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Objectives: Bridging from a temporary microaxial left ventricular assist device (tLVAD) to a durable left ventricular assist device (dLVAD) is playing an increasing role in the treatment of terminally ill patients with heart failure. Scant data exist about the best implant strategy. The goal of this study was to analyse differences in the dLVAD implant technique and effects on patient outcomes., Methods: Data from 341 patients (19 European centres) who underwent a bridge-to-bridge implant from tLVAD to dLVAD between January 2017 and October 2022 were retrospectively analysed. The outcomes of the different implant techniques with the patient on cardiopulmonary bypass, extracorporeal life support or tLVAD were compared., Results: A durable LVAD implant was performed employing cardiopulmonary bypass in 70% of cases (n = 238, group 1), extracorporeal life support in 11% (n = 38, group 2) and tLVAD in 19% (n = 65, group 3). Baseline characteristics showed no significant differences in age (P = 0.140), body mass index (P = 0.388), creatinine level (P = 0.659), the Model for End-Stage Liver Disease (MELD) score (P = 0.190) and rate of dialysis (P = 0.110). Group 3 had significantly fewer patients with preoperatively invasive ventilation and cardiopulmonary resuscitation before the tLVAD was implanted (P = 0.009 and P < 0.001 respectively). Concomitant procedures were performed more often in groups 1 and 2 compared to group 3 (24%, 37% and 5%, respectively, P < 0.001). The 30-day mortality data showed significantly better survival after an inverse probability of treatment weighting in group 3, but the 1-year mortality showed no significant differences among the groups (P = 0.012 and 0.581, respectively). Postoperative complications like the rate of right ventricular assist device (RVAD) implants or re-thoracotomy due to bleeding, postoperative respiratory failure and renal replacement therapy showed no significant differences among the groups. Freedom from the first adverse event like stroke, driveline infection or pump thrombosis during follow-up was not significantly different among the groups. Postoperative blood transfusions within 24 h were significantly higher in groups 1 and 2 compared to surgery on tLVAD support (P < 0.001 and P = 0.003, respectively)., Conclusions: In our analysis, the transition from tLVAD to dLVAD without further circulatory support did not show a difference in postoperative long-term survival, but a better 30-day survival was reported. The implant using only tLVAD showed a reduction in postoperative transfusion rates, without increasing the risk of postoperative stroke or pump thrombosis. In this small cohort study, our data support the hypothesis that a dLVAD implant on a tLVAD is a safe and feasible technique in selected patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: A left ventricular assist device (LVAD) is a life-saving but intensive therapy for patients with end-stage heart failure. We evaluated the healthcare consumption in a cohort of LVAD patients in our centre over 6 years., Methods: All patients with a primary LVAD implantation at the University Medical Centre Utrecht in Utrecht, the Netherlands from 2016 through 2021 were included in this analysis. Subsequent hospital stay, outpatient clinic visits, emergency department visits and readmissions were recorded., Results: During the investigated period, 226 LVADs were implanted, ranging from 32 in 2016 to 45 in 2020. Most LVADs were implanted in patients aged 40-60 years, while they were supported by or sliding on inotropes (Interagency Registry for Mechanically Assisted Circulatory Support class 2 or 3). Around the time of LVAD implantation, the median total hospital stay was 41 days. As the size of the LVAD cohort increased over time, the total annual number of outpatient clinic visits also increased, from 124 in 2016 to 812 in 2021 (p = 0.003). The numbers of emergency department visits and readmissions significantly increased in the 6‑year period as well, with a total number of 553 emergency department visits and 614 readmissions. Over the years, the annual number of outpatient clinic visits decreased by 1 per patient-year follow-up, while the annual numbers of emergency department visits and readmissions per patient-year remained stable., Conclusion: The number of patients supported by an LVAD has grown steadily over the last years, requiring a more specialised healthcare in this particular population., (© 2024. The Author(s).)

Background and Aims: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups., Methods: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented., Results: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing., Conclusions: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms., Methods: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death., Conclusion: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers., Methods and Results: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF., Conclusion: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In refractory cardiogenic shock, temporary mechanical support (tMCS) may be crucial for maintaining tissue perfusion and oxygen delivery. tMCS can serve as a bridge-to-decision to assess eligibility for left ventricular assist device (LVAD) implantation or heart transplantation, or as a bridge-to-recovery. ECPELLA is a novel tMCS configuration combining venoarterial extracorporeal membrane oxygenation with Impella. The present study presents the clinical parameters, outcomes, and complications of patients supported with ECPELLA., Methods: All patients supported with ECPELLA at University Medical Centre Utrecht between December 2020 and August 2023 were included. The primary outcome was 30-day mortality, and secondary outcomes were LVAD implantation/heart transplantation and safety outcomes., Results: Twenty patients with an average age of 51 years, and of whom 70% were males, were included. Causes of cardiogenic shock were acute heart failure (due to acute coronary syndrome, myocarditis, or after cardiac surgery) or chronic heart failure, respectively 70 and 30% of cases. The median duration of ECPELLA support was 164 h (interquartile range 98-210). In 50% of cases, a permanent LVAD was implanted. Cardiac recovery within 30 days was seen in 30% of cases and 30-day mortality rate was 20%. ECPELLA support was associated with major bleeding (40%), haemolysis (25%), vascular complications (30%), kidney failure requiring replacement therapy (50%), and Impella failure requiring extraction (15%)., Conclusion: ECPELLA can be successfully used as a bridge to LVAD implantation or as a bridge-to-recovery in patients with refractory cardiogenic shock. Despite a significant number of complications, 30-day mortality was lower than observed in previous cohorts., (© 2024. The Author(s).)

Background: Stroke after durable left ventricular assist device (d-LVAD) implantation portends high mortality. The incidence of ischemic and hemorrhagic stroke and the impact on stroke outcomes of temporary mechanical circulatory support (tMCS) management among patients requiring bridge to d-LVAD with micro-axial flow-pump (mAFP, Abiomed) is unsettled., Methods: Consecutive patients, who underwent d-LVAD implantation after being bridged with mAFP at 19 institutions, were retrospectively included. The incidence of early ischemic and hemorrhagic stroke after d-LVAD implantation (<60 days) and association of pre-d-LVAD characteristics and peri-procedural management with a specific focus on tMCS strategies were studied., Results: Among 341 patients, who underwent d-LVAD implantation after mAFP implantation (male gender 83.6%, age 58 [48-65] years, mAFP 5.0/5.5 72.4%), the early ischemic stroke incidence was 10.8% and early hemorrhagic stroke 2.9%. The tMCS characteristics (type of mAFP device and access, support duration, upgrade from intra-aortic balloon pump, ECMELLA, ECMELLA at d-LVAD implantation, hemolysis, and bleeding) were not associated with ischemic stroke after d-LVAD implant. Conversely, the device model (mAFP 2.5/CP vs. mAFP 5.0/5.5: HR 5.6, 95%CI 1.4-22.7, p = 0.015), hemolysis on mAFP support (HR 10.5, 95% CI 1.3-85.3, p = 0.028) and ECMELLA at d-LVAD implantation (HR 5.0, 95% CI 1.4-18.7, p = 0.016) were associated with increased risk of hemorrhagic stroke after d-LVAD implantation. Both early ischemic (HR 2.7, 95% CI 1.9-4.5, p < 0.001) and hemorrhagic (HR 3.43, 95% CI 1.49-7.88, p = 0.004) stroke were associated with increased 1-year mortality., Conclusions: Among patients undergoing d-LVAD implantation following mAFP support, tMCS characteristics do not impact ischemic stroke occurrence, while several factors are associated with hemorrhagic stroke suggesting a proactive treatment target to reduce this complication., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Aims: The number of patients on left ventricular assist device (LVAD) support increases due to the growing number of patients with end-stage heart failure and the limited number of donor hearts. Despite improving survival rates, patients frequently suffer from adverse events such as cardiac arrhythmia and major bleeding. Telemonitoring is a potentially powerful tool to early detect deteriorations and may further improve outcome after LVAD implantation. Hence, we developed a personalized algorithm to remotely monitor HeartMate3 (HM3) pump parameters aiming to early detect unscheduled admissions due to cardiac arrhythmia or major bleeding., Methods and Results: The source code of the algorithm is published in an open repository. The algorithm was optimized and tested retrospectively using HeartMate 3 (HM3) power and flow data of 120 patients, including 29 admissions due to cardiac arrhythmia and 14 admissions due to major bleeding. Using a true alarm window of 14 days prior to the admission date, the algorithm detected 59 and 79% of unscheduled admissions due to cardiac arrhythmia and major bleeding, respectively, with a false alarm rate of 2%., Conclusion: The proposed algorithm showed that the personalized algorithm is a viable approach to early identify cardiac arrhythmia and major bleeding by monitoring HM3 pump parameters. External validation is needed and integration with other clinical parameters could potentially improve the predictive value. In addition, the algorithm can be further enhanced using continuous data., Competing Interests: Conflict of interest: M.M., L.N., M.S., N.K., F.W.A, and E.A. report no competing interests. L.W.L. received consultancy fees from Medtronic, Abbott Vifor, Novartis, outside the submitted work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Venoarterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used in cardiogenic shock for rapid stabilization and bridging towards recovery, long-term mechanical circulatory support or transplant. Although technological advances have instigated its widespread use, the complex, long-lasting ECMO care creates a significant strain on hospital staff and resources. Therefore, optimal clinical management including timely decisions on ECMO removal and further therapy are pivotal, yet require a well-structured weaning approach. Although dedicated guidelines are lacking, a variety of weaning protocols have distillated echocardiographic and hemodynamic predictors for successful weaning. Nevertheless, a strikingly high mortality up to 70% after initial successful weaning raises concerns about the validity of current weaning strategies. Here, we plead for a patient-tailored approach including a bailout strategy when weaning fails. This should account not only for left- but also right ventricular function and interdependence, as well as the temporal course of cardiac recovery in function of extracorporeal support. Patients with a high risk of weaning failure should be identified early, enabling timely transportation to an advanced heart failure center. This review summarizes predictors of successful weaning and discusses all relevant elements for a structured weaning approach with a central role for patient-specific clinical considerations and echocardiography., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JAJ Hermens, CL Meuwese, M Symanski and M Gianoli declare that they have no competing interests. DW Donker reported speaker fees and research cooperation with Getinge Maquet, Fresenius-Xenios-NovaLung and Abiomed.

Introduction: From the start of the coronavirus disease 2019 (COVID-19) pandemic, international guidelines have recommended pre-operative screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before heart transplantation (HTx). Due to the changing prevalence of COVID-19, the chances of false positive results have increased. Because of increased immunity in the population and evolution of SARS-CoV-2 to current Omicron variants, associated mortality and morbidity have decreased. We set out to investigate the yield and side effects of SARS-CoV-2 screening in our center., Methods: We performed a retrospective cohort study in the University Medical Center Utrecht. The study period was from March 2019 to January 2023. All data from patients who underwent HTx were collected, including all pre-operative and post-operative SARS-CoV-2 tests. Furthermore, all clinical SARS-CoV-2 tests for the indication of potential HTx were screened., Results: In the period under study, 51 patients underwent HTx. None of the recipients reported any symptoms of a viral infection. Fifty HTx recipients were screened for SARS-CoV-2. Forty-nine out of fifty patients tested negative. One patient had a false positive result, potentially delaying the HTx procedure. There were no cancelled HTx procedures due to a true positive SARS-CoV-2 test result., Conclusion: Pre-operative SARS-CoV-2 screening in asymptomatic HTx recipients did not lead to any true positive cases. In 2% of the cases, screening resulted in a false positive test result. With the current Omicron variants, in combination with a low-prevalence situation, we propose to abandon pre-operative SARS-CoV-2 screening and initiate a symptom-driven approach for the general viral testing of patients who are called in for a potential HTx.

Background: The effect of haemodynamic monitoring of pulmonary artery pressure has predominantly been studied in the USA. There is a clear need for randomised trial data from patients treated with contemporary guideline-directed-medical-therapy with long-term follow-up in a different health-care system., Methods: MONITOR-HF was an open-label, randomised trial, done in 25 centres in the Netherlands. Eligible patients had chronic heart failure of New York Heart Association class III and a previous heart failure hospitalisation, irrespective of ejection fraction. Patients were randomly assigned (1:1) to haemodynamic monitoring (CardioMEMS-HF system, Abbott Laboratories, Abbott Park, IL, USA) or standard care. All patients were scheduled to be seen by their clinician at 3 months and 6 months, and every 6 months thereafter, up to 48 months. The primary endpoint was the mean difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 months. All analyses were by intention-to-treat. This trial was prospectively registered under the clinical trial registration number NTR7673 (NL7430) on the International Clinical Trials Registry Platform., Findings: Between April 1, 2019, and Jan 14, 2022, we randomly assigned 348 patients to either the CardioMEMS-HF group (n=176 [51%]) or the control group (n=172 [49%]). The median age was 69 years (IQR 61-75) and median ejection fraction was 30% (23-40). The difference in mean change in KCCQ overall summary score at 12 months was 7·13 (95% CI 1·51-12·75; p=0·013) between groups (+7·05 in the CardioMEMS group, p=0·0014, and -0·08 in the standard care group, p=0·97). In the responder analysis, the odds ratio (OR) of an improvement of at least 5 points in KCCQ overall summary score was OR 1·69 (95% CI 1·01-2·83; p=0·046) and the OR of a deterioration of at least 5 points was 0·45 (0·26-0·77; p=0·0035) in the CardioMEMS-HF group compared with in the standard care group. The freedom of device-related or system-related complications and sensor failure were 97·7% and 98·8%, respectively., Interpretation: Haemodynamic monitoring substantially improved quality of life and reduced heart failure hospitalisations in patients with moderate-to-severe heart failure treated according to contemporary guidelines. These findings contribute to the aggregate evidence for this technology and might have implications for guideline recommendations and implementation of remote pulmonary artery pressure monitoring., Funding: The Dutch Ministry of Health, Health Care Institute (Zorginstituut), and Abbott Laboratories., Competing Interests: Declaration of interests JJB received an independent research grant from Abbott for investigator-initiated studies to the hospital and reports speaker engagement or advisory board fees from Astra Zeneca, Abbott, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Novartis, and Vifor. CAdF received consulting or speaker fees from Astra Zeneca, Abbott, Boehringer Ingelheim, Novartis, Pfizer, Bristol Myers Squibb, Philips, and Servier. CJWB served on advisory boards, or had speaker engagements with Abbott, AstraZeneca, Boehringer Ingelheim, and Novartis. HPB-LR reports unrestricted research grants from Vifor, Novartis, and Roche Diagnostics, and reports consultancy fees and payments for lectures from Vifor, Novartis, Boehringer Ingelheim, AstraZeneca, and Roche Diagnostic. RAdB has received research grants or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Immunocompromised patients are at high risk of complicated severe acute respiratory coronavirus 2 infection. The aim of this retrospective study was to describe the characteristics and outcomes of heart transplantation (HTx) recipients with coronavirus disease 2019 (COVID-19) in the Netherlands., Methods: HTx patients from one of the three HTx centres in the Netherlands with COVID-19 (proven by positive reverse-transcription polymerase chain reaction or serology test result) between February 2020 and June 2021 were included. The primary endpoint was all-cause mortality and the secondary endpoint was disease severity., Results: COVID-19 was diagnosed in 54/665 HTx patients (8%), with a mean (± standard deviation (SD)) time after HTx of 11 ± 8 years. Mean (± SD) age was 53 ± 14 years and 39% were female. Immunosuppressive therapy dosage was reduced in 37% patients (20/54). Hospitalisation was required in 39% patients (21/54), and 13% patients (7/54) had severe COVID-19 (leading to intensive care unit (ICU) admission or death). In-hospital mortality was 14% (3/21), and all-cause mortality was 6%. Compared with patients with moderate COVID-19 (hospitalised without ICU indication), severe COVID-19 patients tended to be transplanted earlier and had a significantly higher mean (± SD) body mass index (26 ± 3 vs 30 ± 3 kg/m 2 , p = 0.01). Myocardial infarction, cellular rejection and pulmonary embolism were observed once in three different HTx patients., Conclusion: HTx patients were at increased risk of complicated COVID-19 with frequent hospitalisation, but the all-cause mortality was substantially lower than previously described (7-33%)., (© 2022. The Author(s).)

Objectives: The purpose of this study was to examine whether peak oxygen uptake (pVO 2 ) and other cardiopulmonary exercise test (CPET)-derived variables could predict intermediate-term mortality in stable continuous flow LVAD recipients., Background: pVO 2 is a cornerstone in the selection of patients for heart transplantation, but the prognostic power of pVO 2 obtained in patients treated with a left ventricular assist device (LVAD) is unknown., Methods: We collected data for pVO 2 and outcomes in adult LVAD recipients in a retrospective, multicenter study and evaluated cutoff values for pVO 2 including: 1) values above or below medians; 2) grouping patients in tertiles; and 3) pVO 2  ≤14 ml/kg/min if the patient was not treated with beta-blockers (BB) or pVO 2  ≤12 ml/kg/min if the patient was taking BB therapy., Results: Nine centers contributed data from 450 patients. Patients were 53 ± 13 years of age; 78% were male; body mass index was 25 ± 5 kg/m 2 with few comorbidities (stroke: 11%; diabetes: 18%; and peripheral artery disease: 4%). The cause of heart failure (HF) was most often nonischemic (66%). Devices included were the HeartMate II and 3 (Abbott); and Heartware ventricular assist devices Jarvik and Duraheart (Medtronic). The index CPET was performed at a median of 189 days (154-225 days) after LVAD implantation, and mean pVO 2 was 14.1 ± 5 ml/kg/min (47% ± 14% of predicted value). Lower pVO 2 values were strongly associated with poorer survival regardless of whether patients were analyzed for absolute pVO 2 in ml/kg/min, pVO 2  ≤12 BB/14 ml/kg/min, or as a percentage of predicted pVO 2 values (P ≤ 0.001 for all). For patients with pVO 2 >12 BB/14 and ventilation/carbon dioxide relationship (VE/VCO 2 ) slope <35, the 1-year survival was 100%., Conclusions: Even after LVAD implantation, pVO 2 has prognostic value, similar to HF patients not supported by mechanical circulatory support devices. (PROgnostic Value of Exercise Capacity Measured as Peak Oxygen Uptake [pVO 2 ] in Recipients of Left Ventricular Assist Devices [PRO-VAD]; NCT04423562)., Competing Interests: Funding Support and Author Disclosures Dr Mirza received Danish funding from Skibsreder Per Henriksen, R og hustrus Fond grant 10403/53 and Jascha Fonden grants 6186 and 7724. Dr Gustafsson is supported by research grant NNF20OC006056 from the Novo Nordisk Foundation. Dr Brahmbhatt has received travel support from Abbott, Biotronik; and has received honoraria, travel support, and research funding from Boston Scientific (all outside the submitted work). Dr Hsu has received U.S. National Institutes of Health funding (grant K23-HL146889) (all outside the submitted work). Dr MacGowan is supported by EU Horizon 2020 and United Kingdom National Institute of Health Research. Dr Jakovljevic is supported by EU Horizon 2020 Research and Innovation Programme under grant agreements 777204 and 952603. Dr Gustafsson has received personal fees from Abbott, Carmat, Pfizer, Novartis, Orion Pharma, Boehringer Ingelheim, Pharmacosmos, Amgen, Bayer, and AstraZeneca; and is a consultant for Abbott, Carmat, Pfizer, Novartis, Orion Pharma, Boehringer-Ingelheim, Pharmacosmos, Amgen, Bayer and AstraZeneca (all outside the submitted work). Dr Russell is a consultant for Medtronic and Abbott (all outside the submitted work). Dr Jorde is a consultant for Abbott (all outside the submitted work). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The leaf epidermis is a dynamic biomechanical shell that integrates growth across spatial scales to influence organ morphology. Pavement cells, the fundamental unit of this tissue, morph irreversibly into highly lobed cells that drive planar leaf expansion. Here, we define how tissue-scale cell wall tensile forces and the microtubule-cellulose synthase systems dictate the patterns of interdigitated growth in real time. A morphologically potent subset of cortical microtubules span the periclinal and anticlinal cell faces to pattern cellulose fibres that generate a patch of anisotropic wall. The subsequent local polarized growth is mechanically coupled to the adjacent cell via a pectin-rich middle lamella, and this drives lobe formation. Finite element pavement cell models revealed cell wall tensile stress as an upstream patterning element that links cell- and tissue-scale biomechanical parameters to interdigitated growth. Cell lobing in leaves is evolutionarily conserved, occurs in multiple cell types and is associated with important agronomic traits. Our general mechanistic models of lobe formation provide a foundation to analyse the cellular basis of leaf morphology and function.

Various cell-based therapies are currently investigated in an attempt to tackle the high morbidity and mortality associated with heart failure. The need for these therapies to move towards the clinic is pressing. Therefore, preclinical large animal studies that use non-autologous cells are needed to evaluate their potential. However, non-autologous cells are highly immunogenic and trigger immune rejection responses resulting in potential loss of efficacy. To overcome this issue, adequate immunosuppressive regimens are of imminent importance but clear guidelines are currently lacking. In this review, we assess the immunological barriers regarding non-autologous cell transplantation and immune modulation with immunosuppressive drugs. In addition, we provide recommendations with respect to immunosuppressive regimens in preclinical cardiac cell-replacement studies.

Cardiac dysfunction leads to decreased organ perfusion. We aimed to measure cardiac and renal perfusion simultaneously with the use of (13)N-NH3-microPET in different rat models. Ten male Wistar rats underwent sham surgery (n = 5) or permanent coronary artery ligation to induce myocardial infarction (MI, n = 5). Eleven weeks later (13)N-NH3-microPET scan was performed to study the cardiac and renal perfusion. Cardiac perfusion was significantly reduced in MI group, directly correlated with ejection fraction and inversely correlated with MI size (r = 0.89; p < 0.001 and r = -0.86; p < 0.001 respectively). Renal perfusion showed a notional 17 % non-significant reduction in MI group when compared to sham (3.44 ± 0.40 vs. 4.12 ± 0.48 ml/g/min). There was a trend towards greater reduction of perfusion in cortical than medullar region. Cortex perfusion was negatively correlated with histological changes. (13)N-NH3-microPET may be a potential tool for evaluation of cardiac and renal functional and perfusion changes in presence of cardiac dysfunction in rat models.

Objectives: Chronic renal dysfunction severely increases cardiovascular risk. Adverse cardiac remodeling is suggested to play a major role as predisposition for increased cardiac ischemic vulnerability. The aim of the present study was to examine the role of adverse cardiac remodeling in cardiac sensitivity to acute ischemia/reperfusion damage in a rat model for renal dysfunction., Methods: Munich Wistar Fromter (MWF) rats, developing spontaneous progressive renal dysfunction and mild hypertension, were compared to healthy Wistar rats, and to nonproteinuric spontaneously hypertensive rats (SHRs). In MWF rats, renal dysfunction and mild hypertension were confirmed. Hearts were analyzed for adverse cardiac remodeling, including myocyte hypertrophy, capillary density, and interstitial fibrosis, by histology. In parallel, sensitivity to cardiac ischemia/reperfusion damage was obtained from infarct size measured after 30-min coronary artery occlusion, followed by 24  h of reperfusion., Results: Infarcts were larger in MWF rats [56 ± 3% of risk area (P = 0.04)], but at a similar extent in SHRs [52 ± 4% (P = 0.16)], when compared to Wistar rats (45 ± 4%). However, whereas SHRs showed pronounced adverse cardiac remodeling, MWF rats did not: no left ventricular hypertrophy (myocyte size MWF rats +29%; SHRs +72%), no lower capillary density (MWF rats +34%; SHRs -13%), and no interstitial fibrosis (MWF rats -16%; SHRs +70%)., Conclusion: Data indicate that chronic renal dysfunction in MWF rats is associated with elevated cardiac sensitivity to acute ischemia/reperfusion damage, as reflected by larger infarcts. Comparing results to SHRs suggests that this higher susceptibility could not be attributed to hypertension or adverse cardiac remodeling.

Aims: The renin-angiotensin system plays a central role in patients with established cardiovascular (CV) disease, but the prognostic effect of plasma renin in the community is unclear., Methods and Results: The relationship between plasma renin concentration and CV events was studied in 6228 subjects who were enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, and who were not using antihypertensive medication. Plasma renin concentration was measured using a direct automated immunochemiluminescent assay. The mean (± SD) age was 47(± 12) years, 49% were male; the mean follow-up was 10.5 years. The median (Q1-Q3) plasma renin was 17.6 (10.9-27.2) µIU/mL, and plasma aldosterone was 119 (93-153) ng/L. The primary outcome was a composite of fatal (n = 27) and non-fatal (n = 408) CV events. Adjusted for age and sex each doubling of plasma renin was associated with a hazard ratio (HR) for the primary outcome of 1.22 (95% CI: 1.04-1.43; P= 0.015). In a multivariable model, plasma renin showed a positive correlation with heart rate and male sex and a negative correlation with blood pressure, urinary sodium, glucose, and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (adjusted R(2): 0.167, P< 0.001). After adjustment for covariates associated with plasma renin, the HR for reaching the primary outcome was 1.28 (95% CI: 1.09-1.49, P= 0.002). Plasma renin was associated with CV events regardless of blood pressure, but in subjects using antihypertensive medication this association was absent., Conclusion: Plasma renin concentration is associated with an increased risk for CV events in a community-based cohort not on antihypertensive medication.

Introduction: Myocardial perfusion gating techniques offer the possibility of measurement of left ventricular end-systolic (ESV) and end-diastolic volume (EDV) and left ventricular ejection fraction (LVEF) in clinical and preclinical trials. The aim of this study was to evaluate left ventricular volumes (LVV) and LVEF with 13N-NH3 in comparison with the reference 18F-FDG in different rat models., Methods: In this study, 18 male Wistar rats, 12 control rats and 6 rats with myocardial infarction (MI) were imaged with micro-PET. The ratswere scanned with gated 13N-NH3 and 18F-FDG sequentially for the assessment of LVV and LVEF. A validated three-dimensional segmentation algorithm was used to calculate LVV and LVEF., Results: Mean LVEF measured with 13N-NH3 was 45.6±8.9 and 75.3±9.4%, mean ESV was 0.40±0.12 and 0.14±0.11 ml, and mean EDVwas 0.53±16 and 0.75±0.18 ml for MI and control rats, respectively. Moderate to good correlations were observed between values of 13N-NH3 and 18F-FDG for calculation of ESV [r=0.80, P<.0001, standard error of estimate (SEE)=0.10], EDV (r=0.63, P=.005, SEE=0.14) and LVEF (r=0.84, P<.0001, SEE=9.5). LVEF measured with 13N-NH3 was significantly lower in MI rats in comparison to measurement with 18F-FDG (45.6±8.9 vs 54.9±9.3 %; P=.04)., Conclusion: Correlations were moderate to good for the assessment of ESV, EDV and LVEF between gated 13N-NH3 and 18F-FDG. LVEF was underestimated with gated 13N-NH3 in rats with myocardial infarction. In healthy rats, LV volumes and LVEF can be measured reproducibly with either approach., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The incidence of heart failure and renal failure is increasing and is associated with poor prognosis. Moreover, these conditions do often coexist and this coexistence results in worsened outcome. Various mechanisms have been proposed as an explanation of this interrelation, including changes in hemodynamics, endothelial dysfunction, inflammation, activation of renin-angiotensin-aldosterone system, and/or sympathetic nervous system. However, the exact mechanisms initializing and maintaining this interaction are still unknown. In many experimental studies on cardiac or renal dysfunction, the function of the other organ was either not addressed or the authors failed to show any decline in its function despite histological changes. There are few studies in which the dysfunction of both heart and kidney function has been described. In this review, we discuss animal models of combined cardiorenal dysfunction. We show that translation of the results from animal studies is limited, and there is a need for new and better models of the cardiorenal interaction to improve our understanding of this syndrome. Finally, we propose several requirements that a new animal model should meet to serve as a tool for studies on the cardiorenal syndrome.

Primary chronic kidney disease is associated with high cardiovascular risk. However, the exact mechanisms behind this cardiorenal interaction remain unclear. We investigated the interaction between heart and kidneys in novel animal model for cardiorenal interaction. Normal Wistar rats and Munich Wistar Fromter rats, spontaneously developing renal dysfunction, were subjected to experimental myocardial infarction to induce cardiac dysfunction (CD) and combined cardiorenal dysfunction (CRD), respectively (N = 5-10). Twelve weeks later, cardiac- and renal parameters were evaluated. Cardiac, but not renal dysfunction was exaggerated in CRD. Accelerated cardiac dysfunction in CRD was indicated by decreased cardiac output (CD 109 ± 10 vs. CRD 79 ± 8 ml/min), diastolic dysfunction (E/e') (CD 26 ± 2 vs. CRD 50 ± 5) and left ventricular overload (LVEDP CD 10.8 ± 2.8 vs. CRD 21.6 ± 1.7 mmHg). Congestion in CRD was confirmed by increased lung and atrial weights, as well as exaggerated right ventricular hypertrophy. Absence of accelerated renal dysfunction, measured by increased proteinuria, was supported by absence of additional focal glomerulosclerosis or further decline of renal blood flow in CRD. Only advanced peripheral endothelial dysfunction, as found in CRD, appeared to correlate with both renal and cardiac dysfunction parameters. Thus, proteinuric rats with myocardial infarction showed accelerated cardiac but not renal dysfunction. As parameters mimic the cardiorenal syndrome, these rats may provide a clinically relevant model to study increased cardiovascular risk due to renal dysfunction. Peripheral endothelial dysfunction was the only parameter that correlated with both renal and cardiac dysfunction, which may indicate a mediating role in cardiorenal interaction.

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure-associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1-7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.

Background: The renin-angiotensin-aldosterone system (RAAS) plays a key role in the progression of heart failure (HF) and concomitant kidney dysfunction. Despite the use of RAAS blockade, sustained activation of RAAS has been suggested to link with adverse outcome. We aimed to investigate the prognostic value of active plasma renin concentration (APRC) and prorenin in patients with HF treated with RAAS-blocking agents and its relationship with kidney function parameters., Methods: One hundred clinically stable patients with HF, treated with RAAS-blocking agents, were studied. Renal function parameters including effective renal plasma flow and glomerular filtration rate were measured invasively. The combined end point consisted of all-cause mortality, heart transplantation, and admission to hospital for HF., Results: Mean age was 58 ± 12 years, and 76% were men. Mean left ventricular ejection fraction was 28 ± 9, and median APRC levels were 24.3 ng/mL per hour. Active plasma renin concentration was most strongly associated with mean arterial pressure (r = 0.60, P < .001). In multivariate linear regression analysis, age, mean arterial pressure, angiotensin II concentration, and use of aldosterone antagonists were significantly related with APRC (adjusted R(2) = 0.53). Patients in the highest quartile of APRC had a worse prognosis. In multivariate analysis, APRC remained associated with worse prognosis: HR 2.87 (95% CI 1.14-7.20), P = .025. Prorenin did not show prognostic value. The prognostic value of APRC was strongest in patients with decreased kidney function., Conclusions: Our data indicate that APRC is a strong prognostic factor in patients with HF in the presence of RAAS inhibition, especially in patients with kidney dysfunction., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Aims: Vitamin D status has been implicated in the pathophysiology of heart failure (HF). The aims of this study were to determine whether a low vitamin D status is associated with prognosis in HF and whether activation of the renin-angiotensin system (RAS) and inflammatory markers could explain this potential association., Methods and Results: We measured 25-hydroxy-vitamin D (25(OH)D), plasma renin activity (PRA), interleukin-6 (IL-6), C-reactive protein (CRP), and the incidence of death or HF rehospitalization in 548 patients with HF. Median age was 74 (64-80) years, left ventricular ejection fraction was 30% (23-42), and mean follow-up was 18 months. Low 25(OH)D levels were associated with female gender (P< 0.001), higher age (P= 0.002), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P< 0.001). Multivariable linear regression analysis showed that PRA (P= 0.048), and CRP levels (P= 0.006) were independent predictors of 25(OH)D levels. During follow-up, 155 patients died and 142 patients were rehospitalized. Kaplan-Meier analysis showed that lower 25(OH)D concentration was associated with an increased risk for the combined endpoint (all-cause mortality and HF rehospitalization; log rank test P= 0.045) and increased risk for all-cause mortality (log rank test P= 0.014). After adjustment in a multivariable Cox regression analysis, low 25(OH)D concentration remained independently associated with an increased risk for the combined endpoint [hazard ratio (HR) 1.09 per 10 nmol/L decrease; 95% confidence interval (CI) 1.00-1.16; P= 0.040] and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI 1.00-1.22; P= 0.049)., Conclusion: A low 25(OH)D concentration is associated with a poor prognosis in HF patients. Activation of the RAS and inflammation may confer the adverse effects of low vitamin D levels.

Diuretics, when added to angiotensin-converting enzyme inhibitors (ACE inhibitors) treatment, can augment the response to ACE inhibitors, but may have adverse effects on renal function, which negatively affect prognosis. While in heart failure rats combined therapy initially improved cardiac function and prognosis, this benefit was completely lost at later stages. We now studied renal effects of adding hydrochlorothiazide to ACE inhibitor after myocardial infarction in rats. Rats were randomized to ACE inhibitor quinapril monotherapy or quinapril with add-on hydrochlorothiazide. Survival was monitored for 14 months. Plasma creatinine, measured at 4 months, was increased by 40% in quinapril with add-on hydrochlorothiazide compared to quinapril. Although overall 14-months mortality was similar in quinapril with add-on hydrochlorothiazide and quinapril, stratification based on plasma creatinine showed increased mortality in the tertile with highest plasma creatinine (P=0.03, Log rank). With add-on hydrochlorotiazide, renal morphology displayed severe renal interstitial lesions; tubular dilatation and fibrosis. Interstitial myofibroblast transformation (alpha-smooth muscle actine staining) was increased at 8 and 14 months, and coincided with collagen deposition and interstitial inflammation (macrophage influx). In rats with quinapril monotherapy or untreated rats, renal structure was normal. Thus, adding hydrochlorotiazide to ACE inhibitor detrimentally affected not only renal function, but also renal structure in rats with myocardial infarction. Altered pharmacokinetics, resulting from a vicious circle of reduced renal function and increased circulating drug levels, may provide an explanation for the adverse renal effects and may exert unfavorable effects on long-term prognosis after myocardial infarction.

Searches for extrasolar planets have uncovered an astonishing diversity of planetary systems, yet the frequency of solar system analogs remains unknown. The gravitational microlensing planet search method is potentially sensitive to multiple-planet systems containing analogs of all the solar system planets except Mercury. We report the detection of a multiple-planet system with microlensing. We identify two planets with masses of approximately 0.71 and approximately 0.27 times the mass of Jupiter and orbital separations of approximately 2.3 and approximately 4.6 astronomical units orbiting a primary star of mass approximately 0.50 solar mass at a distance of approximately 1.5 kiloparsecs. This system resembles a scaled version of our solar system in that the mass ratio, separation ratio, and equilibrium temperatures of the planets are similar to those of Jupiter and Saturn. These planets could not have been detected with other techniques; their discovery from only six confirmed microlensing planet detections suggests that solar system analogs may be common.

Observations of the gravitational microlensing event MOA 2003-BLG-32/OGLE 2003-BLG-219 are presented, for which the peak magnification was over 500, the highest yet reported. Continuous observations around the peak enabled a sensitive search for planets orbiting the lens star. No planets were detected. Planets 1.3 times heavier than Earth were excluded from more than 50% of the projected annular region from approximately 2.3 to 3.6 astronomical units surrounding the lens star, Uranus-mass planets were excluded from 0.9 to 8.7 astronomical units, and planets 1.3 times heavier than Saturn were excluded from 0.2 to 60 astronomical units. These are the largest regions of sensitivity yet achieved in searches for extrasolar planets orbiting any star.