Publications by authors named "Folkert W Asselbergs"

369 Publications

Heart failure medication dosage and survival in women and men seen at outpatient clinics.

Heart 2021 Jul 14. Epub 2021 Jul 14.

Laboratory for Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands

Objective: Women with heart failure with reduced ejection fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended medication dose. This study investigates prescription practice and its relation with survival of patients with HF in daily care.

Methods: Electronic health record data from 13 Dutch outpatient cardiology clinics were extracted for HF receiving at least one guideline-recommended HF medication. Dose changes over consecutive prescriptions were modelled using natural cubic splines. Inverse probability-weighted Cox regression was used to assess the relationship between dose (reference≥50% target dose) and all-cause mortality.

Results: The study population comprised 561 women (29% HFrEF (ejection fraction (EF)<40%), 49% heart failure with preserved ejection fraction (EF≥50%); HFpEF and 615 men (47% and 25%, respectively). During a median follow-up of 3.7 years, 252 patients died (48% women; 167 HFrEF, 84 HFpEF). Nine hundred thirty-four patients (46% women) received ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 795 (48% women) beta blockers and 178 (42% women) mineralocorticoid receptor antagonists (MRAs). In both sexes, the mean target dose across prescriptions was 50% for ACEI/ARBs and beta blockers, and 100% for MRAs. ACEI/ARB dose of <50% was associated with lower mortality in women but not in men with HFrEF. This was not seen in patients with HFpEF. Beta-blocker dose was not associated with all-cause mortality.

Conclusion: Patients with HF seen in outpatient cardiology clinics receive half of the guideline-recommended medication dose. Lower ACEI/ARB dose was associated with improved survival in women with HFrEF. These results underscore the importance of (re)defining optimal medical therapy for women with HFrEF.
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http://dx.doi.org/10.1136/heartjnl-2021-319229DOI Listing
July 2021

A novel risk model for predicting potentially life-threatening arrhythmias in non-ischemic dilated cardiomyopathy (DCM-SVA risk).

Int J Cardiol 2021 Jul 7. Epub 2021 Jul 7.

University Hospital of Heidelberg, Cardiology, Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany; Department of Genetics, Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Background: Non-ischemic dilated cardiomyopathy (DCM) can be complicated by sustained ventricular arrhythmias (SVA) and sudden cardiac death (SCD). By now, left-ventricular ejection fraction (LV-EF) is the main guideline criterion for primary prophylactic ICD implantation, potentially leading either to overtreatment or failed detection of patients at risk without severely impaired LV-EF. The aim of the European multi-center study DETECTIN-HF was to establish a clinical risk calculator for individualized risk stratification of DCM patients.

Methods: 1393 patients (68% male, mean age 50.7 ± 14.3y) from four European countries were included. The outcome was occurrence of first potentially life-threatening ventricular arrhythmia. The model was developed using Cox proportional hazards, and internally validated using cross validation. The model included seven independent and easily accessible clinical parameters sex, history of non-sustained ventricular tachycardia, history of syncope, family history of cardiomyopathy, QRS duration, LV-EF, and history of atrial fibrillation. The model was also expanded to account for presence of LGE as the eight8h parameter for cases with available cMRI and scar information.

Results: During a mean follow-up period of 57.0 months, 193 (13.8%) patients experienced an arrhythmic event. The calibration slope of the developed model was 00.97 (95% CI 0.90-1.03) and the C-index was 0.72 (95% CI 0.71-0.73). Compared to current guidelines, the model was able to protect the same number of patients (5-year risk ≥8.5%) with 15% fewer ICD implantations.

Conclusions: This DCM-SVA risk model could improve decision making in primary prevention of SCD in non-ischemic DCM using easily accessible clinical information and will likely reduce overtreatment.
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http://dx.doi.org/10.1016/j.ijcard.2021.07.002DOI Listing
July 2021

Prevalence of carriers in Saudi ischemic stroke patients and the suitability of using genotyping to guide antiplatelet therapy in a university hospital setup.

Drug Metab Pers Ther 2021 Jul 8. Epub 2021 Jul 8.

Department of Clinical Biochemistry, College of Medicine, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.

Objectives: To mitigate the incidence of recurrent stroke in patients, dual antiplatelet therapy comprising aspirin and clopidogrel is usually administered. Clopidogrel is a prodrug and its bioactivation is catalyzed by cytochrome P450 (CYP)2C19. The main objective of this work was to determine the prevalence of carriers in Saudi ischemic stroke patients and assess the suitability of using genotyping to guide antiplatelet therapy in a university hospital setup.

Methods: This prospective (2018-2019) study was conducted on 256 patients (age 61 ± 12.5) clinically diagnosed with ischemic stroke who were genotyped using Spartan RX assay.

Results: From the total patient group (256), upon admission, 210 patients were prescribed either aspirin, clopidogrel or dual antiplatelet therapy. Of the 27 patients with the allele who were prescribed clopidogrel (18) or dual antiplatelet therapy (9), only 21 patients could be followed up for a period of six months post stroke event, in addition to 21 age- and sex-matched patients with the normal allele. The allele carriers had a statistically significant increased risk of recurrent stroke compared to patients carrying the normal allele.

Conclusions: This study shows the suitability of using genotyping to guide antiplatelet therapy in ischemic stroke patients in a clinical setting.
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http://dx.doi.org/10.1515/dmdi-2021-0104DOI Listing
July 2021

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction.

Eur Heart J 2021 Jun 11. Epub 2021 Jun 11.

Heart Center, Department of Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands.

Aims: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model.

Methods And Results: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75).

Conclusion: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.
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http://dx.doi.org/10.1093/eurheartj/ehab294DOI Listing
June 2021

Routine clinical care data from thirteen cardiac outpatient clinics: design of the Cardiology Centers of the Netherlands (CCN) database.

BMC Cardiovasc Disord 2021 Jun 10;21(1):287. Epub 2021 Jun 10.

Department of Cardiology, Amsterdam University Medical Centres, location VUmc, Amsterdam, The Netherlands.

Background: Despite the increasing availability of clinical data due to the digitalisation of healthcare systems, data often remain inaccessible due to the diversity of data collection systems. In the Netherlands, Cardiology Centers of the Netherlands (CCN) introduced "one-stop shop" diagnostic clinics for patients suspected of cardiac disease by their general practitioner. All CCN clinics use the same data collection system and standardised protocol, creating a large regular care database. This database can be used to describe referral practices, evaluate risk factors for cardiovascular disease (CVD) in important patient subgroups, and develop prediction models for use in daily care.

Construction And Content: The current database contains data on all patients who underwent a cardiac workup in one of the 13 CCN clinics between 2007 and February 2018 (n = 109,151, 51.9% women). Data were pseudonymised and contain information on anthropometrics, cardiac symptoms, risk factors, comorbidities, cardiovascular and family history, standard blood laboratory measurements, transthoracic echocardiography, electrocardiography in rest and during exercise, and medication use. Clinical follow-up is based on medical need and consisted of either a repeat visit at CCN (43.8%) or referral for an external procedure in a hospital (16.5%). Passive follow-up via linkage to national mortality registers is available for 95% of the database.

Utility And Discussion: The CCN database provides a strong base for research into historically underrepresented patient groups due to the large number of patients and the lack of in- and exclusion criteria. It also enables the development of artificial intelligence-based decision support tools. Its contemporary nature allows for comparison of daily care with the current guidelines and protocols. Missing data is an inherent limitation, as the cardiologist could deviate from standardised protocols when clinically indicated.

Conclusion: The CCN database offers the opportunity to conduct research in a unique population referred from the general practitioner to the cardiologist for diagnostic workup. This, in combination with its large size, the representation of historically underrepresented patient groups and contemporary nature makes it a valuable tool for expanding our knowledge of cardiovascular diseases.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s12872-021-02020-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191101PMC
June 2021

Persistent Symptoms and Health Needs of Women and Men With Non-Obstructed Coronary Arteries in the Years Following Coronary Angiography.

Front Cardiovasc Med 2021 3;8:670843. Epub 2021 May 3.

Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

The prognosis of women and men with persistent anginal complaints and non-obstructed coronary arteries is impaired as compared with asymptomatic women and men. The increased healthcare burden in the hospital due to repeated coronary angiography in these women and men has been documented, yet little is known about the percentage of women and men who remain symptomatic and under care of the general practitioner in the years following a coronary angiographic outcome of non-obstructed coronary arteries. From the Utrecht Coronary Biobank study, including individuals who underwent a coronary angiography from 2011 to 2015 ( = 2,546, 27% women), we selected women and men with non-obstructed coronary arteries ( = 687, 39% women). This population was linked to the Julius General Practitioners Network (JGPN); a database with routine care data of general practitioners. For every individual with non-obstructed coronary arteries, we selected an asymptomatic non-referred age-, sex-, and general practitioner-matched individual from the JGPN. We compared the healthcare consumption of men and women with non-obstructed coronary arteries to these matched individuals. The McNemar's test was used for pairwise comparison, and sex differences were assessed using stratified analyses. The prevalence of non-obstructed coronary arteries was higher in women as compared with men (39 vs. 23%). During a median follow-up of 7 years [IQR 6.4-8.0], 89% of the individuals with non-obstructed coronary arteries (91% women and 87% men) visited their general practitioner for one or more cardiovascular consultations. This was compared to 34% of the matched individuals (89 vs. 34%, < 0.001). The consultations were most often for angina (equivalents) (57 vs. 11%, < 0.001) and heart failure (10 vs. 2%, = 0.015). In addition, they more often consulted the general practitioner for psychosocial complaints (31 vs. 15%, = 0.005). Findings were similar for women and men. A coronary angiographic outcome of non-obstructed coronary arteries is more common in women than in men. In the years following the coronary angiography, the majority of the population remains symptomatic. Both women and men with non-obstructed coronary arteries had higher health needs for angina, heart failure, and psychosocial complaints than matched asymptomatic individuals.
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http://dx.doi.org/10.3389/fcvm.2021.670843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126611PMC
May 2021

Residual cardiovascular risk reduction guided by lifetime benefit estimation in patients with symptomatic atherosclerotic disease: effectiveness and cost-effectiveness.

Eur J Prev Cardiol 2021 May 2. Epub 2021 May 2.

Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands.

Aims: To determine the (cost)-effectiveness of blood pressure lowering, lipid-lowering, and antithrombotic therapy guided by predicted lifetime benefit compared to risk factor levels in patients with symptomatic atherosclerotic disease.

Methods And Results : For all patients with symptomatic atherosclerotic disease in the UCC-SMART cohort (1996-2018; n = 7697) two treatment strategies were compared. The lifetime benefit-guided strategy was based on individual estimation of gain in cardiovascular disease (CVD)-free life with the SMART-REACH model. In the risk factor-based strategy, all patients were treated the following: low-density lipoprotein cholesterol (LDL-c) < 1.8 mmol/L, systolic blood pressure <140 mmHg, and antithrombotic medication. Outcomes were evaluated for the total cohort using a microsimulation model. Effectiveness was evaluated as total gain in CVD-free life and events avoided, cost-effectiveness as incremental cost-effectivity ratio (ICER). In comparison to baseline treatment, treatment according to lifetime benefit would lead to an increase of 24 243 CVD-free life years [95% confidence interval (CI) 19 980-29 909] and would avoid 940 (95% CI 742-1140) events in the next 10 years. For risk-factor based treatment, this would be an increase of 18 564 CVD-free life years (95% CI 14 225-20 456) and decrease of 857 (95% CI 661-1057) events. The ICER of lifetime benefit-based treatment with a treatment threshold of ≥1 year additional CVD-free life per therapy was €15 092/QALY gained and of risk factor-based treatment €9933/QALY gained. In a direct comparison, lifetime benefit-based treatment compared to risk factor-based treatment results in 1871 additional QALYs for the price of €36 538/QALY gained.

Conclusion : Residual risk reduction guided by lifetime benefit estimation results in more CVD-free life years and more CVD events avoided compared to the conventional risk factor-based strategy. Lifetime benefit-based treatment is an effective and potentially cost-effective strategy for reducing residual CVD risk in patients with clinical manifest vascular disease.
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http://dx.doi.org/10.1093/eurjpc/zwab028DOI Listing
May 2021

Relationship between classic vascular risk factors and cumulative recurrent cardiovascular event burden in patients with clinically manifest vascular disease: results from the UCC-SMART prospective cohort study.

BMJ Open 2021 03 8;11(3):e038881. Epub 2021 Mar 8.

Department of Vascular Medicine, Utrecht University, Utrecht, The Netherlands

Objective: The aim of the current study was to assess the relationship between classic cardiovascular risk factors and risk of not only the first recurrent atherosclerotic cardiovascular event, but also the total number of non-fatal and fatal cardiovascular events in patients with recently clinically manifest cardiovascular disease (CVD).

Design: Prospective cohort study.

Setting: Tertiary care centre.

Participants: 7239 patients with a recent first manifestation of CVD from the prospective UCC-SMART (Utrecht Cardiovascular Cohort - Second Manifestations of ARTerial disease) cohort study.

Outcome Measures: Total cardiovascular events, including myocardial infarction, stroke, vascular interventions, major limb events and cardiovascular mortality.

Results: During a median follow-up of 8.9 years, 1412 patients had one recurrent cardiovascular event, while 1290 patients had two or more recurrent events, with a total of 5457 cardiovascular events during follow-up. The HRs for the first recurrent event and cumulative event burden using Prentice-Williams-Peterson models, respectively, were 1.36 (95% CI 1.25 to 1.48) and 1.26 (95% CI 1.17 to 1.35) for smoking, 1.14 (95% CI 1.11 to 1.18) and 1.09 (95% CI 1.06 to 1.12) for non-high-density lipoprotein (HDL) cholesterol, and 1.05 (95% CI 1.03 to 1.07) and 1.04 (95% CI 1.03 to 1.06) for systolic blood pressure per 10 mm Hg.

Conclusions: In a cohort of patients with established CVD, systolic blood pressure, non-HDL cholesterol and current smoking are important risk factors for not only the first, but also subsequent recurrent events during follow-up. Recurrent event analysis captures the full cumulative burden of CVD in patients.
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http://dx.doi.org/10.1136/bmjopen-2020-038881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942272PMC
March 2021

Common Variants Associated With Expression Contribute to Carotid Plaque Vulnerability, but Not to Cardiovascular Disease in Humans.

Front Cardiovasc Med 2021 20;8:658915. Epub 2021 Apr 20.

Central Diagnostics Laboratory, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands.

Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in and its receptors, and , on overall plaque vulnerability, plaque phenotype, intraplaque and expression, coronary artery calcification burden and cardiovascular disease susceptibility. We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased expression and that rs10491509 (A allele) was associated with increased expression in arterial tissues. No variant was significantly associated with expression. We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, = 3.00 × 10, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, = 4.66 × 10, C allele) and collagen content (β = -0.259 ± s.e. = 0.095, = 6.22 × 10, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque expression. Neither was intraplaque expression associated with plaque vulnerability and no known eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the locus. Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility.
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http://dx.doi.org/10.3389/fcvm.2021.658915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093786PMC
April 2021

Apparent treatment resistant hypertension and the risk of recurrent cardiovascular events and mortality in patients with established vascular disease.

Int J Cardiol 2021 Jul 29;334:135-141. Epub 2021 Apr 29.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Aim: To quantify the relation between apparent treatment resistant hypertension (aTRH) and the risk of recurrent major adverse cardiovascular events (MACE including stroke, myocardial infarction and vascular death) and mortality in patients with stable vascular disease.

Methods: 7455 hypertensive patients with symptomatic vascular disease were included from the ongoing UCC-SMART cohort between 1996 and 2019. aTRH was defined as an office blood pressure ≥140/90 mmHg despite treatment with ≥3 antihypertensive drugs including a diuretic. Cox proportional hazard models were used to quantify the relation between aTRH and the risk of recurrent MACE and all-cause mortality. In addition, survival for patients with aTRH was assessed, taking competing risk of non-vascular mortality into account.

Results: A total of 1557 MACE and 1882 deaths occurred during a median follow-up of 9.0 years (interquartile range 4.8-13.1 years). Compared to patients with non-aTRH, the 614 patients (8%) with aTRH were at increased risk of cardiovascular mortality (HR 1.27; 95% CI 1.03-1.56) and death from any cause (HR 1.25; 95% CI 1.07-1.45) but not recurrent MACE (HR 1.13; 95% CI 0.95-1.34). At the age of 50 years, patients with aTRH after a first cardiovascular event on average had a 6.4 year shorter median life expectancy free of recurrent MACE than patients with non-aTRH.

Conclusion: In hypertensive patients with clinically manifest vascular disease, aTRH is related to a higher risk of vascular death and death from any cause. Moreover, patients with aTRH after a first cardiovascular event have a 6.4 year shorter median life expectancy free of recurrent cardiovascular disease.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.047DOI Listing
July 2021

The Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy.

Circulation 2021 Apr 30. Epub 2021 Apr 30.

Cardiovascular Institute, Stanford University, Stanford, CA; Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA.

Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy (DCM) with a high prevalence of ventricular arrhythmias. How the R14 deletion causes DCM is poorly understood and there are no disease-specific therapies. We used single-cell RNA sequencing to uncover PLN R14del disease-mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We utilized both 2D and 3D functional contractility assays to evaluate the impact of modulating disease relevant pathways in PLN R14del hiPSC-CMs. Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease . Single-cell RNA sequencing revealed the induction of the unfolded protein response pathway (UPR) in PLN R14del compared to isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the three main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP protein Inducer X (BiX). PLN R14del hiPSC-CMs treated with BiX showed a dose-dependent amelioration of the contractility deficit of in both 2D cultures and 3D engineered heart tissues without affecting calcium homeostasis. Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049844DOI Listing
April 2021

Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients.

Int J Cardiol 2021 Jul 20;334:10-17. Epub 2021 Apr 20.

Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands. Electronic address:

Background: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically.

Methods: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding).

Results: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77-1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66-1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62-1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively.

Conclusion: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.029DOI Listing
July 2021

Internal-external cross-validation helped to evaluate the generalizability of prediction models in large clustered datasets.

J Clin Epidemiol 2021 Apr 6;137:83-91. Epub 2021 Apr 6.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands; Health Data Research UK and Institute of Health Informatics, University College London, Gibbs Building, 215 Euston Road, London, NW1 2BE, United Kingdom. Electronic address:

Objective: To illustrate how to evaluate the need of complex strategies for developing generalizable prediction models in large clustered datasets.

Study Design And Setting: We developed eight Cox regression models to estimate the risk of heart failure using a large population-level dataset. These models differed in the number of predictors, the functional form of the predictor effects (non-linear effects and interaction) and the estimation method (maximum likelihood and penalization). Internal-external cross-validation was used to evaluate the models' generalizability across the included general practices.

Results: Among 871,687 individuals from 225 general practices, 43,987 (5.5%) developed heart failure during a median follow-up time of 5.8 years. For discrimination, the simplest prediction model yielded a good concordance statistic, which was not much improved by adopting complex strategies. Between-practice heterogeneity in discrimination was similar in all models. For calibration, the simplest model performed satisfactorily. Although accounting for non-linear effects and interaction slightly improved the calibration slope, it also led to more heterogeneity in the observed/expected ratio. Similar results were found in a second case study involving patients with stroke.

Conclusion: In large clustered datasets, prediction model studies may adopt internal-external cross-validation to evaluate the generalizability of competing models, and to identify promising modelling strategies.
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http://dx.doi.org/10.1016/j.jclinepi.2021.03.025DOI Listing
April 2021

Identification of distinct phenotypic clusters in heart failure with preserved ejection fraction.

Eur J Heart Fail 2021 Jun 1;23(6):973-982. Epub 2021 May 1.

Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Aims: We aimed to derive and validate clinically useful clusters of patients with heart failure with preserved ejection fraction (HFpEF; left ventricular ejection fraction ≥50%).

Methods And Results: We derived a cluster model from 6909 HFpEF patients from the Swedish Heart Failure Registry (SwedeHF) and externally validated this in 2153 patients from the Chronic Heart Failure ESC-guideline based Cardiology practice Quality project (CHECK-HF) registry. In SwedeHF, the median age was 80 [interquartile range 72-86] years, 52% of patients were female and most frequent comorbidities were hypertension (82%), atrial fibrillation (68%), and ischaemic heart disease (48%). Latent class analysis identified five distinct clusters: cluster 1 (10% of patients) were young patients with a low comorbidity burden and the highest proportion of implantable devices; cluster 2 (30%) patients had atrial fibrillation, hypertension without diabetes; cluster 3 (25%) patients were the oldest with many cardiovascular comorbidities and hypertension; cluster 4 (15%) patients had obesity, diabetes and hypertension; and cluster 5 (20%) patients were older with ischaemic heart disease, hypertension and renal failure and were most frequently prescribed diuretics. The clusters were reproduced in the CHECK-HF cohort. Patients in cluster 1 had the best prognosis, while patients in clusters 3 and 5 had the worst age- and sex-adjusted prognosis.

Conclusions: Five distinct clusters of HFpEF patients were identified that differed in clinical characteristics, heart failure drug therapy and prognosis. These results confirm the heterogeneity of HFpEF and form a basis for tailoring trial design to individualized drug therapy in HFpEF patients.
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http://dx.doi.org/10.1002/ejhf.2169DOI Listing
June 2021

Novel CineECG enables anatomical 3D localization and classification of bundle branch blocks.

Europace 2021 Mar;23(Supplement_1):i80-i87

Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht 3508 GA, Heidelberglaan 100, Utrecht, The Netherlands.

Aims: Ventricular conduction disorders can induce arrhythmias and impair cardiac function. Bundle branch blocks (BBBs) are diagnosed by 12-lead electrocardiogram (ECG), but discrimination between BBBs and normal tracings can be challenging. CineECG computes the temporo-spatial trajectory of activation waveforms in a 3D heart model from 12-lead ECGs. Recently, in Brugada patients, CineECG has localized the terminal components of ventricular depolarization to right ventricle outflow tract (RVOT), coincident with arrhythmogenic substrate localization detected by epicardial electro-anatomical maps. This abnormality was not found in normal or right BBB (RBBB) patients. This study aimed at exploring whether CineECG can improve the discrimination between left BBB (LBBB)/RBBB, and incomplete RBBB (iRBBB).

Methods And Results: We utilized 500 12-lead ECGs from the online Physionet-XL-PTB-Diagnostic ECG Database with a certified ECG diagnosis. The mean temporo-spatial isochrone trajectory was calculated and projected into the anatomical 3D heart model. We established five CineECG classes: 'Normal', 'iRBBB', 'RBBB', 'LBBB', and 'Undetermined', to which each tracing was allocated. We determined the accuracy of CineECG classification with the gold standard diagnosis. A total of 391 ECGs were analysed (9 ECGs were excluded for noise) and 240/266 were correctly classified as 'normal', 14/17 as 'iRBBB', 55/55 as 'RBBB', 51/51 as 'LBBB', and 31 as 'undetermined'. The terminal mean temporal spatial isochrone contained most information about the BBB localization.

Conclusion: CineECG provided the anatomical localization of different BBBs and accurately differentiated between normal, LBBB and RBBB, and iRBBB. CineECG may aid clinical diagnostic work-up, potentially contributing to the difficult discrimination between normal, iRBBB, and Brugada patients.
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http://dx.doi.org/10.1093/europace/euaa396DOI Listing
March 2021

End-stage kidney disease in patients with clinically manifest vascular disease; incidence and risk factors: results from the UCC-SMART cohort study.

J Nephrol 2021 Mar 13. Epub 2021 Mar 13.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Patients with cardiovascular disease (CVD) are at increased risk of end-stage kidney disease (ESKD). Insights into the incidence and role of modifiable risk factors for end-stage kidney disease may provide means for prevention in patients with cardiovascular disease.

Methods: We included 8402 patients with stable cardiovascular disease. Incidence rates (IRs) for end-stage kidney disease were determined stratified according to vascular disease location. Cox proportional hazard models were used to assess the risk of end-stage kidney disease for the different determinants.

Results: Sixty-five events were observed with a median follow-up of 8.6 years. The overall incidence rate of end-stage kidney disease was 0.9/1000 person-years. Patients with polyvascular disease had the highest incidence rate (1.8/1000 person-years). Smoking (Hazard ratio (HR) 1.87; 95% CI 1.10-3.19), type 2 diabetes (HR 1.81; 95% CI 1.05-3.14), higher systolic blood pressure (HR 1.37; 95% CI 1.24-1.52/10 mmHg), lower estimated glomerular filtration rate (eGFR) (HR 2.86; 95% CI 2.44-3.23/10 mL/min/1.73 m) and higher urine albumin/creatinine ratio (uACR) (HR 1.19; 95% CI 1.15-1.23/10 mg/mmol) were independently associated with elevated risk of end-stage kidney disease. Body mass index (BMI), waist circumference, non-HDL-cholesterol and exercise were not independently associated with risk of end-stage kidney disease.

Conclusions: Incidence of end-stage kidney disease in patients with cardiovascular disease varies according to vascular disease location. Several modifiable risk factors for end-stage kidney disease were identified in patients with cardiovascular disease. These findings highlight the potential of risk factor management in patients with manifest cardiovascular disease.
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http://dx.doi.org/10.1007/s40620-021-00996-1DOI Listing
March 2021

One year improvement of exercise capacity in patients with mechanical circulatory support as bridge to transplantation.

ESC Heart Fail 2021 06 12;8(3):1796-1805. Epub 2021 Mar 12.

Department of Cardiology, University Medical Center of Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.

Aims: Mechanical circulatory support (MCS) results in substantial improvement of prognosis and functional capacity. Currently, duration of MCS as a bridge to transplantation (BTT) is often prolonged due to shortage of donor hearts. Because long-term results of exercise capacity after MCS are largely unknown, we studied serial cardiopulmonary exercise tests (CPETs) during the first year after MCS implantation.

Methods And Results: Cardiopulmonary exercise tests at 6 and 12 months after MCS implantation in BTT patients were retrospectively analysed, including clinical factors related to exercise capacity. A total of 105 MCS patients (67% male, 50 ± 12 years) underwent serial CPET at 6 and 12 months after implantation. Power (105 ± 35 to 114 ± 40 W; P ≤ 0.001) and peak VO2 per kilogram (pVO2/kg) improved significantly (16.5 ± 5.0 to 17.2 ± 5.5 mL/kg/min (P = 0.008)). Improvement in pVO2 between 6 and 12 months after LVAD implantation was not related to heart failure aetiology or haemodynamic severity prior to MCS. We identified maximal heart rate at exercise as an important factor for pVO2. Younger age and lower BMI were related to further improvement. At 12 months, 25 (24%) patients had a normal exercise capacity (Weber classification A, pVO2 > 20 mL/kg/min).

Conclusions: Exercise capacity (power and pVO2) increased significantly between 6 and 12 months after MCS independent of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile or heart failure aetiology. Heart rate at exercise importantly relates to exercise capacity. This long-term improvement in exercise capacity is important information for the growing group of long-term MCS patients as this is critical for the quality of life of patients.
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http://dx.doi.org/10.1002/ehf2.13234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120393PMC
June 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 05;42(20):2000-2011

Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139853PMC
May 2021

Temporal trends in heart failure medication prescription in a population-based cohort study.

BMJ Open 2021 03 2;11(3):e043290. Epub 2021 Mar 2.

Institute of Health Informatics, University College London, London, UK.

Objective: We examined temporal heart failure (HF) prescription patterns in a large representative sample of real-world patients in the UK, using electronic health records (EHR).

Methods: From primary and secondary care EHR, we identified 85 732 patients with a HF diagnosis between 2002 and 2015. Almost 50% of patients with HF were women and the median age was 79.1 (IQR 70.2-85.7) years, with age at diagnosis increasing over time.

Results: We found several trends in pharmacological HF management, including increased beta blocker prescriptions over time (29% in 2002-2005 and 54% in 2013-2015), which was not observed for mineralocorticoid receptor-antagonists (MR-antagonists) (18% in 2002-2005 and 18% in 2013-2015); higher prescription rates of loop diuretics in women and elderly patients together with lower prescription rates of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, beta blockers or MR-antagonists in these patients; little change in medication prescription rates occurred after 6 months of HF diagnosis and, finally, patients hospitalised for HF who had no recorded follow-up in primary care had considerably lower prescription rates compared with patients with a HF diagnosis in primary care with or without HF hospitalisation.

Conclusion: In the general population, the use of MR-antagonists for HF remained low and did not change throughout 13 years of follow-up. For most patients, few changes were seen in pharmacological management of HF in the 6 months following diagnosis.
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http://dx.doi.org/10.1136/bmjopen-2020-043290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929882PMC
March 2021

Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics.

J Clin Med 2021 Feb 26;10(5). Epub 2021 Feb 26.

Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3582 CX Utrecht, The Netherlands.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and life-threatening ventricular arrhythmias (LTVA). Work-up and risk stratification of DCM is clinically challenging, as there is great heterogeneity in phenotype and genotype. Throughout the last decade, improved genetic testing of patients has identified genotype-phenotype associations and enhanced evaluation of at-risk relatives leading to better patient prognosis. The field is now ripe to explore opportunities to improve personalised risk assessments. Multivariable risk models presented as "risk calculators" can incorporate a multitude of clinical variables and predict outcome (such as heart failure hospitalisations or LTVA). In addition, genetic risk scores derived from genome/exome-wide association studies can estimate an individual's lifetime genetic risk of developing DCM. The use of clinically granular investigations, such as late gadolinium enhancement on cardiac magnetic resonance imaging, is warranted in order to increase predictive performance. To this end, constructing big data infrastructures improves accessibility of data by using electronic health records, existing research databases, and disease registries. By applying methods such as machine and deep learning, we can model complex interactions, identify new phenotype clusters, and perform prognostic modelling. This review aims to provide an overview of the evolution of DCM definitions as well as its clinical work-up and considerations in the era of genomics. In addition, we present exciting examples in the field of big data infrastructures, personalised prognostic assessment, and artificial intelligence.
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http://dx.doi.org/10.3390/jcm10050921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956169PMC
February 2021

Automatic multilabel detection of ICD10 codes in Dutch cardiology discharge letters using neural networks.

NPJ Digit Med 2021 Feb 26;4(1):37. Epub 2021 Feb 26.

Department of Cardiology, Division of Heart & Lungs, University Medical Centre Utrecht, University of Utrecht, Utrecht, The Netherlands.

Standard reference terminology of diagnoses and risk factors is crucial for billing, epidemiological studies, and inter/intranational comparisons of diseases. The International Classification of Disease (ICD) is a standardized and widely used method, but the manual classification is an enormously time-consuming endeavor. Natural language processing together with machine learning allows automated structuring of diagnoses using ICD-10 codes, but the limited performance of machine learning models, the necessity of gigantic datasets, and poor reliability of terminal parts of these codes restricted clinical usability. We aimed to create a high performing pipeline for automated classification of reliable ICD-10 codes in the free medical text in cardiology. We focussed on frequently used and well-defined three- and four-digit ICD-10 codes that still have enough granularity to be clinically relevant such as atrial fibrillation (I48), acute myocardial infarction (I21), or dilated cardiomyopathy (I42.0). Our pipeline uses a deep neural network known as a Bidirectional Gated Recurrent Unit Neural Network and was trained and tested with 5548 discharge letters and validated in 5089 discharge and procedural letters. As in clinical practice discharge letters may be labeled with more than one code, we assessed the single- and multilabel performance of main diagnoses and cardiovascular risk factors. We investigated using both the entire body of text and only the summary paragraph, supplemented by age and sex. Given the privacy-sensitive information included in discharge letters, we added a de-identification step. The performance was high, with F1 scores of 0.76-0.99 for three-character and 0.87-0.98 for four-character ICD-10 codes, and was best when using complete discharge letters. Adding variables age/sex did not affect results. For model interpretability, word coefficients were provided and qualitative assessment of classification was manually performed. Because of its high performance, this pipeline can be useful to decrease the administrative burden of classifying discharge diagnoses and may serve as a scaffold for reimbursement and research applications.
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http://dx.doi.org/10.1038/s41746-021-00404-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910461PMC
February 2021

Propensity score-based analysis of long-term outcome of patients on HeartWare and HeartMate 3 left ventricular assist device support.

ESC Heart Fail 2021 04 26;8(2):1596-1603. Epub 2021 Feb 26.

Department of Cardiology, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.

Aims: Left ventricular assist device therapy has become the cornerstone in the treatment of end-stage heart failure and is increasingly used as destination therapy next to bridge to transplant or recovery. HeartMate 3 (HM3) and HeartWare (HVAD) are centrifugal continuous flow devices implanted intrapericardially and most commonly used worldwide. No randomized controlled trials have been performed yet. Analysis based on large registries may be considered as the best alternative but has the disadvantage of different standard of care between centres and missing data. Bias is introduced, because the decision which device to use was not random, even more so because many centres use only one type of left ventricular assist device. Therefore, we performed a propensity score (PS)-based analysis of long-term clinical outcome of patients that received HM3 or HVAD in a single centre.

Methods And Results: Between December 2010 and December 2019, 100 patients received HVAD and 81 patients HM3 as primary implantation at the University Medical Centre Utrecht. We performed PS matching with an extensive set of covariates, resulting in 112 matched patients with a median follow-up of 28 months. After PS matching, survival was not significantly different (P = 0.21) but was better for HM3. The cumulative incidences for haemorrhagic stroke (P = 0.01) and pump thrombosis (P = 0.02) were significantly higher for HVAD patients. The cumulative incidences for major bleeding, ischaemic stroke, right heart failure, and driveline infection were not different between the groups. We found no interaction between the surgeon who performed the implantation and survival (P = 0.59, P = 0.78, and P = 0.89). Sensitivity analysis was performed, by PS matching without patients on preoperative temporary support resulting in 74 matched patients. This also resulted in a non-significant difference in survival (P = 0.07). The PS-adjusted Cox regression showed a worse but non-significant (P = 0.10) survival for HVAD patients with hazard ratio 1.71 (95% confidence interval 0.91-3.24).

Conclusions: Survival was not significantly different between both groups after PS matching, but was better for HM3, with a significantly lower incidence of haemorrhagic stroke and pump thrombosis for HM3. These results need to be interpreted carefully, because matching may have introduced greater imbalance on unmeasured covariates. A multicentre approach of carefully selected centres is recommended to enlarge the number of matched patients.
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http://dx.doi.org/10.1002/ehf2.13267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006731PMC
April 2021

Massive expansion and cryopreservation of functional human induced pluripotent stem cell-derived cardiomyocytes.

STAR Protoc 2021 Mar 9;2(1):100334. Epub 2021 Feb 9.

Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.

Since the discovery of human induced pluripotent stem cells (hiPSCs), numerous strategies have been established to efficiently derive cardiomyocytes from hiPSCs (hiPSC-CMs). Here, we describe a cost-effective strategy for the subsequent massive expansion (>250-fold) of high-purity hiPSC-CMs relying on two aspects: removal of cell-cell contacts and small-molecule inhibition with CHIR99021. The protocol maintains CM functionality, allows cryopreservation, and the cells can be used in downstream assays such as disease modeling, drug and toxicity screening, and cell therapy. For complete details on the use and execution of this protocol, please refer to Buikema (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881265PMC
March 2021

P62-positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy.

J Cell Mol Med 2021 Mar 18;25(6):3160-3166. Epub 2021 Feb 18.

Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Genetic cardiomyopathy is caused by mutations in various genes. The accumulation of potentially proteotoxic mutant protein aggregates due to insufficient autophagy is a possible mechanism of disease development. The objective of this study was to investigate the distribution in the myocardium of such aggregates in relation to specific pathogenic genetic mutations in cardiomyopathy hearts. Hearts from 32 genetic cardiomyopathy patients, 4 non-genetic cardiomyopathy patients and 5 controls were studied. Microscopic slices from an entire midventricular heart slice were stained for p62 (sequestosome-1, marker for aggregated proteins destined for autophagy). The percentage of cardiomyocytes with p62 accumulation was higher in cardiomyopathy hearts (median 3.3%) than in healthy controls (0.3%; P < .0001). p62 accumulation was highest in the desmin (15.6%) and phospholamban (7.2%) groups. P62 accumulation was homogeneously distributed in the myocardium. Fibrosis was not associated with p62 accumulation in subgroup analysis of phospholamban hearts. In conclusion, accumulation of p62-positive protein aggregates is homogeneously distributed in the myocardium independently of fibrosis distribution and associated with desmin and phospholamban cardiomyopathy. Proteotoxic protein accumulation is a diffuse process in the myocardium while a more localized second hit, such as local strain during exercise, might determine whether this leads to regional myocyte decay.
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http://dx.doi.org/10.1111/jcmm.16388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957157PMC
March 2021

Right Ventricular Functional Abnormalities in Arrhythmogenic Cardiomyopathy: Association With Life-Threatening Ventricular Arrhythmias.

JACC Cardiovasc Imaging 2021 May 10;14(5):900-910. Epub 2021 Feb 10.

Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address:

Objectives: This study aimed to perform an external validation of the value of right ventricular (RV) deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). Secondly, this study assessed the association of these parameters with life-threatening ventricular arrhythmia (VA).

Background: Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared.

Methods: We analyzed AC probands and mutation-positive family members, matched from 2 large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, or aborted cardiac arrest.

Results: We included 160 subjects, 80 from each center (43% proband, 55% women, age 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms; p < 0.001 for the total cohort). Both parameters were independently associated to VA (adjusted odds ratio: 2.71 [95% confidence interval: 1.47 to 5.00] per class step-up, and 1.26 [95% confidence interval: 1.07 to 1.49]/10 ms, respectively). The association with VA significantly improved when adding RV mechanical dispersion to pattern recognition (net reclassification improvement 0.42; p = 0.02 and integrated diagnostic improvement 0.06; p = 0.01).

Conclusions: We externally validated 2 RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value.
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http://dx.doi.org/10.1016/j.jcmg.2020.12.028DOI Listing
May 2021

COVID-19 related thrombi in ascending and descending thoracic aorta with peripheral embolization: a case report.

Eur Heart J Case Rep 2021 Feb 4;5(2):ytaa525. Epub 2021 Feb 4.

Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: COVID-19 (severe acute respiratory syndrome coronavirus 2) infected patients have increased risk for thrombotic events, which initially may have been under recognized. The existence of cardiovascular emboli can be directly life threatening when obstructing the blood flow to vital organs such as the brain or other parts of the body. The exact mechanism for this hypercoagulable state in COVID-19 patients yet remains to be elucidated.

Case Summary: A 72-year-old man critically ill with COVID-19 was diagnosed with a free-floating and mural thrombus in the thoracic aorta. Subsequent distal embolization to the limbs led to ischaemia and necrosis of the right foot. Treatment with heparin and anticoagulants reduced thrombus load in the ascending and thoracic aorta.

Discussion: One-third of COVID-19 patients show major thrombotic events, mostly pulmonary emboli. The endothelial expression of angiotensin-converting enzyme-2 receptors makes it feasible that in patients with viraemia direct viral-toxicity to the endothelium of also the large arteries results in local thrombus formation. Up to date, prophylactic anticoagulants are recommended in all patients that are hospitalized with COVID-19 infections to prevent venous and arterial thrombotic complications.
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http://dx.doi.org/10.1093/ehjcr/ytaa525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859600PMC
February 2021

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

Eur Heart J 2021 03;42(9):919-933

Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.

Aims: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.

Methods And Results: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.

Conclusions: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
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http://dx.doi.org/10.1093/eurheartj/ehaa1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936531PMC
March 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259PMC
February 2021