Search

Background and Aims: Risk stratification of sudden cardiac death after myocardial infarction and prevention by defibrillator rely on left ventricular ejection fraction (LVEF). Improved risk stratification across the whole LVEF range is required for decision-making on defibrillator implantation., Methods: The analysis pooled 20 data sets with 140 204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging. Separate analyses were performed in patients (i) carrying a primary prevention cardioverter-defibrillator with LVEF ≤ 35% [implantable cardioverter-defibrillator (ICD) patients], (ii) without cardioverter-defibrillator with LVEF ≤ 35% (non-ICD patients ≤ 35%), and (iii) without cardioverter-defibrillator with LVEF > 35% (non-ICD patients >35%). Primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy. Using a competing risk framework and systematic internal-external cross-validation, a model using LVEF only, a multivariable flexible parametric survival model, and a multivariable random forest survival model were developed and externally validated. Predictive performance was assessed by random effect meta-analysis., Results: There were 1326 primary outcomes in 7543 ICD patients, 1193 in 25 058 non-ICD patients ≤35%, and 1567 in 107 603 non-ICD patients >35% during mean follow-up of 30.0, 46.5, and 57.6 months, respectively. In these three subgroups, LVEF poorly predicted sudden cardiac death (c-statistics between 0.50 and 0.56). Considering additional parameters did not improve calibration and discrimination, and model generalizability was poor., Conclusions: More accurate risk stratification for sudden cardiac death and identification of low-risk individuals with severely reduced LVEF or of high-risk individuals with preserved LVEF was not feasible, neither using LVEF nor using other predictors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Aim: Blood pressure (BP) responses to exercise are frequently measured, with the concern that greater increases are a marker of disease. We sought to characterize the normal exercise BP response in healthy adults and its relationships with age, sex, and fitness., Methods: 589 participants (median age 46 [IQR 24-56] years, 81% male) underwent cardiopulmonary exercise testing with repeated, automated BP measures. An exaggerated maximal systolic BP (SBPmax) was defined from current guidelines as ≥210 mmHg in males and ≥190 mmHg in females. Individual linear regression analyses defined the relationship between BP and workload (SBP/W-slope and DBP/W-slope). Participants with or without an exaggerated SBPmax and above or below median SBP/W-slope were compared., Results: An exaggerated SBPmax was found in 51% of males and 64% of females and was more prevalent in endurance-trained athletes (males 58%, females 72%, p<0.001). The mean SBP/W-slope was lower in males (0.24±0.10 mmHg/W) than females (0.27±0.12 mmHg/W), p=0.031. In both sexes, peak oxygen uptake (VO2peak) was inversely correlated with SBP/W-slope (p<0.01). Those with an exaggerated SBPmax and below-median SBP/W-slope were 10 years younger and had a 20% higher VO2peak, on average (p<0.001). A non-exaggerated SBPmax and above-median SBP/W-slope was observed in older individuals with the lowest VO2peak., Conclusion: In a large cohort of healthy individuals, an exaggerated SBPmax was common and associated with higher fitness. In contrast, higher SBP indexed to workload was associated with older age, lower fitness, and female sex. Thus, sex, age and fitness should be considered when evaluating BP response to exercise., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: New methods to identify patients who benefit from a primary prophylactic implantable cardioverter-defibrillator (ICD) are needed. T-wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention., Methods and Results: In the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter-Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24-hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all-cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points <47 μV and <60 μV. The final cohort included 1734 valid T-wave alternans samples, 1211 patients with ICD, and 523 control patients with conservative treatment, with a mean follow-up time of 2.3 years. TWA ≥60 μV was a predicter for a higher all-cause death in patients with an ICD on the basis of a univariate Cox regression model (hazard ratio, 1.484 [95% CI, 1.024-2.151]; P =0.0374; concordance statistic, 0.51). In multivariable models, TWA was not prognostic of death or appropriate shocks in patients with an ICD. In addition, TWA was not prognostic of death in control patients. In a propensity score-adjusted Cox regression model, TWA was not a predictor of ICD benefit., Conclusions: T-wave alternans is poorly prognostic in patients with a primary prophylactic ICD. Although it may be prognostic of life-threatening arrhythmias and sudden cardiac death in several patient populations, it does not seem to be useful in assessing benefit from ICD therapy in primary prevention among patients with an ejection fraction of ≤35%.

Background: Mitral valve prolapse (MVP) and mitral annular disjunction (MAD) are common valvular abnormalities that have been associated with ventricular arrhythmias (VA). Cardiac magnetic resonance imaging (CMR) has a key role in risk stratification of VA, including assessment of late gadolinium enhancement (LGE). Methods: Single-center retrospective analysis of patients with MVP or MAD who had >1 CMR and >1 24 h Holter registration available. Data are presented in detail, including evolution of VA and presence of LGE over time. Results: A total of twelve patients had repeated CMR and Holter registrations available, of which in four (33%) patients, it was conducted before and after minimal invasive mitral valve repair (MVR). After a median of 4.7 years, four out of eight (50%) patients without surgical intervention had new areas of LGE. New LGE was observed in the papillary muscles and the mid to basal inferolateral wall. In four patients, presenting with syncope or high-risk non-sustained ventricular tachycardia (VT), programmed ventricular stimulation was performed and in two (50%), sustained monomorphic VT was easily inducible. In two patients who underwent MVR, new LGE was observed in the basal inferolateral wall of which one presented with an increased burden of VA. Conclusions: In patients with MVP and MAD, repeat CMR may show new LGE in a small subset of patients, even shortly after MVR. A subgroup of patients who presented with an increase in VA burden showed new LGE upon repeat CMR. VA in patients with MVP and MAD are part of a heterogeneous spectrum that requires further investigation to establish risk stratification strategies.

Long considered to fluctuate between pro- and anti-inflammatory states, it has now become evident that microglia occupy a variegated phenotypic landscape with relevance to aging and neurodegeneration. However, whether specific microglial subsets converge in or contribute to both processes that eventually affect brain function is less clear. To investigate this, we analyzed microglial heterogeneity in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (Senescence-Accelerated Mouse-Prone 8, SAMP8) using cellular indexing of transcriptomes and epitopes by sequencing. We found that widespread tau pathology in K18-seeded P301L mice caused a significant change in the number and morphology of microglia, but only a mild overrepresentation of disease-associated microglia. At the cell population-level, we observed a marked upregulation of the calprotectin-encoding genes S100a8 and S100a9. In 9-month-old SAMP8 mice, we identified a unique microglial subpopulation that showed partial similarity with the disease-associated microglia phenotype and was additionally characterized by a high expression of the same calprotectin gene set. Immunostaining for S100A8 revealed that this population was enriched in the hippocampus, correlating with the cognitive impairment observed in this model. However, incomplete colocalization between their residence and markers of neuronal loss suggests regional specificity. Importantly, S100A8-positive microglia were also retrieved in brain biopsies of human AD and tauopathy patients as well as in a biopsy of an aged individual without reported pathology. Thus, the emergence of S100A8-positive microglia portrays a conspicuous commonality between accelerated aging and tauopathy progression, which may have relevance for ensuing brain dysfunction., (© 2024 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes., Methods: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years., Results: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P =0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P <0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P =0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile ( P =0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%., Conclusions: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate., Registration: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268., Competing Interests: Disclosures None.

Purpose: Several high-income countries install Cash-for-Care Schemes (CCSs) by granting budgets to care users. However, little quantitative evidence exist on empowerment and client-centered care levels, due to a lack of validated scales. This research aimed to validate the Psychological Empowerment Scale (PE scale) and Client-Centered Care Questionnaire (CCCQ) in budget holders with disabilities., Methods: A survey was developed based on a literature review and experts and budget holders input. Principal Axis Factoring with direct oblimin rotation, Cronbach's Alpha, and hypotheses testing with socio-demographic and budget characteristics as independent variables, and PE scale and CCCQ as dependent, were undertaken to assess both scales' internal consistency and validity., Results: A convenience sample of 224 Flemish (proxy) budget holders completed the survey. Our analysis showed a two-factor solution for both scales; for the PE scale consisting of "meaning" and "competence," and "self-determination" and "impact," for CCCQ consisting of items 1-7 (conduct by caregiver) and items 8-15 (autonomy). Cronbach's Alpha of both scales was 0.94. The majority of our hypotheses were confirmed., Conclusions: The findings show that both scales are valid and internally consistent, meaning that they can be further tested in a respondent sample of people with disabilities and in other care contexts.

Background: Telemonitoring patients with cardiac implantable electronic devices (CIEDs) can improve their care management. However, the results of cost-effectiveness studies are heterogeneous. Therefore, it is still a matter of debate whether telemonitoring is worth the investment., Objective: This systematic review aims to investigate the cost-effectiveness of telemonitoring patients with CIEDs, focusing on its key drivers, and the impact of the varying perspectives., Methods: A systematic review was performed in PubMed, Web of Science, Embase, and EconLit. The search was completed on July 7, 2022. Studies were included if they fulfilled the following criteria: patients had a CIED, comparison with standard care, and inclusion of health economic evaluations (eg, cost-effectiveness analyses and cost-utility analyses). Only complete and peer-reviewed studies were included, and no year limits were applied. The exclusion criteria included studies with partial economic evaluations, systematic reviews or reports, and studies without standard care as a control group. Besides general study characteristics, the following outcome measures were extracted: impact on total cost or income, cost or income drivers, cost or income drivers per patient, cost or income drivers as a percentage of the total cost impact, incremental cost-effectiveness ratios, or cost-utility ratios. Quality was assessed using the Consensus Health Economic Criteria checklist., Results: Overall, 15 cost-effectiveness analyses were included. All studies were performed in Western countries, mainly Europe, and had primarily a male participant population. Of the 15 studies, 3 (20%) calculated the incremental cost-effectiveness ratio, 1 (7%) the cost-utility ratio, and 11 (73%) the health and cost impact of telemonitoring. In total, 73% (11/15) of the studies indicated that telemonitoring of patients with implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy ICDs was cost-effective and cost-saving, both from a health care and patient perspective. Cost-effectiveness results for telemonitoring of patients with pacemakers were inconclusive. The key drivers for cost reduction from a health care perspective were hospitalizations and scheduled in-office visits. Hospitalization costs were reduced by up to US $912 per patient per year. Scheduled in-office visits included up to 61% of the total cost reduction. Key drivers for cost reduction from a patient perspective were loss of income, cost for scheduled in-office visits and transport. Finally, of the 15 studies, 8 (52%) reported improved quality of life, with statistically significance in only 1 (13%) study (P=.03)., Conclusions: From a health care and patient perspective, telemonitoring of patients with an ICD or a cardiac resynchronization therapy ICD is a cost-effective and cost-saving alternative to standard care. Inconclusive results were found for patients with pacemakers. However, telemonitoring can lead to a decrease in providers' income, mainly due to a lack of reimbursement. Introducing appropriate reimbursement could make telemonitoring sustainable for providers while still being cost-effective from a health care payer perspective., Trial Registration: PROSPERO CRD42022322334; https://tinyurl.com/puunapdr., (©Sarah Raes, Andrea Prezzi, Rik Willems, Hein Heidbuchel, Lieven Annemans. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 19.04.2024.)

Takotsubo syndrome (TTS) is a transient left ventricle dysfunction usually caused by a stressful trigger (emotional or physical). We report the case of a 77 year-old female patient who presented with TTS caused by a pheochromocytoma, a catecholamine-producing neuroendocrine tumour. Diagnosis was facilitated by acute kidney injury prompting renal ultrasound, recurrence of TTS and symptoms of episodic palpitations, profuse sweating and labile blood pressure. Furthermore, during her hospitalisation the patient also developed an Ogilvie syndrome, an acute colonic pseudo-obstruction, due to the catecholamine-excess. Treatment consisted of betablocker and angiotensin-converting enzyme inhibitor for TTS, neostigmine for Ogilvie syndrome, in combination with alpha-blocker and surgical removal of the tumour after recuperation of left ventricular function and colonic pseudo-obstruction. To our knowledge, this is the first case report of the pathophysiological triad of pheochromocytoma leading to Takotsubo and Ogilvie syndrome in a single patient.

Objectives: This study primarily aimed to develop a validated Dutch translation of the 28 items of the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) II. A secondary aim was to provide a worked example of a scientifically valid translation process., Methods: A four-step process was applied: (1) forward translation, (2) backward translation, (3) quantitative validation (two back-translated English versions vs. original English version), and (4) qualitative validation (one Dutch version vs. original English version), resulting in the final Dutch CHEERS II checklist., Results: During quantitative validation, the average scores indicated high language comparability (1.88 (SD 0.70); 1.70 (SD 0.73)) and interpretation similarity (1.77 (SD 0.81); 1.54 (SD 0.74)). Four items required formal revision. In the qualitative validation step, feedback primarily focused on specific terms 'outcomes,' 'benefits and harms,' '(year of) conversion,' 'any,' and 'characterizing.', Conclusion: Despite English being the common language of science, translating research instruments remains relevant to enhance clarity, accessibility, and inclusivity. The Dutch translation can be used by students, regulators, researchers, or others to report and evaluate reporting of economic evaluations. Our detailed description of the applied methodology can facilitate future translations of research instruments.

Aims: Cardiotoxicity is a serious side effect of anthracycline treatment, most commonly manifesting as a reduction in left ventricular ejection fraction (EF). Early recognition and treatment have been advocated, but robust, convenient, and cost-effective alternatives to cardiac imaging are missing. Recent developments in artificial intelligence (AI) techniques applied to electrocardiograms (ECGs) may fill this gap, but no study so far has demonstrated its merit for the detection of an abnormal EF after anthracycline therapy., Methods and Results: Single centre consecutive cohort study of all breast cancer patients with ECG and transthoracic echocardiography (TTE) evaluation before and after (neo)adjuvant anthracycline chemotherapy. Patients with HER2-directed therapy, metastatic disease, second primary malignancy, or pre-existing cardiovascular disease were excluded from the analyses as were patients with EF decline for reasons other than anthracycline-induced cardiotoxicity. Primary readout was the diagnostic performance of AI-ECG by area under the curve (AUC) for EFs < 50%. Of 989 consecutive female breast cancer patients, 22 developed a decline in EF attributed to anthracycline therapy over a follow-up time of 9.8 ± 4.2 years. After exclusion of patients who did not have ECGs within 90 days of a TTE, 20 cases and 683 controls remained. The AI-ECG model detected an EF < 50% and ≤ 35% after anthracycline therapy with an AUC of 0.93 and 0.94, respectively., Conclusion: These data support the use of AI-ECG for cardiotoxicity screening after anthracycline-based chemotherapy. This technology could serve as a gatekeeper to more costly cardiac imaging and could enable patients to monitor themselves over long periods of time., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cardiac resynchronization therapy (CRT) has evolved into an established therapy for patients with chronic heart failure and a wide QRS complex. Data on long-term outcomes over time are scarce and the criteria for implantation remain a subject of investigation. Methods: An international, multicenter, retrospective registry includes 2275 patients who received CRT between 30 November 2000 and 31 December 2019, with a mean follow-up of 3.6 ± 2.7 years. Four time periods were defined, based on landmark trials and guidelines. The combined endpoint was a composite of all-cause mortality, heart transplantation, or left ventricular assist device implantation. Results: The composite endpoint occurred in 656 patients (29.2%). The mean annual implantation rate tripled from 31.5 ± 17.4/year in the first period to 107.4 ± 62.4/year in the last period. In the adjusted Cox regression analysis, the hazard ratio for the composite endpoint was not statistically different between time periods. When compared to sinus rhythm with left bundle branch block (LBBB), a non-LBBB conduction pattern (sinus rhythm: HR 1.51, 95% CI 1.12-2.03; atrial fibrillation: HR 2.08, 95% CI 1.30-3.33) and a QRS duration below 130 ms (HR 1.64, 95% CI 1.29-2.09) were associated with a higher hazard ratio. Conclusions: Despite innovations, an adjusted regression analysis revealed stable overall survival over time, which can at least partially be explained by a shift in patient characteristics.

We present a case of a 79-year-old man on apixaban for atrial fibrillation who suffered multiple ischaemic strokes and was found to have mobile structures attached to his pacemaker lead on transesophageal echocardiography. Based on the Modified Duke Criteria, there was no evidence of infectious endocarditis. Since there were no signs of a patent foramen ovale or arteriovenous malformations in the lungs, the mobile structures probably were not the cause of the ischaemic strokes. After the visualisation of the mobile structures, apixaban was switched to dabigatran with a clear decrease in the size of the structures. Blood cultures remained negative and there was no fever or increase in inflammatory parameters. It was therefore suspected that the structures were thrombus material rather than vegetations of infectious endocarditis.There is uncertainty surrounding the clinical relevance and indication for treatment of incidentally found mobile structures on pacemaker leads. Multiple studies with different imaging modalities show a significant difference in the prevalence of thrombi. More studies with longer follow-ups are needed to investigate the prevalence and need for treatment of these incidentally found structures on pacemaker leads.

Aim: Cardiac resynchronization therapy (CRT) is a cornerstone in the management of chronic heart failure in patients with a broad or paced QRS. However, data on long-term outcome after upgrade to CRT are scarce., Methods and Results: This international, multicentre retrospective registry included 2275 patients who underwent a de novo or upgrade CRT implantation with a mean follow-up of 3.6 ± 2.7 years. The primary composite endpoint included all-cause mortality, heart transplantation, or ventricular assist device implantation. The secondary endpoint was first heart failure admission. Multivariable Cox regression and propensity score matching (PSM) analyses were performed. Patients who underwent CRT upgrade (n = 605, 26.6%) were less likely female (19.7% vs. 28.8%, p < 0.001), more often had ischeemic cardiomyopathy (49.8% vs. 40.2%, p < 0.001), and had worse renal function (median estimated glomerular filtration rate 50.3 ml/min/1.73 m 2 [35.8-69.5] vs. 59.9 ml/min/1.73 m 2 [43.0-76.5], p < 0.001). The incidence rate of the composite endpoint was 10.8%/year after CRT upgrade versus 7.1%/year for de novo implantations (p < 0.001). PSM for the primary endpoint resulted in 488 pairs. After propensity score matching, upgrade to CRT was associated with a higher chance to reach the composite endpoint (multivariable hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.08-1.70), for both upgrade from pacemaker (multivariable HR 1.33, 95% CI 1.03-1.70) and implantable cardioverter-defibrillator (ICD) (multivariable HR 1.40, 95% CI 1.01-1.95). PSM for the secondary endpoint resulted in 277 pairs. After PSM, upgrade to CRT was associated with a higher chance for heart failure admission (HR 1.74, 95% CI 1.26-2.41)., Conclusion: In this retrospective analysis, the outcome of patients who underwent upgrades to CRT differed significantly from patients who underwent de novo CRT implantation, particularly for upgrades from ICD. Importantly, this difference in outcome does not imply a causal relation between therapy and outcome but rather a difference between two different patient populations., (© 2023 European Society of Cardiology.)

Background: Patients with cirrhosis have a normal to increased thrombin generation (TG) capacity in platelet-poor plasma (PPP). By reflecting the contribution of all circulating blood cells, whole blood (WB) TG may allow a more physiological assessment of coagulation., Objectives: We compared WB-TG vs PPP-TG in patients with cirrhosis., Methods: Assessment of coagulation included routine tests, factor VIII, natural anticoagulants, PPP-TG, and WB-TG. TG assays were performed with and without thrombomodulin. Twenty-five healthy subjects were included as controls., Results: We included 108 patients (Child-Pugh A/B/C, 44/24/40). Compared with controls, patients had significantly lower platelet count, longer international normalized ratio, higher FVIII, and lower levels of protein C/S and antithrombin. Regarding thrombomodulin-modified TG assays, in compensated cirrhosis, both PPP-TG and WB-TG indicated an increased TG capacity, as reflected by an endogenous thrombin potential (ETP) significantly higher than controls. In contrast, in decompensated cirrhosis, PPP-TG indicated a hypercoagulable state with increased ETP, higher peak height, and shorter time-to-peak than controls, whereas WB-TG revealed a progressive impairment of TG kinetics and total capacity, ultimately resulting in a profound hypocoagulable state in patients with Child-Pugh C cirrhosis (ie, significant prolongation of lag time and time-to-peak with reduction of both ETP and peak height). In decompensated patients, bacterial infections and severity of anemia were associated with a further reduction of both ETP and peak height., Conclusion: Compensated cirrhosis is associated with an increased TG capacity. In decompensated cirrhosis, contrary to PPP-TG, which indicates hypercoagulability, WB-TG shows a significant hypocoagulable state. The clinical value of these findings deserves further investigation., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objective: To test the hypothesis that in recipients of primary prophylactic implantable cardioverter-defibrillators (ICDs), the non-planarity of ECG vector loops predicts (a) deaths despite ICD protection and (b) appropriate ICD shocks., Methods: Digital pre-implant ECGs were collected in 1948 ICD recipients: 21.4% females, median age 65 years, 61.5% ischaemic heart disease (IHD). QRS and T wave three-dimensional loops were constructed using singular value decomposition that allowed to measure the vector loop planarity. The non-planarity, that is, the twist of the three-dimensional loops out of a single plane, was related to all-cause mortality (n=294; 15.3% females; 68.7% IHD) and appropriate ICD shocks (n=162; 10.5% females; 87.7% IHD) during 5-year follow-up after device implantation. Using multivariable Cox regression, the predictive power of QRS and T wave non-planarity was compared with that of age, heart rate, left ventricular ejection fraction, QRS duration, spatial QRS-T angle, QTc interval and T-peak to T-end interval., Results: QRS non-planarity was significantly (p<0.001) associated with follow-up deaths despite ICD protection with HR of 1.339 (95% CI 1.165 to 1.540) but was only univariably associated with appropriate ICD shocks. Non-planarity of the T wave loop was the only ECG-derived index significantly (p<0.001) associated with appropriate ICD shocks with multivariable Cox regression HR of 1.364 (1.180 to 1.576) but was not associated with follow-up mortality., Conclusions: The analysed data suggest that QRS and T wave non-planarity might offer distinction between patients who are at greater risk of death despite ICD protection and those who are likely to use the defibrillator protection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Antimicrobial resistance genes (ARG) are commonly found on acquired mobile genetic elements (MGEs) such as plasmids or transposons. Understanding the spread of resistance genes associated with mobile elements (mARGs) across different hosts and environments requires linking ARGs to the existing mobile reservoir within bacterial communities. However, reconstructing mARGs in metagenomic data from diverse ecosystems poses computational challenges, including genome fragment reconstruction (assembly), high-throughput annotation of MGEs, and identification of their association with ARGs. Recently, several bioinformatics tools have been developed to identify assembled fragments of plasmids, phages, and insertion sequence (IS) elements in metagenomic data. These methods can help in understanding the dissemination of mARGs. To streamline the process of identifying mARGs in multiple samples, we combined these tools in an automated high-throughput open-source pipeline, MetaMobilePicker, that identifies ARGs associated with plasmids, IS elements and phages, starting from short metagenomic sequencing reads. This pipeline was used to identify these three elements on a simplified simulated metagenome dataset, comprising whole genome sequences from seven clinically relevant bacterial species containing 55 ARGs, nine plasmids and five phages. The results demonstrated moderate precision for the identification of plasmids (0.57) and phages (0.71), and moderate sensitivity of identification of IS elements (0.58) and ARGs (0.70). In this study, we aim to assess the main causes of this moderate performance of the MGE prediction tools in a comprehensive manner. We conducted a systematic benchmark, considering metagenomic read coverage, contig length cutoffs and investigating the performance of the classification algorithms. Our analysis revealed that the metagenomic assembly process is the primary bottleneck when linking ARGs to identified MGEs in short-read metagenomics sequencing experiments rather than ARGs and MGEs identification by the different tools., Competing Interests: The authors declare there are no competing interests., (©2024 Kerkvliet et al.)

Background: Over half of the European population aged minimum 65 years presents with at least two chronic diseases. Attention towards these diseases exhibits disparities, with limited primary care physician (PCP) attention for osteoporosis. This was confirmed in a previous integrated osteoporosis care (IOC) project in which notable difficulties to enlist PCPs arose. Consequently, this study was initiated in Flemish PCPs for in-depth analysis of underlying mechanisms hampering PCPs to fully commit to osteoporosis care., Methods: A qualitative Electronic Medical Record (EMR)-facilitated clinical reasoning study was conducted. A semi-structured interview guide was employed to guide PCPs from reflections on their own patients to broader views regarding osteoporosis care. An inductive thematic analysis was performed using NVivo 12., Results: Thirteen PCPs were interviewed. They stated that osteoporosis patients often had complex (medical) profiles. PCPs emphasised the ongoing necessity for prioritisation within this context. This leads to a competition for PCP attention during consultations at three levels: i. between acute versus preventive care; ii. between primary fracture prevention and other preventive services and iii. between secondary fracture prevention and other preventive services; spanning eight areas of competition: disease significance, perceived impact, PCP awareness, the patient agenda, PCP competence, PCP support, perceived patient burden, and efficiency of care provision. Applicability of these areas of competition differed between levels., Conclusion: The intricate context in which PCPs operate, creates a competition for PCP attention leading to a lack of attention for fracture prevention. To preserve efforts in fracture prevention, areas of competition should be systematically addressed., Trial Registration: Approval for the study has been provided by the Ghent University Hospital Ethics Committee (BC-09797)., (© 2023. The Author(s).)

Background: Leadless pacemakers (PMs) were recently introduced to overcome lead-related complications. They showed high safety and efficacy profiles. Prospective studies assessing long-term safety on cardiac structures are still missing., Objective: The purpose of this study was to compare the mechanical impact of Micra with conventional PM on heart function., Methods: We conducted a non-inferiority trial in patients with an indication for single chamber ventricular pacing. Patients were 1:1 randomized to undergo implantation of either Micra or conventional monochamber ventricular pacemaker (PM). Patients underwent echocardiography at baseline, 6 and 12 months after implantation. Analysis included left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and valve function. N-terminal-pro hormone B-type natriuretic peptide (NT-pro-BNP) levels were measured at baseline and 12 months., Results: Fifty-one patients (27 in Micra group and 24 in conventional group) were included. Baseline characteristics were similar for both groups. At 12 months, (1) the left ventricular function as assessed by LVEF and GLS worsened similarly in both groups (∆LVEF -10 ± 7.3% and ∆GLS +5.7 ± 6.4 in Micra group vs. -13.4 ± 9.9% and +5.2 ± 3.2 in conventional group) (p = 0.218 and 0.778, respectively), (2) the severity of tricuspid valve regurgitation was significantly lower with Micra than conventional pacing (p = 0.009) and (3) median NT-pro-BNP was lower in Micra group (970 pg/dL in Micra group versus 1394 pg/dL in conventional group, p = 0.041)., Conclusion: Micra is non inferior to conventional PMs concerning the evolution of left ventricular function at 12-month follow-up. Our data suggest that Micra has a comparable mechanical impact on the ventricular systolic function but resulted in less valvular dysfunction., (© 2023 Wiley Periodicals LLC.)

Background: Recently, an expert consensus statement proposed indications where implantation of a primary prevention implantable cardioverter-defibrillator (ICD) may be reasonable in patients with mitral valve prolapse (MVP). The objective was to evaluate the proposed risk stratification by the expert consensus statement., Methods: Consecutive patients with MVP without alternative arrhythmic substrates with cardiac magnetic resonance imaging (CMR) were included in a single-center retrospective registry. Arrhythmic MVP (AMVP) was defined as a total premature ventricular complex burden ≥5%, non-sustained ventricular tachycardia (VT), VT, or ventricular fibrillation. The end point was a composite of SCD, VT, inducible VT, and appropriate ICD shocks., Results: In total, 169 patients (52.1% male, median age 51.4 years) were included and 99 (58.6%) were classified as AMVP. Multivariate logistic regression identified the presence of late gadolinium enhancement (OR 2.82, 95%CI 1.45-5.50) and mitral annular disjunction (OR 1.98, 95%CI 1.02-3.86) as only predictors of AMVP. According to the EHRA risk stratification, 5 patients with AMVP (5.1%) had a secondary prevention ICD indication, while in 69 patients (69.7%) the implantation of an ICD may be reasonable. During a median follow-up of 8.0 years (IQR 5.0-15.6), the incidence rate for the composite arrhythmic end point was 0.3%/year (95%CI 0.1-0.8)., Conclusion: More than half of MVP patients referred for CMR met the AMVP diagnostic criteria. Despite low long-term event rates, in 70% of patients with AMVP the implantation of an ICD may be reasonable. Risk stratification of SCD in MVP remains an important knowledge gap and requires urgent investigation., Competing Interests: Disclosures The authors have no disclosures related to this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Whereas truncating variants of the giant protein Titin (TTNtv) are the main cause of familial dilated cardiomyopathy (DCM), recently Filamin C truncating variants (FLNCtv) were identified as a cause of arrhythmogenic cardiomyopathy (ACM). Our aim was to characterize and compare clinical and MRI features of TTNtv and FLNCtv in the Belgian population. In index patients referred for genetic testing of ACM/DCM, FLNCtv and TTNtv were found in 17 (3.6%) and 33 (12.3%) subjects, respectively. Further family cascade screening yielded 24 and 19 additional truncating variant carriers in FLNC and TTN, respectively. The main phenotype was ACM in FLNCtv carriers whereas TTNtv carriers showed either an ACM or DCM phenotype. Non-sustained Ventricular Tachycardia was frequent in both populations. MRI data, available in 28/40 FLNCtv and 32/52 TTNtv patients, showed lower Left Ventricular (LV) ejection fraction and lower LV strain in TTNtv patients (p < 0.01). Conversely, both the frequency (68% vs 22%) and extent of non-ischemic myocardial late gadolinium enhancement (LGE) was significantly higher in FLNCtv patients (p < 0.01). Hereby, ring-like LGE was found in 16/19 (84%) FLNCtv versus 1/7 (14%) of TTNtv patients (p < 0.01). In conclusion, a large number of FLNCtv and TTNtv patients present with an ACM phenotype but can be separated by cardiac MRI. Whereas FLNCtv patients often have extensive myocardial fibrosis, typically following a ring-like pattern, LV dysfunction without or limited replacement fibrosis is the common TTNtv phenotype., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Purpose: Although cardiac troponin I (cTnI) increase following strenuous exercise has been observed, the development of exercise-induced myocardial edema remains unclear. Cardiac magnetic resonance (CMR) native T1/T2 mapping is sensitive to the pathological increase of myocardial water content. Therefore, we evaluated exercise-induced acute myocardial changes in recreational cyclists by incorporating biomarkers, echocardiography and CMR., Methods: Nineteen male recreational participants (age: 48 ± 5 years) cycled the 'L'étape du tour de France" (EDT) 2021' (175 km, 3600 altimeters). One week before the race, a maximal graded cycling test was conducted to determine individual heart rate (HR) training zones. One day before and 3-6 h post-exercise 3 T CMR and echocardiography were performed to assess myocardial native T1/T2 relaxation times and cardiac function, and blood samples were collected. All participants were asked to cycle 2 h around their anaerobic gas exchange threshold (HR zone 4)., Results: Eighteen participants completed the EDT stage in 537 ± 58 min, including 154 ± 61 min of cycling time in HR zone 4. Post-race right ventricular (RV) dysfunction with reduced strain and increased volumes (p < 0.05) and borderline significant left ventricular global longitudinal strain reduction (p = 0.05) were observed. Post-exercise cTnI (0.75 ± 5.1 ng/l to 69.9 ± 41.6 ng/l; p < 0.001) and T1 relaxation times (1133 ± 48 ms to 1182 ± 46 ms, p < 0.001) increased significantly with no significant change in T2 (p = 0.474). cTnI release correlated with increase in T1 relaxation time (p = 0.002; r = 0.703), post-race RV dysfunction (p < 0.05; r = 0.562) and longer cycling in HR zone 4 (p < 0.05; r = 0.607)., Conclusion: Strenuous exercise causes early post-race cTnI increase, increased T1 relaxation time and RV dysfunction in recreational cyclists, which showed interdependent correlation. The long-term clinical significance of these changes needs further investigation., Trial Registration Numbers and Date: NCT04940650 06/18/2021. NCT05138003 06/18/2021., (© 2023. The Author(s).)

Background and aim: The presence of mechanical dyssynchrony on echocardiography is associated with reverse remodelling and decreased mortality after cardiac resynchronization therapy (CRT). Contrarily, myocardial scar reduces the effect of CRT. This study investigated how well a combined assessment of different markers of mechanical dyssynchrony and scarring identifies CRT responders. Methods: In a prospective multicentre study of 170 CRT recipients, septal flash (SF), apical rocking (ApRock), systolic stretch index (SSI), and lateral-to-septal (LW-S) work differences were assessed using echocardiography. Myocardial scarring was quantified using cardiac magnetic resonance imaging (CMR) or excluded based on a coronary angiogram and clinical history. The primary endpoint was a CRT response, defined as a ≥15% reduction in LV end-systolic volume 12 months after implantation. The secondary endpoint was time-to-death. Results: The combined assessment of mechanical dyssynchrony and septal scarring showed AUCs ranging between 0.81 (95%CI: 0.74-0.88) and 0.86 (95%CI: 0.79-0.91) for predicting a CRT response, without significant differences between the markers, but significantly higher than mechanical dyssynchrony alone. QRS morphology, QRS duration, and LV ejection fraction were not superior in their prediction. Predictive power was similar in the subgroups of patients with ischemic cardiomyopathy. The combined assessments significantly predicted all-cause mortality at 44 ± 13 months after CRT with a hazard ratio ranging from 0.28 (95%CI: 0.12-0.67) to 0.20 (95%CI: 0.08-0.49). Conclusions: The combined assessment of mechanical dyssynchrony and septal scarring identified CRT responders with high predictive power. Both visual and quantitative markers were highly feasible and demonstrated similar results. This work demonstrates the value of imaging LV mechanics and scarring in CRT candidates, which can already be achieved in a clinical routine.

Digital health interventions have been shown to be clinically-effective for type 2 diabetes mellitus (T2DM) and hypertension prevention and treatment. This study synthesizes and compares the cost-effectiveness of text-messaging, smartphone application, and websites by searching CINAHL, Cochrane Central, Embase, Medline and PsycInfo for full economic or cost-minimisation studies of digital health interventions in adults with or at risk of T2DM and/or hypertension. Costs and health effects are synthesised narratively. Study quality appraisal using the Consensus on Health Economic Criteria (CHEC) list results in recommendations for future health economic evaluations of digital health interventions. Of 3056 records identified, 14 studies are included (7 studies applied text-messaging, 4 employed smartphone applications, and 5 used websites). Ten studies are cost-utility analyses: incremental cost-utility ratios (ICUR) vary from dominant to €75,233/quality-adjusted life year (QALY), with a median of €3840/QALY (interquartile range €16,179). One study finds no QALY difference. None of the three digital health intervention modes is associated with substantially better cost-effectiveness. Interventions are consistently cost-effective in populations with (pre)T2DM but not in populations with hypertension. Mean quality score is 63.0% (standard deviation 13.7%). Substandard application of time horizon, sensitivity analysis, and subgroup analysis next to transparency concerns (regarding competing alternatives, perspective, and costing) downgrades quality of evidence. In conclusion, smartphone application, text-messaging, and website-based interventions are cost-effective without substantial differences between the different delivery modes. Future health economic studies should increase transparency, conduct sufficient sensitivity analyses, and appraise the ICUR more critically in light of a reasoned willingness-to-pay threshold.Registration: PROSPERO (CRD42021247845)., (© 2023. Springer Nature Limited.)

Background: A proportion of patients with Lyme borreliosis (LB) report long-term persisting signs and symptoms, even after recommended antibiotic treatment, which is termed post-treatment Lyme disease syndrome (PTLDS). Consensus on guidance regarding diagnosis and treatment is currently lacking. Consequently, patients suffer and are left searching for answers, negatively impacting their quality of life and healthcare expenditure. Yet, health economic data on PTLDS remain scarce. The aim of this article is therefore to assess the cost-of-illness related to PTLDS, including the patient perspective., Methods: PTLDS patients (N = 187) with confirmed diagnosis of LB were recruited by a patient organization. Patients completed a self-reported questionnaire on LB-related healthcare utilization, absence from work and unemployment. Unit costs (reference year 2018) were obtained from national databases and published literature. Mean costs and uncertainty intervals were calculated via bootstrapping. Data were extrapolated to the Belgian population. Generalized linear models were used to determine associated covariates with total direct costs and out-of-pocket expenditures., Results: Mean annual direct costs amounted to €4618 (95% CI €4070-5152), of which 49.5% were out-of-pocket expenditures. Mean annual indirect costs amounted to €36 081 (€31 312-40 923). Direct and indirect costs at the population level were estimated at €19.4 and 151.5 million, respectively. A sickness or disability benefit as source of income was associated with higher direct and out-of-pocket costs., Conclusions: The economic burden associated with PTLDS on patients and society is substantial, with patients consuming large amounts of non-reimbursed healthcare resources. Guidance on adequate diagnosis and treatment of PTLDS is needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Public Health Association.)

Aim: To provide a detailed description of the workflow at our telecardiology centre and to analyse the workload of real-world remote monitoring with the aim to assess the feasibility to outsource this service., Methods: A retrospective analysis was conducted on the telecardiology service provided at the University Hospitals of Leuven by extracting patient demographic data, general time usage and detailed information about the type of remote contacts. 10,869 contacts in 948 patients have been included. A 2-week prospective study was conducted on the same service by documenting and monitoring every action performed by specialised nurses when analysing and solving remote monitoring transmissions. 337 contacts in 262 patients were collected during this period., Results: Both analyses indicated similar numbers of events and interventions. Unplanned transmissions were more challenging and required more interventions than planned transmissions. Relatively little time (retrospective median: 1.83 min; prospective median: 1.56 min, per event) was spent on incoming non-actionable 'normal' transmissions (retrospective: 46%; prospective: 40% of all events). Retrospectively 54% and prospectively 60% of transmissions showed abnormalities and were responsible for most of the time expended. Disease-related issues were the most frequent cause for these 'abnormal' alerts. Contacting patients and physicians were key interventions undertaken. Interaction initiated by patients mainly involved the installation process (42%) and bedside monitoring problems (32%)., Conclusion: External data centres could deal with 40% of the transmissions, but the decline in workload would be negligible for the in-hospital remote monitoring team, because very little time is spent dealing with the many 'non-event' transmissions whereas most of the time is spent solving clinical problems. Providing sufficient resources and optimising communication protocols is necessary to aid in managing the workload of the remote monitoring team., Implications for practiceContacting patients and physicians are key interventions for specialist nurses in remote monitoring centres.Detailed timing confirmed that most time was spent on relevant disease-related clinical problems.Despite dealing with ∼40% of transmissions, outsourcing to external data centres would decrease the workload only by 15-25%.Patient initiated contacts with questions concerning remote monitoring form a high burden and should be countered by scaling the service and creating communication protocols.

Background: Spatial heterogeneity in repolarization plays an important role in generating and sustaining cardiac arrhythmias. Reliable determination of repolarization times remains challenging., Objectives: The goal of this study was to improve processing of densely sampled noncontact unipolar electrograms to yield reliable high-resolution activation and repolarization maps., Methods: Endocardial noncontact unipolar electrograms were both simulated and recorded in pig left ventricle. Electrical activity on the endocardial surface was processed in terms of a pseudo-electric field. Activation and repolarization times were calculated by using an amplitude-weighted average on QRS and T waves (ie, the E-field method). This was compared vs the conventional Wyatt method on unipolar electrograms. Timing maps were validated against timing on endocardial action potentials in a simulation study. In vivo, activation and repolarization times determined by using this alternative E-field method were validated against simultaneously recorded endocardial monophasic action potentials (MAPs)., Results: Simulation showed that the E-field method provides viable measurements of local endocardial action potential activation and repolarization times. In vivo, correlation of E-field activation times with MAP activation times (r E  = 0.76; P < 0.001) was similar to those of Wyatt (r Wyatt  = 0.80, P < 0.001; P[h 1 :r E > r Wyatt ] = 0.82); for repolarization times, correlation improved significantly (r E  = 0.96, P < 0.001; r Wyatt  = 0.82, P < 0.001; P[h 1 :r E > r Wyatt ] < 0.00001). This resulted in improved correlations of activation-repolarization intervals to endocardial action potential duration on MAP (r E  = 0.96, P < 0.001; r Wyatt  = 0.86, P < 0.001; P[h 1 :r E > r Wyatt ] < 0.00001). Spatial beat-to-beat variation of repolarization could only be calculated by using the E-field methodology and correlated well with the MAP beat-to-beat variation of repolarization (r E  = 0.76; P = 0.001)., Conclusions: The E-field method substantially enhances information from endocardial noncontact electrogram data, allowing for dense maps of activation and repolarization times and derived parameters., Competing Interests: Funding Support and Author Disclosures The work was supported by grants from KU Leuven BOF, C14/18/079, to Drs Willems and Claus and from Fund for Scientific Research-Flanders (FWO) G097021N to Drs Claus and Sipido. Dr Willems is supported as Senior Clinical Investigator and Dr Amoni as PhD fellow by the Fund for Scientific Research-Flanders (FWO)., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background. The analysis of multi-lead electrocardiographic (ECG) signals requires integrating the information derived from each lead to reach clinically relevant conclusions. This analysis could benefit from data-driven methods compacting the information in those leads into lower-dimensional representations (i.e. 2 or 3 dimensions instead of 12). Objective. We propose Laplacian Eigenmaps (LE) to create a unified framework where ECGs from different subjects can be compared and their abnormalities are enhanced. Approach. We conceive a normal reference ECG space based on LE, calculated using signals of healthy subjects in sinus rhythm. Signals from new subjects can be mapped onto this reference space creating a loop per heartbeat that captures ECG abnormalities. A set of parameters, based on distance metrics and on the shape of loops, are proposed to quantify the differences between subjects. Main results. This methodology was applied to find structural and arrhythmogenic changes in the ECG. The LE framework consistently captured the characteristics of healthy ECGs, confirming that normal signals behaved similarly in the LE space. Significant differences between normal signals, and those from patients with ischemic heart disease or dilated cardiomyopathy were detected. In contrast, LE biomarkers did not identify differences between patients with cardiomyopathy and a history of ventricular arrhythmia and their matched controls. Significance. This LE unified framework offers a new representation of multi-lead signals, reducing dimensionality while enhancing imperceptible abnormalities and enabling the comparison of signals of different subjects., (Creative Commons Attribution license.)

Aims: Papillary muscle (PM) abnormalities are considered part of the phenotypic spectrum of hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the presence and frequency of PM displacement in different HCM phenotypes., Methods and Results: We retrospectively analysed cardiovascular magnetic resonance (CMR) findings in 156 patients (25% females, median age 57 years). Patients were divided into three groups: septal hypertrophy (Sep-HCM, n = 70, 45%), mixed hypertrophy (Mixed-HCM, n = 48, 31%), and apical hypertrophy (Ap-HCM, n = 38, 24%). Fifty-five healthy subjects were enrolled as controls. Apical PM displacement was observed in 13% of controls and 55% of patients, which was most common in the Ap-HCM group, followed by the Mixed-HCM and Sep-HCM groups (respectively: inferomedial PM 92 vs. 65 vs. 13%, P < 0.001; anterolateral PM 61 vs. 40 vs. 9%, P < 0.001). Significant differences in PM displacement were found when comparing healthy controls with patients with Ap- and Mixed-HCM subtypes but not when comparing them with patients with the Sep-HCM subtype. T-wave inversion in the inferior and lateral leads was more frequent in patients with Ap-HCM (100 and 65%, respectively) when compared with Mixed-HCM (89 and 29%, respectively) and Sep-HCM (57 and 17%, respectively; P < 0.001 for both). Eight patients with Ap-HCM had prior CMR examinations because of T-wave inversion [median interval 7 (3-8) years], and in the first CMR study, none showed apical hypertrophy [median apical wall thickness 8 (7-9) mm], while all of them presented with apical PM displacement., Conclusion: Apical PM displacement is part of the phenotypic Ap-HCM spectrum and may precede the development of hypertrophy. These observations suggest a potential pathogenetic, mechanical link between apical PM displacement and Ap-HCM., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: None to declare.

Recent studies have shown that patients with pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant chemo(radio)therapy followed by surgery have an improved outcome compared to patients treated with upfront surgery. Hence, patients with PDAC are more and more frequently treated with chemotherapy in the neoadjuvant setting. PDAC patients are at a high risk of developing venous thromboembolism (VTE), which is associated with decreased survival rates. As patients with PDAC were historically offered immediate surgical resection, data on VTE incidence and associated preoperative risk factors are scarce. Current guidelines recommend primary prophylactic anticoagulation in selected groups of patients with advanced PDAC. However, recommendations for patients with (borderline) resectable PDAC treated with chemotherapy in the neoadjuvant setting are lacking. Nevertheless, the prevention of complications is crucial to maintain the best possible condition for surgery. This narrative review summarizes current literature on VTE incidence, associated risk factors, risk assessment tools, and primary thromboprophylaxis in PDAC patients treated with neoadjuvant chemo(radio)therapy.

Aims: The impact of long-term endurance sport participation (on top of a healthy lifestyle) on coronary atherosclerosis and acute cardiac events remains controversial., Methods and Results: The Master@Heart study is a well-balanced prospective observational cohort study. Overall, 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after 30 years of age), and 176 healthy non-athletes, all male with a low cardiovascular risk profile, were included. Peak oxygen uptake quantified fitness. The primary endpoint was the prevalence of coronary plaques (calcified, mixed, and non-calcified) on computed tomography coronary angiography. Analyses were corrected for multiple cardiovascular risk factors. The median age was 55 (50-60) years in all groups. Lifelong and late-onset athletes had higher peak oxygen uptake than non-athletes [159 (143-177) vs. 155 (138-169) vs. 122 (108-138) % predicted]. Lifelong endurance sports was associated with having ≥1 coronary plaque [odds ratio (OR) 1.86, 95% confidence interval (CI) 1.17-2.94], ≥ 1 proximal plaque (OR 1.96, 95% CI 1.24-3.11), ≥ 1 calcified plaques (OR 1.58, 95% CI 1.01-2.49), ≥ 1 calcified proximal plaque (OR 2.07, 95% CI 1.28-3.35), ≥ 1 non-calcified plaque (OR 1.95, 95% CI 1.12-3.40), ≥ 1 non-calcified proximal plaque (OR 2.80, 95% CI 1.39-5.65), and ≥1 mixed plaque (OR 1.78, 95% CI 1.06-2.99) as compared to a healthy non-athletic lifestyle., Conclusion: Lifelong endurance sport participation is not associated with a more favourable coronary plaque composition compared to a healthy lifestyle. Lifelong endurance athletes had more coronary plaques, including more non-calcified plaques in proximal segments, than fit and healthy individuals with a similarly low cardiovascular risk profile. Longitudinal research is needed to reconcile these findings with the risk of cardiovascular events at the higher end of the endurance exercise spectrum., Competing Interests: Conflict of interest: All authors declare no conflict of interest for this contribution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Ventricular arrhythmia (VT/VF) can complicate acute myocardial ischemia (AMI). Regional instability of repolarization during AMI contributes to the substrate for VT/VF. Beat-to-beat variability of repolarization (BVR), a measure of repolarization lability increases during AMI. We hypothesized that its surge precedes VT/VF. We studied the spatial and temporal changes in BVR in relation to VT/VF during AMI. In 24 pigs, BVR was quantified on 12-lead electrocardiogram recorded at a sampling rate of 1 kHz. AMI was induced in 16 pigs by percutaneous coronary artery occlusion (MI), whereas 8 underwent sham operation (sham). Changes in BVR were assessed at 5 min after occlusion, 5 and 1 min pre-VF in animals that developed VF, and matched time points in pigs without VF. Serum troponin and ST deviation were measured. After 1 mo, magnetic resonance imaging and VT induction by programmed electrical stimulation were performed. During AMI, BVR increased significantly in inferior-lateral leads correlating with ST deviation and troponin increase. BVR was maximal 1 min pre-VF (3.78 ± 1.36 vs. 5 min pre-VF, 1.67 ± 1.56, P < 0.0001). After 1 mo, BVR was higher in MI than in sham and correlated with the infarct size (1.43 ± 0.50 vs. 0.57 ± 0.30, P = 0.009). VT was inducible in all MI animals and the ease of induction correlated with BVR. BVR increased during AMI and temporal BVR changes predicted imminent VT/VF, supporting a possible role in monitoring and early warning systems. BVR correlated to arrhythmia vulnerability suggesting utility in risk stratification post-AMI. NEW & NOTEWORTHY The key finding of this study is that BVR increases during AMI and surges before ventricular arrhythmia onset. This suggests that monitoring BVR may be useful for monitoring the risk of VF during and after AMI in the coronary care unit settings. Beyond this, monitoring BVR may have value in cardiac implantable devices or wearables.

Objectives: Globally, patients with osteoporosis have unmet needs in terms of care accessibility, patient-centredness and care comprehensiveness. The WHO developed the Integrated, People-Centred Health Services (IPCHS) framework to reorient and integrate healthcare systems using 5 interdependent strategies and 20 substrategies. Patients' perspectives with regard to these strategies are poorly understood. We sought to relate patient-experienced gaps in osteoporosis care to the IPCHS strategies and identify key strategies to guide osteoporosis care reforms., Design, Setting and Participants: Qualitative online study of the experiences of international patients with osteoporosis., Procedure: Two researchers conducted semi-structured interviews in English, Dutch, Spanish and French that were recorded and transcribed verbatim. Patients were categorised according to their countries' healthcare systems (universal, public/private and private) and fracture status. A hybrid (sequential theory-driven and data-driven) analysis was performed, with the IPCHS framework used for the theory-driven analysis., Results: Thirty-five patients (33 women) from 14 countries participated. Twenty-two patients had universal healthcare and 18 had experienced fragility fractures. Prioritised substrategies overlapped among healthcare systems, with reported shortcomings related primarily to 'empowering and engaging individuals and families' and 'coordinating care' (at varying levels). Patients with all healthcare types prioritised 'reorienting care', with different substrategies prioritised. Patients with private healthcare called for 'improving funding and reforming payment systems'. Substrategy prioritisation did not differ between those receiving primary and secondary fracture prevention., Conclusion: Patients' experiences with osteoporosis care are universal. Given the current care gaps and associated patient burdens, policymakers should make osteoporosis a(n) (inter)national health priority. Integrated osteoporosis care reforms should focus on patient-reported experiences with and be guided by priorities in IPCHS strategies, taking into account the healthcare system context., Competing Interests: Competing interests: BL participates in meetings of the Global Coalition of Ageing as an expert, but has received no grant or fee for this participation. BL has received grants or fees from Amgen for consultancy, speaking and podcast activities. CV and RW have no competing interest to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Diagnosis of Long QT syndrome (LQTS) is based on prolongation of the QT interval corrected for heart rate (QTc) on surface ECG and genotyping. However, up to 25% of genotype positive patients have a normal QTc interval. We recently showed that individualized QT interval (QTi) derived from 24 h holter data and defined as the QT value at the intersection of an RR interval of 1,000 ms with the linear regression line fitted through QT-RR data points of each individual patient was superior over QTc to predict mutation status in LQTS families. This study aimed to confirm the diagnostic value of QTi, fine-tune its cut-off value and evaluate intra-individual variability in patients with LQTS., Methods: From the Telemetric and Holter ECG Warehouse, 201 recordings from control individuals and 393 recordings from 254 LQTS patients were analysed. Cut-off values were obtained from ROC curves and validated against an in house LQTS and control cohort., Results: ROC curves indicated very good discrimination between controls and LQTS patients with QTi, both in females (AUC 0.96) and males (AUC 0.97). Using a gender dependent cut-off of 445 ms in females and 430 ms in males, a sensitivity of 88% and specificity of 96% were achieved, which was confirmed in the validation cohort. No significant intra-individual variability in QTi was observed in 76 LQTS patients for whom at least two holter recordings were available (483 ± 36 ms vs. 489 ± 42 ms, p  = 0.11)., Conclusions: This study confirms our initial findings and supports the use of QTi in the evaluation of LQTS families. Using the novel gender dependent cut-off values, a high diagnostic accuracy was achieved., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor JE is currently organizing a Research Topic with the author BV., (© 2023 Robyns, Nuyens, Vandenberk, Haemers, Breckpot, Garweg, Ector and Willems.)

Background: After myocardial infarction, the infarct border zone (BZ) is the dominant source of life-threatening arrhythmias, where fibrosis and abnormal repolarization create a substrate for reentry. We examined whether repolarization abnormalities are heterogeneous within the BZ in vivo and could be related to heterogeneous cardiomyocyte remodeling., Methods: Myocardial infarction was induced in domestic pigs by 120-minute ischemia followed by reperfusion. After 1 month, remodeling was assessed by magnetic resonance imaging, and electroanatomical mapping was performed to determine the spatial distribution of activation-recovery intervals. Cardiomyocytes were isolated and tissue samples collected from the BZ and remote regions. Optical recording allowed assessment of action potential duration (di-8-ANEPPS, stimulation at 1 Hz, 37 °C) of large cardiomyocyte populations while gene expression in cardiomyocytes was determined by single nuclear RNA sequencing., Results: In vivo, activation-recovery intervals in the BZ tended to be longer than in remote with increased spatial heterogeneity evidenced by a greater local SD (3.5±1.3 ms versus remote: 2.0±0.5 ms, P =0.036, n pigs =5). Increased activation-recovery interval heterogeneity correlated with enhanced arrhythmia susceptibility. Cellular population studies (n cells =635-862 cells per region) demonstrated greater heterogeneity of action potential duration in the BZ (SD, 105.9±17.0 ms versus remote: 73.9±8.6 ms; P =0.001; n pigs =6), which correlated with heterogeneity of activation-recovery interval in vivo. Cell-cell gene expression heterogeneity in the BZ was evidenced by increased Euclidean distances between nuclei of the BZ (12.1 [9.2-15.0] versus 10.6 [7.5-11.6] in remote; P <0.0001). Differentially expressed genes characterizing BZ cardiomyocyte remodeling included hypertrophy-related and ion channel-related genes with high cell-cell variability of expression. These gene expression changes were driven by stress-responsive TFs (transcription factors). In addition, heterogeneity of left ventricular wall thickness was greater in the BZ than in remote., Conclusions: Heterogeneous cardiomyocyte remodeling in the BZ is driven by uniquely altered gene expression, related to heterogeneity in the local microenvironment, and translates to heterogeneous repolarization and arrhythmia vulnerability in vivo., Competing Interests: Disclosures Dr Willems reports research funding and speakers and consultancy fees from Abbott. The other authors report no conflicts.

Integrated Osteoporosis Care (IOC) has been emerging over the past decade. To support integrated care initiatives, the World Health Organisation (WHO) has developed the Integrated People Centred Health Services (IPCHS) framework, which consists of five interdependent strategies. Five electronic databases (PubMed, Embase, World of Science, CINAHL, and Scopus) were searched for relevant studies published from January 1, 2010 to December 2022. Initiatives implementing collaborative practices and at least two IPCHS strategies were included. Quality assessment was performed using the Effective Public Health Practice Project checklist. Seventy-six publications describing 69 implementations met the inclusion criteria; 90% of them were implemented at the hospital level, and over half focused on secondary fracture prevention. Three implementations captured all five IPCHS strategies, and half applied three. Substrategies targeting individuals as beneficiaries were frequently employed. Substrategies requiring fundamental shifts (e.g., systemic coordination and updating) were seldomly implemented. Substantive heterogeneity in substrategy operationalization was observed. Patient education, standardized care, team-based care, care coordinators, and health care provider training were commonly pursued. IOC interventions have focused mainly on secondary fracture prevention in a hospital setting and have been narrowly operationalized. Future implementation should: employ all five IPCHS strategies; better align programmes, providers, and regulatory frameworks, while adapting funding mechanisms; and operationalize broader and more innovative substrategies.Registration: This review has been registered at the international prospective register of systematic reviews PROSPERO (CRD42021250244)., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

O -β-linked N -acetylglucosaminylation ( O -GlcNAcylation) modulates tau phosphorylation and aggregation: the pharmacological increase of tau O -GlcNAcylation upon treatment with inhibitors of O -GlcNAc hydrolase (OGA) constitutes a potential strategy to tackle neurodegenerative diseases. Analysis of tau O -GlcNAcylation could potentially be used as a pharmacodynamic biomarker both in preclinical and clinical studies. The goal of the current study was to confirm tau O -GlcNAcylation at S400 as a pharmacodynamic readout of OGA inhibition in P301S transgenic mice overexpressing human tau and treated with the OGA inhibitor Thiamet G and to explore if additional O -GlcNAcylation sites on tau could be identified. As a first step, an immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC-MS) methodology was developed to monitor changes in O -GlcNAcylation around S400 of tau in mouse brain homogenate (BH) extracts. Second, additional O -GlcNAc sites were identified in in-house produced recombinant O -GlcNAcylated human tau at relatively high concentrations, thereby facilitating collection of informative LC-MS data for identification of low-concentration O -GlcNAc-tryptic tau peptides in human transgenic mouse BH extracts. This strategy enabled, for the first time, identification of three low abundant N-terminal and mid-domain O -GlcNAc sites of tau (at S208, S191, and S184 or S185) in human transgenic mouse BH. Data are openly available at data.mendeley.com (doi: 10.17632/jp57yk9469.1; doi: 10.17632/8n5j45dnd8.1; doi: 10.17632/h5vdrx4n3d.1).

Background: The frequency of family meals has been suggested as a protective factor against obesity among children., Objective: This study aimed to investigate the cross-sectional and longitudinal associations between family meals frequency and children's overweight/obesity in families at high risk of type 2 diabetes (T2D) across six European countries., Methods: 989 parent-child dyads (52% girls and 72% mothers) were included. Participants completed validated measures to assess the frequency of family meals and anthropometrics. Multivariable regression models were applied to examine the longitudinal associations between family meals frequency and overweight/obesity in children. Logistic regression was performed to predict the odds of having overweight/obesity depending on changes in family meals frequency over a two-year follow-up period. Analyses were stratified for children's sex., Results: High frequency of family breakfasts and/or dinners was inversely associated with children's BMI in boys and girls at T2. Results showed decreased odds of overweight/obesity at follow-up among both boys (OR = 0.65; 95% CI 0.41, 0.96) and girls (OR = 0.53; 95% CI 0.31, 0.87) who consumed minimum of three times family breakfasts and/or family dinners a week at baseline. An increase in family breakfasts and/or dinners frequency was associated with lower odds of overweight/obesity in both boys and girls at follow-up., Conclusion: A high frequency of family breakfasts and/or dinners but not lunch during childhood is associated with lower odds of overweight/obesity development in children from families at high risk of T2D. The promotion of family meals could help in preventing the development of overweight/obesity among children., (© 2023 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Telemedicine is already in use in daily practice, but appropriate reimbursement and physician payment is falling behind in many countries. One reason is the limited availability of research on the matter. This research therefore examined physicians' views on the optimal use and payment modalities for telemedicine., Methods: Sixty-one semi-structured interviews were conducted with physicians from 19 medical disciplines. Interviews were encoded using thematic analysis., Results: Telephone and video televisits tend not to be used as a first patient contact, except for triage of patients in urgency situations. Several minimum required modalities for the payment system of televisits and telemonitoring were identified. For televisits these were: (i) remuneration of both telephone- and videovisits to increase healthcare equity, (ii) little or no differentiation between videovisit and in-person visit fee to make videovisits financially attractive and sustainable for physicians, (iii) differentiation of televisit fee per medical discipline, and (iv) quality requirements such as mandatory reporting in the patient's medical file. The identified minimum required modalities for telemonitoring were: (i) an alternative payment scheme than fee-for-service, (ii) remunerating not only physicians but also other involved health professionals, (iii) designating and remunerating a coordinator, and (iv) distinguishing sporadic vs. continuously follow-up., Conclusions: This research investigated the telemedicine usage behavior of physicians. Moreover, several minimum required modalities were identified for a physician-supported payment system of telemedicine, as these innovations necessitate challenging and innovation of the healthcare payment systems as well., (© 2023. The Author(s).)

Purpose: Electrocardiogram (ECG) QRS voltages correlate poorly with left ventricular mass (LVM). Body composition explains some of the QRS voltage variability. The relation between QRS voltages, LVM and body composition in endurance athletes is unknown., Methods: Elite endurance athletes from the Pro@Heart trial were evaluated with 12-lead ECG for Cornell and Sokolow-Lyon voltage and product. Cardiac magnetic resonance imaging assessed LVM. Dual energy x-ray absorptiometry assessed fat mass (FM) and lean mass of the trunk and whole body (LBM). The determinants of QRS voltages and LVM were identified by multivariable linear regression. Models combining ECG, demographics, DEXA and exercise capacity to predict LVM were developed., Results: In 122 athletes (19 years, 71.3% male) LVM was a determinant of the Sokolow-Lyon voltage and product (β = 0.334 and 0.477, p < 0.001) but not of the Cornell criteria. FM of the trunk (β = - 0.186 and - 0.180, p < 0.05) negatively influenced the Cornell voltage and product but not the Sokolow-Lyon criteria. DEXA marginally improved the prediction of LVM by ECG (r = 0.773 vs 0.510, p < 0.001; RMSE = 18.9 ± 13.8 vs 25.5 ± 18.7 g, p > 0.05) with LBM as the strongest predictor (β = 0.664, p < 0.001). DEXA did not improve the prediction of LVM by ECG and demographics combined and LVM was best predicted by including VO 2 max (r = 0.845, RMSE = 15.9 ± 11.6 g)., Conclusion: LVM correlates poorly with QRS voltages with adipose tissue as a minor determinant in elite endurance athletes. LBM is the strongest single predictor of LVM but only marginally improves LVM prediction beyond ECG variables. In endurance athletes, LVM is best predicted by combining ECG, demographics and VO 2 max., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Digital health interventions have shown promising results for the management of type 2 diabetes, but a comparison of the effectiveness and implementation of the different modes is not currently available. Therefore, this study aimed to compare the effectiveness of SMS, smartphone application, and website-based interventions on improving glycaemia in adults with type 2 diabetes and report on their reach, uptake, and feasibility., Methods: In this systematic review and meta-analysis, we searched CINAHL, Cochrane Central, Embase, MEDLINE, and PsycInfo on May 25, 2022, for randomised controlled trials (RCTs) that examined the effectiveness of digital health interventions in reducing glycated haemoglobin A 1c (HbA 1c ) in adults with type 2 diabetes, published in English from Jan 1, 2009. Screening was carried out using Covidence, and data were extracted following Cochrane's guidelines. The primary endpoint assessed was the change in the mean (and 95% CI) plasma concentration of HbA 1c at 3 months or more. Cochrane risk of bias 2 was used to assess risk of bias. Data on reach, uptake, and feasibility were summarised narratively and data on HbA 1c reduction were synthesised in a meta-analysis. Grading of Recommendations, Assessment, Development, and Evaluation criteria was used to evaluate the level of evidence. The study was registered with PROSPERO, CRD42021247845., Findings: Of the 3236 records identified, 56 RCTs from 24 regions (n=11 486 participants), were included in the narrative synthesis, and 26 studies (n=4546 participants) in the meta-analysis. 20 studies used SMS as the primary mode of delivery of the digital health intervention, 25 used smartphone applications, and 11 implemented interventions via websites. Smartphone application interventions reported higher reach compared with SMS and website-based interventions, but website-based interventions reported higher uptake compared with SMS and smartphone application interventions. Effective interventions, in general, included people with greater severity of their condition at baseline (ie, higher HbA 1c ) and administration of a higher dose intensity of the intervention, such as more frequent use of smartphone applications. Overall, digital health intervention group participants had a -0·30 (95% CI -0·42 to -0·19) percentage point greater reduction in HbA 1c , compared with control group participants. The difference in HbA 1c reduction between groups was statistically significant when interventions were delivered through smartphone applications (-0·42% [-0·63 to -0·20]) and via SMS (-0·37% [-0·57 to -0·17]), but not when delivered via websites (-0·09% [-0·64 to 0·46]). Due to the considerable heterogeneity between included studies, the level of evidence was moderate overall., Interpretation: Smartphone application and SMS interventions, but not website-based interventions, were associated with better glycaemic control. However, the studies' heterogeneity should be recognised. Considering that both smartphone application and SMS interventions are effective for diabetes management, clinicians should consider factors such as reach, uptake, patient preference, and context of the intervention when deciding on the mode of delivery of the intervention. Nine in ten people worldwide own a feature phone and can receive SMS and four in five people have access to a smartphone, with numerous smartphone applications being available for diabetes management. Clinicians should familiarise themselves with this modality of programme delivery and encourage people with type 2 diabetes to use evidence-based applications for improving their self-management of diabetes. Future research needs to describe in detail the mediators and moderators of the effectiveness and implementation of SMS and smartphone application interventions, such as the optimal dose, frequency, timing, user interface, and communication mode to both further improve their effectiveness and to increase their reach, uptake, and feasibility., Funding: EU's Horizon 2020 Research and Innovation Programme., Competing Interests: Declaration of interests LA received consulting fees from Mundipharma for advice on cost-effectiveness of SGLT2 inhibitors for the management of type 2 diabetes; honoraria from Boehringer Ingelheim and from Mundipharma for lectures on health economic aspects of diabetes; and is a member of the board of the AstraZeneca Foundation. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Digital health interventions are effective for hypertension self-management, but a comparison of the effectiveness and implementation of the different modes of interventions is not currently available. This study aimed to compare the effectiveness of SMS, smartphone application, and website interventions on improving blood pressure in adults with hypertension, and to report on their reach, uptake, and feasibility., Methods: In this systematic review and meta-analysis we searched CINAHL Complete, Cochrane Central Register of Controlled Trials, Ovid Embase, Ovid MEDLINE, and APA PsycInfo on May 25, 2022, for randomised controlled trials (RCTs) published in English from Jan 1, 2009, that examined the effectiveness of digital health interventions on reducing blood pressure in adults with hypertension. Screening was carried out using Covidence, and data were extracted following Cochrane's guidelines. The primary endpoint was change in the mean of systolic blood pressure. Risk of bias was assessed with Cochrane Risk of Bias 2. Data on systolic and diastolic blood pressure reduction were synthesised in a meta-analysis, and data on reach, uptake and feasibility were summarised narratively. Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to evaluate the level of evidence. The study was registered with PROSPERO CRD42021247845., Findings: Of the 3235 records identified, 29 RCTs from 13 regions (n=7592 participants) were included in the systematic review, and 28 of these RCTs (n=7092 participants) were included in the meta-analysis. 11 studies used SMS as the primary mode of delivery of the digital health intervention, 13 used smartphone applications, and five used websites. Overall, digital health intervention group participants had a -3·62 mm Hg (95% CI -5·22 to -2·02) greater reduction in systolic blood pressure, and a -2·45 mm Hg (-3·83 to -1·07) greater reduction in diastolic blood pressure, compared with control group participants. No statistically significant differences between the three different modes of delivery were observed for both the systolic (p=0·73) and the diastolic blood pressure (p=0·80) outcomes. Smartphone application interventions had a statistically significant reduction in diastolic blood pressure (-2·45 mm Hg [-4·15 to -0·74]); however, there were no statistically significant reductions for SMS interventions (-1·80 mm Hg [-4·60 to 1·00]) or website interventions (-3·43 mm Hg [-7·24 to 0·38]). Due to the considerable heterogeneity between included studies and the high risk of bias in some, the level of evidence was assigned a low overall score. Interventions were more effective among people with greater severity of hypertension at baseline. SMS interventions reported higher reach and smartphone application studies reported higher uptake, but differences were not statistically significant., Interpretation: SMS, smartphone application, and website interventions were associated with statistically and clinically significant systolic and diastolic blood pressure reductions, compared with usual care, regardless of the mode of delivery of the intervention. This conclusion is tempered by the considerable heterogeneity of included studies and the high risk of bias in most. Future studies need to describe in detail the mediators and moderators of the effectiveness and implementation of these interventions, to both further improve their effectiveness as well as increase their reach, uptake, and feasibility., Funding: European Union's Horizon 2020 Research and Innovation Programme., Competing Interests: Declaration of interests LA received consulting fees from Mundipharma for advice on cost-effectiveness of SGLT2 inhibitors for the management of type 2 diabetes; received honoraria from Boehringer Ingelheim and Mundipharma for lectures on health economic aspects of diabetes; and is a member of the board of the AstraZeneca Foundation. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims: The contribution of adverse ventricular interdependence remains undervalued in heart failure or pulmonary vascular disease, and not much is known about its dynamic nature during exercise and respiration. In this study, we evaluated ventricular interaction during exercise in patients with heart failure with preserved ejection fraction (HFpEF) and patients with chronic thromboembolic pulmonary hypertension (CTEPH) as compared with healthy controls., Methods and Results: Forty-six subjects (10 controls, 19 CTEPH patients, and 17 HFpEF patients) underwent cardiac magnetic resonance imaging during exercise. Ventricular interaction was determined through analysis of the septal curvature (SC) of a mid-ventricular short-axis slice at end-diastole, end-systole, and early-diastole, both in expiration and inspiration. Exercise amplified ventricular interaction in CTEPH patients and to a lesser extent in HFpEF patients (P < 0.05 for decrease in SC with exercise). Adverse interaction was most profound in early-diastole and most pronounced in CTEPH patients (P < 0.05 interaction group * exercise) because of a disproportionate increase RV afterload (P < 0.05 to both controls and HFpEF) and diastolic pericardial restraint (P < 0.001 for interaction group * exercise) during exercise. Inspiration enhanced diastolic interdependence in CTEPH and HFpEF patients (P < 0.05 vs. expiration). Both at rest and during exercise, SC strongly correlated with RV volumes and pulmonary artery pressures (all P < 0.05)., Conclusions: Exercise amplifies adverse right-left ventricular interactions in CTEPH, while a more moderate effect is observed in isolated post-capillary HFpEF. Given the strong link with RV function and pulmonary hemodynamic, assessing ventricular interaction with exCMR might be valuable from a diagnostic or therapeutic perspective., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)