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Abstract Background Major bleeding, and intracranial bleeding specifically, are severe complications related to the use of anticoagulation. To what extent the risk for major bleeding is elevated among frail older people is not well known because they are underrepresented in the randomized clinical trials (RCTs). This study investigates the risk for major bleeding (MB) and intra cranial haemorrhage (ICH) in frail older people who fall. Methods All patients 65 years and older visiting the Fall and Syncope Clinic, between November 2011 and January 2020, and underwent a MRI of the brain were eligible. Frailty was assessed with a Frailty Index, based on the accumulation of deficits model. Cerebral small vessel disease was described and evaluated as proposed in the position paper of Wardlaw and colleagues in 2013. Results 479 patients were included in this analysis. Mean follow-up was 7 years per patient (ranging from 1 month to 8 years and 5 months). 368 patients (77%) were frail. A total of 81 patients used oral anticoagulation (OAC). 17 extracranial MB of which 3 were traumatic and 14 gastrointestinal, and 16 ICH occurred. There was a total of 603.4 treatment years with OAC, and 8 MBs occurred among patients on OAC (bleeding rate 1.32 per 100 treatment years), of which 2 ICHs (bleeding rate 0.33 per 100 treatment years). The risk for extracranial MB was increased by the use of antiplatelet agents (APA) (adjusted OR 6.9, CI 95% 1.2–38.3), and by the use of OAC (adjusted OR 9.8, CI 95% 1.7–56.1). The risk for ICH was only heightened by white matter hyperintensities (WMH) (adjusted OR 3.8, CI 95% 1.0-13.4). The use of APA (adjusted OR 0.9, CI 95% 0.3–3.3) or OAC (adjusted OR 0.6, CI 95% 0.1–3.3) did not elevate the risk for ICH. Conclusion In contrast to common belief, frail patients on OAC with repeated falls show a comparable bleeding rate as in the large RCTs, and the use of OAC did not increase the risk for ICH. However, the number of MBs was low, and of ICHs very low, despite extensive follow-up in this registry.

Background: This study investigates the effects of spondylodiscitis on the inflammation burden in infective endocarditis patients., Methods: A prospective, observational study was conducted between September 2018 and October 2022 in a non-surgical teaching hospital. Patients with a definite or possible and treated as infective endocarditis were recruited from the Alkmaar Endocarditis Team meetings. Spondylodiscitis was diagnosed based on symptoms and radiological findings. The inflammation burden was defined as the area under the C‑reactive protein (CRP) curve., Results: 174 consecutive patients with infective endocarditis were included (mean age 73 years, 34.5% female). Concomitant spondylodiscitis was present in 32 patients (18%), frequently associated with Streptococcus species (38%). At admission, the mean level of CRP was significantly higher in patients with concomitant spondylodiscitis (p = 0.004). The median CRP area under the curve was significantly higher in spondylodiscitis patients (4.2 × 10 6  min.mg/l [1.2 × 10 5  - 1.6 × 10 7  min.mg/l] vs 2.0 × 10 6  min.mg/l [8.7 × 10 4  - 1.6 × 10 7  min.mg/l], p < 0.001). This difference remained during the whole treatment period. At 6 months of follow-up, rates of mortality and relapse of infective endocarditis were not significantly different., Conclusion: The prevalence of spondylodiscitis in non-referred patients with infective endocarditis was 18%. Endocarditis patients with spondylodiscitis had an increased inflammation burden at and during admission. This difference in normalisation of CRP levels was particularly apparent in the final phase of antibiotic treatment but not related to infectious complications. Despite an augmented inflammation burden, spondylodiscitis was not associated with mortality, cardiac surgery or infectious relapse., Competing Interests: Conflict of interest: E. Ulas, M. Duffels, O. Drexhage, T. Germans, J. Wagenaar and V. Umans declare that they have no competing interests., (© 2024. The Author(s).)

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. The impact of HCM on quality of life (QoL) and societal costs remains poorly understood. This prospective multi-centre burden of disease study estimated QoL and societal costs of genotyped HCM patients and genotype-positive phenotype-negative (G+/P-) subjects., Methods: Participants were categorized into three groups based on genotype and phenotype: 1) G+/P- (left ventricular (LV) wall thickness <13 mm), 2) non-obstructive HCM (nHCM, LV outflow tract (LVOT) gradient <30 mmHg), and 3) obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). We assessed QoL with EQ-5D-5L and Kansas City Cardiomyopathy Questionnaires (KCCQ). Societal costs were measured using medical consumption (iMCQ) and productivity cost (iPCQ) questionnaires. We performed subanalyses within three age groups: <40, 40-59, and ≥60 years., Results: From three Dutch hospitals, 506 subjects were enrolled (84 G+/P-, 313 nHCM, 109 oHCM; median age 59 years, 39% female). HCM (both nHCM and oHCM) patients reported reduced QoL vs G+/P- subjects (KCCQ: 88 vs 98, EQ-5D-5L: 0.88 vs 0.96; both p<0.001). oHCM patients reported lower KCCQ scores than nHCM patients (83 vs 89, p=0.036). Societal costs were significantly higher in HCM patients (€19,035/year vs €7,385/year) compared to G+/P- controls, mainly explained by higher healthcare costs and productivity losses. Being symptomatic and of younger age (<60 years) particularly led to decreased QoL and increased costs., Conclusion: HCM is associated with decreased QoL and increased societal costs, especially in younger and symptomatic patients. oHCM patients were more frequently symptomatic than nHCM patients. This study highlights the substantial disease burden of HCM and can aid in assessing new therapy cost-effectiveness for HCM in the future., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a multimodality prediction model., Objective: This study aimed to investigate whether an explainable deep learning-based approach allows risk prediction with only electrocardiogram (ECG) data., Methods: A total of 679 PLN p.(Arg14del) carriers without MVA at baseline were identified. A deep learning-based variational auto-encoder, trained on 1.1 million ECGs, was used to convert the 12-lead baseline ECG into its FactorECG, a compressed version of the ECG that summarizes it into 32 explainable factors. Prediction models were developed by Cox regression., Results: The deep learning-based ECG-only approach was able to predict MVA with a C statistic of 0.79 (95% CI, 0.76-0.83), comparable to the current prediction model (C statistic, 0.83 [95% CI, 0.79-0.88]; P = .054) and outperforming a model based on conventional ECG parameters (low-voltage ECG and negative T waves; C statistic, 0.65 [95% CI, 0.58-0.73]; P < .001). Clinical simulations showed that a 2-step approach, with ECG-only screening followed by a full workup, resulted in 60% less additional diagnostics while outperforming the multimodal prediction model in all patients. A visualization tool was created to provide interactive visualizations (https://pln.ecgx.ai)., Conclusion: Our deep learning-based algorithm based on ECG data only accurately predicts the occurrence of MVA in PLN p.(Arg14del) carriers, enabling more efficient stratification of patients who need additional diagnostic testing and follow-up., Competing Interests: Disclosures The UMC Groningen, which employs several of the authors, received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche (outside the submitted work). Rudolf A. de Boer has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche (outside the submitted work). Rutger R. van de Leur and René van Es are cofounders, shareholders, and board members of Cordys Analytics B.V., a spin-off of the UMC Utrecht that has licensed AI-ECG algorithms, not including the algorithm studied in the current manuscript. The UMC Utrecht receives royalties from Cordys Analytics for potential future revenues. Pieter A. Doevendans is founder and shareholder of HeartEye B.V., an ECG-device company. The other authors declare that there is no conflict of interest., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up., Methods and Results: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97., Conclusion: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up., Competing Interests: Conflict of interest: The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. R.A.deB. has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. T.G. has had speaker engagements with Bristol Myers Squibb. M.Y.C.vd.H. and A.A.M.W. report grants from PLN foundation, grants from CVON Netherlands Heart Foundation (PREDICT2) and ZonMw (PSIDER-Heart) during this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Particularly in frail patients, anticoagulation may be underused because of the fear of bleeding., Objective: To determine whether the use of antithrombotic medication is an independent risk factor for mortality in frail elderly with repeated falls., Methods: All patients aged 65 years or older at the Fall and Syncope Clinic were eligible. Frailty was calculated with a Frailty Index (FI) based on the accumulation of deficits model. Risks were calculated with a cox regression analysis, adjusted for age, sex, and Frailty Index., Results: 663 patients were included in this analysis. The median age was 80 years, 438 were women (66%), 73% had polypharmacy, and 380 patients (57%) had cognitive impairment. The mean FI was 0.23 (sd 0.09), 182 patients were moderately frail (27.5%), and 259 (39.1%) were severely frail. A total of 140 (21%) used oral anticoagulation and 223 (34%) used antiplatelet agents. A total of 196 patients (29.6%) died during follow-up. In the adjusted cox regression model, the use of neither antiplatelets nor anticoagulation was associated with mortality. A strong association was found with frailty (HR 74.0, 95% CI 13.1-417.3) and a weak association with age (HR 1.05, 95% CI 1.03-1.08). A lower risk of mortality was seen in women (HR 0.5, 95% CI 0.3-0.6)., Conclusions: In this cohort of frail older patients, there was no independent association between the use of antithrombotic medication and mortality. A strong association with mortality was found with frailty, a weak association was found with age, and a lower mortality risk was found in women. Our data indicate that the fear of bleeding or increased mortality in frail patients with an indication for oral anticoagulation may be unjustified.

Aims: Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse events. In this study, we aim to derive a small set out of 4210 repeatedly measured proteins, which, along with clinical characteristics and established biomarkers, carry optimal prognostic capacity for adverse events, in patients with HFrEF., Methods and Results: In 382 patients, we performed repeated blood sampling (median follow-up: 2.1 years) and applied an aptamer-based multiplex proteomic approach. We used machine learning to select the optimal set of predictors for the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization). The association between repeated measures of selected proteins and PEP was investigated by multivariable joint models. Internal validation (cross-validated c -index) and external validation (Henry Ford HF PharmacoGenomic Registry cohort) were performed. Nine proteins were selected in addition to the MAGGIC risk score, N-terminal pro-hormone B-type natriuretic peptide, and troponin T: suppression of tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein 2, anthrax toxin receptor 1, and cathepsin D. N-terminal pro-hormone B-type natriuretic peptide and angiotensinogen showed the strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) and 0.66 (0.49-0.88), respectively]. The multivariable model yielded a c -index of 0.85 upon internal validation and c -indices up to 0.80 upon external validation. The c -index was higher than that of a model containing established risk factors ( P = 0.021)., Conclusion: Nine serially measured proteins captured the most essential prognostic information for the occurrence of adverse events in patients with HFrEF, and provided incremental value for HF prognostication beyond established risk factors. These proteins could be used for dynamic, individual risk assessment in a prospective setting. These findings also illustrate the potential value of relatively 'novel' biomarkers for prognostication., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24., Competing Interests: Conflict of interest: R.O. is employed by Somalogic Inc. D.L. reports non-financial support from Somalogic Inc., during the conduct of the study; grants and personal fees from Janssen, personal fees from Ortho Diagnostics, personal fees from DCRI (Novartis), grants from Bayer, grants from Astra Zeneca, grants from Critical Diagnostics, non-financial support from Somalogic, grants from Lilly, personal fees from ACI (Abbott Laboratories), personal fees from Martin Pharmaceuticals, personal fees from Illumina, personal fees from Vicardia, other from Hridaya, grants and personal fees from Amgen, personal fees from Cytokinetics, outside the submitted work. In addition, D.L. has a patent genomic predictors of BB response issued. The other authors have no disclosures to report., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Infective endocarditis is a severe and potentially lethal cardiac disease. Recognition of the clinical features of endocarditis, such as distant embolisation, and adequate treatment should be initiated promptly given the grim perspective of upcoming virulent pathogens., Methods: We report on our registry-based experience with outcomes of consecutive patients with infective endocarditis with distant embolisation. We aimed to describe the patient characteristics of infective endocarditis complicated by distant organ embolisation and the safety aspects of continuing endocarditis treatment at home in these patients., Results: From November 2018 through April 2022, 157 consecutive patients were diagnosed with infective endocarditis. Of them, 38 patients (24%) experienced distant embolisation, either in the cerebrum (n = 18), a visceral organ (n = 5), the lungs (n = 7) or the myocardium (n = 8). Pathogens identified in blood cultures were predominantly streptococcal variants (43%), with only one culture-negative endocarditis case. Of the 18 patients with cerebral embolisation, 12 had neurological complaints and most often discrete abnormal findings on neurological examination. Six of the 8 cardiac embolism patients experienced chest pain before admission. Visceral organ and pulmonary embolism occurred silently. Of the 38 patients with distant embolisation, 17 could be discharged earlier by providing antibiotic treatment at home without complications., Conclusion: This registry-based single-centre experience showed an incidence of distant embolisation in daily care of 24%. Cerebral and coronary embolisation provoked symptoms, while visceral emboli remained silent. Pulmonary emboli may present with inflammatory signs. Distant embolisation was not in itself a contra-indication for outpatient endocarditis@home treatment., (© 2023. The Author(s).)

Septal midwall late gadolinium enhancement (LGE) is a characteristic finding on cardiac magnetic resonance imaging (CMR) in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse events. Its significance in ischemic cardiomyopathy (ICM) is unknown. With this multicenter observational study, we aimed to study the characteristics of septal midwall LGE and evaluate its prognostic value in ICM. A total of 1,084 patients with an impaired left ventricular (LV) ejection fraction (<50%) on LGE-CMR, either because of ICM (53%) or DCM, were included retrospectively. Septal midwall LGE was defined as midmyocardial stripe-like or patchy LGE in septal segments and was present in 10% of patients with ICM compared with 34% of patients with DCM (p <0.001). It was significantly associated with larger LV volumes and lower LV ejection fraction, irrespective of etiology. The primary endpoint was all-cause mortality and secondary endpoint was ventricular arrhythmias (VAs), including resuscitated cardiac arrest, sustained VA, and appropriate implantable cardioverter-defibrillator (ICD) therapy. During a median follow-up of 2.7 years, we found a significant association between septal midwall LGE and mortality in patients with DCM (hazard ratio [HR] 1.92, p = 0.03), but not in patients with ICM (HR 1.35, p = 0.39). Risk of VAs was significantly higher in patients with septal midwall LGE on CMR, both in DCM (HR 2.80, p <0.01) and in ICM (HR 2.70, p <0.01). In conclusion, septal midwall LGE, typically seen in DCM, was also present in 10% of patients with ICM and was associated with increased LV dilation and worse function, irrespective of etiology. When present, septal midwall LGE was associated with adverse outcome., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Major bleeding, and intracranial bleeding specifically, are severe complications related to the use of anticoagulation. To what extent the risk for major bleeding is elevated among frail older people is not well known because they are underrepresented in the randomized clinical trials (RCTs). This study investigates the risk for major bleeding (MB) and intra cranial haemorrhage (ICH) in frail older people who fall., Methods: All patients 65 years and older visiting the Fall and Syncope Clinic, between November 2011 and January 2020, and underwent a MRI of the brain were eligible. Frailty was assessed with a Frailty Index, based on the accumulation of deficits model. Cerebral small vessel disease was described and evaluated as proposed in the position paper of Wardlaw and colleagues in 2013., Results: 479 patients were included in this analysis. Mean follow-up was 7 years per patient (ranging from 1 month to 8 years and 5 months). 368 patients (77%) were frail. A total of 81 patients used oral anticoagulation (OAC). 17 extracranial MB of which 3 were traumatic and 14 gastrointestinal, and 16 ICH occurred. There was a total of 603.4 treatment years with OAC, and 8 MBs occurred among patients on OAC (bleeding rate 1.32 per 100 treatment years), of which 2 ICHs (bleeding rate 0.33 per 100 treatment years). The risk for extracranial MB was increased by the use of antiplatelet agents (APA) (adjusted OR 6.9, CI 95% 1.2-38.3), and by the use of OAC (adjusted OR 9.8, CI 95% 1.7-56.1). The risk for ICH was only heightened by white matter hyperintensities (WMH) (adjusted OR 3.8, CI 95% 1.0-13.4). The use of APA (adjusted OR 0.9, CI 95% 0.3-3.3) or OAC (adjusted OR 0.6, CI 95% 0.1-3.3) did not elevate the risk for ICH., Conclusion: In contrast to common belief, frail patients on OAC with repeated falls show a comparable bleeding rate as in the large RCTs, and the use of OAC did not increase the risk for ICH. However, the number of MBs was low, and of ICHs very low, despite extensive follow-up in this registry., (© 2023. The Author(s).)

Bacterial endocarditis is associated with high morbidity and mortality and requires a long hospitalization due to long-term intravenous antimicrobial therapy. It is possible to partially treat selected and stable patients at home. We present 3 patients partially treated at home with intravenous antibiotics for proven complicated endocarditis. Patient A presented with a septic shock and mitral valve endocarditis. Patient B presented with an ICD lead endocarditis and patient C presented with an mitral valve endocarditis. All 3 patients had a complicated endocarditis and presented with extensive embolic dissemination. Following the initial complicated clinical course, the patients were discharged for antibiotic home treatment after clinical improvement. Subsequent treatment was successful and reduced their hospital stay with more than 14 days. Thanks to transmural cooperation with the home-care colleagues, we can safely provide antibiotic care at home so that stabilized endocarditis patients can be treated in their own habitat.

Background: Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes., Methods: In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 [13-31] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing., Results: In 104 women and 278 men (mean age 62 and 64 years, respectively) cumulative PEP incidence at 30 months was 25% and 35%, respectively. At baseline, 55 (5%) out of the 1105 proteins were significantly different between women and men. The female protein profile was most strongly associated with extracellular matrix organization, while the male profile was dominated by regulation of cell death. The association of endothelin-1 (P interaction  < 0.001) and somatostatin (P interaction  = 0.040) with the PEP was modified by sex, independent of clinical characteristics. Endothelin-1 was more strongly associated with the PEP in men (HR 2.62 [95%CI, 1.98, 3.46], p < 0.001) compared to women (1.14 [1.01, 1.29], p = 0.036). Somatostatin was positively associated with the PEP in men (1.23 [1.10, 1.38], p < 0.001), but inversely associated in women (0.33 [0.12, 0.93], p = 0.036)., Conclusion: Baseline cardiovascular protein levels differ between women and men. However, the predictive value of repeatedly measured circulating proteins does not seem to differ except for endothelin-1 and somatostatin., (© 2023. The Author(s).)

Background Late gadolinium enhancement and left ventricular (LV) ejection fraction on cardiovascular magnetic resonance (CMR) are prognostic markers, but their predictive value for incident heart failure or life-threatening arrhythmias in acute myocarditis patients is limited. CMR-derived feature tracking provides a more sensitive analysis of myocardial function and may improve risk stratification in myocarditis. In this study, the prognostic value of LV, right ventricular, and left atrial strain in acute myocarditis patients is evaluated. Methods and Results In this multicenter retrospective study, patients with CMR-proven acute myocarditis were included. The primary end point was occurrence of major adverse cardiovascular events: all-cause mortality, heart transplantation, heart failure hospitalizations, and life threatening arrhythmias. LV global longitudinal strain, global circumferential strain and global radial strain, right ventricular-global longitudinal strain and left atrial strain were measured. Unadjusted and adjusted cox proportional hazard regression analysis were performed. In total, 162 CMR-proven myocarditis patients were included (41 ± 17 years, 75% men). Mean LV ejection fraction was 51 ± 12%, and 144 (89%) patients had presence of late gadolinium enhancement. Major adverse cardiovascular events occurred in 29 (18%) patients during a follow-up of 5.5 (2.2-8.3) years. All LV strain parameters were independent predictors of outcome beyond clinical features, LV ejection fraction and late gadolinium enhancement (LV-global longitudinal strain: hazard ratio [HR] 1.07, P =0.02; LV-global circumferential strain: HR 1.15, P =0.02; LV-global radial strain: HR 0.98, P =0.03), but right ventricular or left atrial strain did not predict outcome. Conclusions CMR-derived LV strain analysis provides independent prognostic value on top of clinical parameters, LV ejection fraction and late gadolinium enhancement in acute myocarditis patients, while left atrial and right ventricular strain seem to be of less importance.

Background: This study aimed to identify heart failure (HF) subphenotypes using 92 repeatedly measured circulating proteins in 250 patients with heart failure with reduced ejection fraction, and to investigate their clinical characteristics and prognosis., Methods: Clinical data and blood samples were collected tri-monthly until the primary endpoint (PEP) or censoring occurred, with a maximum of 11 visits. The Olink Cardiovascular III panel was measured in baseline samples and the last two samples before the PEP (in 66 PEP cases), or the last sample before censoring (in 184 PEP-free patients). The PEP comprised cardiovascular death, heart transplantation, Left Ventricular Assist Device implantation, and hospitalization for HF. Cluster analysis was performed on individual biomarker trajectories to identify subphenotypes. Then biomarker profiles and clinical characteristics were investigated, and survival analysis was conducted., Results: Clustering revealed three clinically diverse subphenotypes. Cluster 3 was older, with a longer duration of, and more advanced HF, and most comorbidities. Cluster 2 showed increasing levels over time of most biomarkers. In cluster 3, there were elevated baseline levels and increasing levels over time of 16 remaining biomarkers. Median follow-up was 2.2 (1.4-2.5) years. Cluster 3 had a significantly poorer prognosis compared to cluster 1 (adjusted event-free survival time ratio 0.25 (95%CI:0.12-0.50), p < 0.001). Repeated measurements clusters showed incremental prognostic value compared to clusters using single measurements, or clinical characteristics only., Conclusions: Clustering based on repeated biomarker measurements revealed three clinically diverse subphenotypes, of which one has a significantly worse prognosis, therefore contributing to improved (individualized) prognostication., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 ., (© 2022. The Author(s).)

Hypertrophic Cardiomyopathy (HCM) is a common inherited heart disease with poor risk prediction due to incomplete penetrance and a lack of clear genotype-phenotype correlations. Advanced imaging techniques have shown altered myocardial energetics already in preclinical gene variant carriers. To determine whether disturbed myocardial energetics with the potential to serve as biomarkers are also reflected in the serum metabolome, we analyzed the serum metabolome of asymptomatic carriers in comparison to healthy controls and obstructive HCM patients (HOCM). We performed non-quantitative direct-infusion high-resolution mass spectrometry-based untargeted metabolomics on serum from fasted asymptomatic gene variant carriers, symptomatic HOCM patients and healthy controls ( n = 31, 14 and 9, respectively). Biomarker panels that discriminated the groups were identified by performing multivariate modeling with gradient-boosting classifiers. For all three group-wise comparisons we identified a panel of 30 serum metabolites that best discriminated the groups. These metabolite panels performed equally well as advanced cardiac imaging modalities in distinguishing the groups. Seven metabolites were found to be predictive in two different comparisons and may play an important role in defining the disease stage. This study reveals unique metabolic signatures in serum of preclinical carriers and HOCM patients that may potentially be used for HCM risk stratification and precision therapeutics.

Objective: Viral myocarditis (VM) can induce changes in myocardial electrical conduction and arrhythmia. However, their relationship with myocarditis-associated arrhythmic substrates in the heart such as inflammation and fibrosis is relatively unknown. This we have analyzed in the present study., Methods: C3H mice were infected with 1×10 5 plaque-forming units Coxsackievirus B3 (CVB3, n=68) and were compared with uninfected control mice (n=10). Electrocardiograms (ECGs) were recorded in all conscious mice shortly before sacrifice and included heart rate; P-R interval; QRS duration; QTc interval and R-peak amplitude of lead II and aVF. Mice were sacrificed at 4, 7, 10, 21, 35 or 49 days post-infection. Cardiac lesion size, calcification, fibrosis and cellular infiltration of CD45+ lymphocytes, MAC3+ macrophages, Ly6G+ neutrophils and mast cells were quantitatively determined in cross-sections of the ventricles. Putative relations between ECG changes and lesion size and/or cardiac inflammation were then analyzed., Results: Significant transient reductions in QRS duration and R-peak amplitude occurred between 4 and 14 days post-infection and returned to baseline values thereafter. The magnitude of these ECG changes strongly correlated to the extent of lymphocyte (days 7 and 14), macrophage (days 7 and 10) and neutrophil (days 7) infiltration. The ECG changes did not significantly correlate with lesion size and fibrosis., Conclusion: VM induces transient changes in myocardial electrical conduction that are strongly related to cellular inflammation of the heart. These data show that even in mild VM, with relatively little cardiac damage, the inflammatory infiltrate can form an important arrhythmogenic substrate., (Copyright © 2021. Published by Elsevier Inc.)

Background: We aimed to assess differences in clinical characteristics, prognosis, and the temporal evolution of circulating biomarkers in male and female patients with HFrEF., Methods: We included 250 patients (66 women) with chronic heart failure (CHF) between 2011 and 2013 and performed trimonthly blood sampling during a median follow-up of 2.2 years [median (IQR) of 8 (5-10) urine and 9 (5-10) plasma samples per patient]. After completion of follow-up we measured 8 biomarkers. The primary endpoint (PE) was the composite of cardiac death, cardiac transplantation, left ventricular assist device implantation, and hospitalization due to acute or worsened CHF. Joint models were used to determine whether there were differences in the temporal patterns of the biomarkers between men and women as the PE approached., Results: A total of 66 patients reached the PE of which 52 (78.8%) were male and 14 (21.2%) were female. The temporal patterns of all studied biomarkers were associated with the PE, and overall showed disadvantageous changes as the PE approached. For NT-proBNP, HsTnT, and CRP, women showed higher levels over the entire follow-up duration and concomitant numerically higher hazard ratios [NT-proBNP: women: HR(95%CI) 7.57 (3.17-21.93), men: HR(95%CI) 3.14 (2.09-4.79), p for interaction = 0.104, HsTnT: women: HR(95%CI) 6.38 (2.18-22.46), men: HR(95%CI) 4.91 (2.58-9.39), p for interaction = 0.704, CRP: women: HR(95%CI) 7.48 (3.43-19.53), men: HR(95%CI) 3.29 [2.27-5.44], p for interaction = 0.106). In contrast, temporal patterns of glomerular and tubular renal markers showed similar associations with the PE in men and women., Conclusion: Although interaction terms are not statistically significant, the associations of temporal patterns of NT-proBNP, HsTnT, and CRP appear more outspoken in women than in men with HFrEF, whereas associations seem similar for temporal patterns of creatinine, eGFR, Cystatin C, KIM-1 and NAG. Larger studies are needed to confirm these potential sex differences., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

We recently showed more severe diastolic dysfunction at the time of myectomy in female compared to male patients with obstructive hypertrophic cardiomyopathy. Early recognition of aberrant cardiac contracility using cardiovascular magnetic resonance (CMR) imaging may identify women at risk of cardiac dysfunction. To define myocardial function at an early disease stage, we studied regional cardiac function using CMR imaging with tissue tagging in asymptomatic female gene variant carriers. CMR imaging with tissue tagging was done in 13 MYBPC3, 11 MYH7 and 6 TNNT2 gene carriers and 16 age-matched controls. Regional peak circumferential strain was derived from tissue tagging images of the basal and midventricular segments of the septum and lateral wall. Left ventricular wall thickness and global function were comparable between MYBPC3, MYH7, TNNT2 carriers and controls. MYH7 gene variant carriers showed a different strain pattern as compared to the other groups, with higher septal peak circumferential strain at the basal segments compared to the lateral wall, whereas MYBPC3, TNNT2 carriers and controls showed higher strain at the lateral wall compared to the septum. Only subtle gene-specific changes in strain pattern occur in the myocardium preceding development of cardiac hypertrophy. Overall, our study shows that there are no major contractile deficits in asymptomatic females carrying a pathogenic gene variant, which would justify the use of CMR imaging for earlier diagnosis.

Background In survivors of sudden cardiac arrest with obstructive coronary artery disease, it remains challenging to distinguish ischemia as a reversible cause from irreversible scar-related ventricular arrhythmias. We aimed to evaluate the value of implantable cardioverter-defibrillator (ICD) implantation in sudden cardiac arrest survivors with presumably reversible ischemia and complete revascularization. Methods and Results This multicenter retrospective cohort study included 276 patients (80% men, age 67±10 years) receiving ICD implantation for secondary prevention. Angiography was performed before ICD implantation. A subgroup of 166 (60%) patients underwent cardiac magnetic resonance imaging with late gadolinium enhancement before implantation. Patients were divided in 2 groups, (1) ICD-per-guideline, including 228 patients with incomplete revascularization or left ventricular ejection fraction ≤35%, and (2) ICD-off-label, including 48 patients with complete revascularization and left ventricular ejection fraction >35%. The primary outcome was time to appropriate device therapy (ADT). During 4.0 years (interquartile range, 3.5-4.6) of follow-up, ADT developed in 15% of the ICD-off-label group versus 43% of the ICD-per-guideline group. Time to ADT was comparable in the ICD-off-label and ICD-per-guideline groups (hazard ratio (HR), 0.46; P =0.08). No difference in mortality was observed (HR, 0.95; P =0.93). Independent predictors of ADT included age (HR, 1.03; P =0.01), left ventricular end-diastolic volume HR, (1.05 per 10 mL increase; P <0.01) and extent of transmural late gadolinium enhancement (HR, 1.12; P =0.04). Conclusions This study demonstrates that sudden cardiac arrest survivors with coronary artery disease remain at high risk of recurrent ventricular arrhythmia, even after complete revascularization and with preserved left ventricular function. Late gadolinium enhancement-cardiac magnetic resonance imaging derived left ventricular volumes and extent of myocardial scar were independently associated with.

Aims: In non-ischaemic dilated cardiomyopathy (DCM), concomitant right ventricular (RV) dysfunction is frequently observed. This study sought to determine the correlation of RV dysfunction with several cardiac magnetic resonance (CMR) imaging characteristics in patients with DCM, and the prognostic value of RV dysfunction on all-cause mortality and ventricular arrhythmias (VA) was evaluated., Methods and Results: Consecutive patients with DCM and left ventricular (LV) dysfunction (ejection fraction < 50%) on CMR were included retrospectively. Left atrial (LA), LV, and RV volumes and function were quantified. RV systolic dysfunction was defined as RVEF<45%. The presence and pattern of late gadolinium enhancement (LGE) on CMR were assessed visually. Septal midwall LGE was defined as midmyocardial stripe-like or patchy hyperenhancement in the septal segments, and the extent was quantified using the full width at half maximum method. Primary endpoint was a composite of all-cause mortality and VA, including resuscitated cardiac arrest, sustained VA, and appropriate implantable cardioverter defibrillator therapy. Secondary endpoints were time to all-cause mortality alone and time to VA alone. A total of 216 DCM patients were included (42% female, age 58 ± 14 years). Mean RVEF was 46 ± 12%, and RV dysfunction was present in 38%. RVEF was moderately correlated with LA dilation (LA minimal volume ρ = -0.38, P < 0.001) and strongly correlated with LA and LV dysfunction (LA emptying fraction r = 0.58, P < 0.001 and LVEF ρ = 0.52, P < 0.001). Septal midwall LGE was more often observed in patients with RV dysfunction compared with patients with preserved RV function (respectively 40% vs. 26%, P = 0.04). No correlation was found between RVEF and the extent of septal midwall LGE (ρ = -0.12, P = 0.34). During a median follow-up of 2.2 years [IQR 1.6-2.8], 30 patients experienced the primary endpoint. RV dysfunction was significantly associated with shorter time to the composite primary endpoint (HR 3.19 [95% CI 1.49-6.84], P < 0.01) and to the secondary endpoint of VA alone (HR 6.48 [95% CI 1.83-22.98], P < 0.01). There was a trend towards increased mortality when RV dysfunction was present (HR 2.54 [95% CI 0.99-6.57], P = 0.05)., Conclusions: Right ventricular dysfunction was predominantly observed in patients with DCM with advanced heart failure and pronounced myocardial remodelling, defined as increased LV and LA dilation and dysfunction and the presence of septal midwall LGE on CMR. During follow-up, RV dysfunction was associated with shorter time to all-cause mortality and ventricular arrhythmic events., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients., Methods: Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation., Results: The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR., Conclusion: Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery.

Aim: To investigate the temporal evolution of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor (LDLR) and myeloperoxidase (MPO) in relation to clinical outcome in chronic heart failure (CHF). Methodology & results: Trimonthly blood sampling was performed during a median follow-up of 2.2 (IQR 1.4-2.5) years in 263 CHF patients. Seventy patients reached the primary end point (PE) (cardiovascular death, heart transplantation, left ventricular assist device implantation or HF-hospitalization). MPO level was independently associated with the PE; the adjusted (for clinical factors) hazard ratio (aHR) per standard deviation difference in MPO was 1.71 (95% CI: 1.23-2.43) at any time during follow-up. PCSK9 level (HR: 1.45 [1.04-2.06]) and LDLR (HR: 0.66 [0.49-0.87]) were statistical significantly associated with the PE but only in unadjusted analyses. Slope of temporal MPO evolution (aHR: 1.34 [1.12-1.76] per 0.1 standard deviation/year difference in slope) and LDLR (aHR: 0.78 [0.61-0.90]) however, were associated with PE. Conclusion: Temporal patterns of MPO and LDLR are independently associated with clinical outcome in CHF, which illustrates the importance of assessing temporal evolutions. Clinical trial registration information: registered in ClinicalTrials.gov, number NCT01851538. https://clinicaltrials.gov/ct2/show/NCT01851538.

In this prospective cohort study of 250 stable heart failure patients with trimonthly blood sampling, we investigated associations of 17 repeatedly measured cytokines and cytokine receptors with clinical outcome during a median follow-up of 2.2 (25th-75th percentile, 1.4-2.5) years. Sixty-six patients reached the primary end point (composite of cardiovascular mortality, heart failure hospitalization, heart transplantation, left ventricular assist device implantation). Repeatedly measured levels of 8 biomarkers correlated with clinical outcomes independent of clinical characteristics. Rates of change over time (slopes of biomarker evolutions) remained independently associated with outcome for 15 biomarkers. Thus, temporal patterns of cytokines and cytokine receptors, in particular tumour necrosis factor ligand superfamily member 13B and interleukin-1 receptor type 1, might contribute to personalized risk assessment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Evidence on the association of macrophage- and neutrophil-related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C-reactive protein, no data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF)., Methods and Results: In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine-rich type 1 protein M130 (CD163), tartrate-resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin-1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow-up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event-free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow-up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics [hazard ratio (95% confidence interval) per 1-standard deviation change in biomarker]: CD163 [2.07(1.47-2.98), P < 0.001], TRAP [0.62 (0.43-0.90), P = 0.009], GRN [2.46 (1.64-3.84), P < 0.001], SPON1 [3.94 (2.50-6.50), P < 0.001], and PGLYRP1 [1.62 (1.14-2.31), P = 0.006]., Conclusions: Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes., Hypothesis: Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants., Methods: During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-β-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation., Results: Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m 2 eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m 2 eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0])., Conclusion: Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: Atrial fibrillation (AF) is associated with cognitive decline and dementia. This study investigates whether the Montreal Cognitive Assessment (MoCA) detects more cognitive decline than the Mini Mental State Examination (MMSE) in patients with AF. Secondary aims were to assess the rate of white matter hyperintensities (WMH) and mesotemporal atrophy (MTA) in patients with AF., Methods: Observational cohort study. Patients of 65 years and older that visited the Fall and Syncope Clinic were eligible. Patients were included if both a MoCA and MMSE were completed. In patients of whom an MRI was performed WMH were assessed with the Fazekas score and MTA was assessed with the MTA score. To assess frailty a Frailty Index (FI) was calculated., Results: 428 patients were included. Mean age was 80 years, 66% was female. The mean FI was 0.28 (CI 0.11 to 0.45), indicative of severe frailty. In 90 patients AF was known and in 9 patients it was first diagnosed, overall prevalence 23%. Cognitive impairment was found with the MoCA in 80% of patients with persistent AF, versus in 33% with the MMSE. Patients with paroxysmal AF had more WMH than patients with SR (p 0.04). No differences were found in relevant MTA between patients with AF or SR., Conclusions: Cognitive decline in patients with AF is better detected using the MoCA than the MMSE. This means that in daily clinical practice, the MOCA should be used instead of the MMSE for patients with AF.

Background Hypertrophic cardiomyopathy is caused by pathogenic sarcomere gene variants. Individuals with a thin-filament variant present with milder hypertrophy than carriers of thick-filament variants, although prognosis is poorer. Herein, we defined if decreased energetic status of the heart is an early pathomechanism in TNNT2 (troponin T gene) variant carriers. Methods and Results Fourteen individuals with TNNT2 variants (genotype positive), without left ventricular hypertrophy (G+/LVH-; n=6) and with LVH (G+/LVH+; n=8) and 14 healthy controls were included. All participants underwent cardiac magnetic resonance and [ 11 C]-acetate positron emission tomography imaging to assess LV myocardial oxygen consumption, contractile parameters and myocardial external efficiency. Cardiac efficiency was significantly reduced compared with controls in G+/LVH- and G+/LVH+. Lower myocardial external efficiency in G+/LVH- is explained by higher global and regional oxygen consumption compared with controls without changes in contractile parameters. Reduced myocardial external efficiency in G+/LVH+ is explained by the increase in LV mass and higher oxygen consumption. Septal oxygen consumption was significantly lower in G+/LVH+ compared with G+/LVH-. Although LV ejection fraction was higher in G+/LVH+, both systolic and diastolic strain parameters were lower compared with controls, which was most evident in the hypertrophied septal wall. Conclusions Using cardiac magnetic resonance and [ 11 C]-acetate positron emission tomography imaging, we show that G+/LVH- have an initial increase in oxygen consumption preceding contractile dysfunction and cardiac hypertrophy, followed by a decline in oxygen consumption in G+/LVH+. This suggests that high oxygen consumption and reduced myocardial external efficiency characterize the early gene variant-mediated disease mechanisms that may be used for early diagnosis and development of preventive treatments.

Objective: To determine the diagnostic yield of repeated screening for atrial fibrillation (AF) among geriatric patients., Methods: A pragmatic prospective cohort study into applying opportunistic screening for AF with a handheld single lead ECG device (SLD) in a geriatric cohort. Consecutive patients of 65 years old and older visiting the geriatric outpatient clinic were eligible for inclusion. A 12 lead ECG was performed, followed by measurements with the SLD during every visit to the geriatric outpatient clinic. A frailty index was based on the accumulation of deficits model., Results: 478 patients were eligible. Patients were excluded if they did not give informed consent (17 patients), had a pacemaker or implantable cardioverter defibrillator (20 patients), or had incomplete medical files (two patients). After exclusion, 439 patients participated in this study. The mean age was 78 years (range 65 to 100 years), 54% were female. AF was known in 89 patients (20%), first detected on the baseline ECG in four patients (1%) and first detected with the SLD in 20 patients (5%) during follow up visits. Sensitivity of the SLD was 90.0%, specificity 99.0%, negative predictive value 99.7%, and positive predictive value 73.5%. Most patients (82%) with AF were frail and 53% were severely frail., Conclusion: Repeated screening in geriatric patients has a five times higher diagnostic yield than usual care. It was easily combined with usual care. Because of the positive predictive value of 73.5%, it remains necessary to confirm AF with a 12 lead ECG or 24-h Holter monitoring., (Institute of Geriatric Cardiology.)

Background: Septal midwall late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is a characteristic finding in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse cardiac events. QRS-prolongation in DCM is also frequently present and a predictor of arrhythmic events and mortality. Since the His-Purkinje fibres are located in the interventricular septum, QRS-prolongation may directly result from septal fibrosis, visualized by LGE. Our aim was to study the correlation of the presence and extent of septal midwall LGE and QRS-duration., Methods: DCM-patients with left ventricular (LV) dysfunction (LVEF < 50%) were included. LV volumes, systolic function and nonischemic septal midwall LGE, defined as patchy or stripe-like LGE in the septal segments, were quantified. QRS-duration on standard 12-lead ECG was measured., Results: 165 DCM-patients were included (62% male, mean age 59 ± 15 years) with a median LVEF of 36% [24-44]. Fifty-one patients (31%) demonstrated septal midwall LGE with a median extent of 8.1 gram [4.3-16.8]. Patients with midwall LGE had increased LV end-diastolic volumes (EDV) 248 mL [193-301] vs. 193 mL [160-239], p < 0.001) and lower LVEF (26% [18-35] vs. 40% [32-45], p < 0.001). Median QRS-duration was 110 ms [95-146] without a correlation to the presence nor extent of midwall LGE. QRS-duration was moderately correlated with LV-dilation and mass (respectively r = 0.35, p < 0.001 and r = 0.30, p < 0.001)., Conclusion: In DCM-patients, QRS-prolongation and septal midwall LGE are frequently present and often co-exist. However, they are not correlated. This suggests that the assessment of LGE-CMR has complementary value to ECG evaluation in the clinical assessment and risk stratification of DCM-patients., Competing Interests: No conflict of interest. No grants or other form of financial support received., (© 2020 The Authors.)

Cardiovascular inflammation and vascular endothelial dysfunction are involved in chronic heart failure (CHF), and cellular adhesion molecules are considered to play a key role in these mechanisms. We evaluated temporal patterns of 12 blood biomarkers of cell adhesion in patients with CHF. In 263 ambulant patients, serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (1.4-2.5) years. The primary endpoint (PE) was a composite of cardiovascular mortality, HF hospitalization, heart transplantation and implantation of a left ventricular assist device and was reached in 70 patients. We selected the baseline blood samples in all patients, the two samples closest to a PE, or, for event-free patients, the last sample available. In these 567 samples, associations between biomarkers and PE were investigated by joint modelling. The median age was 68 (59-76) years, with 72% men and 74% New York Heart Association class I-II. Repeatedly measured levels of Complement component C1q receptor (C1qR), Cadherin 5 (CDH5), Chitinase-3-like protein 1 (CHI3L1), Ephrin type-B receptor 4 (EPHB4), Intercellular adhesion molecule-2 (ICAM-2) and Junctional adhesion molecule A (JAM-A) were independently associated with the PE. Their rates of change also predicted clinical outcome. Level of CHI3L1 was numerically the strongest predictor with a hazard ratio (HR) (95% confidence interval) of 2.27 (1.66-3.16) per SD difference in level, followed by JAM-A (2.10, 1.42-3.23) and C1qR (1.90, 1.36-2.72), adjusted for clinical characteristics. In conclusion, temporal patterns of C1qR, CDH5, CHI3L1, EPHB4, ICAM2 and JAM-A are strongly and independently associated with clinical outcome in CHF patients., Competing Interests: One of the co-authors, Henk Mouthaan, is employed by Olink Proteomics.

Background Remodeling biomarkers carry high potential for predicting adverse events in chronic heart failure ( CHF ) patients. However, temporal patterns during the course of CHF , and especially the trajectory before an adverse event, are unknown. We studied the prognostic value of temporal patterns of 14 cardiac remodeling biomarker candidates in stable patients with CHF from the Bio-SHiFT (Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis) study. Methods and Results In 263 CHF patients, we performed trimonthly blood sampling during a median follow-up of 2.2 years. For the analysis, we selected all baseline samples, the 2 samples closest to the primary end point ( PE ), or the last sample available for end point-free patients. Thus, in 567 samples, we measured suppression of tumorigenicity-2, galectin-3, galectin-4, growth differentiation factor-15, matrix metalloproteinase-2, 3, and 9, tissue inhibitor metalloproteinase-4, perlecan, aminopeptidase-N, caspase-3, cathepsin-D, cathepsin-Z, and cystatin-B. The PE was a composite of cardiovascular mortality, heart transplantation, left ventricular assist device implantation, and HF hospitalization. Associations between repeatedly measured biomarker candidates and the PE were investigated by joint modeling. Median age was 68 (interquartile range: 59-76) years with 72% men; 70 patients reached the PE . Repeatedly measured suppression of tumorigenicity-2, galectin-3, galectin-4, growth differentiation factor-15, matrix metalloproteinase-2 and 9, tissue inhibitor metalloproteinase-4, perlecan, cathepsin-D, and cystatin-B levels were significantly associated with the PE , and increased as the PE approached. The slopes of biomarker trajectories were also predictors of clinical outcome, independent of their absolute level. Associations persisted after adjustment for clinical characteristics and pharmacological treatment. Suppression of tumorigenicity-2 was the strongest predictor (hazard ratio: 7.55 per SD difference, 95% CI : 5.53-10.30), followed by growth differentiation factor-15 (4.06, 2.98-5.54) and matrix metalloproteinase-2 (3.59, 2.55-5.05). Conclusions Temporal patterns of remodeling biomarker candidates predict adverse clinical outcomes in CHF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01851538.

Background: Our aim was to explore potential use of temporal profiles of seven emerging cardio-renal and two pulmonary candidate biomarkers for predicting future adverse clinical outcome in stable patients with chronic heart failure (CHF)., Methods: In 263 CHF patients, we determined the risk of a composite endpoint of HF-hospitalization, cardiac death, LVAD-placement and heart transplantation in relation to repeatedly assessed (567 samples in total) blood biomarker levels, and slopes of their temporal trajectories (i.e., rate of biomarker change per year). In each patient, we estimated biomarker trajectories using repeatedly measured osteopontin (OPN), osteoprotegerin (OPG), epidermal growth factor receptor (EGFR), heparin-binding protein (HBP), trefoil factor-3 (TFF3), kallikrein-6 (KLK-6), matrix extracellular phosphoglycoprotein (MEPE), pulmonary surfactant-associated protein-D (PSP-D), and secretoglobulin family 3A-member-2 (SCGB3A2)., Results: During 2.2 years of follow-up, OPN, OPG, and HBP levels predicted the composite endpoint (univariable hazard ratio [95% confidence interval] per 1SD increase: 2.31 [1.76-3.15], 2.23 [1.69-3.00], and 1.36[1.09-1.70]). Independently of the biomarkers' levels, the slopes of OPG, TFF-3, PSP-D trajectories were also strong clinical predictors (per 0.1SD increase: 1.24 [1.14-1.38], 1.31 [1.17-1.49], and 1.32 [1.21-1.47]). All associations persisted after multivariable adjustment for baseline characteristics, and repeatedly assessed CHF pharmacological treatment and cardiac biomarkers NT-proBNP and troponin T., Conclusions: Repeatedly-measured levels of OPN, OPG, and HBP, and slopes of OPG, TFF-3, and PSP-D strongly predict clinical outcome. These candidate biomarkers may be clinically relevant as they could further define a patient's risk and provide additional pathophysiological insights into CHF., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Multiple hormonal and metabolic alterations occur in chronic heart failure (CHF), but their proper monitoring during clinically silent progression of CHF remains challenging. Hence, our objective was to explore whether temporal patterns of six emerging cardiometabolic biomarkers predict future adverse clinical events in stable patients with CHF., Methods: In 263 patients with CHF, we determined the risk of a composite end point of heart failure hospitalization, cardiac death, left ventricular assist device implantation, and heart transplantation in relation to serially assessed blood biomarker levels and slopes (i.e., rate of biomarker change per year). During 2.2 years of follow-up, we repeatedly measured IGF binding proteins 1, 2, and 7 (IGFBP-1, IGFBP-2, IGFBP-7), adipose fatty acid binding protein 4 (FABP-4), resistin, and chemerin (567 samples in total)., Results: Serially measured IGFBP-1, IGFBP-2, IGFBP-7, and FABP-4 levels predicted the end point [univariable hazard ratio (95% CI) per 1-SD increase: 3.34 (2.43 to 4.87), 2.86 (2.10 to 3.92), 2.45 (1.91 to 3.13), and 2.46 (1.88 to 3.24), respectively]. Independently of the biomarkers' levels, their slopes were also strong clinical predictors [per 0.1-SD increase: 1.20 (1.11 to 1.31), 1.27 (1.14 to 1.45), 1.23 (1.11 to 1.37), and 1.27 (1.12 to 1.48)]. All associations persisted after multivariable adjustment for patient baseline characteristics, baseline N-terminal pro-hormone brain natriuretic peptide and cardiac troponin T, and pharmacological treatment during follow-up., Main Conclusions: The temporal patterns of IGFBP-1, IGFBP-2, IGFBP-7, and adipose FABP-4 predict adverse clinical outcomes during outpatient follow-up of patients with CHF and may be clinically relevant as they could help detect more aggressive CHF forms and assess patient prognosis, as well as ultimately aid in designing more effective biomarker-guided therapy.

Objectives: This review and meta-analysis reviews the prognostic value of cardiac magnetic resonance (CMR) in nonischemic dilated cardiomyopathy (DCM)., Background: Late gadolinium-enhanced (LGE) CMR is a noninvasive method to determine the underlying cause of DCM and previous studies reported the prognostic value of the presence of LGE to identify patients at risk of major adverse cardiovascular events., Methods: PubMed was searched for studies describing the prognostic implication of LGE in patients with DCM for the specified endpoints cardiovascular mortality, major ventricular arrhythmic events including appropriate implantable cardioverter-defibrillator therapy, rehospitalization for heart failure, and left ventricular reverse remodeling., Results: Data from 34 studies were included, with a total of 4,554 patients. Contrast enhancement was present in 44.8% of DCM patients. Patients with LGE had increased cardiovascular mortality (odds ratio [OR]: 3.40; 95% confidence interval [CI]: 2.04 to 5.67), ventricular arrhythmic events (OR: 4.52; 95% CI: 3.41 to 5.99), and rehospitalization for heart failure (OR: 2.66; 95% CI: 1.67 to 4.24) compared with those without LGE. Moreover, the absence of LGE predicted left ventricular reverse remodeling (OR: 0.15; 95% CI: 0.06 to 0.36)., Conclusions: The presence of LGE on CMR substantially worsens prognosis for adverse cardiovascular events in DCM patients, and the absence indicates left ventricular reverse remodeling., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate different patterns of orthostatic hypotension (OH) and its relation to mortality in older patients with unexplained falls or syncope., Methods: This is an observational cohort study in consecutive patients aged ≥ 65 years with unexplained falls or syncope at a Fall Syncope day clinic November 2011 until May 2016. OH is defined as a decrease in systolic blood pressure (BP) ≥ 20 mmHg and/or in diastolic BP ≥ 10 mmHg during standing test. Main outcomes are the baseline characteristics and prevalence of patients with classical OH (decrease BP until 3 min), delayed OH (decrease of BP from 5 to 10 min) and continuous OH (decrease of BP for 10 min). Secondary outcome is the relation between different OH patterns and mortality., Results: Of 374 patients with a mean age of 80 year (SD 6.6), 56% of the patients had OH: 16% had classical OH, 8% delayed OH, 32% had continuous OH and 44% had no OH. Patients with continuous OH and patients with delayed OH tended to have a higher mortality compared to patients with classical OH, 14 vs. 5% (P = 0.07) and 17 vs. 5% (P = 0.06). This possible relation between OH patterns and mortality could not be confirmed in multivariate analysis., Conclusions: In these very old patients, there are various patterns of decline in standing BP. Delayed and continuous OH will be missed if BP is measured only for 3 min during standing. This is important because patients with continuous OH and delayed OH might have a relation with mortality. Our results encourage additional studies investigating the relation between different OH patterns and mortality., (© 2018. European Geriatric Medicine Society.)

We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C-reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d-glucosaminidase and kidney-injury-molecule-1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03-1.22) per 40 mg higher doses. ACE-inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE-inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)