Publications by authors named "Pim van der Harst"

451 Publications

Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals.

Arterioscler Thromb Vasc Biol 2021 Dec 2:ATVBAHA121317007. Epub 2021 Dec 2.

Department of Cardiology, University of Groningen, University Medical Center Groningen, the Netherlands. (M.W.Y., S.W., Y.J.v.d.V., N.V., M.A.S., P.v.d.H.).

Objective: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at <5×10. Seven novel loci (, AD, , , , matrix metalloproteinase [], and ) were identified in all 3 phenotypes. An additional new locus () was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus () in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci (). Transcriptome-wide association analyses implicated additional genes , , and . Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease =0.21 (=1.4×10), peripheral artery disease =0.45 (=5.3×10), and systolic blood pressure =0.30 (=4.0×10). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found =-0.12 (=7.0×10).

Conclusions: Genome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.
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http://dx.doi.org/10.1161/ATVBAHA.121.317007DOI Listing
December 2021

A portable isometric knee extensor strength testing device: test-retest reliability and minimal detectable change scores of the Q-Force ӀӀ in healthy adults.

BMC Musculoskelet Disord 2021 Nov 19;22(1):966. Epub 2021 Nov 19.

Center for Human Movement Sciences, Groningen and Department of Rehabilitation Medicine, University of Groningen, University Medical Center, Groningen, the Netherlands.

Background: Although knee extensors are essential in daily activities (e.g. walking, climbing stairs), knee extensor strength is often not measured in clinical settings. Existing devices to test muscle strength are not always suitable to accurately measure the high forces of this muscle group. Therefore, a device to test muscle strength that is convenient, feasible, reliable, and valid in clinical settings is required. This study evaluated the reliability, responsiveness, and level of discomfort of the newly developed Q-Force ӀӀ (i.e. a portable device to measure isometric knee extensor strength) in healthy middle-aged and elderly adults.

Methods: Participants (n = 22) conducted two standardized test sessions on the Q-Force ӀӀ (five to ten days apart). Each session consisted of one familiarisation trial followed by three trials of peak isometric knee extension per each leg. Per trial, peak and mean knee extension force (N) and torque (Nm) were measured at 90° flexion. The level of discomfort was determined using a visual analog scale (VAS: 0-100). Intra Class Correlation (ICC, model: two-way mixed with absolute agreement), Standard Error of Measurement (SEM), and minimal detectable change (MDC) were determined. A repeated measures ANOVA was used to determine between-test variation.

Results: Excellent test-retest (ICC > 0.95) and inter-trial (ICC > 0.91) reliability for both legs were shown. No significant differences were found in peak and mean knee forces and torques between test and retest of both legs, indicating good test-retest reliability (P-value range: 0.360-0.538; F(1,21) range: 0.4-0.9). The SEM of the peak and mean forces and torques ranged from 28.0 to 30.4 N (6.0-6.8%) and from 9.2 to 10.4 Nm (6.4-7.7%), respectively. The MDC for these outcomes ranged respectively from 77.6 to 84.1 N (16.5-18.8%) and from 25.5 to 28.9 Nm (17.6-21.4%). The level of discomfort was low (median range: 7-10, IQR: 4-18).

Conclusion: The portable Q-Force ӀӀ is a comfortable, responsive, and relatively cheap device with excellent test-retest reliability. This device would be potentially suitable to measure isometric knee extensor strength in clinical settings.
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http://dx.doi.org/10.1186/s12891-021-04848-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602994PMC
November 2021

3-Year Clinical Outcomes After Implantation of Permanent-Polymer Versus Polymer-Free Stent: ReCre8 Landmark Analysis.

JACC Cardiovasc Interv 2021 Nov;14(22):2477-2486

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

Objectives: The aim of this analysis was to assess long-term clinical outcomes of the polymer-free Amphilimus-eluting stent (PF-AES) compared with a latest generation permanent-polymer drug-eluting stent (DES) in an all-comers population.

Background: PF-AES possess multiple properties improving targeted drug elution without the presence of polymers. Evaluation of long-term clinical performance of PF-AES versus latest generation permanent-polymer DES has not yet been performed in a large randomized trial introducing shortened dual-antiplatelet therapy.

Methods: In this physician-initiated, multicenter, randomized, all-comers trial, patients undergoing percutaneous coronary intervention with implantation of DES were enrolled. Patients were stratified for diabetes and troponin status and randomized to implantation of a permanent-polymer zotarolimus-eluting stent (PP-ZES) or a PF-AES. Dual-antiplatelet therapy duration was 12 months in troponin-positive patients and 1 month in troponin-negative patients. A noninferiority analysis was conducted to compare the 2 arms regarding target lesion failure (TLF) between 1 and 3 years.

Results: A total of 1,491 patients were randomized and treated. In this landmark analysis, between 1- and 3-year follow-up, TLF occurred in 35 patients (4.9%) in the PP-ZES arm and 37 PF-AES patients (5.1%). Clinical noninferiority of the PF-AES was confirmed, with a risk difference of 0.2% (upper limit 1-sided 95% CI: 2.2%; P = 0.0031).

Conclusions: ReCre8 (Randomized "All-Comer" Evaluation of a Permanent Polymer Resolute Integrity Stent Versus a Polymer Free Cre8 Stent) is the first randomized, multicenter trial with a head-to-head comparison of PP-ZES compared with PF-AES to investigate clinical outcomes of these new-generation DES in an all-comers population with long-term follow-up. On the basis of the present results, PF-AES are clinically noninferior to PP-ZES regarding TLF between 1 and 3 years. (Randomized "All-Comer" Evaluation of a Permanent Polymer Resolute Integrity Stent Versus a Polymer Free Cre8 Stent; NCT02328898).
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http://dx.doi.org/10.1016/j.jcin.2021.08.078DOI Listing
November 2021

Outcomes in patients with a first episode of chest pain undergoing early coronary CT imaging.

Heart 2021 Nov 15. Epub 2021 Nov 15.

Department of Cardiology, Amsterdam UMC VUMC Site, Amsterdam, The Netherlands

Objectives: To investigate the impact of a CT-first strategy on all-cause and cardiovascular mortality in patients presenting with chest pain in outpatient cardiology clinics.

Methods: Patients with a first presentation of suspected angina pectoris were identified and their data linked to the registrations of Statistics Netherlands for information on mortality. The linked database consisted of 33 068 patients. CT-first patients were defined as patients with a CT calcium score and coronary CT angiography, within 6 weeks after their initial visit. Propensity score matching (1:5) was used to match patients with and without a CT-first strategy. After matching, 12 545 patients were included of which 2308 CT-first patients and 10 237 patients that underwent usual care.

Results: Mean age was 57 years, 56.3% were women and median follow-up was 4.9 years. All-cause mortality was significantly lower in CT-first patients (n=43, 1.9%) compared with patients without CT (n=363, 3.5%) (HR: 0.51, 95% CI 0.37 to 0.70). Furthermore, CT-first patients were more likely to receive cardiovascular preventative and antianginal medication (aspirin: 44.9% vs 27.1%, statins: 48.7% vs 30.3%, beta-blockers: 37.8% vs 25.5%, in CT-first and without CT-first patients, respectively) and to undergo downstream diagnostics and interventions (coronary interventions: 8.5% vs 5.7%, coronary angiography: 16.2% vs 10.6% in CT-first and without CT-first patients, respectively).

Conclusions: In a real-world regular care database, a CT-first strategy in patients suspected of angina pectoris was associated with a lowering of all-cause mortality.
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http://dx.doi.org/10.1136/heartjnl-2021-319747DOI Listing
November 2021

What really matters: a patient-centered instrument to evaluate health-related quality of life in cardiovascular disease.

Eur Heart J Qual Care Clin Outcomes 2021 Nov 8. Epub 2021 Nov 8.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Aims: Patient-reported outcome measures (PROMs) to assess health-related quality of life (HRQoL) are increasingly used to guide decision making in cardiovascular care. However, many of the existing PROMs are developed with limited patient involvement and overlook personal health preferences. We aim to develop a cardiovascular disease (CVD)-specific patient-centered preference-based PROM to assess and monitor HRQoL in CVD patients.

Methods And Results: A mixed-method study consisting of several phases was conducted to identify important health items: (1) a scoping literature review, (2) first and second-round expert group meetings, (3) interviews with CVD patients, and (4) an online survey asking CVD patients to indicate from a large set those health items that are considered most important. The literature review, expert group meetings and patient interviews resulted in a list of 55 items potentially important to CVD patients. In total, 666 CVD patients responded to the survey. The following nine items were considered most important by CVD patients: mobility, activities, self-reliance, fatigue, shortness of breath, chest pain, palpitations, anxiety/worrying and sexual limitations. An electronic preference-based PROM consisting of these nine items was developed within a cloud based environment for clinical implementation.

Conclusion: Nine items considered most important for health by CVD patients were identified and included in a new preference-based patient-centered PROM. This new CVD-specific PROM can be easily implemented using the electronic application and has the potential to improve quality of care for CVD patients.
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http://dx.doi.org/10.1093/ehjqcco/qcab079DOI Listing
November 2021

Targeted Temperature Management in Out-of-Hospital Cardiac Arrest With Shockable Rhythm: A Post Hoc Analysis of the Coronary Angiography After Cardiac Arrest Trial.

Crit Care Med 2021 Sep 22. Epub 2021 Sep 22.

Department of Cardiology, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands. Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands. Department of Intensive Care Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Department of Cardiology, Amphia Hospital, Breda, The Netherlands. Department of Intensive Care Medicine, Amphia Hospital, Breda, The Netherlands. Department of Cardiology, Rijnstate Hospital, Arnhem, The Netherlands. Department of Intensive Care Medicine, Rijnstate Hospital, Arnhem, The Netherlands. Department of Cardiology, HAGA Hospital, Den Haag, The Netherlands. Department of Intensive Care Medicine, HAGA Hospital, Den Haag, The Netherlands. Department of Cardiology, Maasstad Hospital, Rotterdam, The Netherlands. Department of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Maasstad Hospital, Rotterdam, The Netherlands. Department of Intensive Care Medicine, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Maastricht University Medical Center, University Maastricht, Maastricht, The Netherlands. Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Medisch Spectrum Twente, Enschede, The Netherlands. Department of Cardiology, Medisch Spectrum Twente, Enschede, The Netherlands. Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Cardiology, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands. Department of Intensive Care Medicine, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands. Department of Cardiology, OLVG, Amsterdam, The Netherlands. Department of Intensive Care Medicine, OLVG, Amsterdam, The Netherlands. Department of Cardiology, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands. Department of Intensive Care Medicine, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands. Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands. Department of Cardiology, Scheper Hospital, Emmen, The Netherlands. Department of Cardiology, Haaglanden Medical Center, Den Haag, The Netherlands. Department of Cardiology, Isala Hospital, Zwolle, The Netherlands. Department of Cardiology, Tergooi Hospital, Blaricum, The Netherlands. Department of Cardiology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands. Department of Epidemiology and Data Science, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands.

Objectives: The optimal targeted temperature in patients with shockable rhythm is unclear, and current guidelines recommend targeted temperature management with a correspondingly wide range between 32°C and 36°C. Our aim was to study survival and neurologic outcome associated with targeted temperature management strategy in postarrest patients with initial shockable rhythm.

Design: Observational substudy of the Coronary Angiography after Cardiac Arrest without ST-segment Elevation trial.

Setting: Nineteen hospitals in The Netherlands.

Patients: The Coronary Angiography after Cardiac Arrest trial randomized successfully resuscitated patients with shockable rhythm and absence of ST-segment elevation to a strategy of immediate or delayed coronary angiography. In this substudy, 459 patients treated with mild therapeutic hypothermia (32.0-34.0°C) or targeted normothermia (36.0-37.0°C) were included. Allocation to targeted temperature management strategy was at the discretion of the physician.

Interventions: None.

Measurements And Main Results: After 90 days, 171 patients (63.6%) in the mild therapeutic hypothermia group and 129 (67.9%) in the targeted normothermia group were alive (hazard ratio, 0.86 [95% CI, 0.62-1.18]; log-rank p = 0.35; adjusted odds ratio, 0.89; 95% CI, 0.45-1.72). Patients in the mild therapeutic hypothermia group had longer ICU stay (4 d [3-7 d] vs 3 d [2-5 d]; ratio of geometric means, 1.32; 95% CI, 1.15-1.51), lower blood pressures, higher lactate levels, and increased need for inotropic support. Cerebral Performance Category scores at ICU discharge and 90-day follow-up and patient-reported Mental and Physical Health Scores at 1 year were similar in the two groups.

Conclusions: In the context of out-of-hospital cardiac arrest with shockable rhythm and no ST-elevation, treatment with mild therapeutic hypothermia was not associated with improved 90-day survival compared with targeted normothermia. Neurologic outcomes at 90 days as well as patient-reported Mental and Physical Health Scores at 1 year did not differ between the groups.
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http://dx.doi.org/10.1097/CCM.0000000000005271DOI Listing
September 2021

Association of Circulating Ketone Bodies With Functional Outcomes After ST-Segment Elevation Myocardial Infarction.

J Am Coll Cardiol 2021 Oct;78(14):1421-1432

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Circulating ketone bodies (KBs) are increased in patients with heart failure (HF), corresponding with increased cardiac KB metabolism and HF severity. However, the role of circulating KBs in ischemia/reperfusion remains unknown.

Objectives: This study sought to investigate longitudinal changes of KBs and their associations with functional outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI).

Methods: KBs were measured in 369 participants from a randomized trial on early metformin therapy after STEMI. Nonfasting plasma concentrations of KBs (β-hydroxybutyrate, acetoacetate, and acetone) were measured by nuclear magnetic resonance spectroscopy at presentation, at 24 hours, and after 4 months. Myocardial infarct size and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging at 4 months. Associations of circulating KBs with infarct size and LVEF were determined using multivariable linear regression analyses.

Results: Circulating KBs were high at presentation with STEMI (median total KBs: 520 μmol/L; interquartile range [IQR]: 315-997 μmol/L). At 24 hours after reperfusion, KBs were still high compared with levels at 4-month follow-up (206 μmol/L [IQR: 174-246] vs 166 μmol/L [IQR: 143-201], respectively; P < 0.001). Increased KB concentrations at 24 hours were independently associated with larger myocardial infarct size (total KBs, per 100 μmol/L: β = 1.56; 95% confidence interval: 0.29-2.83; P = 0.016) and lower LVEF (β = -1.78; 95% CI: (-3.17 to -0.39; P = 0.012).

Conclusions: Circulating KBs are increased in patients presenting with STEMI. Higher KBs at 24 hours are associated with functional outcomes after STEMI, which suggests a potential role for ketone metabolism in response to myocardial ischemia. (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III): a Randomized Controlled Trial; NCT01217307).
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http://dx.doi.org/10.1016/j.jacc.2021.07.054DOI Listing
October 2021

Dynamic Myocardial Perfusion CT for the Detection of Hemodynamically Significant Coronary Artery Disease.

JACC Cardiovasc Imaging 2021 Sep 8. Epub 2021 Sep 8.

Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Cardiology, Erasmus University Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands; Stanford University School of Medicine and Cardiovascular Institute, Stanford, California, USA. Electronic address:

Objectives: In this international, multicenter study, using third-generation dual-source computed tomography (CT), we investigated the diagnostic performance of dynamic stress CT myocardial perfusion imaging (CT-MPI) in addition to coronary CT angiography (CTA) compared to invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR).

Background: CT-MPI combined with coronary CTA integrates coronary artery anatomy with inducible myocardial ischemia, showing promising results for the diagnosis of hemodynamically significant coronary artery disease in single-center studies.

Methods: At 9 centers in Europe, Japan, and the United States, 132 patients scheduled for ICA were enrolled; 114 patients successfully completed coronary CTA, adenosine-stress dynamic CT-MPI, and ICA. Invasive FFR was performed in vessels with 25% to 90% stenosis. Data were analyzed by independent core laboratories. For the primary analysis, for each coronary artery the presence of hemodynamically significant obstruction was interpreted by coronary CTA with CT-MPI compared to coronary CTA alone, using an FFR of ≤0.80 and angiographic severity as reference. Territorial absolute myocardial blood flow (MBF) and relative MBF were compared using C-statistics.

Results: ICA and FFR identified hemodynamically significant stenoses in 74 of 289 coronary vessels (26%). Coronary CTA with ≥50% stenosis demonstrated a per-vessel sensitivity, specificity, and accuracy for the detection of hemodynamically significant stenosis of 96% (95% CI: 91-100), 72% (95% CI: 66-78), and 78% (95% CI: 73-83), respectively. Coronary CTA with CT-MPI showed a lower sensitivity (84%; 95% CI: 75-92) but higher specificity (89%; 95% CI: 85-93) and accuracy (88%; 95% CI: 84-92). The areas under the receiver-operating characteristic curve of absolute MBF and relative MBF were 0.79 (95% CI: 0.71-0.86) and 0.82 (95% CI: 0.74-0.88), respectively. The median dose-length product of CT-MPI and coronary CTA were 313 mGy·cm and 138 mGy·cm, respectively.

Conclusions: Dynamic CT-MPI offers incremental diagnostic value over coronary CTA alone for the identification of hemodynamically significant coronary artery disease. Generalized results from this multicenter study encourage broader consideration of dynamic CT-MPI in clinical practice. (Dynamic Stress Perfusion CT for Detection of Inducible Myocardial Ischemia [SPECIFIC]; NCT02810795).
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http://dx.doi.org/10.1016/j.jcmg.2021.07.021DOI Listing
September 2021

Rationale and Design of the Groningen Intervention Study for the Preservation of Cardiac Function with Sodium Thiosulfate after St-segment Elevation Myocardial Infarction (GIPS-IV) trial.

Am Heart J 2022 Jan 15;243:167-176. Epub 2021 Sep 15.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: Ischemia and subsequent reperfusion cause myocardial injury in patients presenting with ST-segment elevation myocardial infarction (STEMI). Hydrogen sulfide (HS) reduces "ischemia-reperfusion injury" in various experimental animal models, but has not been evaluated in humans. This trial will examine the efficacy and safety of the HS-donor sodium thiosulfate (STS) in patients presenting with a STEMI.

Study Design: The Groningen Intervention study for the Preservation of cardiac function with STS after STEMI (GIPS-IV) trial (NCT02899364) is a double-blind, randomized, placebo-controlled, multicenter trial, which will enroll 380 patients with a first STEMI. Patients receive STS 12.5 grams intravenously or matching placebo in addition to standard care immediately at arrival at the catheterization laboratory after providing consent. A second dose is administered 6 hours later at the coronary care unit. The primary endpoint is myocardial infarct size as quantified by cardiac magnetic resonance imaging 4 months after randomization. Secondary endpoints include the effect of STS on peak CK-MB during admission and left ventricular ejection fraction and NT-proBNP levels at 4 months follow-up. Patients will be followed-up for 2 years to assess clinical endpoints.

Conclusions: The GIPS-IV trial is the first study to determine the effect of a HS-donor on myocardial infarct size in patients presenting with STEMI.
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http://dx.doi.org/10.1016/j.ahj.2021.08.012DOI Listing
January 2022

Cost Effectiveness of a CYP2C19 Genotype-Guided Strategy in Patients with Acute Myocardial Infarction: Results from the POPular Genetics Trial.

Am J Cardiovasc Drugs 2021 Sep 7. Epub 2021 Sep 7.

Unit of Global Health, Department of Health Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Introduction: The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2Y inhibitor strategy reduced bleeding rates compared with standard treatment with ticagrelor or prasugrel without increasing thrombotic event rates after primary percutaneous coronary intervention (PCI).

Objective: In this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel.

Methods: A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2Y inhibitor strategy in patients with myocardial infarction undergoing primary PCI. The cost-effectiveness analysis was conducted from a Dutch healthcare system perspective. Within-trial survival and utility data were combined with lifetime projections to evaluate lifetime cost effectiveness for a cohort of 1000 patients. Costs and utilities were discounted at 4 and 1.5%, respectively, according to Dutch guidelines for health economic studies. Besides deterministic and probabilistic sensitivity analyses, several scenario analyses were also conducted (different time horizons, different discount rates, equal prices for P2Y inhibitors, and equal distribution of thrombotic events between the two strategies).

Results: Base-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant.

Conclusion: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings.

Trial Registration: Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872.
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http://dx.doi.org/10.1007/s40256-021-00496-4DOI Listing
September 2021

The genomics of heart failure: design and rationale of the HERMES consortium.

ESC Heart Fail 2021 Sep 3. Epub 2021 Sep 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.

Methods And Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 under an additive genetic model.

Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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http://dx.doi.org/10.1002/ehf2.13517DOI Listing
September 2021

Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment.

Genes (Basel) 2021 07 29;12(8). Epub 2021 Jul 29.

Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the gene or within 25kb of the 5' and 3' flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5' or 3' prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to . In conclusion, no genetic variant was found mimicking SGLT2i based on their location near and their association with sodium excretion or HbA1c and expression or function.
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http://dx.doi.org/10.3390/genes12081174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391850PMC
July 2021

Polygenic risk score and coronary artery disease: A meta-analysis of 979,286 participant data.

Atherosclerosis 2021 09 12;333:48-55. Epub 2021 Aug 12.

Department of Cardiology, Heart and Lung Division, University Medical Center Utrecht, Utrecht, the Netherlands.

Background And Aims: Coronary artery disease (CAD) is a complex disease with a strong genetic basis. While previous studies have combined common single-nucleotide polymorphisms (SNPs) into a polygenic risk score (PRS) to predict CAD risk, this association is poorly characterised. We performed a meta-analysis to estimate the effect of PRS on the risk of CAD.

Methods: Online databases were searched for studies reporting PRS and CAD. PRS computation was based on log-odds (PRS), pruning or clumping and thresholding (PRS), Lassosum regression (PRS), LDpred (PRS), or metaGRS (PRS). The reported odds ratio (OR), hazard ratio (HR), C-indexes and their corresponding 95% confidence interval (95% CI) were pooled in a random-effects meta-analysis.

Results: Forty-nine studies were included (979,286 individuals). There was a significant association between 1-standard deviation [SD] increment in PRS and adjusted risks of both incident and prevalent CAD (OR [95% CI]: 1.67 [1.57-1.77] for PRS, 1.46 [1.26-1.68] for PRS). The risk of incident CAD was highest for PRS (HR [95% CI]: 1.49 [1.26-1.78]), PRS (1.37 [1.27-1.47]), and PRS (1.36 [1.31-1.42]). Analysis of model performance demonstrated that PRS predicted incident CAD with C-index of up to 0.71. Importantly, addition of PRS to clinical risk scores resulted in modest but statistically significant improvements in CAD risk prediction, with 1.5% observed for PRS (p < 0.001) and 1.6% for PRS (p < 0.001).

Conclusions: Polygenic risk score is strongly associated with increased risks of CAD. Future prospective studies should explore the usefulness of polygenic risk scores for identifying individuals at a high risk of developing CAD.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.08.020DOI Listing
September 2021

Prehospital risk stratification in patients with chest pain.

Emerg Med J 2021 Nov 9;38(11):814-819. Epub 2021 Aug 9.

Expirimental Cardiology, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: The History, ECG, Age, Risk Factors and Troponin (HEART) Score is a decision support tool applied by physicians in the emergency department developed to risk stratify low-risk patients presenting with chest pain. We assessed the potential value of this tool in prehospital setting, when applied by emergency medical services (EMS), and derived and validated a tool adapted to the prehospital setting in order to determine if it could assist with decisions regarding conveyance to a hospital.

Methods: EMS personnel prospectively determined the HEART Score, including point-of-care (POC) troponin measurements, in patients presenting with chest pain, in the north of the Netherlands. The primary endpoint was a major adverse cardiac event (MACE), consisting of acute myocardial infarction or death, within 3 days. The components of the HEART Score were evaluated for their discriminatory value, cut-offs were calibrated for the prehospital setting and sex was substituted for cardiac risk factors to develop a prehospital HEART (preHEART) Score. This score was validated in an independent prospective cohort of 435 patients in 2018.

Results: Among 1208 patients prospectively recruited in the first cohort, 123 patients (10.2%) developed a MACE. The HEART Score had a negative predictive value (NPV) of 98.4% (96.4-99.3), a positive predictive value (PPV) of 35.5% (31.8-39.3) and an area under the receiver operating characteristic curve (AUC) of 0.81 (0.78-0.85). The preHEART Score had an NPV of 99.3% (98.1-99.8), a PPV of 49.4% (42.0-56.9) and an AUC of 0.85 (0.82-0.88), outperforming the HEART Score or POC troponin measurements on their own. Similar results were found in a validation cohort.

Conclusions: The HEART Score can be used in the prehospital setting to assist with conveyance decisions and choice of hospitals; however, the preHEART Score outperforms both the HEART Score and single POC troponin measurements when applied by EMS personnel in the prehospital setting.
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http://dx.doi.org/10.1136/emermed-2020-210212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551969PMC
November 2021

Validation and comparison of 28 risk prediction models for coronary artery disease.

Eur J Prev Cardiol 2021 Jul 30. Epub 2021 Jul 30.

Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.

Aims: Risk prediction models (RPMs) for coronary artery disease (CAD), using variables to calculate CAD risk, are potentially valuable tools in prevention strategies. However, their use in the clinical practice is limited by a lack of poor model description, external validation, and head-to-head comparisons.

Methods And Results: CAD RPMs were identified through Tufts PACE CPM Registry and a systematic PubMed search. Every RPM was externally validated in the three cohorts (the UK Biobank, LifeLines, and PREVEND studies) for the primary endpoint myocardial infarction (MI) and secondary endpoint CAD, consisting of MI, percutaneous coronary intervention, and coronary artery bypass grafting. Model discrimination (C-index), calibration (intercept and regression slope), and accuracy (Brier score) were assessed and compared head-to-head between RPMs. Linear regression analysis was performed to evaluate predictive factors to estimate calibration ability of an RPM. Eleven articles containing 28 CAD RPMs were included. No single best-performing RPM could be identified across all cohorts and outcomes. Most RPMs yielded fair discrimination ability: mean C-index of RPMs was 0.706 ± 0.049, 0.778 ± 0.097, and 0.729 ± 0.074 (P < 0.01) for prediction of MI in UK Biobank, LifeLines, and PREVEND, respectively. Endpoint incidence in the original development cohorts was identified as a significant predictor for external validation performance.

Conclusion: Performance of CAD RPMs was comparable upon validation in three large cohorts, based on which no specific RPM can be recommended for predicting CAD risk.
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http://dx.doi.org/10.1093/eurjpc/zwab095DOI Listing
July 2021

Prehabilitation to prevent complications after cardiac surgery - A retrospective study with propensity score analysis.

PLoS One 2021 16;16(7):e0253459. Epub 2021 Jul 16.

Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, Groningen, The Netherlands.

Background: The rising prevalence of modifiable lifestyle-related risk factors (e.g. overweight and physical inactivity) suggests the need for effective and safe preoperative interventions to improve outcomes after cardiac surgery. This retrospective study explored potential short-term postoperative benefits and unintended consequences of a multidisciplinary prehabilitation program regarding in-hospital complications.

Methods: Data on patients who underwent elective cardiac surgery between January 2014 and April 2017 were analyzed retrospectively. Pearson's chi-squared tests were used to compare patients who followed prehabilitation (three times per week, at a minimum of three weeks) during the waiting period with patients who received no prehabilitation. Sensitivity analyses were performed using propensity-score matching, in which the propensity score was based on the baseline variables that affected the outcomes.

Results: Of 1201 patients referred for elective cardiac surgery, 880 patients met the inclusion criteria, of whom 91 followed prehabilitation (53.8% ≥ 65 years, 78.0% male, median Euroscore II 1.3, IQR, 0.9-2.7) and 789 received no prehabilitation (60.7% ≥ 65 years, 69.6% male, median Euroscore II 1.6, IQR, 1.0-2.8). The incidence of atrial fibrillation (AF) was significantly lower in the prehabilitation group compared to the unmatched and matched standard care group (resp. 14.3% vs. 23.8%, P = 0.040 and 14.3% vs. 25.3%, P = 0.030). For the other complications, no between-group differences were found.

Conclusions: Prehabilitation might be beneficial to prevent postoperative AF. Patients participated safely in prehabilitation and were not at higher risk for postoperative complications. However, well-powered randomized controlled trials are needed to confirm and deepen these results.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253459PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284810PMC
November 2021

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

Heart 2021 11 14;107(21):1748-1755. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522453PMC
November 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

The effect of immediate coronary angiography after cardiac arrest without ST-segment elevation on left ventricular function. A sub-study of the COACT randomised trial.

Resuscitation 2021 07 28;164:93-100. Epub 2021 Apr 28.

Department of Intensive care medicine, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands.

Background: The effect of immediate coronary angiography and percutaneous coronary intervention (PCI) in patients who are successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) on left ventricular function is currently unknown.

Methods: This prespecified sub-study of a multicentre trial evaluated 552 patients, successfully resuscitated from out-of-hospital cardiac arrest without signs of STEMI. Patients were randomized to either undergo immediate coronary angiography or delayed coronary angiography, after neurologic recovery. All patients underwent PCI if indicated. The main outcomes of this analysis were left ventricular ejection fraction and end-diastolic and systolic volumes assessed by cardiac magnetic resonance imaging or echocardiography.

Results: Data on left ventricular function was available for 397 patients. The mean (± standard deviation) left ventricular ejection fraction was 45.2% (±12.8) in the immediate angiography group and 48.4% (±13.2) in the delayed angiography group (mean difference: -3.19; 95% confidence interval [CI], -6.75 to 0.37). Median left ventricular end-diastolic volume was 177 ml in the immediate angiography group compared to 169 ml in the delayed angiography group (ratio of geometric means: 1.06; 95% CI, 0.95-1.19). In addition, mean left ventricular end-systolic volume was 90 ml in the immediate angiography group compared to 78 ml in the delayed angiography group (ratio of geometric means: 1.13; 95% CI 0.97-1.32).

Conclusion: In patients successfully resuscitated after out-of-hospital cardiac arrest and without signs of STEMI, immediate coronary angiography was not found to improve left ventricular dimensions or function compared with a delayed angiography strategy.

Clinical Trial Registration: Netherlands Trial Register number, NTR4973.
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http://dx.doi.org/10.1016/j.resuscitation.2021.04.020DOI Listing
July 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

Prevalence, predictors, and outcomes of clonal hematopoiesis in individuals aged ≥80 years.

Blood Adv 2021 04;5(8):2115-2122

Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Clonal hematopoiesis (CH), characterized by a fraction of peripheral blood cells carrying an acquired genetic variant, emerges with age. Although in general CH is associated with increased mortality and morbidity, no higher risk of death was observed for individuals ≥80 years. Here, we investigated CH in 621 individuals aged ≥80 years from the population-based LifeLines cohort. Sensitive error-corrected sequencing of 27 driver genes at a variant allele frequency ≥1% revealed CH in the majority (62%) of individuals, independent of gender. The observed mutational spectrum was dominated by DNMT3A and TET2 variants, which frequently (29%) displayed multiple mutations per gene. In line with previous results in individuals ≥80 years, the overall presence of CH did not associate with a higher risk of death (hazard ratio, 0.91; 95% confidence interval, 0.70-1.18; P = .48). Being able to assess the causes of death, we observed no difference between individuals with or without CH, except for deaths related to hematological malignancies. Interestingly, comparison of mutational spectra confined to DNMT3A and TET2 vs spectra containing other mutated genes, showed a higher risk of death when mutations other than DNMT3A or TET2 were present (hazard ratio, 1.48; 95% confidence interval, 1.06-2.08; P = .025). Surprisingly, no association of CH with cardiovascular morbidity was found, irrespective of clone size. Further, CH associated with chronic obstructive pulmonary disease. Data on estimated exposure to DNA damaging toxicities (ie, smoking, a history of cancer [as a proxy for previous genotoxic therapy], and job-related pesticide exposure) showed an association with spliceosome and ASXL1 variants, but not with DNMT3A and TET2 variants.
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http://dx.doi.org/10.1182/bloodadvances.2020004062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095141PMC
April 2021

Atrial fibrillation and left atrial size and function: a Mendelian randomization study.

Sci Rep 2021 04 19;11(1):8431. Epub 2021 Apr 19.

Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Atrial fibrillation (AF) patients have enlarged left atria (LA), but prior studies suggested enlarged atria as both cause and consequence of AF. The aim of this study is to investigate the causal association between AF and LA size and function. In the UK Biobank, all individuals with contoured cardiovascular magnetic resonance data were selected. LA maximal volume (LA max), LA minimal volume (LA min), LA stroke volume and LA ejection fraction were measured and indexed to body surface area (BSA). Two-sample Mendelian randomization analyses were performed using 84 of the known genetic variants associated with AF to assess the association with all LA size and function in individuals without prevalent AF. A total of 4274 individuals (mean age 62.0 ± 7.5 years, 53.2% women) were included. Mendelian randomization analyses estimated a causal effect between genetically determined AF and BSA-indexed LA max, LA min, and LA ejection fraction, but not between AF and LA stroke volume. Leave-one-out analyses showed that the causal associations were attenuated after exclusion of rs67249485, located near PITX2 gene. Our results suggest that AF causally increases LA size and decreases LA ejection fraction. The AF risk allele of rs67249485, located near the PITX2 gene, contributes strongly to these associations.
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http://dx.doi.org/10.1038/s41598-021-87859-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055882PMC
April 2021

Focal pericoronary adipose tissue attenuation is related to plaque presence, plaque type, and stenosis severity in coronary CTA.

Eur Radiol 2021 Oct 16;31(10):7251-7261. Epub 2021 Apr 16.

Department of Radiology, University Medical Center Groningen, University of Groningen, EB44, Hanzeplein 1, 9713, Groningen, GZ, Netherlands.

Objectives: To investigate the association of pericoronary adipose tissue mean attenuation (PCAT) with coronary artery disease (CAD) characteristics on coronary computed tomography angiography (CCTA).

Methods: We retrospectively investigated 165 symptomatic patients who underwent third-generation dual-source CCTA at 70kVp: 93 with and 72 without CAD (204 arteries with plaque, 291 without plaque). CCTA was evaluated for presence and characteristics of CAD per artery. PCAT was measured proximally and across the most severe stenosis. Patient-level, proximal PCAT was defined as the mean of the proximal PCAT of the three main coronary arteries. Analyses were performed on patient and vessel level.

Results: Mean proximal PCAT was -96.2 ± 7.1 HU and -95.6 ± 7.8HU for patients with and without CAD (p = 0.644). In arteries with plaque, proximal and lesion-specific PCAT was similar (-96.1 ± 9.6 HU, -95.9 ± 11.2 HU, p = 0.608). Lesion-specific PCAT of arteries with plaque (-94.7 HU) differed from proximal PCAT of arteries without plaque (-97.2 HU, p = 0.015). Minimal stenosis showed higher lesion-specific PCAT (-94.0 HU) than severe stenosis (-98.5 HU, p = 0.030). Lesion-specific PCAT of non-calcified, mixed, and calcified plaque was -96.5 HU, -94.6 HU, and -89.9 HU (p = 0.004). Vessel-based total plaque, lipid-rich necrotic core, and calcified plaque burden showed a very weak to moderate correlation with proximal PCAT.

Conclusions: Lesion-specific PCAT was higher in arteries with plaque than proximal PCAT in arteries without plaque. Lesion-specific PCAT was higher in non-calcified and mixed plaques compared to calcified plaques, and in minimal stenosis compared to severe; proximal PCAT did not show these relationships. This suggests that lesion-specific PCAT is related to plaque development and vulnerability.

Key Points: • In symptomatic patients undergoing CCTA at 70 kVp, PCAT was higher in coronary arteries with plaque than those without plaque. • PCAT was higher for non-calcified and mixed plaques compared to calcified plaques, and for minimal stenosis compared to severe stenosis. • In contrast to PCAT measurement of the proximal vessels, lesion-specific PCAT showed clear relationships with plaque presence and stenosis degree.
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http://dx.doi.org/10.1007/s00330-021-07882-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452552PMC
October 2021

Improving patient identification for advanced cardiac imaging through machine learning-integration of clinical and coronary CT angiography data.

Int J Cardiol 2021 07 6;335:130-136. Epub 2021 Apr 6.

University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9700RB Groningen, the Netherlands; Turku PET Centre, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland; Department of Cardiology, Hart and Lung Division, University Medical Centre Utrecht, Heidelberglaan 100, 3508, GA, Utrecht, the Netherlands. Electronic address:

Background: Standard computed tomography angiography (CTA) outputs a myriad of interrelated variables in the evaluation of suspected coronary artery disease (CAD). But an important proportion of obstructive lesions does not cause significant myocardial ischemia. Nowadays, machine learning (ML) allows integration of numerous variables through complex interdependencies that optimize classification and prediction at the individual level. We evaluated ML performance in integrating CTA and clinical variables to identify patients that demonstrate myocardial ischemia through PET and those who ultimately underwent early revascularization.

Methods And Results: 830 patients with CTA and selective PET were analyzed. Nine clinical and 58 CTA variables were integrated through ensemble-boosting ML to identify patients with ischemia and those who underwent early revascularization. ML performance was compared against expert CTA interpretation, calcium score and clinical variables. While ML using all CTA variables achieved an AUC = 0.85, it was outperformed by expert CTA interpretation (AUC = 0.87, p < 0.01 for comparison), comparable to ML integration of CTA variables with clinical variables. However, the best performance was achieved by ML integration of expert CTA interpretation and clinical variables for both dependent variables (AUCs = 0.91 and 0.90, p < 0.001).

Conclusions: Machine learning integration of diagnostic CTA and clinical data may improve identification of patients with myocardial ischemia and those requiring early revascularization at the individual level. This could potentially aid in sparing the need for subsequent advanced imaging and better identifying patients in ultimate need for revascularization. While ML integrating all CTA variables did not outperform expert CTA interpretation, ML data integration from different sources consistently improves diagnostic performance.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.009DOI Listing
July 2021

Clinical outcomes after permanent polymer or polymer-free stent implantation in patients with diabetes mellitus: The ReCre8 diabetes substudy.

Catheter Cardiovasc Interv 2021 Apr 3. Epub 2021 Apr 3.

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

Objectives: The purpose of this analysis was to compare target-lesion failure (TLF) of a permanent polymer zotarolimus-eluting stent (PP-ZES) versus a polymer-free amphilimus-eluting stent (PF-AES) in diabetics.

Background: The improvement of outcomes with new-generation drug-eluting stent as seen in the general population is less pronounced among diabetics. The PF-AES introduces an elution-technology with potential enhanced performance in diabetics.

Methods: In this subanalysis of the ReCre8 trial, patients were randomized to either a PP-ZES or PF-AES after stratification for diabetes and troponin status. The primary device-oriented endpoint was TLF, a composite of cardiac death, target-vessel myocardial infarction and target-lesion revascularization.

Results: In the ReCre8 trial, 304 (20%) patients were diabetic and 96 (6%) had insulin-dependent diabetes mellitus. There was no statistically significant difference between the two study arms regarding the primary endpoint (PP-ZES 7.2% vs. PF-AES 4.0%; p = .21), although the composite of net adverse clinical events was higher in the PP-ZES arm (15.7 vs. 8.0%; p = .035). Stent thrombosis was low in both groups with no cases in the PP-ZES arm and 1 case in the PF-AES arm (p = .32). Regarding insulin-treated diabetics, TLF was higher in the PP-ZES arm (14.9 vs. 2.1%; p = .022).

Conclusions: Diabetics could potentially benefit from a dedicated stent, releasing sirolimus with a lipophilic carrier (amphilimus-formulation). Future trials should confirm the potential benefit of a PF-AES in this population.
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http://dx.doi.org/10.1002/ccd.29685DOI Listing
April 2021

Telomere length is independently associated with all-cause mortality in chronic heart failure.

Heart 2021 Mar 31. Epub 2021 Mar 31.

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Objective: Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure.

Methods: We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation.

Results: In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66×10), an effect equivalent to that of being four years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04×10). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80×10). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855).

Conclusion: In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality.
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http://dx.doi.org/10.1136/heartjnl-2020-318654DOI Listing
March 2021

The Groningen electrocardiographic criteria for left ventricular hypertrophy: a sex-specific analysis.

Sci Rep 2021 03 23;11(1):6662. Epub 2021 Mar 23.

The Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

The sensitivity of electrocardiogram (ECG) criteria to detect left ventricular hypertrophy (LVH) is low, especially in women. We determined sex-specific sensitivities of ECG-LVH criteria, and developed new criteria, using cardiovascular magnetic resonance imaging (CMR). Sensitivities of ECG-LVH criteria were determined in participants of the UK Biobank (N = 3632). LVH was defined when left ventricular mass was > 95% confidence interval (CI) according to age and sex. In a training cohort (75%, N = 2724), sex-specific ECG-LVH criteria were developed by investigating all possible sums of QRS-amplitudes in all 12 leads, and selecting the sum with the highest pseudo-R and area under the curve to detect LVH. Performance was assessed in a validation cohort (25%, N = 908), and association with blood pressure change was investigated in an independent cohort. Sensitivities of ECG-LVH criteria were low, especially in women. Newly developed Groningen-LVH criterion for women (Q + R + R + R + S + S + S + S) outperformed all ECG-LVH criteria with a sensitivity of 42% (95% CI 35-49%). In men, newly developed criterion ((R + R + S + S + S) × QRS duration) was equally sensitive as 12-lead sum with a sensitivity of 44% (95% CI 37-51%) and outperformed the other criteria. In an independent cohort, the Groningen-LVH criteria were strongest associated with change in systolic blood pressure. Our proposed CMR sex-specific Groningen-LVH criteria improve the sensitivity to detect LVH, especially in women. Further validation and its association with clinical outcomes is warranted.
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http://dx.doi.org/10.1038/s41598-021-83137-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988153PMC
March 2021

Age dependent associations of risk factors with heart failure: pooled population based cohort study.

BMJ 2021 03 23;372:n461. Epub 2021 Mar 23.

Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

Objective: To assess age differences in risk factors for incident heart failure in the general population.

Design: Pooled population based cohort study.

Setting: Framingham Heart Study, Prevention of Renal and Vascular End-stage Disease Study, and Multi-Ethnic Study of Atherosclerosis.

Participants: 24 675 participants without a history of heart failure stratified by age into young (<55 years; n=11 599), middle aged (55-64 years; n=5587), old (65-74 years; n=5190), and elderly (≥75 years; n=2299) individuals.

Main Outcome Measure: Incident heart failure.

Results: Over a median follow-up of 12.7 years, 138/11 599 (1%), 293/5587 (5%), 538/5190 (10%), and 412/2299 (18%) of young, middle aged, old, and elderly participants, respectively, developed heart failure. In young participants, 32% (n=44) of heart failure cases were classified as heart failure with preserved ejection fraction compared with 43% (n=179) in elderly participants. Risk factors including hypertension, diabetes, current smoking history, and previous myocardial infarction conferred greater relative risk in younger compared with older participants (P for interaction <0.05 for all). For example, hypertension was associated with a threefold increase in risk of future heart failure in young participants (hazard ratio 3.02, 95% confidence interval 2.10 to 4.34; P<0.001) compared with a 1.4-fold risk in elderly participants (1.43, 1.13 to 1.81; P=0.003). The absolute risk for developing heart failure was lower in younger than in older participants with and without risk factors. Importantly, known risk factors explained a greater proportion of overall population attributable risk for heart failure in young participants (75% 53% in elderly participants), with better model performance (C index 0.79 0.64). Similarly, the population attributable risks of obesity (21% 13%), hypertension (35% 23%), diabetes (14% 7%), and current smoking (32% 1%) were higher in young compared with elderly participants.

Conclusions: Despite a lower incidence and absolute risk of heart failure among younger compared with older people, the stronger association and greater attributable risk of modifiable risk factors among young participants highlight the importance of preventive efforts across the adult life course.
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http://dx.doi.org/10.1136/bmj.n461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986583PMC
March 2021
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