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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Sekar Kathiresan,
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer,
Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer,
Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani,
Klaus Stark
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Sekar Kathiresan,
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer,
Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The short inversion time inversion recovery (STIR) black-blood technique has been used to visualize myocardial edema, and thus to differentiate acute from chronic myocardial lesions. However, some cardiovascular magnetic resonance (CMR) groups have reported variable image quality, and hence the diagnostic value of STIR in routine clinical practice has been put into question. The aim of our study was to analyze image quality and diagnostic performance of STIR using a set of pulse sequence parameters dedicated to edema detection, and to discuss possible factors that influence image quality. We hypothesized that STIR imaging is an accurate and robust way of detecting myocardial edema in non-selected patients with acute myocardial infarction.
Forty-six consecutive patients with acute myocardial infarction underwent CMR (day 4.5, +/- 1.6) including STIR for the assessment of myocardial edema and late gadolinium enhancement (LGE) for quantification of myocardial necrosis. Thirty of these patients underwent a follow-up CMR at approximately six months (195 +/- 39 days). Both STIR and LGE images were evaluated separately on a segmental basis for image quality as well as for presence and extent of myocardial hyper-intensity, with both visual and semi-quantitative (threshold-based) analysis. LGE was used as a reference standard for localization and extent of myocardial necrosis (acute) or scar (chronic).
Image quality of STIR images was rated as diagnostic in 99.5% of cases. At the acute stage, the sensitivity and specificity of STIR to detect infarcted segments on visual assessment was 95% and 78% respectively, and on semi-quantitative assessment was 99% and 83%, respectively. STIR differentiated acutely from chronically infarcted segments with a sensitivity of 95% by both methods and with a specificity of 99% by visual assessment and 97% by semi-quantitative assessment. The extent of hyper-intense areas on acute STIR images was 85% larger than those on LGE images, with a larger myocardial salvage index in reperfused than in non-reperfused infarcts (p = 0.035).
STIR with appropriate pulse sequence settings is accurate in detecting acute myocardial infarction (MI) and distinguishing acute from chronic MI with both visual and semi-quantitative analysis. Due to its unique technical characteristics, STIR should be regarded as an edema-weighted rather than a purely T2-weighted technique.
Journal of Cardiovascular Magnetic Resonance 03/2012; 14:22. · 3.72 Impact Factor
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ABSTRACT: Objective: To investigate the accuracy of stent measurements using coronary x-ray angiograms with a computer based stent enhancement algorithm applied (StentBoost, SB). To derive recommendations for best practice when using such systems. Background: Computer enhancement algorithms allow better visualization of intracoronary stents to assist in ensuring adequate stent deployment. Factors that affect the accuracy of measurements taken on such systems are yet to be fully understood. Methods: We analysed stent deployment of 43 stents in 33 patients measuring minimum stent diameter and cross sectional area (CSA) using intravascular ultrasound (IVUS), SB enhanced x-ray images, and quantitative coronary angiography (QCA). We investigated if the use of two projections and method of calibration influenced correlation between IVUS and SB measurements. Results: Using two views and performing calibration via the guide catheter improved agreement between SB and IVUS measurements. For example, minimum stent diameter assessed with SB using one view and balloon markers for calibration produced a correlation coefficient, r, of 0.21, whereas using two views and the guide catheter for calibration increased agreement to r = 0.62. Relative measures of stent deployment, such as the ratio of minimum to maximum CSA, produced good correlation between IVUS and SB (r = 0.74). Conclusions: When using the SB system, two projection angles should be used to image the stent. For absolute measurements, the guide catheter should be used for calibration purposes. Relative measures of stent size, which are probably sufficient for assessment of deployment, also give good agreement with similar measures on IVUS, and require no calibration. © 2011 Wiley Periodicals, Inc.
Catheterization and Cardiovascular Interventions 01/2012; · 2.29 Impact Factor
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Heribert Schunkert,
Inke R König,
Sekar Kathiresan,
Muredach P Reilly,
Themistocles L Assimes,
Hilma Holm,
Michael Preuss,
Alexandre F R Stewart,
Maja Barbalic,
Christian Gieger, [......],
Alistair S Hall,
Panos Deloukas,
John R Thompson,
Kari Stefansson,
Robert Roberts,
Unnur Thorsteinsdottir,
Christopher J O'Donnell,
Ruth McPherson,
Jeanette Erdmann,
Nilesh J Samani
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[hide abstract]
ABSTRACT: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
Nature Genetics 03/2011; 43(4):333-8. · 35.53 Impact Factor
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ABSTRACT: LVH [LV (left ventricular) hypertrophy] is an independent risk factor for CHD (coronary heart disease). During LVH, the preferred cardiac energy substrate switches from FAs (fatty acids) to glucose. LPL (lipoprotein lipase) is the key enzyme in triacylglycerol (triglyceride) hydrolysis and supplies FAs to the heart. To investigate whether substrate utilization influences cardiac growth and CHD risk, we examined the association between the functional LPL S447X (rs328) variant and hypertension-induced LV growth and CHD risk. LPL-X447 has been shown to be more hydrolytically efficient and would therefore release more free FAs than LPL-S477. In a cohort of 190 hypertensive subjects, LPL X447 was associated with a greater LV mass index [85.2 (1.7) in S/S compared with 91.1 (3.4) in S/X+X/X; P=0.01], but no such association was seen in normotensive controls (n=60). X447 allele frequency was higher in hypertensives with than those without LVH {0.14 [95% CI (confidence interval), 0.08-0.19] compared with 0.07 (95% CI, 0.05-0.10) respectively; odds ratio, 2.52 (95% CI, 1.17-5.40), P=0.02}. The association of LPL S447X with CHD risk was then examined in a prospective study of healthy middle-aged U.K. men (n=2716). In normotensive individuals, compared with S447 homozygotes, X447 carriers were protected from CHD risk [HR (hazard ratio), 0.48 (95% CI, 0.23-1.00); P=0.05], whereas, in the hypertensives, X447 carriers had increased risk [HR, 1.54 (95% CI, 1.13-2.09) for S/S (P=0.006) and 2.30 (95% CI, 1.53-3.45) for X447+ (P<0.0001)] and had a significant interaction with hypertension in CHD risk determination (P=0.007). In conclusion, hypertensive LPL X447 carriers have increased risk of LVH and CHD, suggesting that altered FA delivery constitutes a mechanism through which LVH and CHD are associated in hypertensive subjects.
Clinical Science 07/2007; 112(12):617-24. · 4.61 Impact Factor
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ABSTRACT: To compare left ventricular mass (LVM) as measured by two-dimensional (2D) echocardiography using two different calculation methods: truncated ellipse (TE) and area length (AL), in both fundamental and tissue harmonic imaging frequencies, to LVM as measured by, the current gold standard, cardiac magnetic resonance imaging (MRI). Turbo gradient echo (TGE) pulse sequence was utilized for MRI.
Thirty-two subjects with history of hypertension were recruited. The images were acquired, contours were traced and the LVM was calculated for all four different echocardiography methods as well as for the cardiac MRI method. The intra-observer variabilities were calculated. The four different echocardiography methods were compared to cardiac MRI using the method described by Bland and Altman.
Twenty-five subjects had adequate paired data sets. The mean LVM as measured by cardiac MRI was 162+/-55 g and for the four different echocardiography methods were: fundamental AL 165+/-55 g, harmonic AL 168+/-53 g, fundamental TE 148+/-50 g, harmonic TE 149+/-45 g. The intra-observer variability for cardiac MRI method, expressed as bias +/- 1 standard deviation of the difference (S.D.D.), was 2.3+/-9.2 g and for the four different echocardiography methods were: fundamental TE 0.4+/-26.8 g, fundamental AL 0.6+/-27.0 g, harmonic TE 6.7+/-21.8 g, harmonic AL 6.4+/-22.9 g. The mean LVM for the AL method was closest to the cardiac MRI technique, while TE underestimated LVM. The 95% limits of agreement were consistently wide for all the 2D echocardiography modalities when compared with the cardiac MRI technique.
The intra-observer variability in measurements of 2D echocardiographic LVM, together with the wide limits of agreement when compared to the gold standard (cardiac MRI) are sufficiently large to make serial estimates of LVM, of single patients or small groups of subjects, by 2D echocardiography, unreliable.
European Journal of Radiology 12/2004; 52(2):103-9. · 2.61 Impact Factor
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ABSTRACT: Cardiac magnetic resonance imaging is currently the technique of choice for precise measurements of ventricular volumes, function and left ventricular (LV) mass. The technique is 3D and hence independent of geometrical assumptions; this, along with its excellent definition of endocardial and epicardial borders, makes it highly accurate and reproducible. Cardiac magnetic resonance (CMR) is particularly useful in research, as it is highly sensitive to small changes in ejection fraction and mass, and only a small number of subjects are required for a study. The excellent reproducibility makes temporal follow-up of any individual patient in the clinical setting a realistic possibility. This review examines the merits of CMR and describes the techniques used.
European Radiology 11/2004; 14(10):1813-22. · 3.22 Impact Factor
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ABSTRACT: ECG criteria for left ventricular hypertrophy (LVH) were mostly validated using left ventricular mass (LVM) as measured by M-mode echocardiography. LVM as measured by cardiac MRI has been demonstrated to be much more accurate and reproducible. We reevaluated the sensitivity and specificity of 4 ECG criteria of LVH against LVM as measured by cardiac MRI. Patients with systemic hypertension (n=288) and 60 normal volunteers had their LVM measured using a 1.5-Tesla MRI system. A 12-lead ECG was recorded, and 4 ECG criteria were evaluated: Sokolow-Lyon voltage, Cornell voltage, Cornell product, and Sokolow-Lyon product. Based on a cardiac MRI normal range, 39.9% of the hypertensive males and 36.7% of the hypertensive females had elevated LVM index. At a specificity of 95%, the Sokolow-Lyon product criterion had the highest sensitivity in females (26.2%), the Cornell criterion had the highest sensitivity in males (26.2%), and the Cornell product criteria had a relatively high sensitivity in both males and females (25.0% and 23.8%). Receiver operating characteristic curves showed the Cornell and Cornell product criteria to be superior for males whereas the Sokolow-Lyon product criterion was superior for females. Comparing the mean LVM index values of the subjects who were ECG LVH positive to the normal volunteers indicated that the ECG LVH criteria detect individuals with an LVM index substantially above the normal range. We have redefined the partition values for 4 different ECG LVH criteria, according to gender, and found that they detect subjects with markedly elevated LVM index.
Hypertension 09/2004; 44(2):175-9. · 6.21 Impact Factor
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ABSTRACT: A common intronic polymorphism, (-1332 G/A) of the angiotensin type-2 receptor gene, located on the X-chromosome, has been reported to be functional. The aim of our study was to evaluate this polymorphism for an association with left ventricular hypertrophy. Left ventricle (LV) mass was measured in 197 patients with systemic hypertension and 60 normal volunteers using a 1.5-Tesla Philips MRI system. Genotyping was performed using a restriction enzyme digestion of an initial 310-bp polymerase chain reaction product that included the angiotensin type-2 (-1332 G/A) locus. The mean LV mass index for the male patients was 94.3+/-19.6 g/m2 (n=125) and for the female patients was 71.2+/-12.0 g/m2 (n=72). Seventy-three (37.1%) of all patients had an elevated LV mass index, defined as the mean LV mass index for normal volunteers plus 2 SD (males 77.8+/-9.1 g/m2, n=30; females 61.5+/-7.5 g/m2, n=30). Comparison of LV mass index of the A_/AA genotype (mean LV mass index=82.4+/-21.1 g/m2; n=123) against that of the G_/GG genotype (mean LV mass index=88.1+/-19.0 g/m2; n=89) as a continuous variable was significant by ANOVA (P=0.044). chi2 Comparison between subjects with and subjects without left ventricular hypertrophy revealed an excess of the G_/GG genotype among the group with LV hypertrophy (P=0.031). We observed an association between the angiotensin type-2 receptor (-1332 G) allele and the presence of left ventricular hypertrophy in hypertensive subjects.
Hypertension 07/2004; 43(6):1189-94. · 6.21 Impact Factor
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Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2004; 43(5).
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ABSTRACT: To compare right ventricular (RV) volume measurements and their reproducibility between axial and short axis orientation acquisition techniques.
Measurements of RV volumes from data sets acquired in axial and short axis orientations were compared in 20 normal subjects. The observer variabilities were assessed and the left ventricle (LV) and RV stroke volumes (SV) were compared.
There was a significant and systematic difference in the EDV and ESV volumes between the axial and short axis methods. The latter method resulted in larger volumes (mean bias EDV 7.5 +/- 13.2, 4.7% difference; ESV 7.2 +/- 8.6, 10.7% difference). The axial method had lower intra- and interobserver variability than the short axis method. The standard deviation of the difference (SDD) and the limits of agreement were consistently lower for the axial method. The mean differences between LV and RV stroke volumes expressed as mean +/- 1 SD (r(2) =correlation coefficient) were: axial 7.6 +/- 9.1 (r(2) = 0.93); and short axis 7.4 +/- 10.8 (r(2) = 0.90).
There is a significant systematic difference between volumes measured using the two different orientations. The axial orientation resulted in better inter- and intraobserver reproducibility.
Journal of Magnetic Resonance Imaging 08/2003; 18(1):25-32. · 2.70 Impact Factor
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ABSTRACT: A commonly used method for analysis of first pass myocardial perfusion imaging is the calculation of a myocardial perfusion reserve index (MPRI) obtained by dividing the upslopes of the time-intensity curves at stress and rest. Perfusion data can be acquired with several different sequences with images acquired at every single, 2nd, or 3rd heartbeat. During data acquisition, some images of the dynamic series can be missed due to extra beats. Twenty-six patients underwent first-pass magnetic resonance perfusion imaging, acquiring images every heartbeat at rest and stress. The maximal upslopes of the myocardium and the left ventricle were calculated for the original image series and for the image series from which dynamics of every 2nd heartbeat were removed. Additionally for each of these situations the upslope calculations were repeated but with the removal of one or two dynamics during the maximal upslope. Images acquired every 2nd heartbeat yielded a lower upslope for the myocardium and the left ventricle, but the resulting MPRI was unchanged. Removing dynamics during the upslope resulted in a change of the MPRI by up to 44% for every heartbeat acquisition and by up to 56% for an alternate sampling. In conclusion, missing data points may affect the calculation of MPRI values and should be taken into account when using such values to define a threshold, which discriminates between normally and abnormally perfused myocardium. Furthermore, it may lead to false positive or negative results in individual cases. This effect is increased if data are acquired only every 2nd heartbeat.
Journal of Cardiovascular Magnetic Resonance 02/2003; 5(2):343-52. · 3.72 Impact Factor
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ABSTRACT: A case of a congenital fistulous communication between the left circumflex coronary artery and coronary sinus that presented as a pericardial effusion and was diagnosed using a comprehensive cardiac magnetic resonance imaging (MRI) evaluation is presented. This is an unusual presentation of an uncommon condition, and the MRI features have not been described previously. Noninvasive cardiac assessment via MRI allows for identification of the anatomic basis and functional consequences of an unusual anomaly such as a coronary artery fistula.
Journal of Computer Assisted Tomography 30(2):250-3. · 1.22 Impact Factor
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ABSTRACT: A common intronic polymorphism, (1332 G/A) of the angiotensin type-2 receptor gene, located on the X-chromosome, has been reported to be functional. The aim of our study was to evaluate this polymorphism for an association with left ventricular hypertrophy. Left ventricle (LV) mass was measured in 197 patients with systemic hypertension and 60 normal volunteers using a 1.5-Tesla Philips MRI system. Genotyping was performed using a restriction enzyme digestion of an initial 310-bp polymerase chain reaction product that included the angiotensin type-2 (1332 G/A) locus. The mean LV mass index for the male patients was 94.319.6 g/m2 (n125) and for the female patients was 71.212.0 g/m2 (n72). Seventy-three (37.1%) of all patients had an elevated LV mass index, defined as the mean LV mass index for normal volunteers plus 2 SD (males 77.89.1 g/m2 ,n 30; females 61.57.5g/m2 ,n 30). Comparison of LV mass index of the A_/AA genotype (mean LV mass index82.421.1 g/m2 ;n 123) against that of the G_/GG genotype (mean LV mass index88.119.0 g/m2 ;n 89) as a continuous variable was significant by ANOVA (P0.044). 2 Comparison between subjects with and subjects without left ventricular hypertrophy revealed an excess of the G_/GG genotype among the group with LV hypertrophy (P0.031). We observed an association between the angiotensin type-2 receptor (1332 G) allele and the presence of left ventricular hypertrophy in hypertensive subjects. (Hypertension. 2004;43:1189-1194.)
