Publications by authors named "Matthijs F L Meijs"

36 Publications

Detection of Major Cardioembolic Sources in Real-World Patients with Ischemic Stroke or Transient Ischemic Attack of Undetermined Cause.

Cerebrovasc Dis Extra 2021 Feb 1;11(1):22-28. Epub 2021 Feb 1.

Department of Neurology, Isala Hospital, Zwolle, The Netherlands.

Background/aim: Current guidelines recommend transthoracic echocardiography (TTE) and ambulatory rhythm monitoring following ischemic stroke or transient ischemic attack (TIA) of undetermined cause for identifying cardioembolic sources (CES). Due to ongoing controversies about this routine strategy, we evaluated its yield in a real-world setting.

Methods: In a tertiary medical center, we retrospectively evaluated consecutive patients with ischemic stroke or TIA of undetermined cause, who (after standard work-up) underwent TTE, ambulatory rhythm monitoring, or both. CES were classified as major if probably related to ischemic events and warranting a change of therapy.

Results: Between January 2014 and December 2017, 674 patients had ischemic stroke or TIA of undetermined cause. Of all 484 patients (71.8%) who underwent TTE, 9 (1.9%) had a major CES. However, 7 of them had already been identified for cardiac evaluation due to new major electrocardiographic abnormalities or cardiac symptoms. Thus, only 2 patients (0.4%) truly benefitted from unselected TTE screening. Ambulatory rhythm monitoring was performed in 411 patients (61.0%) and revealed AF in 10 patients (2.4%).

Conclusion: Detecting a major CES is essential because appropriate treatment lowers the risk of recurrent stroke. Nonetheless, in this real-world study that aimed at routine use of TTE and ambulatory rhythm monitoring in patients with ischemic stroke or TIA of undetermined cause, the prevalence of major CES was low. Most patients with major CES on TTE already had an indication for referral to a cardiologist, suggesting that major CES might also have been identified with a much more selective use of TTE.
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http://dx.doi.org/10.1159/000512743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989814PMC
February 2021

The additional value of an algorithm for atrial fibrillation at the stroke unit.

J Stroke Cerebrovasc Dis 2020 Aug 3;29(8):104930. Epub 2020 Jun 3.

Department of Neurology, Isala, Zwolle, the Netherlands. Electronic address:

Background And Purpose: The rate of newly detected (paroxysmal) atrial fibrillation (AF) during inpatient cardiac telemetry is low. The objective of this study was to evaluate the additional diagnostic yield of an automated detection algorithm for AF on telemetric monitoring compared with routine detection by a stroke unit team in patients with recent ischemic stroke or TIA.

Methods: Patients admitted to the stroke unit of Medisch Spectrum Twente with acute ischemic stroke or TIA and no history of AF were prospectively included. All patients had telemetry monitoring, routinely assessed by the stroke unit team. The ST segment and arrhythmia monitoring (ST/AR) algorithm was active, with deactivated AF alarms. After 24 h the detections were analyzed and compared with routine evaluation.

Results: Five hundred and seven patients were included (52.5% male, mean age 70.2 ± 12.9 years). Median monitor duration was 24 (interquartile range 22-27) h. In 6 patients (1.2%) routine analysis by the stroke unit team concluded AF. In 24 patients (4.7%), the ST/AR Algorithm suggested AF. Interrater reliability was low (κ, 0.388, p < 0.001). Suggested AF by the algorithm turned out to be false positive in 11 patients. In 13 patients (2.6%) AF was correctly diagnosed by the algorithm. None of the cases detected by routine analysis were missed by the algorithm.

Conclusions: Automated AF detection during 24-h telemetry in ischemic stroke patients is of additional value to detect paroxysmal AF compared with routine analysis by the stroke unit team alone. Automated detections need to be carefully evaluated.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104930DOI Listing
August 2020

Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data.

BMJ 2019 06 12;365:l1945. Epub 2019 Jun 12.

Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

Objective: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients.

Design: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies.

Data Sources: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators.

Eligibility Criteria For Selecting Studies: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups.

Results: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% 86.5%, P=0.002) and specificity (84.4% 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)).

Conclusions: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients.

Systematic Review Registration: PROSPERO CRD42012002780.
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http://dx.doi.org/10.1136/bmj.l1945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561308PMC
June 2019

Correction to: Applicability and accuracy of pretest probability calculations implemented in the NICE clinical guideline for decision making about imaging in patients with chest pain of recent onset.

Eur Radiol 2018 11;28(11):4919-4921

Department of Radiology, Charité - Universitätsmedizin Berlin Campus Mitte, Humboldt-Universität zu Berlin, Freie Universität Berlin, Charitéplatz 1, 10117, Berlin, Germany.

The original version of this article, published on 19 March 2018, unfortunately contained a mistake. The following correction has therefore been made in the original: The names of the authors Philipp A. Kaufmann, Ronny Ralf Buechel and Bernhard A. Herzog were presented incorrectly.
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http://dx.doi.org/10.1007/s00330-018-5521-0DOI Listing
November 2018

Applicability and accuracy of pretest probability calculations implemented in the NICE clinical guideline for decision making about imaging in patients with chest pain of recent onset.

Eur Radiol 2018 Sep 19;28(9):4006-4017. Epub 2018 Mar 19.

Department of Radiology, Charité - Universitätsmedizin Berlin Campus Mitte, Humboldt-Universität zu Berlin, Freie Universität Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Objectives: To analyse the implementation, applicability and accuracy of the pretest probability calculation provided by NICE clinical guideline 95 for decision making about imaging in patients with chest pain of recent onset.

Methods: The definitions for pretest probability calculation in the original Duke clinical score and the NICE guideline were compared. We also calculated the agreement and disagreement in pretest probability and the resulting imaging and management groups based on individual patient data from the Collaborative Meta-Analysis of Cardiac CT (CoMe-CCT).

Results: 4,673 individual patient data from the CoMe-CCT Consortium were analysed. Major differences in definitions in the Duke clinical score and NICE guideline were found for the predictors age and number of risk factors. Pretest probability calculation using guideline criteria was only possible for 30.8 % (1,439/4,673) of patients despite availability of all required data due to ambiguity in guideline definitions for risk factors and age groups. Agreement regarding patient management groups was found in only 70 % (366/523) of patients in whom pretest probability calculation was possible according to both models.

Conclusions: Our results suggest that pretest probability calculation for clinical decision making about cardiac imaging as implemented in the NICE clinical guideline for patients has relevant limitations.

Key Points: • Duke clinical score is not implemented correctly in NICE guideline 95. • Pretest probability assessment in NICE guideline 95 is impossible for most patients. • Improved clinical decision making requires accurate pretest probability calculation. • These refinements are essential for appropriate use of cardiac CT.
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http://dx.doi.org/10.1007/s00330-018-5322-5DOI Listing
September 2018

Diagnostic evaluation and treatment strategy in patients with suspected prosthetic heart valve dysfunction: The incremental value of MDCT.

J Cardiovasc Comput Tomogr 2016 Sep-Oct;10(5):398-406. Epub 2016 Jul 13.

Department of Radiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

Background: In patients with suspected prosthetic heart valve (PHV) dysfunction, routine evaluation echocardiography and fluoroscopy may provide unsatisfactory results for identifying the cause of dysfunction. This study assessed the value of MDCT as a routine, complementary imaging modality in suspected PHV-dysfunction for diagnosing the cause of PHV dysfunction and proposing a treatment strategy.

Methods: Patients with suspected PHV dysfunction were prospectively recruited. All patients underwent routine diagnostic work-up (TTE, TEE ± fluoroscopy) and additional MDCT imaging. An expert panel reviewed all cases and assessed the diagnosis and treatment strategy, first based on routine evaluation only, second with additional MDCT information.

Results: Forty-two patients were included with suspected PHV obstruction (n = 30) and PHV regurgitation (n = 12). The addition of MDCT showed incremental value to routine evaluation in 26/30 (87%) cases for detecting the specific cause of PHV obstruction and in 7/12 (58%) regurgitation cases for assessment of complications and surgical planning. The addition of MDCT resulted in treatment strategy change in 8/30 (27%) patients with suspected obstruction and 3/12 (25%) patients with regurgitation.

Conclusion: In addition to echocardiography and fluoroscopy, MDCT may identify the cause of PHV dysfunction and alter the treatment strategy.
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http://dx.doi.org/10.1016/j.jcct.2016.07.008DOI Listing
April 2017

Baseline MDCT findings after prosthetic heart valve implantation provide important complementary information to echocardiography for follow-up purposes.

Eur Radiol 2016 Apr 16;26(4):997-1006. Epub 2015 Oct 16.

Department of Radiology, University Medical Center Utrecht, Huispostnummer E01.132, Heidelberglaan 100, PO Box 85500, 3508 GA, Utrecht, The Netherlands.

Objectives: Recent studies have proposed additional multidetector-row CT (MDCT) for prosthetic heart valve (PHV) dysfunction. References to discriminate physiological from pathological conditions early after implantation are lacking. We present baseline MDCT findings of PHVs 6 weeks post implantation.

Methods: Patients were prospectively enrolled and TTE was performed according to clinical guidelines. 256-MDCT images were systematically assessed for leaflet excursions, image quality, valve-related artefacts, and pathological and additional findings.

Results: Forty-six patients were included comprising 33 mechanical and 16 biological PHVs. Overall, MDCT image quality was good and relevant regions remained reliably assessable despite mild-moderate PHV-artefacts. MDCT detected three unexpected valve-related pathology cases: (1) prominent subprosthetic tissue, (2) pseudoaneurysm and (3) extensive pseudoaneurysms and valve dehiscence. The latter patient required valve surgery to be redone. TTE only showed trace periprosthetic regurgitation, and no abnormalities in the other cases. Additional findings were: tilted aortic PHV position (n = 3), pericardial haematoma (n = 3) and pericardial effusion (n = 3). Periaortic induration was present in 33/40 (83 %) aortic valve patients.

Conclusions: MDCT allowed evaluation of relevant PHV regions in all valves, revealed baseline postsurgical findings and, despite normal TTE findings, detected three cases of unexpected, clinically relevant pathology.

Key Points: • Postoperative MDCT presents baseline morphology relevant for prosthetic valve follow-up. • 83 % of patients show periaortic induration 6 weeks after aortic valve replacement. • MDCT detected three cases of clinically relevant pathology not found with TTE. • Valve dehiscence detection by MDCT required redo valve surgery in one patient. • MDCT is a suitable and complementary imaging tool for follow-up purposes.
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http://dx.doi.org/10.1007/s00330-015-3918-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778148PMC
April 2016

Presence of albuminuria predicts left ventricular mass in patients with chronic systemic arterial hypertension.

Eur J Clin Invest 2015 Jun 4;45(6):550-6. Epub 2015 May 4.

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

Background: Increased left ventricular mass (LVM) is known to predict cardiovascular morbidity and mortality. LVM is high in patients with advanced kidney disease. Our aim was to study the relationship between renal parameters and LVM in hypertensive subjects at high risk of cardiovascular disease.

Design: Cardiac MRI was performed in 527 patients participating in the single-centre SMART cohort study. Participants free from previous symptomatic coronary heart disease but with a history of hypertension were recruited. Subjects were screened for cardiovascular risk factors in a standardized way. Multivariable linear regression was used to study the relationship of both estimated glomerular filtration rate (eGFR) and presence of albuminuria with left ventricular mass.

Results: Mean LVM was 121 g for men (SD 26) and 87 g for women (SD 20). Mean eGFR was 82 mL/min/1.73 m(²) (SD 19). A total of 73 patients (14%) had albuminuria. After adjusting for known determinants of LVM (height, weight, sex and age) eGFR did not relate to LVM while presence of albuminuria did (mean change in LVM per 10 mL/min/1.73 m(2) change in eGFR 0.79 g, 95% CI -0.33 to 1.91, P = 0.17, mean change in LVM in presence vs. absence of albuminuria 9.9 g, 95% CI 4.33 to 15.45, P = 0.001). Additional adjustment for systolic blood pressure did not change results (B for eGFR 0.54, 95% CI -0.58 to 1.66, P = 0.35, B for albuminuria 9.09, 95% CI 3.57 to 14.60, P = 0.001).

Conclusions: In this study in hypertensive patients with high vascular risk, albuminuria was related to increased LVM and eGFR was not.
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http://dx.doi.org/10.1111/eci.12433DOI Listing
June 2015

Coronary artery assessment on electrocardiogram-gated thoracoabdominal multidetector computed tomographic angiography for aortic evaluation.

J Comput Assist Tomogr 2014 Mar-Apr;38(2):185-9

From the Departments of *Radiology, †Cardiology, and ‡Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: The objective of this study was to evaluate coronary image quality, stenosis grade, and diagnostic confidence in patients undergoing electrocardiogram-gated thoracoabdominal multidetector computed tomographic angiography (CTA) for aortic evaluation.

Methods: Seventy-five consecutive patients underwent retrospectively electrocardiogram-gated thoracoabdominal CTA reconstructed at each 12.5% of the R wave to R wave (R-R) interval. Two observers in consensus scored the coronary arteries per segment (15-segment American Heart Association model) for image quality, stenosis grade, and stenosis-assessment confidence.

Results: Nondiagnostic image quality prohibited coronary evaluation in 14 patients. In the remaining patients, 2% of segments was scored absent, 24% was scored nondiagnostic, 12% was scored diagnostically limited, and 61% was scored at least acceptable. Acceptable or higher image quality was seen in 82% of the proximal and middle segments. Significant stenosis (>50%) was seen in 57% of the patients. Stenosis-severity scoring confidence was moderate to high in 79% of 673 assessable segments.

Conclusions: Electrocardiogram-gated thoracoabdominal CTA allows concomitant assessment of the proximal and middle coronary arteries and may serve as a combined tool for aortic-disease workup. Aortic CTA showed significant coronary artery stenosis in 57% of the patients evaluated for aortic pathology.
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http://dx.doi.org/10.1097/RCT.0b013e3182ab2addDOI Listing
May 2014

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

Authors:
Vinicius Tragante Michael R Barnes Santhi K Ganesh Matthew B Lanktree Wei Guo Nora Franceschini Erin N Smith Toby Johnson Michael V Holmes Sandosh Padmanabhan Konrad J Karczewski Berta Almoguera John Barnard Jens Baumert Yen-Pei Christy Chang Clara C Elbers Martin Farrall Mary E Fischer Tom R Gaunt Johannes M I H Gho Christian Gieger Anuj Goel Yan Gong Aaron Isaacs Marcus E Kleber Irene Mateo Leach Caitrin W McDonough Matthijs F L Meijs Olle Melander Christopher P Nelson Ilja M Nolte Nathan Pankratz Tom S Price Jonathan Shaffer Sonia Shah Maciej Tomaszewski Peter J van der Most Erik P A Van Iperen Judith M Vonk Kate Witkowska Caroline O L Wong Li Zhang Amber L Beitelshees Gerald S Berenson Deepak L Bhatt Morris Brown Amber Burt Rhonda M Cooper-DeHoff John M Connell Karen J Cruickshanks Sean P Curtis George Davey-Smith Christian Delles Ron T Gansevoort Xiuqing Guo Shen Haiqing Claire E Hastie Marten H Hofker G Kees Hovingh Daniel S Kim Susan A Kirkland Barbara E Klein Ronald Klein Yun R Li Steffi Maiwald Christopher Newton-Cheh Eoin T O'Brien N Charlotte Onland-Moret Walter Palmas Afshin Parsa Brenda W Penninx Mary Pettinger Ramachandran S Vasan Jane E Ranchalis Paul M Ridker Lynda M Rose Peter Sever Daichi Shimbo Laura Steele Ronald P Stolk Barbara Thorand Mieke D Trip Cornelia M van Duijn W Monique Verschuren Cisca Wijmenga Sharon Wyatt J Hunter Young Aeilko H Zwinderman Connie R Bezzina Eric Boerwinkle Juan P Casas Mark J Caulfield Aravinda Chakravarti Daniel I Chasman Karina W Davidson Pieter A Doevendans Anna F Dominiczak Garret A FitzGerald John G Gums Myriam Fornage Hakon Hakonarson Indrani Halder Hans L Hillege Thomas Illig Gail P Jarvik Julie A Johnson John J P Kastelein Wolfgang Koenig Meena Kumari Winfried März Sarah S Murray Jeffery R O'Connell Albertine J Oldehinkel James S Pankow Daniel J Rader Susan Redline Muredach P Reilly Eric E Schadt Kandice Kottke-Marchant Harold Snieder Michael Snyder Alice V Stanton Martin D Tobin André G Uitterlinden Pim van der Harst Yvonne T van der Schouw Nilesh J Samani Hugh Watkins Andrew D Johnson Alex P Reiner Xiaofeng Zhu Paul I W de Bakker Daniel Levy Folkert W Asselbergs Patricia B Munroe Brendan J Keating

Am J Hum Genet 2014 Mar 20;94(3):349-60. Epub 2014 Feb 20.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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http://dx.doi.org/10.1016/j.ajhg.2013.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951943PMC
March 2014

Loci influencing blood pressure identified using a cardiovascular gene-centric array.

Authors:
Santhi K Ganesh Vinicius Tragante Wei Guo Yiran Guo Matthew B Lanktree Erin N Smith Toby Johnson Berta Almoguera Castillo John Barnard Jens Baumert Yen-Pei Christy Chang Clara C Elbers Martin Farrall Mary E Fischer Nora Franceschini Tom R Gaunt Johannes M I H Gho Christian Gieger Yan Gong Aaron Isaacs Marcus E Kleber Irene Mateo Leach Caitrin W McDonough Matthijs F L Meijs Olle Mellander Cliona M Molony Ilja M Nolte Sandosh Padmanabhan Tom S Price Ramakrishnan Rajagopalan Jonathan Shaffer Sonia Shah Haiqing Shen Nicole Soranzo Peter J van der Most Erik P A Van Iperen Jessica Van Setten Jessic A Van Setten Judith M Vonk Li Zhang Amber L Beitelshees Gerald S Berenson Deepak L Bhatt Jolanda M A Boer Eric Boerwinkle Ben Burkley Amber Burt Aravinda Chakravarti Wei Chen Rhonda M Cooper-Dehoff Sean P Curtis Albert Dreisbach David Duggan Georg B Ehret Richard R Fabsitz Myriam Fornage Ervin Fox Clement E Furlong Ron T Gansevoort Marten H Hofker G Kees Hovingh Susan A Kirkland Kandice Kottke-Marchant Abdullah Kutlar Andrea Z Lacroix Taimour Y Langaee Yun R Li Honghuang Lin Kiang Liu Steffi Maiwald Rainer Malik Gurunathan Murugesan Christopher Newton-Cheh Jeffery R O'Connell N Charlotte Onland-Moret Willem H Ouwehand Walter Palmas Brenda W Penninx Carl J Pepine Mary Pettinger Joseph F Polak Vasan S Ramachandran Jane Ranchalis Susan Redline Paul M Ridker Lynda M Rose Hubert Scharnag Nicholas J Schork Daichi Shimbo Alan R Shuldiner Sathanur R Srinivasan Ronald P Stolk Herman A Taylor Barbara Thorand Mieke D Trip Cornelia M van Duijn W Monique Verschuren Cisca Wijmenga Bernhard R Winkelmann Sharon Wyatt J Hunter Young Bernhard O Boehm Mark J Caulfield Daniel I Chasman Karina W Davidson Pieter A Doevendans Garret A Fitzgerald John G Gums Hakon Hakonarson Hans L Hillege Thomas Illig Gail P Jarvik Julie A Johnson John J P Kastelein Wolfgang Koenig Winfried März Braxton D Mitchell Sarah S Murray Albertine J Oldehinkel Daniel J Rader Muredach P Reilly Alex P Reiner Eric E Schadt Roy L Silverstein Harold Snieder Alice V Stanton André G Uitterlinden Pim van der Harst Yvonne T van der Schouw Nilesh J Samani Andrew D Johnson Patricia B Munroe Paul I W de Bakker Xiaofeng Zhu Daniel Levy Brendan J Keating Folkert W Asselbergs

Hum Mol Genet 2013 Apr 8;22(8):1663-78. Epub 2013 Jan 8.

Division of Cardiovascular Medicine, University of Michigan Health System, Ann Arbor, MI, USA.

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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http://dx.doi.org/10.1093/hmg/dds555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657476PMC
April 2013

Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.

Authors:
Folkert W Asselbergs Yiran Guo Erik P A van Iperen Suthesh Sivapalaratnam Vinicius Tragante Matthew B Lanktree Leslie A Lange Berta Almoguera Yolande E Appelman John Barnard Jens Baumert Amber L Beitelshees Tushar R Bhangale Yii-Der Ida Chen Tom R Gaunt Yan Gong Jemma C Hopewell Toby Johnson Marcus E Kleber Taimour Y Langaee Mingyao Li Yun R Li Kiang Liu Caitrin W McDonough Matthijs F L Meijs Rita P S Middelberg Kiran Musunuru Christopher P Nelson Jeffery R O'Connell Sandosh Padmanabhan James S Pankow Nathan Pankratz Suzanne Rafelt Ramakrishnan Rajagopalan Simon P R Romaine Nicholas J Schork Jonathan Shaffer Haiqing Shen Erin N Smith Sam E Tischfield Peter J van der Most Jana V van Vliet-Ostaptchouk Niek Verweij Kelly A Volcik Li Zhang Kent R Bailey Kristian M Bailey Florianne Bauer Jolanda M A Boer Peter S Braund Amber Burt Paul R Burton Sarah G Buxbaum Wei Chen Rhonda M Cooper-Dehoff L Adrienne Cupples Jonas S deJong Christian Delles David Duggan Myriam Fornage Clement E Furlong Nicole Glazer John G Gums Claire Hastie Michael V Holmes Thomas Illig Susan A Kirkland Mika Kivimaki Ronald Klein Barbara E Klein Charles Kooperberg Kandice Kottke-Marchant Meena Kumari Andrea Z LaCroix Laya Mallela Gurunathan Murugesan Jose Ordovas Willem H Ouwehand Wendy S Post Richa Saxena Hubert Scharnagl Pamela J Schreiner Tina Shah Denis C Shields Daichi Shimbo Sathanur R Srinivasan Ronald P Stolk Daniel I Swerdlow Herman A Taylor Eric J Topol Elina Toskala Joost L van Pelt Jessica van Setten Salim Yusuf John C Whittaker A H Zwinderman Sonia S Anand Anthony J Balmforth Gerald S Berenson Connie R Bezzina Bernhard O Boehm Eric Boerwinkle Juan P Casas Mark J Caulfield Robert Clarke John M Connell Karen J Cruickshanks Karina W Davidson Ian N M Day Paul I W de Bakker Pieter A Doevendans Anna F Dominiczak Alistair S Hall Catharina A Hartman Christian Hengstenberg Hans L Hillege Marten H Hofker Steve E Humphries Gail P Jarvik Julie A Johnson Bernhard M Kaess Sekar Kathiresan Wolfgang Koenig Debbie A Lawlor Winfried März Olle Melander Braxton D Mitchell Grant W Montgomery Patricia B Munroe Sarah S Murray Stephen J Newhouse N Charlotte Onland-Moret Neil Poulter Bruce Psaty Susan Redline Stephen S Rich Jerome I Rotter Heribert Schunkert Peter Sever Alan R Shuldiner Roy L Silverstein Alice Stanton Barbara Thorand Mieke D Trip Michael Y Tsai Pim van der Harst Ellen van der Schoot Yvonne T van der Schouw W M Monique Verschuren Hugh Watkins Arthur A M Wilde Bruce H R Wolffenbuttel John B Whitfield G Kees Hovingh Christie M Ballantyne Cisca Wijmenga Muredach P Reilly Nicholas G Martin James G Wilson Daniel J Rader Nilesh J Samani Alex P Reiner Robert A Hegele John J P Kastelein Aroon D Hingorani Philippa J Talmud Hakon Hakonarson Clara C Elbers Brendan J Keating Fotios Drenos

Am J Hum Genet 2012 Nov 11;91(5):823-38. Epub 2012 Oct 11.

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

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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http://dx.doi.org/10.1016/j.ajhg.2012.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487124PMC
November 2012

Prediction model to estimate presence of coronary artery disease: retrospective pooled analysis of existing cohorts.

BMJ 2012 Jun 12;344:e3485. Epub 2012 Jun 12.

Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, Netherlands.

Objectives: To develop prediction models that better estimate the pretest probability of coronary artery disease in low prevalence populations.

Design: Retrospective pooled analysis of individual patient data.

Setting: 18 hospitals in Europe and the United States.

Participants: Patients with stable chest pain without evidence for previous coronary artery disease, if they were referred for computed tomography (CT) based coronary angiography or catheter based coronary angiography (indicated as low and high prevalence settings, respectively).

Main Outcome Measures: Obstructive coronary artery disease (≥ 50% diameter stenosis in at least one vessel found on catheter based coronary angiography). Multiple imputation accounted for missing predictors and outcomes, exploiting strong correlation between the two angiography procedures. Predictive models included a basic model (age, sex, symptoms, and setting), clinical model (basic model factors and diabetes, hypertension, dyslipidaemia, and smoking), and extended model (clinical model factors and use of the CT based coronary calcium score). We assessed discrimination (c statistic), calibration, and continuous net reclassification improvement by cross validation for the four largest low prevalence datasets separately and the smaller remaining low prevalence datasets combined.

Results: We included 5677 patients (3283 men, 2394 women), of whom 1634 had obstructive coronary artery disease found on catheter based coronary angiography. All potential predictors were significantly associated with the presence of disease in univariable and multivariable analyses. The clinical model improved the prediction, compared with the basic model (cross validated c statistic improvement from 0.77 to 0.79, net reclassification improvement 35%); the coronary calcium score in the extended model was a major predictor (0.79 to 0.88, 102%). Calibration for low prevalence datasets was satisfactory.

Conclusions: Updated prediction models including age, sex, symptoms, and cardiovascular risk factors allow for accurate estimation of the pretest probability of coronary artery disease in low prevalence populations. Addition of coronary calcium scores to the prediction models improves the estimates.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374026PMC
http://dx.doi.org/10.1136/bmj.e3485DOI Listing
June 2012

Relation between abdominal obesity, insulin resistance and left ventricular hypertrophy diagnosed by electrocardiogram and magnetic resonance imaging in hypertensive patients.

Am J Cardiol 2012 Jul 5;110(2):227-33. Epub 2012 Apr 5.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Obesity is related to left ventricular hypertrophy (LVH). Whether LVH on electrocardiography (ECG-LVH) is a result of increased cardiac electrical activity or due to increased left ventricular mass (LVM) remains to be determined. The aims of the present study were to investigate the relation between obesity and ECG-LVH and LVM by magnetic resonance imaging (MRI-LVM) in patients with hypertension and to investigate the relation of insulin resistance (IR) and LVH. Patients with hypertension (n = 421) were evaluated using Sokolow-Lyon voltage, Cornell voltage, and cardiac magnetic resonance imaging. Waist circumference was used as a measure of abdominal obesity. Linear regression analysis revealed an inverse relation (adjusted β = -0.02, 95% confidence interval -0.02 to -0.01) between waist circumference and Sokolow-Lyon voltage, indicating a decrease of 0.02 mV per 1-cm increase in waist circumference. There was a positive relation between waist circumference and MRI-LVM (β = 0.49, 95% confidence interval 0.32 to 0.67). Patients in the highest quartile of LVM had a worse metabolic profile than patients with the Sokolow-Lyon voltage criterion. The relations of IR with ECG-LVH and MRI-LVM were similar to those of waist circumference in relation to ECG-LVH and MRI-LVM. In conclusion, there is an inverse relation between waist circumference and ECG-LVH and a positive relation between waist circumference and MRI-LVM. This study indicates that obesity has a different relation to voltage criteria for LVH compared to anatomic criteria for LVH, supporting the hypothesis that IR decreases electrocardiographic voltages, despite an increase in MRI-LVM. The clinical implication is that especially in patients with IR, Sokolow-Lyon voltage is low in contrast to high MRI-LVM.
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http://dx.doi.org/10.1016/j.amjcard.2012.03.016DOI Listing
July 2012

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

Authors:
Richa Saxena Clara C Elbers Yiran Guo Inga Peter Tom R Gaunt Jessica L Mega Matthew B Lanktree Archana Tare Berta Almoguera Castillo Yun R Li Toby Johnson Marcel Bruinenberg Diane Gilbert-Diamond Ramakrishnan Rajagopalan Benjamin F Voight Ashok Balasubramanyam John Barnard Florianne Bauer Jens Baumert Tushar Bhangale Bernhard O Böhm Peter S Braund Paul R Burton Hareesh R Chandrupatla Robert Clarke Rhonda M Cooper-DeHoff Errol D Crook George Davey-Smith Ian N Day Anthonius de Boer Mark C H de Groot Fotios Drenos Jane Ferguson Caroline S Fox Clement E Furlong Quince Gibson Christian Gieger Lisa A Gilhuijs-Pederson Joseph T Glessner Anuj Goel Yan Gong Struan F A Grant Diederick E Grobbee Claire Hastie Steve E Humphries Cecilia E Kim Mika Kivimaki Marcus Kleber Christa Meisinger Meena Kumari Taimour Y Langaee Debbie A Lawlor Mingyao Li Maximilian T Lobmeyer Anke-Hilse Maitland-van der Zee Matthijs F L Meijs Cliona M Molony David A Morrow Gurunathan Murugesan Solomon K Musani Christopher P Nelson Stephen J Newhouse Jeffery R O'Connell Sandosh Padmanabhan Jutta Palmen Sanjey R Patel Carl J Pepine Mary Pettinger Thomas S Price Suzanne Rafelt Jane Ranchalis Asif Rasheed Elisabeth Rosenthal Ingo Ruczinski Sonia Shah Haiqing Shen Günther Silbernagel Erin N Smith Annemieke W M Spijkerman Alice Stanton Michael W Steffes Barbara Thorand Mieke Trip Pim van der Harst Daphne L van der A Erik P A van Iperen Jessica van Setten Jana V van Vliet-Ostaptchouk Niek Verweij Bruce H R Wolffenbuttel Taylor Young M Hadi Zafarmand Joseph M Zmuda Michael Boehnke David Altshuler Mark McCarthy W H Linda Kao James S Pankow Thomas P Cappola Peter Sever Neil Poulter Mark Caulfield Anna Dominiczak Denis C Shields Deepak L Bhatt Deepak Bhatt Li Zhang Sean P Curtis John Danesh Juan P Casas Yvonne T van der Schouw N Charlotte Onland-Moret Pieter A Doevendans Gerald W Dorn Martin Farrall Garret A FitzGerald Anders Hamsten Robert Hegele Aroon D Hingorani Marten H Hofker Gordon S Huggins Thomas Illig Gail P Jarvik Julie A Johnson Olaf H Klungel William C Knowler Wolfgang Koenig Winfried März James B Meigs Olle Melander Patricia B Munroe Braxton D Mitchell Susan J Bielinski Daniel J Rader Muredach P Reilly Stephen S Rich Jerome I Rotter Danish Saleheen Nilesh J Samani Eric E Schadt Alan R Shuldiner Roy Silverstein Kandice Kottke-Marchant Philippa J Talmud Hugh Watkins Folkert W Asselbergs Folkert Asselbergs Paul I W de Bakker Jeanne McCaffery Cisca Wijmenga Marc S Sabatine James G Wilson Alex Reiner Donald W Bowden Hakon Hakonarson David S Siscovick Brendan J Keating

Am J Hum Genet 2012 Mar 9;90(3):410-25. Epub 2012 Feb 9.

Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
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http://dx.doi.org/10.1016/j.ajhg.2011.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309185PMC
March 2012

A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension.

Eur Heart J 2011 Jun 2;32(11):1316-30. Epub 2011 Mar 2.

Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Aims: The aim was to validate, update, and extend the Diamond-Forrester model for estimating the probability of obstructive coronary artery disease (CAD) in a contemporary cohort.

Methods And Results: Prospectively collected data from 14 hospitals on patients with chest pain without a history of CAD and referred for conventional coronary angiography (CCA) were used. Primary outcome was obstructive CAD, defined as ≥ 50% stenosis in one or more vessels on CCA. The validity of the Diamond-Forrester model was assessed using calibration plots, calibration-in-the-large, and recalibration in logistic regression. The model was subsequently updated and extended by revising the predictive value of age, sex, and type of chest pain. Diagnostic performance was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) and reclassification was determined. We included 2260 patients, of whom 1319 had obstructive CAD on CCA. Validation demonstrated an overestimation of the CAD probability, especially in women. The updated and extended models demonstrated a c-statistic of 0.79 (95% CI 0.77-0.81) and 0.82 (95% CI 0.80-0.84), respectively. Sixteen per cent of men and 64% of women were correctly reclassified. The predicted probability of obstructive CAD ranged from 10% for 50-year-old females with non-specific chest pain to 91% for 80-year-old males with typical chest pain. Predictions varied across hospitals due to differences in disease prevalence.

Conclusion: Our results suggest that the Diamond-Forrester model overestimates the probability of CAD especially in women. We updated the predictive effects of age, sex, type of chest pain, and hospital setting which improved model performance and we extended it to include patients of 70 years and older.
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http://dx.doi.org/10.1093/eurheartj/ehr014DOI Listing
June 2011

A prediction model for left ventricular mass in patients at high cardiovascular risk.

Eur J Cardiovasc Prev Rehabil 2010 Dec;17(6):621-7

Department of Cardiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.

Background: Left ventricular (LV) mass has a continuous relation with cardiovascular risk, and regression of LV mass induced by pharmacological treatment is associated with improved prognosis. Therefore, early identification of patients with a large LV mass is desired. We developed a model to predict LV mass in individual hypertensives at high cardiovascular risk.

Design And Methods: We analyzed data of 536 hypertensives with symptomatic extracardiac atherosclerotic disease or marked risk factors for atherosclerosis from a cross-sectional study in a tertiary referral center. LV mass was measured by cardiac MRI. We developed the prediction rule with multivariable linear regression analysis and stepwise backward elimination. Internal validation was assessed with bootstrap sampling to obtain an estimate of model performance (R²) that may be expected for new patients.

Results: Important predictors for LV mass included sex, height, body mass index, systolic blood pressure, and previous aneurysm of the abdominal aorta. R² of the prediction model was 45% after internal validation, which was considerably higher than the R² of previously reported models (range 1-38%). Addition of electrocardiography data showed limited improvement of the model performance (R²=47%).

Conclusion: We present a prediction model for LV mass in hypertensives at high cardiovascular risk. After external validation, this model may be used in clinical practice to estimate LV mass for early identification of large LV mass. The predictions of the model may support appropriate medical care in the prevention of cardiovascular disease.
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http://dx.doi.org/10.1097/HJR.0b013e328332d4bcDOI Listing
December 2010

Biphasic contrast medium injection in cardiac CT: moderate versus high concentration contrast material at identical iodine flux and iodine dose.

Eur Radiol 2010 Aug 20;20(8):1917-25. Epub 2010 Mar 20.

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

Objective: To prospectively investigate the influence of contrast material concentration on enhancement in cardiac CT by using a biphasic single-injection protocol.

Methods: Sixty-four-row multidetector cardiac CT angiography was performed in 159 patients randomised to a moderate or high contrast medium concentration. Contrast material injection included a first phase for enhancement of the coronary arteries and a second phase, at half the iodine flux, targeted at enhancement of the right ventricle. Contrast medium injection was followed by a saline flush. For both concentrations, injection duration (and thus total iodine dose) was adapted to the duration of the CT data acquisition and iodine flux was adjusted to patient weight. Attenuation was measured at various levels in the heart and vessels and the two concentrations compared, overall and per weight group.

Results: Enhancement of the aorta and left ventricle was significantly greater with the moderate than with the high concentration contrast medium. This remained true for the two higher weight groups. No difference was found in the lowest weight group or in the right ventricle and pulmonary outflow tract.

Conclusion: With a biphasic injection protocol, enhancement of the aorta and left ventricle was weaker with the higher concentration of contrast material.
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http://dx.doi.org/10.1007/s00330-010-1752-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899014PMC
August 2010

Does slice thickness affect diagnostic performance of 64-slice CT coronary angiography in stable and unstable angina patients with a positive calcium score?

Acta Radiol 2010 May;51(4):427-30

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

Background: Coronary calcification can lead to over-estimation of the degree of coronary stenosis.

Purpose: To evaluate whether thinner reconstruction thickness improves the diagnostic performance of 64-slice CT coronary angiography (CTCA) in angina patients with a positive calcium score.

Material And Methods: We selected 20 scans from a clinical study comparing CTCA to conventional coronary angiography (CCA) in stable and unstable angina patients based on a low number of motion artifacts and a positive calcium score. All images were acquired at 64 x 0.625 mm and each CTCA scan was reconstructed at slice thickness/increment 0.67 mm/0.33 mm, 0.9 mm/0.45 mm, and 1.4 mm/0.7 mm. Two reviewers blinded for CCA results independently evaluated the scans for the presence of significant coronary artery disease (CAD) in three randomly composed series, with > or =2 weeks in between series. The diagnostic performance of CTCA was compared for the different slice thicknesses using a pooled analysis of both reviewers. Significant CAD was defined as >50% diameter narrowing on quantitative CCA. Image noise (standard deviation of CT numbers) was measured in all scans. Inter-observer variability was assessed with kappa.

Results: Significant CAD was present in 8% of 304 available segments. Median total Agatston calcium score was 181.8 (interquartile range 34.9-815.6). Sensitivity at 0.67 mm, 0.9 mm, and 1.4 mm slice thickness was 70% (95% confidence interval 57-83%), 74% (62-86%), and 70% (57-83%), respectively. Specificity was 85% (82-88%), 84% (81-87%), and 84% (81-87%), respectively. The positive predictive value was 30 (21-38%), 29 (21-37%), and 28 (20-36%), respectively. The negative predictive value was 97% (95-98%), 97% (96-99%), and 97% (96-99%), respectively. Kappa for inter-observer agreement was 0.56, 0.58, and 0.59. Noise decreased from 32.9 HU at 0.67 mm, to 23.2 HU at 1.4 mm (P<0.001).

Conclusion: Diagnostic performance of CTCA in angina patients with a positive calcium score was not markedly affected by modest variations in reconstruction slice thickness.
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http://dx.doi.org/10.3109/02841851003649274DOI Listing
May 2010

CT coronary angiography in patients suspected of having coronary artery disease: decision making from various perspectives in the face of uncertainty.

Radiology 2009 Dec 28;253(3):734-44. Epub 2009 Oct 28.

Department of Radiology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

Purpose: To determine the cost-effectiveness of computed tomographic (CT) coronary angiography as a triage test, performed prior to conventional coronary angiography, by using a Markov model.

Materials And Methods: A Markov model was used to analyze the cost-effectiveness of CT coronary angiography performed as a triage test prior to conventional coronary angiography from the perspective of the patient, physician, hospital, health care system, and society by using recommendations from the United Kingdom, the United States, and the Netherlands for cost-effectiveness analyses. For CT coronary angiography, a range of sensitivities (79%-100%) and specificities (63%-94%) were used to help diagnose significant coronary artery disease (CAD). Optimization criteria (ie, outcomes considered) were: revised posttest probability of CAD, life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Extensive sensitivity analysis was performed.

Results: For a prior probability of CAD of less than 40%, the probability of CAD after CT coronary angiography with negative results was less than 1%. The Markov model calculations from the patient/physician perspective suggest that CT coronary angiography maximizes life-years respectively in 60-year-old men and women at a prior probability of less than 38% and 24% and maximizes QALYs at a prior probability of less than 17% and 11%. From the hospital/health care perspective, CT coronary angiography helps reduce health care and direct nonhealth care-related costs (according to UK/U.S. recommendations), regardless of prior probability, and lowers all costs, including production losses (Netherlands recommendations) at a prior probability of less than 87%-92%. Analysis performed from a societal perspective by using a willingness-to-pay threshold level of euro 80,000/QALY suggests that CT coronary angiography is cost-effective when the prior probability is lower than 44% and 37% in men and women, respectively. Sensitivity analyses showed that results changed across the reported range of sensitivity of CT coronary angiography.

Conclusion: The optimal diagnostic work-up depends on the optimization criterion, prior probability of CAD, and the diagnostic performance of CT coronary angiography.
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http://dx.doi.org/10.1148/radiol.2533090507DOI Listing
December 2009

Is there a role for CT coronary angiography in patients with symptomatic angina? Effect of coronary calcium score on identification of stenosis.

Int J Cardiovasc Imaging 2009 Dec 1;25(8):847-54. Epub 2009 Aug 1.

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

Present guidelines discourage the use of CT coronary angiography (CTCA) in symptomatic angina patients. We examined the relation between coronary calcium score (CS) and the performance of CTCA in patients with stable and unstable angina in order to understand under which conditions CTCA might be a gate-keeper to conventional coronary angiography (CCA) in such patients. We included 360 patients between 50 and 70 years old with stable and unstable angina who were clinically referred for CCA irrespective of CS. Patients received CS and CCTA on 64-slice scanners in a multicenter cross-sectional trial. The institutional review board approved the study. Diagnostic performance of CTCA to detect or rule out significant coronary artery disease was calculated on a per patient level in pre-defined CS categories. The prevalence of significant coronary artery disease strongly increased with CS. Negative CTCA were associated with a negative likelihood ratio of <0.1 independent of CS. Positive CTCA was associated with a high positive likelihood ratio of 9.4 if CS was <10. However, for higher CS the positive likelihood ratio never exceeded 3.0 and for CS >400 it decreased to 1.3. In the 62 (17%) patients with CS <10, CTCA reliably identified the 42 (68%) of these patients without significant CAD, at no false negative CTCA scans. In symptomatic angina patients, a negative CTCA reliably excludes significant CAD but the additional value of CTCA decreases sharply with CS >10 and especially with CS >400. In patients with CS <10, CTCA provides excellent diagnostic performance.
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http://dx.doi.org/10.1007/s10554-009-9485-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784513PMC
December 2009

Comparison of frequency of calcified versus non-calcified coronary lesions by computed tomographic angiography in patients with stable versus unstable angina pectoris.

Am J Cardiol 2009 Aug 6;104(3):305-11. Epub 2009 Jun 6.

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

Computed tomographic coronary angiography (CTCA) can noninvasively identify calcified and noncalcified coronary plaques. The aim of this study was to compare the phenotypes of all plaques and of culprit plaques between patients with unstable angina pectoris (UAP) and those with stable angina pectoris (SAP), because plaque characteristics may differ between these patients. In 110 patients with UAP and 189 with SAP from a multicenter study comparing 64-slice CTCA with conventional coronary angiography, the number and phenotypes (noncalcified, mixed, and calcified) of coronary plaques were compared. In a subanalysis in 50 patients with UAP and 64 with SAP, culprit plaque characteristics, including culprit plaque cross-sectional area relative to total vessel cross-sectional area, culprit plaque length, remodeling index, and spotty calcification, were determined. Odds ratios for the presence of UAP, adjusted for clinical variables and the total number of plaques, were calculated for plaque characteristics on CTCA. Although the number of plaques was similar for patients with UAP and those with SAP, plaques in patients with UAP were more frequently noncalcified than in patients with SAP. The odds ratio for UAP was 1.3 (95% confidence interval [CI] 1.1 to 1.5) per noncalcified plaque. In the culprit plaque subanalysis, odds ratios for UAP were 0.99 (95% CI 0.96 to 1.01) per millimeter culprit plaque length, 2.7 (95% CI 1.2 to 6.4) for noncalcified culprit plaque, and 1.06 (95% CI 0.99 to 1.13) per percentage relative culprit plaque cross-sectional area. No significant relation was found between remodeling index or spotty calcification and UAP. In conclusion, noncalcified plaques and large noncalcified culprit plaques are more frequently found in patients with UAP than in those with SAP.
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http://dx.doi.org/10.1016/j.amjcard.2009.03.049DOI Listing
August 2009

Relation of common carotid intima-media thickness with left ventricular mass caused by shared risk factors for hypertrophy.

J Am Soc Echocardiogr 2009 May 9;22(5):499-504. Epub 2009 Mar 9.

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

Background: It is unclear whether the relationship between common carotid intima-media thickness (cCIMT) and left ventricular mass (LVM) is due to shared risk factors for atherosclerosis or for hypertrophy.

Methods: In 525 hypertensive subjects at high cardiovascular risk, the relation of cCIMT to LVM and established vascular risk factors was studied.

Results: CCIMT was positively related to LVM. In a multivariable model including age, gender, height, weight, and LVM, a 1-g increase in LVM related to an increase in cCIMT of 1.6 microm (95% confidence interval, 0.8-2.4). After adjustment for atherosclerotic risk factors, notably previous stroke or transient ischemic attack, peripheral arterial disease, lipid-lowering medication, albuminuria and current smoking, the relation remained unchanged. In contrast, addition of systolic and diastolic blood pressure and hypertension treatment attenuated Beta for the relation between cCIMT and LVM with 19% to 1.3 microm (95% confidence interval, 0.2-2.2).

Conclusion: The relationship between cCIMT and LVM may be due to risk factors for hypertrophy rather than for atherosclerotic factors in a considerable proportion of patients.
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http://dx.doi.org/10.1016/j.echo.2009.01.015DOI Listing
May 2009

Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction.

Circ Res 2009 Mar 24;104(5):699-706. Epub 2009 Jan 24.

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

Myocardial infarction is commonly complicated by left ventricular remodeling, a process that leads to cardiac dilatation, congestive heart failure and death. The innate immune system plays a pivotal role in the remodeling process via nuclear factor (NF)-kappaB activation. The NF-kappaB transcription factor family includes several subunits (p50, p52, p65, c-Rel, and Rel B) that respond to myocardial ischemia. The function of NF-kappaB p50, however, is controversial in this process. To clarify the role of NF-kappaB p50 in postinfarct left ventricular remodeling, myocardial infarction was induced in wild-type 129Bl6 mice and NF-kappaB p50-deficient mice. Without affecting infarct size, deletion of NF-kappaB p50 markedly increased the extent of expansive remodeling (end-diastolic volume: 176+/-13 microL versus 107+/-11 microL; P=0.003) and aggravated systolic dysfunction (left ventricular ejection fraction: 16.1+/-1.5% versus 24.7+/-3.7%; P=0.029) in a 28-day time period. Interstitial fibrosis and hypertrophy in the noninfarcted myocardium was increased in NF-kappaB p50 knockout mice. In the infarct area, a lower collagen density was observed, which was accompanied by an increased number of macrophages, higher gelatinase activity and increased inflammatory cytokine expression. In conclusion, targeted deletion of NF-kappaB p50 results in enhanced cardiac remodeling and functional deterioration following myocardial infarction by increasing matrix remodeling and inflammation.
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http://dx.doi.org/10.1161/CIRCRESAHA.108.189746DOI Listing
March 2009

Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study.

J Am Coll Cardiol 2008 Dec;52(25):2135-44

Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Objectives: This study sought to determine the diagnostic accuracy of 64-slice computed tomographic coronary angiography (CTCA) to detect or rule out significant coronary artery disease (CAD).

Background: CTCA is emerging as a noninvasive technique to detect coronary atherosclerosis.

Methods: We conducted a prospective, multicenter, multivendor study involving 360 symptomatic patients with acute and stable anginal syndromes who were between 50 and 70 years of age and were referred for diagnostic conventional coronary angiography (CCA) from September 2004 through June 2006. All patients underwent a nonenhanced calcium scan and a CTCA, which was compared with CCA. No patients or segments were excluded because of impaired image quality attributable to either coronary motion or calcifications. Patient-, vessel-, and segment-based sensitivities and specificities were calculated to detect or rule out significant CAD, defined as >or=50% lumen diameter reduction.

Results: The prevalence among patients of having at least 1 significant stenosis was 68%. In a patient-based analysis, the sensitivity for detecting patients with significant CAD was 99% (95% confidence interval [CI]: 98% to 100%), specificity was 64% (95% CI: 55% to 73%), positive predictive value was 86% (95% CI: 82% to 90%), and negative predictive value was 97% (95% CI: 94% to 100%). In a segment-based analysis, the sensitivity was 88% (95% CI: 85% to 91%), specificity was 90% (95% CI: 89% to 92%), positive predictive value was 47% (95% CI: 44% to 51%), and negative predictive value was 99% (95% CI: 98% to 99%).

Conclusions: Among patients in whom a decision had already been made to obtain CCA, 64-slice CTCA was reliable for ruling out significant CAD in patients with stable and unstable anginal syndromes. A positive 64-slice CTCA scan often overestimates the severity of atherosclerotic obstructions and requires further testing to guide patient management.
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http://dx.doi.org/10.1016/j.jacc.2008.08.058DOI Listing
December 2008

Differences in determinants of left ventricular mass assessed by cardiac magnetic resonance imaging across subjects with and without previous symptomatic atherosclerotic disease.

Int J Cardiol 2010 Jan 19;138(2):145-50. Epub 2008 Sep 19.

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

Background: Most previous studies on determinants of left ventricular (LV) mass have used echocardiography, which is less accurate than cardiac MRI (CMR). Furthermore, studies that used CMR to study the determinants of LV mass were performed in the general population. However, determinants may differ between those with and without previous symptomatic events. We studied the relation between atherosclerotic risk factors and LV mass in subjects free from cardiac disease, yet with and without atherosclerotic disease elsewhere.

Methods: A CMR was performed in 531 hypertensive subjects with clinically manifest extra-cardiac atherosclerotic disease or marked risk factors for atherosclerosis. In all subjects information on atherosclerotic risk factors was collected. Multivariable linear regression was used to study the relation of risk factors with LV mass. Interaction was evaluated with multiplicative interaction terms.

Results: Overall, male gender, weight, height, systolic blood pressure, albuminuria, current smoking, and a history of abdominal aortic aneurysm (AAA) were related to an increased LV mass. In subjects without a history of symptomatic atherosclerotic disease, gender, weight, height and systolic blood pressure were related to LV mass. In addition to these risk factors, albuminuria, current smoking and a history of AAA were related to LV mass in subjects with a history of symptomatic atherosclerotic disease.

Conclusion: Our study points towards differences in risk factor relations across populations with and without symptomatic atherosclerotic disease. The observed relationship between cardiovascular risk factors and LV mass re-emphasizes the importance of adequate treatment of modifiable risk factors in the prevention of cardiovascular disease.
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http://dx.doi.org/10.1016/j.ijcard.2008.08.008DOI Listing
January 2010

Relation of epicardial and pericoronary fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography.

Am J Cardiol 2008 Aug 24;102(4):380-5. Epub 2008 May 24.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Fat surrounding coronary arteries might aggravate coronary artery disease (CAD). We investigated the relation between epicardial adipose tissue (EAT) and pericoronary fat and coronary atherosclerosis and coronary artery calcium (CAC) in patients with suspected CAD and whether this relation is modified by total body weight. This was a cross-sectional study of 128 patients with angina pectoris (61 +/- 6 years of age) undergoing coronary angiography. EAT volume and pericoronary fat thickness were measured with cardiac computed tomography. Severity of coronary atherosclerosis was assessed by the number of stenotic (> or =50%) coronary vessels; extent of CAC was determined by the Agatston score. Patients were stratified for median total body weight (body mass index [BMI] 27 kg/m(2)). Overall, EAT and pericoronary fat were not associated with severity of coronary atherosclerosis and extent of CAC. In patients with low BMI, those with multivessel disease had increased EAT volume (100 vs 67 cm(3), p = 0.04) and pericoronary fat thickness (9.8 vs 8.4 mm, p = 0.06) compared with those without CAD. Also, patients with severe CAC had increased EAT volume (108.0 vs 69 cm(3), p = 0.02) and pericoronary fat thickness (10.0 vs 8.2 mm, p value = 0.01) compared with those with minimal/absent CAC. In conclusion, EAT and pericoronary fat were not associated with severity of coronary atherosclerosis and CAC in patients with suspected CAD. However, in those with low BMI, increased EAT and pericoronary fat were related to more severe coronary atherosclerosis and CAC. Fat surrounding coronary arteries may be involved in the process of coronary atherosclerosis, although this is different for patients with low and high BMIs.
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http://dx.doi.org/10.1016/j.amjcard.2008.04.002DOI Listing
August 2008

Variability of coronary calcium scores throughout the cardiac cycle: implications for the appropriate use of electrocardiogram-dose modulation with retrospectively gated computed tomography.

Invest Radiol 2008 Mar;43(3):187-94

Department of Radiology, University Medical Center Utrecht, Heidelberglaan, Utrecht, The Netherlands.

Objective: To study how much the calcium scores at various phases throughout the cardiac cycle deviate from the score in the most motionless phase during retrospectively electrocardiogram (ECG)-gated multidetector row computed tomography (MDCT) of the heart and to evaluate how to optimize ECG-based tube current modulation so that errors in calcium scoring can be minimized while dose savings can be maximized.

Materials And Methods: In 73 subjects with known or suspected coronary artery disease we performed retrospectively ECG-gated 64-detector row computed tomography for calcium scoring. Four subjects were excluded after scanning because of breathing artifacts or lack of coronary calcification. The scans of 69 subjects (46 men, mean age 62 +/- 6 years) were used for further analysis. Heart rate during the scan was recorded. In each patient, calcium scoring [Agatston score (AS), mass score (MS), and volume score, (VS)] was performed on 10 data sets reconstructed at 10%-intervals throughout the cardiac cycle. The most motionless phase was subjectively determined and used as the reference phase. For the score in each phase, deviation from the score in the reference phase was determined. An ECG-simulator was used to determine the amount of dose saving while scanning with dose modulation and applying diagnostic dose during 1 or several phases.

Results: Mean heart rate was 63 (+/-13) beats per minute (bpm). In 51% of patients the reference phase was the 70% phase. Using the calcium score in the 70% phase (mid-diastole) instead of the reference at heart rates below 70 bpm would have induced a median score deviation of 0% [interquartile range: 0%-6% (AS, MS, and VS)] and using the calcium score in the 40% phase (end-systole) at heart rates > or =70 bpm would also have induced a median score deviation of 0% [interquartile range: 0%-7% (AS), 0%-5% (MS), and 0%-3% (VS)]. Errors in calcium scores of more than 10% occur in around 10% of subjects for all 3 scoring algorithms. Dose savings increased with lower heart rates and shorter application of diagnostic dose.

Conclusions: The optimum phases for dose modulation are 70% (mid-diastole) at heart rates below 70 bpm and 40% (end-systole) at heart rates above 70 bpm. Under these conditions dose saving is maximum and a median error of 0% is found for the various calcium scoring techniques with score errors of more than 10% in around 10% of subjects.
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http://dx.doi.org/10.1097/RLI.0b013e31815cdd56DOI Listing
March 2008