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ABSTRACT: Obesity is a major risk factor for cardiometabolic disease, but the effect of body composition on vascular aging and arterial stiffness remains uncertain. We investigated relationships among body composition, blood pressure, age, and aortic pulse wave velocity in healthy individuals. Pulse wave velocity in the thoracic aorta, an indicator of central arterial stiffness, was measured in 221 volunteers (range, 18-72 years; mean, 40.3±13 years) who had no history of cardiovascular disease using cardiovascular MRI. In univariate analyses, age (r=0.78; P<0.001) and blood pressure (r=0.41; P<0.001) showed a strong positive association with pulse wave velocity. In multivariate analysis, after adjustment for age, sex, and mean arterial blood pressure, elevated body fat% was associated with reduced aortic stiffness until the age of 50 years, thereafter adiposity had an increasingly positive association with aortic stiffness (β=0.16; P<0.001). Body fat% was positively associated with cardiac output when age, sex, height, and absolute lean mass were adjusted for (β=0.23; P=0.002). These findings suggest that the cardiovascular system of young adults may be capable of adapting to the state of obesity and that an adverse association between body fat and aortic stiffness is only apparent in later life.
Hypertension 04/2013; · 6.21 Impact Factor
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Ankur Gulati,
Tevfik F Ismail,
Andrew Jabbour,
Nizar A Ismail,
Kishen Morarji,
Aamir Ali,
Sadaf Raza,
Jahanzaib Khwaja,
Tristan D H Brown,
Emmanouil Liodakis, [......],
Kaushik Guha,
Michael Roughton,
Ricardo Wage, Stuart A Cook,
Francisco Alpendurada,
Ravi G Assomull,
Raad H Mohiaddin,
Martin R Cowie,
Dudley J Pennell,
Sanjay K Prasad
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ABSTRACT: AIMS: Echocardiographic studies have shown that left atrial volume (LAV) predicts adverse outcome in small heart failure (HF) cohorts of mixed aetiology. However, the prognostic value of LAV in non-ischaemic dilated cardiomyopathy (DCM) is unknown. Cardiovascular magnetic resonance (CMR) allows accurate and reproducible measurement of LAV. We sought to determine the long-term prognostic significance of LAV assessed by CMR in DCM. METHODS AND RESULTS: We measured LAV indexed to body surface area (LAVi) in 483 consecutive DCM patients referred for CMR. Patients were prospectively followed up for a primary endpoint of all-cause mortality or cardiac transplantation. During a median follow-up of 5.3 years, 75 patients died and 9 underwent cardiac transplantation. After adjustment for established risk factors, LAVi was an independent predictor of the primary endpoint [hazard ratio (HR) per 10 mL/m2 1.08; 95% confidence interval (CI) 1.01-1.15; P = 0.022]. LAVi was also independently associated with the secondary composite endpoints of cardiovascular mortality or cardiac transplantation (HR per 10 mL/m2 1.11; 95% CI 1.04-1.19; P = 0.003), and HF death, HF hospitalization, or cardiac transplantation (HR per 10 mL/m2 1.11; 95% CI 1.04-1.18; P = 0.001). The optimal LAVi cut-off value for predicting the primary endpoint was 72 mL/m2. Patients with LAVi >72 mL/m2 had a three-fold elevated risk of death or transplantation (HR 3.00; 95% CI 1.92-4.70; P < 0.001). LAVi provided incremental prognostic value for the prediction of transplant-free survival (net reclassification improvement 0.17; 95% CI 0.05-0.29; P = 0.002). CONCLUSIONS: LAVi is a powerful independent predictor of transplant-free survival and HF outcomes in DCM. Assessment of LAV improves risk stratification in DCM and should be incorporated into routine CMR examination.
European Journal of Heart Failure 03/2013; · 4.90 Impact Factor
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Ankur Gulati,
Andrew Jabbour,
Tevfik F Ismail,
Kaushik Guha,
Jahanzaib Khwaja,
Sadaf Raza,
Kishen Morarji,
Tristan D H Brown,
Nizar A Ismail,
Marc R Dweck, [......],
Yousef Daryani,
Rory O'Hanlon,
Mary N Sheppard,
Francisco Alpendurada,
Alexander R Lyon, Stuart A Cook,
Martin R Cowie,
Ravi G Assomull,
Dudley J Pennell,
Sanjay K Prasad
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ABSTRACT: Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions.
To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy.
Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011.
Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation.
Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio [HR], 2.96 [95% CI, 1.87-4.69]; absolute risk difference, 16.2% [95% CI, 8.2%-24.2%]; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 [95% CI, 3.15-8.72]; absolute risk difference, 22.6% [95% CI, 14.6%-30.6%]; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 [95% CI, 1.50-3.92]; P < .001) and the extent (HR, 1.11 [95% CI, 1.06-1.16]; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 [95% CI, 1.95-5.31], P < .001; and by fibrosis extent: HR, 1.15 [95% CI, 1.10-1.20], P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 [95% CI, 2.75-7.74], P < .001; and by fibrosis extent: HR, 1.10 [95% CI, 1.05-1.16], P < .001), and the HF composite (by fibrosis presence: HR, 1.62 [95% CI, 1.00-2.61], P = .049; and by fibrosis extent: HR, 1.08 [95% CI, 1.04-1.13], P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 [95% CI, 0.11-0.41]; P = .001 and 0.29 [95% CI, 0.11-0.48]; P = .002, respectively).
Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation.
JAMA The Journal of the American Medical Association 03/2013; 309(9):896-908. · 30.03 Impact Factor
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Jan Monti,
Judith Fischer,
Svetlana Paskas,
Matthias Heinig,
Herbert Schulz,
Claudia Gösele,
Arnd Heuser,
Robert Fischer,
Cosima Schmidt,
Alexander Schirdewan, [......],
Martin Vingron,
Steven M Weldon,
Klaus Lindpaintner,
Bruce D Hammock,
Klaus Rohde,
Rainer Dietz, Stuart A Cook,
Wolf-Hagen Schunck,
Friedrich C Luft,
Norbert Hubner
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ABSTRACT: OBJECTIVES: Our aim was to evaluate the relationship between the degree of salvage following acute ST elevation myocardial infarction (STEMI) and subsequent reversible contractile dysfunction using cardiac magnetic resonance (CMR) imaging. METHODS: Thirty-four patients underwent CMR examination 1-7 days after primary percutaneous coronary intervention (PPCI) for acute STEMI with follow-up at 1 year. The ischaemic area-at-risk (AAR) was assessed with T2-weighted imaging and myocardial necrosis with late gadolinium enhancement. Myocardial strain was quantified with complementary spatial modulation of magnetisation (CSPAMM) tagging. RESULTS: Ischaemic segments with poor (<25 %) or intermediate (26-50 %) salvage index were associated with worse Eulerian circumferential (Ecc) strain immediately post-PPCI (-9.1 % ± 0.6, P = 0.033 and -11.8 % ± 1.3, P = 0.003, respectively) than those with a high (51-100 %) salvage index (-14.4 % ± 1.3). Mean strain in ischaemic myocardium improved between baseline and follow-up (-10.1 % ± 0.5 vs. -16.2 % ± 0.5 %, P < 0.0001). Segments with poor salvage also showed an improvement in strain by 1 year (-9.1 % ± 0.6 vs. -15.3 % ± 0.6, P = 0.033) although they remained the most functionally impaired. CONCLUSIONS: Partial recovery of peak systolic strain following PPCI is observed even when apparent salvage is less than 25 %. Late gadolinium enhancement (LGE) may not equate to irreversibly injured myocardium and salvage assessment performed within the first week of revascularisation may underestimate the potential for functional recovery. KEY POINTS : • MRI can measure how much myocardium is damaged after a heart attack. • Heart muscle that appears initially non-viable may sometimes partially recover. • Enhancement around the edges of infarcts may resolve over time. • Evaluating new cardio-protective treatments with MRI requires appreciation of its limitations.
European Radiology 11/2012; · 3.22 Impact Factor
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ABSTRACT: AIMS: Human genome-wide association studies (GWAS) of hypertension identified only few susceptibility loci with large-effect that were replicated across populations. The vast majority of genes detected by GWAS have small-effect and the regulatory mechanisms through which these genetic variants cause disease remain mostly unclear. Here, we used comparative genomics between human and an established rat model of hypertension to explore the transcriptional mechanisms mediating the effect of genes identified in 15 hypertension GWAS. METHODS AND RESULTS: Time-series analysis of radiotelemetric blood pressure (BP) was performed to assess eleven parameters of BP-variation in recombinant inbred strains derived from the Spontaneously Hypertensive Rat. BP-data were integrated with ∼27,000 expression QTLs (eQTLs) mapped across seven tissues, detecting >8,000 significant associations between eQTL genes and BP-variation in the rat. We then compiled a large catalogue of human genes from GWAS of hypertension and identified a sub-set of 2,292 rat-human orthologous genes. Expression levels for 795 (34%) of these genes correlated with BP-variation across rat tissues: 51 genes were cis-regulated, whereas 459 were trans-regulated and enriched for 'calcium signalling pathway' (P=9.6x10-6) and 'ion channel' genes (P=3.5x10-7), which are important determinants of hypertension. We identified 158 clusters of trans-eQTLs, annotated the underlying 'master regulator' genes and found significant over-representation in the human hypertension gene-set (enrichment P=5x10-4). CONCLUSION: We showed extensive conservation of trans-regulated genes and their master regulators between rat and human hypertension. These findings reveal that small-effect genes associated with hypertension by human GWAS are likely to exert their action through coordinate regulation of pathogenic pathways.
Cardiovascular research 10/2012; · 5.80 Impact Factor
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ABSTRACT: Integrative Genomics studies have greatly advanced our understanding of cardiovascular pathophysiology over the last decade. Here we highlight the strengths and challenges of this cutting-edge approach and provide examples where novel insights have arisen through integration of multi-level genomic information and cardiac physiology. Going forward, the integration of comprehensive next generation sequencing datasets with quantitative phenotypes at the molecular, cellular and whole heart level using advanced modelling approaches provides an unprecedented opportunity for cardiovascular science.
Cardiovascular research 09/2012; · 5.80 Impact Factor
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Marc R Dweck,
Sanjiv Joshi,
Timothy Murigu,
Ankur Gulati,
Francisco Alpendurada,
Andrew Jabbour,
Alicia Maceira,
Isabelle Roussin,
David B Northridge,
Philip J Kilner, Stuart A Cook,
Nicholas A Boon,
John Pepper,
Raad H Mohiaddin,
David E Newby,
Dudley J Pennell,
Sanjay K Prasad
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ABSTRACT: Cardiovascular magnetic resonance (CMR) is the gold standard non-invasive method for determining left ventricular (LV) mass and volume but has not been used previously to characterise the LV remodeling response in aortic stenosis. We sought to investigate the degree and patterns of hypertrophy in aortic stenosis using CMR.
Patients with moderate or severe aortic stenosis, normal coronary arteries and no other significant valve lesions or cardiomyopathy were scanned by CMR with valve severity assessed by planimetry and velocity mapping. The extent and patterns of hypertrophy were investigated using measurements of the LV mass index, indexed LV volumes and the LV mass/volume ratio. Asymmetric forms of remodeling and hypertrophy were defined by a regional wall thickening ≥13 mm and >1.5-fold the thickness of the opposing myocardial segment.
Ninety-one patients (61±21 years; 57 male) with aortic stenosis (aortic valve area 0.93±0.32cm2) were recruited. The severity of aortic stenosis was unrelated to the degree (r2=0.012, P=0.43) and pattern (P=0.22) of hypertrophy. By univariate analysis, only male sex demonstrated an association with LV mass index (P=0.02). Six patterns of LV adaption were observed: normal ventricular geometry (n=11), concentric remodeling (n=11), asymmetric remodeling (n=11), concentric hypertrophy (n=34), asymmetric hypertrophy (n=14) and LV decompensation (n=10). Asymmetric patterns displayed considerable overlap in appearances (wall thickness 17±2mm) with hypertrophic cardiomyopathy.
We have demonstrated that in patients with moderate and severe aortic stenosis, the pattern of LV adaption and degree of hypertrophy do not closely correlate with the severity of valve narrowing and that asymmetric patterns of wall thickening are common.
ClinicalTrials.gov Reference Number: NCT00930735.
Journal of Cardiovascular Magnetic Resonance 07/2012; 14:50. · 3.72 Impact Factor
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ABSTRACT: Progressive heart failure due to remodeling is a major cause of morbidity and mortality following myocardial infarction. Conventional clinical imaging measures global volume changes, and currently there is no means of assessing regional myocardial dilatation in relation to ischemic burden. Here we use 3D co-registration of Cardiovascular Magnetic Resonance (CMR) images to assess the long-term effects of ischemia-reperfusion injury on left ventricular structure after acute ST-elevation myocardial infarction (STEMI).
Forty six patients (age range 33-77 years) underwent CMR imaging within 7 days following primary percutaneous coronary intervention (PPCI) for acute STEMI with follow-up at one year. Functional cine imaging and Late Gadolinium Enhancement (LGE) were segmented and co-registered. Local left ventricular wall dilatation was assessed by using intensity-based similarities to track the structural changes in the heart between baseline and follow-up. Results are expressed as means, standard errors and 95% confidence interval (CI) of the difference.
Local left ventricular remodeling within infarcted myocardium was greater than in non-infarcted myocardium (1.6%±1.0 vs 0.3%±0.9, 95% CI: -2.4% - -0.2%, P=0.02). One-way ANOVA revealed that transmural infarct thickness had a significant effect on the degree of local remodeling at one year (P<0.0001) with greatest wall dilatation observed when infarct transmurality exceeded 50%. Infarct remodeling was more severe when microvascular obstruction (MVO) was present (3.8%±1.3 vs -1.6%±1.4, 95% CI: -9.1% - -1.5%, P=0.007) and when end-diastolic volume had increased by >20% (4.8%±1.4 vs -0.15%±1.2, 95% CI: -8.9% - -0.9%, P=0.017).
The severity of ischemic injury has a significant effect on local ventricular wall remodeling with only modest dilatation observed within non-ischemic myocardium. Limitation of chronic remodeling may therefore depend on therapies directed at modulating ischemia-reperfusion injury. CMR co-registration has potential for assessing dynamic changes in ventricular structure in relation to therapeutic interventions.
Journal of Cardiovascular Magnetic Resonance 06/2012; 14:41. · 3.72 Impact Factor
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Journal of Cardiovascular Magnetic Resonance 05/2012; 13:1-1. · 3.72 Impact Factor
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Journal of Cardiovascular Magnetic Resonance 05/2012; 12:1-2. · 3.72 Impact Factor
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Chris McDermott-Roe,
Junmei Ye,
Rizwan Ahmed,
Xi-Ming Sun,
Anna Serafín,
James Ware,
Leonardo Bottolo,
Phil Muckett,
Xavier Cañas,
Jisheng Zhang, [......],
Marisol Ruiz-Meana,
David García-Dorado,
Joan X Comella,
Leanne E Felkin,
Paul J R Barton,
Zoltan Arany,
Michal Pravenec,
Enrico Petretto,
Daniel Sanchis, Stuart A Cook
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ABSTRACT: Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.
Nature 10/2011; 478(7367):114-8. · 36.28 Impact Factor
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Chris McDermott-Roe,
Junmei Ye,
Rizwan Ahmed,
Xi-Ming Sun,
Anna,
James Ware,
Leonardo Bottolo,
Phil Muckett,
Xavier,
Jisheng Zhang, [......],
Marisol Ruiz-Meana,
David,
Joan X. Comella,
Leanne E. Felkin,
Paul J. R. Barton,
Zoltan Arany,
Michal Pravenec,
Enrico Petretto,
Daniel Sanchis, Stuart A. Cook
Nature 10/2011; 478(7367):114-118. · 36.28 Impact Factor
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ABSTRACT: High-throughput genomics allows genome-wide quantification of gene expression levels in tissues and cell types and, when combined with sequence variation data, permits the identification of genetic control points of expression (expression QTL or eQTL). Clusters of eQTL influenced by single genetic polymorphisms can inform on hotspots of regulation of pathways and networks, although very few hotspots have been robustly detected, replicated, or experimentally verified. Here we present a novel modeling strategy to estimate the propensity of a genetic marker to influence several expression traits at the same time, based on a hierarchical formulation of related regressions. We implement this hierarchical regression model in a Bayesian framework using a stochastic search algorithm, HESS, that efficiently probes sparse subsets of genetic markers in a high-dimensional data matrix to identify hotspots and to pinpoint the individual genetic effects (eQTL). Simulating complex regulatory scenarios, we demonstrate that our method outperforms current state-of-the-art approaches, in particular when the number of transcripts is large. We also illustrate the applicability of HESS to diverse real-case data sets, in mouse and human genetic settings, and show that it provides new insights into regulatory hotspots that were not detected by conventional methods. The results suggest that the combination of our modeling strategy and algorithmic implementation provides significant advantages for the identification of functional eQTL hotspots, revealing key regulators underlying pathways.
Genetics 09/2011; 189(4):1449-59. · 4.01 Impact Factor
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Marc R Dweck,
Sanjiv Joshi,
Timothy Murigu,
Francisco Alpendurada,
Andrew Jabbour,
Giovanni Melina,
Winston Banya,
Ankur Gulati,
Isabelle Roussin,
Sadaf Raza, [......],
Emiliano Angeloni,
Simone Refice,
Mary Sheppard, Stuart A Cook,
Philip J Kilner,
Dudley J Pennell,
David E Newby,
Raad H Mohiaddin,
John Pepper,
Sanjay K Prasad
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ABSTRACT: The goal of this study was to assess the prognostic significance of midwall and infarct patterns of late gadolinium enhancement (LGE) in aortic stenosis.
Myocardial fibrosis occurs in aortic stenosis as part of the hypertrophic response. It can be detected by LGE, which is associated with an adverse prognosis in a range of other cardiac conditions.
Between January 2003 and October 2008, consecutive patients with moderate or severe aortic stenosis undergoing cardiovascular magnetic resonance with administration of gadolinium contrast were enrolled into a registry. Patients were categorized into absent, midwall, or infarct patterns of LGE by blinded independent observers. Patient follow-up was completed using patient questionnaires, source record data, and the National Strategic Tracing Service.
A total of 143 patients (age 68 ± 14 years; 97 male) were followed up for 2.0 ± 1.4 years. Seventy-two underwent aortic valve replacement, and 27 died (24 cardiac, 3 sudden cardiac deaths). Compared with those with no LGE (n = 49), univariate analysis revealed that patients with midwall fibrosis (n = 54) had an 8-fold increase in all-cause mortality despite similar aortic stenosis severity and coronary artery disease burden. Patients with an infarct pattern (n = 40) had a 6-fold increase. Midwall fibrosis (hazard ratio: 5.35; 95% confidence interval: 1.16 to 24.56; p = 0.03) and ejection fraction (hazard ratio: 0.96; 95% confidence interval: 0.94 to 0.99; p = 0.01) were independent predictors of all-cause mortality by multivariate analysis.
Midwall fibrosis was an independent predictor of mortality in patients with moderate and severe aortic stenosis. It has incremental prognostic value to ejection fraction and may provide a useful method of risk stratification.
Journal of the American College of Cardiology 09/2011; 58(12):1271-9. · 14.16 Impact Factor
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Heart (British Cardiac Society) 04/2011; 97(16):1283. · 4.22 Impact Factor
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ABSTRACT: Mitochondrial dysfunction, caspase activation and caspase-dependent DNA fragmentation are involved in cell damage in many tissues. However, differentiated cardiomyocytes repress the expression of the canonical apoptotic pathway and their death during ischemia is caspase-independent. The atypical BH3-only protein Bnip3 is involved in the process leading to caspase-independent DNA fragmentation in cardiomyocytes. However, the pathway by which DNA degradation ensues following Bnip3 activation is not resolved. To identify the mechanism involved, we analyzed the interdependence of Bnip3, Nix and EndoG in mitochondrial damage and DNA fragmentation during experimental ischemia in neonatal rat ventricular cardiomyocytes. Our results show that the expression of EndoG and Bnip3 increases in the heart throughout development, while the caspase-dependent machinery is silenced. TUNEL-positive DNA damage, which depends on caspase activity in other cells, is caspase-independent in ischemic cardiomyocytes and ischemia-induced DNA high and low molecular weight fragmentation is blocked by repressing EndoG expression. Ischemia-induced EndoG translocation and DNA degradation are prevented by silencing the expression of Bnip3, but not Nix, or by overexpressing Bcl-x(L). These data establish a link between Bnip3 and EndoG-dependent, TUNEL-positive, DNA fragmentation in ischemic cardiomyocytes in the absence of caspases, defining an alternative cell death pathway in postmitotic cells.
PLoS ONE 01/2011; 6(3):e17998. · 4.09 Impact Factor
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ABSTRACT: In patients with acute myocardial infarction, restoration of coronary flow by primary coronary intervention (PCI) can lead to profound ischaemia-reperfusion injury with detrimental effects on myocardial salvage. Non-invasive assessment of interstitial myocardial haemorrhage by T2* cardiac MRI (T2*-CMR) provides a novel and specific biomarker of severe reperfusion injury which may be of prognostic value.
To characterise the determinants of acute ischaemia-reperfusion injury following ST elevation myocardial infarction (STEMI) using CMR.
Fifty patients with acute STEMI who had been successfully treated by PCI were studied. T2*-CMR was used to identify the presence of reperfusion haemorrhage and contrast enhancement was used to measure microvascular obstruction (MVO) and infarct size. Haemorrhagic ischaemia-reperfusion injury was present in 29 patients (58%) following PCI and occurred despite rapid revascularisation (mean 4.2±3.3 h). Haemorrhage was only present when the infarct involved at least 80% (mean±SD 91±5.3%) of the left ventricular wall thickness. There was a strong association between the extent of MVO and reperfusion haemorrhage (r(2)=0.87, p<0.001). Transmural infarcts (n=43) showed significantly impaired systolic wall thickening at the infarct mid point when reperfusion haemorrhage was present (21.5±16.7% vs 3.7±12.9%), p<0.0001) compared with non-haemorrhagic infarcts.
Severe reperfusion injury may occur when there is near-transmural myocardial necrosis despite early and successful revascularisation. Reperfusion haemorrhage is closely associated with the development of MVO. These findings indicate that, once advanced necrosis has developed, the potential for severe myocardial reperfusion injury is significantly enhanced.
Heart (British Cardiac Society) 10/2010; 96(23):1885-91. · 4.22 Impact Factor
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Matthias Heinig,
Enrico Petretto,
Chris Wallace,
Leonardo Bottolo,
Maxime Rotival,
Han Lu,
Yoyo Li,
Rizwan Sarwar,
Sarah R Langley,
Anja Bauerfeind, [......],
Andreas Ziegler,
Laurence Tiret,
Deborah J Smyth,
Michal Pravenec,
Timothy J Aitman,
Francois Cambien,
David Clayton,
John A Todd,
Norbert Hubner, Stuart A Cook
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ABSTRACT: Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.
Nature 09/2010; 467(7314):460-4. · 36.28 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are important for cardiac function and tissue metabolism. The aim of the present study is to investigate the role(s) of miRNAs in the insulin-resistant heart.
Left ventricular biopsies were collected from patients with or without type 2 diabetes and from patients with left ventricular dysfunction. Quantitative miRNA expression analyses of 155 miRNAs revealed that miR-223 was consistently upregulated in the insulin-resistant heart. We assessed the effects of miR-223 on glucose metabolism in neonatal rat cardiomyocytes where adenoviral-mediated overexpression of miR-223 increased glucose uptake. Using in silico miRNA target prediction programs, we prioritized candidate miR-223 target genes, but observed no effect of miR-223 on myocyte enhancer factor 2c or insulin-like growth factor 1 receptor, and an unexpected miR-223-induced increase in nuclear factor IA. We next examined the effects of miR-223 on insulin signalling and glucose transport proteins. Neither phosphoinositide 3-kinase (PI3K) signalling nor AMP kinase activity was affected by miR-223 overexpression, whereas glucose transporter 4 (Glut4) protein expression was increased. miR-223 overexpression-induced Glut4 protein expression in cardiomyocytes was necessary and sufficient for increased glucose uptake as demonstrated by siRNA knockdown of Glut4. Loss-of-function studies in vivo, using a synthetic miR-223 inhibitor, confirmed the effect of miR-223 on Glut4.
These data demonstrate a role for miR-223 in Glut4 regulation and glucose metabolism in the heart, reveal the pleiotropic effects of miRNAs across tissues, and show that miRNAs can upregulate target genes in terminally differentiated cardiomyocytes.
Cardiovascular research 06/2010; 86(3):410-20. · 5.80 Impact Factor
