardiac contractility, a shortened systolic period, inefficient energetics, and prolonged active relaxation but unaltered diastolic passive stiffness. These findings may suggest decreased phosphorylation of myofilament proteins, which represents a potential therapeutic target in TTS. (Optimized Characterization of Takotsubo Syndrome by Obtaining Pressure Volume Loops [OCTOPUS]; NCT03726528) [Display omitted] [ABSTRACT FROM AUTHOR]