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Background Assessing haemodynamic congestion based on filling pressures instead of clinical congestion can be a way to further improve quality of life (QoL) and clinical outcome by intervening before symptoms or weight gain occur in heart failure (HF) patients. The clinical efficacy of remote monitoring of pulmonary artery (PA) pressures (CardioMEMS; Abbott Inc., Atlanta, GA, USA) has been demonstrated in the USA. Currently, the PA sensor is not reimbursed in the European Union as its benefit when applied in addition to standard HF care is unknown in Western European countries, including the Netherlands. Aims To demonstrate the efficacy and cost-effectiveness of haemodynamic PA monitoring in addition to contemporary standard HF care in a high-quality Western European health care system. Methods The current study is a prospective, multi-centre, randomised clinical trial in 340 patients with chronic HF (New York Heart Association functional class III) randomised to HF care including remote monitoring with the CardioMEMS PA sensor or standard HF care alone. Eligible patients have at least one hospitalisation for HF in 12 months before enrolment and will be randomised in a 1:1 ratio. Minimum follow-up will be 1 year. The primary endpoint is the change in QoL as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Secondary endpoints are the number of HF hospital admissions and changes in health status assessed by EQ-5D-5L questionnaire including health care utilisation and formal cost-effectiveness analysis. Conclusion The MONITOR HF trial will evaluate the efficacy and cost-effectiveness of haemodynamic monitoring by CardioMEMS in addition to standard HF care in patients with chronic HF. Clinical Trial Registration number NTR7672.

Background Clinical research on arrhythmogenic cardiomyopathy (ACM) is typically limited by small patient numbers, retrospective study designs, and inconsistent definitions. Aim To create a large national ACM patient cohort with a vast amount of uniformly collected high-quality data that is readily available for future research. Methods This is a multicentre, longitudinal, observational cohort study that includes (1) patients with a definite ACM diagnosis, (2) at-risk relatives of ACM patients, and (3) ACM-associated mutation carriers. At baseline and every follow-up visit, a medical history as well information regarding (non-)invasive tests is collected (e. g. electrocardiograms, Holter recordings, imaging and electrophysiological studies, pathology reports, etc.). Outcome data include (non-)sustained ventricular and atrial arrhythmias, heart failure, and (cardiac) death. Data are collected on a research electronic data capture (REDCap) platform in which every participating centre has its own restricted data access group, thus empowering local studies while facilitating data sharing. Discussion The Netherlands ACM Registry is a national observational cohort study of ACM patients and relatives. Prospective and retrospective data are obtained at multiple time points, enabling both cross-sectional and longitudinal research in a hypothesis-generating approach that extends beyond one specific research question. In so doing, this registry aims to (1) increase the scientific knowledge base on disease mechanisms, genetics, and novel diagnostic and treatment strategies of ACM; and (2) provide education for physicians and patients concerning ACM, e. g. through our website ( www.acmregistry.nl ) and patient conferences.

Background The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results A total of 84 presymptomatic PLN p.Arg14del carriers ( n  = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. Conclusion iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Background Phospholamban ( PLN ) p.Arg14del (R14del, R14 ∆/+ ) is the most commonly identified pathogenic variant that causes cardiomyopathy in the Netherlands. Many disease characteristics are still unclear, including the phenotypic triggers, disease progression and disease-specific biomarkers. We aim to gain a better understanding of the R14 ∆/+ pathophysiology by establishing a cohort across the R14 ∆/+ disease spectrum. Methods The Disease spECifIc PatHways and modifiERs in PhosphoLambaN r14del cardiomyopathy ( DECIPHER-PLN) cohort includes 101 participants, categorised as unaffected R14 ∆/+ ( n  = 21), early affected R14 ∆/+ ( n  = 42), end-stage R14 ∆/+ ( n  = 28) and heart failure (HF) of another aetiology ( n  = 10). R14 ∆/+ category was based on left ventricular ejection fraction, HF symptoms, electrocardiogram (ECG) and N‑terminal pro-brain natriuretic peptide concentrations. Of the 91 included R14 ∆/+ carriers, 46 (51%) were female, with a mean age of 55 years (standard deviation: 14). Low-voltage ECG older age, arrhythmias, and conduction and repolarisation abnormalities were common in (early) affected R14 ∆/+ carriers. Serum and plasma were collected from all participants. Induced pluripotent stem cells were generated from fibroblasts of end-stage R14 ∆/+ patients and unaffected R14 ∆/+ family members ( n  = 4) and differentiated into cardiomyocytes. Explanted heart tissue was obtained from R14 ∆/+ patients undergoing cardiac surgery and patients with other HF aetiologies as control. Abnormal PLN protein localisation was confirmed in R14 ∆/+ carriers. Conclusion DECIPHER-PLN comprises R14 ∆/+ carriers across the disease and non-disease spectrum and can be used to identify disease-specific biological pathways and modifiers that play a role in R14 ∆/+ cardiomyopathy. Using a multi-omics approach and in vitro disease modelling, we aim to identify novel biomarkers and improve our understanding of R14 ∆/+ pathophysiology. Material is available upon request.

Background Screening of high-risk patients is advocated to achieve early detection and treatment of clinical atrial fibrillation (AF). The Dutch-GERAF study will address two major issues. Firstly, the effectiveness and feasibility of an opportunistic screening strategy for clinical AF will be assessed in frail older patients and, secondly, observational data will be gathered regarding the efficacy and safety of oral anticoagulation (OAC). Methods This is a multicentre study on opportunistic screening of geriatric patients for clinical AF using a smartphone photoplethysmography (PPG) application. Inclusion criteria are age ≥ 65 years and the ability to perform at least three PPG recordings within 6 months. Exclusion criteria are the presence of a cardiac implantable device, advanced dementia or a severe tremor. The PPG application records patients’ pulse at their fingertip and determines the likelihood of clinical AF. If clinical AF is suspected after a positive PPG recording, a confirmatory electrocardiogram is performed. Patients undergo a comprehensive geriatric assessment and a frailty index is calculated. Risk scores for major bleeding (MB) are applied. Standard laboratory testing and additional laboratory analyses are performed to determine the ABC-bleeding risk score. Follow-up data will be collected at 6 months, 12 months and 3 years on the incidence of AF, MB, hospitalisation, stroke, progression of cognitive disorders and mortality. Discussion The Dutch-GERAF study will focus on frail older patients, who are underrepresented in randomised clinical trials. It will provide insight into the effectiveness of screening for clinical AF and the efficacy and safety of OAC in this high-risk population. Trial registration NCT05337202.

Background Patients with stable chest pain suspected of coronary artery disease (CAD) usually undergo multiple diagnostic tests to confirm or rule out obstructive CAD. Some tests may not effectively assess the presence of CAD, precluding optimal treatment. A diagnostic strategy of upfront computed tomography coronary angiography (CTCA) combined with optimal medical therapy (OMT) tailored to the extent of CAD may be superior to standard care in preventing major adverse cardiac events. Study design The CLEAR-CAD trial is a prospective, open-label, multicentre, randomised, superiority trial of an upfront CTCA-guided strategy in 6444 patients presenting in an outpatient setting with suspected CAD compared with standard care, in approximately 30 participating centres in the Netherlands. The upfront CTCA-guided strategy consists of an initial CTCA which is assessed using the Coronary Artery Disease-Reporting and Data System (CAD-RADS 2.0). In patients without CAD (CAD-RADS 0) no specific cardiac medication is mandated. Patients with non-obstructive CAD (CAD-RADS 1–2) are treated with preventive OMT. Patients with obstructive CAD (CAD-RADS ≥ 3) are treated with preventive and anti-anginal OMT; in the presence of pharmacologically refractory symptoms patients undergo selective revascularisation after non-invasive functional imaging for myocardial ischaemia (≥ 10%). Patients with significant left main or proximal left anterior descending coronary artery stenosis on CTCA undergo direct invasive coronary angiography and subsequent revascularisation. The primary endpoint is the composite of all-cause death and myocardial infarction. Conclusion The CLEAR-CAD trial is the first randomised study to investigate the efficacy of a combined upfront CTCA-guided medical and selective revascularisation strategy in an outpatient setting with suspected CAD compared with standard care.

Introduction In patients undergoing percutaneous coronary intervention (PCI), personalised medicine is key to the secondary prevention of ischaemic and bleeding events. To provide an extensive overview of the quality of secondary prevention and of personalised medicine, a consortium in the southeastern region of the Netherlands has created a PCI registry: the South-East Netherlands Heart Registry ( Zuid-Oost Nederland Hart Registratie , ZON-HR). Aim To visualise and improve personalised secondary prevention post-PCI, focussing on key elements such as antiplatelet treatment, cholesterol management and comorbidities such as diabetes mellitus. Design and population A prospective multicentre registry of all consecutive patients undergoing PCI at 4 participating PCI centres and 3 referral centres. Treatment Interventional procedures and concomitant pharmaceutical treatment are performed in accordance with the guidelines. The ZON-HR promotes risk stratification after PCI using a simplified protocol for a personalised antiplatelet strategy. Data collection and quality Demographics, laboratory values, baseline procedural characteristics and pharmaceutical treatment data are collected. Outcomes include thromboembolic and bleeding complications and medication changes. Data are pseudonymised, and a clinical event committee will review 20% of the adverse events (randomly selected). Strengths and weaknesses This registry represents the entire PCI population and visualises gaps in secondary prevention. Weaknesses are the collection of outcomes and medication changes using mostly patient-reported outcomes. Conclusion The ZON-HR is a comprehensive PCI registry that provides baseline and follow-up data of a large PCI cohort in the southeastern region of the Netherlands. The ZON-HR aims to improve secondary prevention after PCI and augment personalised treatment that focusses on key elements of secondary prevention.

Background During transcatheter aortic valve implantation (TAVI), secondary access is required for angiographic guidance and temporary pacing. The most commonly used secondary access sites are the femoral artery (angiographic guidance) and the femoral vein (temporary pacing). An upper extremity approach using the radial artery and an upper arm vein instead of the lower extremity approach using the femoral artery and femoral vein may reduce clinically relevant secondary access site-related bleeding complications, but robust evidence is lacking. Trial design The TAVI XS trial is a multicentre, randomised, open-label clinical trial with blinded evaluation of endpoints. A total of 238 patients undergoing transfemoral TAVI will be included. The primary endpoint is the incidence of clinically relevant bleeding (i.e. Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding) of the randomised secondary access site (either diagnostic or pacemaker access, or both) within 30 days after TAVI. Secondary endpoints include time to mobilisation after TAVI, duration of hospitalisation, any BARC type 2, 3 or 5 bleeding, and early safety at 30 days according to Valve Academic Research Consortium‑3 criteria. Conclusion The TAVI XS trial is the first randomised trial comparing an upper extremity approach to a lower extremity approach with regard to clinically relevant secondary access site-related bleeding complications. The results of this trial will provide important insights into the safety and efficacy of an upper extremity approach in patients undergoing transfemoral TAVI.

Background Ever since the first description of hypertrophic cardiomyopathy (HCM), the most common genetic cardiac disease, tremendous progress has been made in the evaluation and management of HCM patients, but little attention has been focused on the impact of HCM on societal costs and quality of life (QoL). Aims This paper describes the study protocol for the AFFECT-HCM study into burden of disease (BoD), which aims to estimate health-related QoL and societal costs in HCM patients and genotype-positive phenotype-negative (G+/P−) relatives during a one-year follow-up study, and relate this to the phenotypical HCM expression. Methods A total of 400 Dutch HCM patients and 100 G+/P− subjects will be followed for one year in a prospective, multi-centre, prevalence-based BoD study. Societal costs will be measured via a bottom-up approach using the cost questionnaires iMCQ and iPCQ. For QoL, the generic EQ-5D-5L and disease-specific Kansas City Cardiomyopathy Questionnaire will be used. QoL and societal costs will be compared with phenotype-specific HCM characteristics and other determinants to identify factors that influence BoD. Accelerometry will test the correlation between BoD and physical activity. Conclusion The AFFECT-HCM study will evaluate the BoD in HCM patients and G+/P− subjects to improve the understanding of the societal and economic impact of HCM.

Introduction Despite major advances in our understanding of genetic cardiomyopathies, they remain the leading cause of premature sudden cardiac death and end-stage heart failure in persons under the age of 60 years. Integrated research databases based on a large number of patients may provide a scaffold for future research. Using routine electronic health records and standardised biobanking, big data analysis on a larger number of patients and investigations are possible. In this article, we describe the UNRAVEL research data platform embedded in routine practice to facilitate research in genetic cardiomyopathies. Design Eligible participants with proven or suspected cardiac disease and their relatives are asked for permission to use their data and to draw blood for biobanking. Routinely collected clinical data are included in a research database by weekly extraction. A text-mining tool has been developed to enrich UNRAVEL with unstructured data in clinical notes. Preliminary results Thus far, 828 individuals with a median age of 57 years have been included, 58% of whom are male. All data are captured in a temporal sequence amounting to a total of 18,565 electrocardiograms, 3619 echocardiograms, data from over 20,000 radiological examinations and 650,000 individual laboratory measurements. Conclusion Integration of routine electronic health care in a research data platform allows efficient data collection, including all investigations in chronological sequence. Trials embedded in the electronic health record are now possible, providing cost-effective ways to answer clinical questions. We explicitly welcome national and international collaboration and have provided our protocols and other materials on www.unravelrdp.nl .