Publications by authors named "Tiong Lim"

41 Publications

Sequential Cohort Analysis After Liver Transplantation Shows de Novo Extended Release Tacrolimus Is Safe, Efficacious, and Minimizes Renal Dysfunction.

Transplant Direct 2020 Feb 17;6(2):e528. Epub 2020 Jan 17.

Institute of Liver Studies, King's College Hospital, Denmark Hill, London, United Kingdom.

The use of once-daily extended-release tacrolimus (ERT) is associated with improved long-term graft and patient survival when compared with twice-daily tacrolimus (BDT), but the underlying reasons for differential survival are unclear. The aim of the study was to compare clinical outcomes known to impact on posttransplant survival for de novo BDT and ERT in liver transplantation (LT) recipients.

Methods: We conducted a single-center, prospective sequential cohort analysis of adult patients undergoing LT during a change in protocol from de novo BDT to ERT, with a 6-month post-LT follow-up.

Results: A total of 160 transplanted patients were evaluated; 82 were in the BDT group and 78 were in the ERT group. The cohorts were matched for standard variables and a similar proportion in each group received induction interleukin-2 receptor antibody (36% and 31%). There were no significant differences in the measured outcomes of patient and graft survival, biopsy-proven acute rejection episodes, post LT diabetes, and toxicity. A significantly lower number of patients developed chronic kidney disease Stage3-4 in the ERT cohort compared with BDT cohort. In patients with pre-LT renal dysfunction who received antibody induction, estimated glomerular filtration rate decreased significantly in the BDT but not the ERT group.

Conclusions: We show that once-daily ERT is as safe and efficacious as BDT in de novo LT but optimally conserves renal function post-LT.
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http://dx.doi.org/10.1097/TXD.0000000000000970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004634PMC
February 2020

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation.

Am J Transplant 2020 04 3;20(4):1125-1136. Epub 2020 Feb 3.

MRC Centre for Transplantation, Peter Gorer Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Regulatory T cells (Tregs) are a lymphocyte subset with intrinsic immunosuppressive properties that can be expanded in large numbers ex vivo and have been shown to prevent allograft rejection and promote tolerance in animal models. To investigate the safety, applicability, and biological activity of autologous Treg adoptive transfer in humans, we conducted an open-label, dose-escalation, Phase I clinical trial in liver transplantation. Patients were enrolled while awaiting liver transplantation or 6-12 months posttransplant. Circulating Tregs were isolated from blood or leukapheresis, expanded under good manufacturing practices (GMP) conditions, and administered intravenously at either 0.5-1 million Tregs/kg or 3-4.5 million Tregs/kg. The primary endpoint was the rate of dose- limiting toxicities occurring within 4 weeks of infusion. The applicability of the clinical protocol was poor unless patient recruitment was deferred until 6-12 months posttransplant. Thus, only 3 of the 17 patients who consented while awaiting liver transplantation were dosed. In contrast, all six patients who consented 6-12 months posttransplant received the cell infusion. Treg transfer was safe, transiently increased the pool of circulating Tregs and reduced anti-donor T cell responses. Our study opens the door to employing Treg immunotherapy to facilitate the reduction or complete discontinuation of immunosuppression following liver transplantation.
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http://dx.doi.org/10.1111/ajt.15700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154724PMC
April 2020

Non-Invasive Markers (ALBI and APRI) Predict Pregnancy Outcomes in Women With Chronic Liver Disease.

Am J Gastroenterol 2019 02;114(2):267-275

Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK.

Objectives: Rates of pregnancy in women with cirrhosis are increasing. Risk of hepatic decompensation during pregnancy, therefore, merits tailored obstetric and hepatology care. Prognostic markers that determine pregnancy outcomes are lacking.

Methods: Medical records of women who attended hepatology clinic at King's College Hospital with chronic liver disease (CLD) who became pregnant from 1983 to 2017 were reviewed. Information on demographics, clinical history, serology, and outcome of pregnancy was collected.

Results: In all, 165 pregnancies occurred in 100 women with CLD including 80 pregnancies in 48 women with cirrhosis. Median age of conception in cirrhotic and non-cirrhotic women were 26 years (16-44) and 28 years (16-51) respectively (p = 0.015). Whilst women with cirrhosis had similar live birth rate to non-cirrhotic women (75 vs. 85% p = 0.119), they were significantly less likely to proceed beyond 37 weeks gestation (45 vs. 58% p = 0.033). Women who received preconception counseling were more likely to have stable liver disease at conception (100 vs 86% p = 0.02). Compared with preconception MELD (model for end stage liver disease), preconception Albumin-Bilirubin score (ALBI) more accurately predicted live birth with an area under the receiver-operator curve (AUROC) of 0.741 (p < 0.001), and preconception AST to platelet ratio index (APRI) more accurately predicted ability to proceed beyond 37 weeks gestation with an AUROC of 0.700 (p < 0.001).

Conclusions: Most women with cirrhosis who conceived achieved a successful pregnancy outcome. ALBI and APRI scores can prognosticate pregnancy outcomes in women with CLD. Preconception counseling by a hepatologist or specialist obstetrician improved patient care in this group.
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http://dx.doi.org/10.1038/s41395-018-0181-xDOI Listing
February 2019

Entecavir or tenofovir monotherapy prevents HBV recurrence in liver transplant recipients: A 5-year follow-up study after hepatitis B immunoglobulin withdrawal.

Dig Liver Dis 2018 Sep 13;50(9):944-953. Epub 2018 Apr 13.

Institute of Liver Studies, King's College Hospital, London, United Kingdom.

Background: Recent data suggest that oral third-generation nucleos(t)ide analogs (NA) monoprophylaxis following hepatitis B immunoglobulin (HBIg) withdrawal may be effective to prevent HBV reinfection after liver transplantation (LT).

Patients And Methods: Between 01/2010 and 03/2012, all HBV monoinfected and HBV/HDV co-infected LT patients followed in our centre withdrew HBIg ± NA and were commenced on either ETV or TDF as monotherapy.

Results: Seventy-seven patients were included in the study (55% TDF, 45% ETV). Group A comprised 69 HBV monoinfected patients and Group B 8 HBV/HDV co-infected patients. After HBIg withdrawal, Groups A and B patients were followed for 69 (range 13-83) months and 61 (range 31-78) months, respectively. No Group B patients had HBsAg or HBV DNA recurrence, while 6 (9%) Group A patients became HBsAg-positive after a median of 18 (range 1-40) months. The cumulative 5-year incidence of HBsAg recurrence was 9%. All 6 patients demonstrated undetectable HBV-DNA levels and stable graft function during 30 months of additional follow-up. In 3/6 patients, seroconversion was transitory, while the remaining 3 showed HBsAg levels <0.13 IU/mL over the entire period of observation. Pre-LT HCC emerged as the strongest predictor of HBsAg recurrence.

Conclusion: HBIG can be safely discontinued in HBsAgpositive LT recipients and replaced by ETV or TDF monotherapy.
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http://dx.doi.org/10.1016/j.dld.2018.03.032DOI Listing
September 2018

Low-Dose Interleukin-2 for Refractory Autoimmune Hepatitis.

Hepatology 2018 10;68(4):1649-1652

Institute of Liver Studies, King's College Hospital, Medical Research Council Centre for Transplantation, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.

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http://dx.doi.org/10.1002/hep.30059DOI Listing
October 2018

Successful pregnancy outcomes following liver transplantation is predicted by renal function.

Liver Transpl 2018 05 10;24(5):606-615. Epub 2018 Apr 10.

Institute of Liver Studies, King's College Hospital, London, United Kingdom.

Liver transplantation (LT) is a successful treatment for both acute liver failure and end-stage liver disease. The number of women of reproductive age undergoing LT is increasing. Pregnancy outcomes are favorable, but there is still a lack of prognostic markers. We aimed to identify factors predictive of adverse pregnancy outcomes in LT recipients. An analysis of all pregnancies occurring in LT recipients from 1989 to 2016 at King's College Hospital was performed. Clinical data of 162 conceptions in 93 women were reviewed. Descriptive and regression analyses were done to examine associations between laboratory markers and hepatological scores with pregnancy outcomes of live birth and preterm birth. Median age at LT was 23 years (range, 1-41 years), with a median age at conception of 30 years (range, 18-47 years). The live birth rate was 75% (n = 121). Of live births, 35% (n = 39/110 available) were delivered preterm. Preconception creatinine levels were higher in patients who had a preterm birth (85 versus 74 μmol/L; P = 0.008), with a preconception estimated glomerular filtration rate (eGFR) <90 mL/minute significantly associated with preterm delivery (P = 0.04). Progressive decline in eGFR predicted outcome, with gestational length declining with increasing chronic kidney disease (CKD) stage: CKD 0-1 = 39 weeks (median), CKD 2 = 37 weeks, and CKD 3 = 35 weeks. The risk of preterm birth was greatest in women with an eGFR <60 mL/minute (P = 0.004). Moreover, hypertension-related complications during pregnancy, such as gestational hypertension, preeclampsia, or eclampsia, were also associated with prematurity (P = 0.01). Women taking steroid-based immunosuppression had an increased risk of infection during pregnancy or postpartum (15% versus 4%; P = 0.02). In conclusion, although the majority of women have a successful pregnancy outcome after LT, preconception renal function predicts pregnancy outcome and steroids increase risk of infection during pregnancy or postpartum. Liver Transplantation 24 606-615 2018 AASLD.
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http://dx.doi.org/10.1002/lt.25034DOI Listing
May 2018

The APEX trial: Effects of allopurinol on exercise capacity, coronary and peripheral endothelial function, and natriuretic peptides in patients with cardiac syndrome X.

Cardiovasc Ther 2018 Feb 26;36(1). Epub 2017 Nov 26.

Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

The role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has recently been recognized. Allopurinol has previously been shown to improve endothelial dysfunction, reduce oxidative stress burden, and improve myocardial efficiency. In this "proof of concept" study, we investigated the effect of allopurinol on exercise capacity, coronary and peripheral endothelial function, and serum B-type natriuretic peptide (BNP: a marker of cardiac function and myocardial ischemia) in patients with cardiac syndrome X.

Methods And Results: This study was a randomized, double-blind, placebo-control crossover trial. Nineteen patients (mean age 59 ± 10 years, 11 women and 8 men) with cardiac syndrome X were randomized to a 6-week treatment with either allopurinol (600 mg/day) or placebo. After 4 weeks of washout period, they were crossed over to the other arm. Outcomes measured at baseline and after treatment were maximum exercise time (ET) derived from Bruce protocol exercise treadmill test, serum BNP measurement, coronary flow reserve (CFR) as assessed by measuring the response of flow velocity in the left anterior descending artery to adenosine, and flow-mediated vasodilatation of the brachial artery (FMD). Allopurinol significantly reduced serum uric acid levels when compared with placebo (-48 ± 24% vs 1.9 ± 11%, P < .001). There was no significant difference in maximum ET, CFR, and FMD between allopurinol and placebo. However, there was a trend that allopurinol reduced serum BNP when compared to placebo (-8% [interquartile range -22% to 65%] vs 44% [interquartile range -18% to 140%]; P = .07).

Conclusion: In patients with cardiac syndrome X, high-dose allopurinol did not improve exercise capacity, and coronary or peripheral endothelial function.
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http://dx.doi.org/10.1111/1755-5922.12311DOI Listing
February 2018

Biomarkers of immunosuppression.

Clin Liver Dis (Hoboken) 2016 Aug 29;8(2):34-38. Epub 2016 Aug 29.

King's College Hospital Institute of Liver Studies London United Kingdom.

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http://dx.doi.org/10.1002/cld.570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490196PMC
August 2016

Vedolizumab in Inflammatory Bowel Disease Associated with Autoimmune Liver Disease Pre- and Postliver Transplantation: A Case Series.

Inflamm Bowel Dis 2016 10;22(10):E39-40

*Gastroenterology Department, King's College Hospital, London, United Kingdom †Gastroenterology Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom ‡Institute of Liver Studies, King's College Hospital, London, United Kingdom.

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http://dx.doi.org/10.1097/MIB.0000000000000906DOI Listing
October 2016

Subacute liver failure secondary to black cohosh leading to liver transplantation.

BMJ Case Rep 2013 Jul 5;2013. Epub 2013 Jul 5.

King's College Hospital, Institute of Liver Studies, London, UK.

The use of herbal medications is increasing significantly in the UK and there is a perception that herbal preparations are without adverse effects. This case report highlights the potential risks of black cohosh, which is one of the most commonly used herbal products. This is a case report of a 60-year-old Caucasian lady who presented with subacute liver failure secondary to taking black cohosh. This was further confirmed by liver biopsy and she subsequently deteriorated and underwent liver transplantation. Available evidence supports an association between black cohosh and risk of hepatotoxicity. In current literature, there have only been four previously reported cases of hepatotoxicity associated with black cohosh, which required liver transplantation. We submit that our patient represents the fifth case. We recommend that patients taking this supplement should have close monitoring of their hepatic function, especially in the presence of other risk factors.
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http://dx.doi.org/10.1136/bcr-2013-009325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736182PMC
July 2013

Population-based reference values for 3D echocardiographic LV volumes and ejection fraction.

JACC Cardiovasc Imaging 2012 Dec;5(12):1191-7

Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, United Kingdom.

Objectives: The purpose of this study was to define age-, sex-, and ethnicity-specific reference values for 3-dimensional echocardiographic (3DE) left ventricular (LV) volumes and LV ejection fraction (LVEF) in a large cohort of European white and Indian Asian subjects.

Background: Transthoracic 3DE imaging is recommended for the routine evaluation of LV volumes and function. However, there remains a lack of population-based reference values for 3DE LV volumes and LVEF, hindering adoption of this technique into routine clinical practice.

Methods: We identified subjects from the LOLIPOP (London Life Sciences Prospective Population) study who were free of clinical cardiovascular disease, hypertension, and type 2 diabetes. All subjects underwent transthoracic 2-dimensional and 3D echocardiography for quantification of LV end-systolic volume index, LV end-diastolic volume index, and LVEF.

Results: 3DE image quality was satisfactory in 978 subjects (89%) for the purposes of LV volumetric analysis. Indexed 3DE LV volumes were significantly smaller in female compared with male subjects and in Indian Asians compared with European whites. Upper limit of normal (mean ± 2 SD) reference values for the LV end-systolic volume index and LV end-diastolic volume index for the 4 ethnicity-sex subgroups were, respectively, as follows: European white men, 29 ml/m(2) and 67 ml/m(2); Indian Asian men, 26 ml/m(2) and 59 ml/m(2); European white women, 24 ml/m(2) and 58 ml/m(2); Indian Asian women, 23 ml/m(2) and 55 ml/m(2), respectively. Compared with 3DE studies, 2-dimensional echocardiography underestimated the LV end-systolic volume index and LV end-diastolic volume index by an average of 2.0 ml/m(2) and 4.7 ml/m(2), respectively. LVEF was similar between in all 4 groups and between 2- and 3-dimensional techniques, with a lower cutoff of 52% for the whole cohort.

Conclusions: These reference values are based on the largest 3DE study performed to date that should facilitate the standardization of the technique and encourage its adoption for the routine assessment of LV volumes and LVEF in the clinical echocardiography laboratory. This study supports the application of ethnicity-specific reference values for indexed LV volumes.
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http://dx.doi.org/10.1016/j.jcmg.2012.07.014DOI Listing
December 2012

ETV6 disruption does not predict indolent clinical behavior in secretory breast carcinoma.

Breast J 2012 Nov-Dec;18(6):604-6. Epub 2012 Oct 19.

Department of Medical Oncology, National Cancer Centre, Singapore.

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http://dx.doi.org/10.1111/tbj.12041DOI Listing
April 2013

Improving the primary prevention of cardiovascular events by using biomarkers to identify individuals with silent heart disease.

J Am Coll Cardiol 2012 Sep 22;60(11):960-8. Epub 2012 Aug 22.

Centre for Cardiovascular and Lung Biology, University of Dundee, United Kingdom.

Objectives: The aim of this study was to examine whether biomarkers can identify silent cardiac target organ damage (cTOD) in a primary prevention population.

Background: One possible way to improve primary prevention of cardiovascular events is to identify those patients who already harbor silent cTOD (i.e., myocardial ischemia, left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, or left atrial enlargement). This might be possible by screening with a biomarker (e.g. high sensitivity cardiac troponin T [hs-cTnT] or B-type natriuretic peptide [BNP]).

Methods: We prospectively recruited 300 asymptomatic individuals already receiving primary prevention therapy. Transthoracic echocardiography, stress echocardiography, and/or myocardial perfusion imaging were performed to identify silent cTOD.

Results: One hundred two (34%) patients had evidence of cTOD. Left ventricular hypertrophy was the most prevalent (29.7%) form of cTOD, followed by diastolic dysfunction (21.3%), left atrial enlargement (15.3%), systolic dysfunction (6.3%), and ischemia (6.3%). The area under the curve (AUC) for BNP to identify any form of silent cTOD was 0.78 overall and 0.82 in men. The equivalent figures for hs-cTnT were 0.70 and 0.75 in women. The AUC for BNP and hs-cTnT together was 0.81 and 0.82 in men. However, the discrimination power of other markers was poor, with AUCs of 0.61 for microalbuminuria, 0.49 for uric acid, and 0.58 for eGFR.

Conclusions: In asymptomatic treated primary prevention patients, BNP screening is able to identify existing silent cTOD. The performance of hs-cTnT was not as good as that of BNP. B-type natriuretic peptide plus hs-cTnT together performed best. Prescreening with BNP ± cTnT followed by targeted phenotyping is worth exploring further as a possible way to improve primary prevention.
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http://dx.doi.org/10.1016/j.jacc.2012.04.049DOI Listing
September 2012

Impact of paravalvular leakage on outcome in patients after transcatheter aortic valve implantation.

JACC Cardiovasc Interv 2012 Aug;5(8):858-65

Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.

Objectives: The aim of this study was to evaluate the performance of the aortic regurgitation (AR) index as a new hemodynamic parameter in an independent transcatheter aortic valve implantation (TAVI) cohort and validate its application.

Background: Increasing evidence associates more-than-mild periprosthetic aortic regurgitation (periAR) with increased mortality and morbidity; therefore precise evaluation of periAR after TAVI is essential. The AR index has been proposed recently as a simple and reproducible indicator for the severity of periAR and predictor of associated mortality.

Methods: The severity of periAR was evaluated by echocardiography, angiography, and periprocedural measurement of the dimensionless AR index = ([diastolic blood pressure - left ventricular end-diastolic pressure]/systolic blood pressure) × 100. A cutoff value of 25 was used to identify patients at risk.

Results: One hundred twenty-two patients underwent TAVI by use of either the Medtronic CoreValve (Medtronic, Minneapolis, Minnesota) (79.5%) or the Edwards-SAPIEN bioprosthesis (Edwards Lifesciences, Irvine, California) (20.5%). The AR index decreased stepwise from 29.4 ± 6.3 in patients without periAR (n = 26) to 28.0 ± 8.5 with mild periAR (n = 76), 19.6 ± 7.6 with moderate periAR (n = 18), and 7.6 ± 2.6 with severe periAR (n = 2) (p < 0.001). Patients with AR index <25 had a significantly increased 1-year mortality rate compared with patients with AR index ≥ 25 (42.3% vs. 14.3%; p < 0.001). Even in patients with none/mild periAR, the 1-year mortality risk could be further stratified by an AR index <25 (31.3% vs. 14.3%; p = 0.04).

Conclusions: The validity of the AR index could be confirmed in this independent TAVI cohort and provided prognostic information that was complementary to the severity of AR.
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http://dx.doi.org/10.1016/j.jcin.2012.04.011DOI Listing
August 2012

B-type natriuretic peptide is an independent predictor of endothelial function in man.

Clin Sci (Lond) 2012 Sep;123(5):307-12

Centre for Cardiovascular and Lung Biology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1±4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFα (tumour necrosis factor α) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium-dependent vasodilatation in response to ACH.
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http://dx.doi.org/10.1042/CS20110168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353736PMC
September 2012

The impact of renin-angiotensin-aldosterone system blockade on heart failure outcomes and mortality in patients identified to have aortic regurgitation: a large population cohort study.

J Am Coll Cardiol 2011 Nov;58(20):2084-91

Centre for Cardiovascular and Lung Biology, Ninewells Hospital and Medical School, Dundee, United Kingdom.

Objectives: The aim of this study was to investigate the effect of renin-angiotensin system blockade on outcomes in patients with aortic regurgitation (AR).

Background: Angiotensin-converting enzyme (ACE) inhibitors have the potential to reduce afterload, blunt left ventricular wall stress, and limit left ventricular dilation and hypertrophy. However, long-term studies have yielded inconsistent results, and very few have assessed clinical outcomes.

Methods: The Health Informatics Centre dispensed prescription and morbidity and mortality database for the population of Tayside, Scotland, was linked through a unique patient identifier to the Tayside echocardiography database. Patients diagnosed with at least moderate AR from 1993 to 2008 were identified. Cox regression analysis was used to assess differences in all-cause mortality and cardiovascular (CV) and AR events (heart failure hospitalizations, heart failure deaths, or aortic valve replacement) between those treated with and without ACE inhibitors or angiotensin receptor blockers (ARBs).

Results: A total of 2,266 subjects with AR (median age 74 years; interquartile range: 64 to 81 years) were studied, with a mean follow-up period of 4.4 ± 3.7 years. Seven hundred and five patients (31%) received ACE inhibitor or ARB therapy. There were 582 all-cause deaths (25.7%). Patients treated with ACE inhibitors or ARBs had significantly lower all-cause mortality and fewer CV and AR events, with adjusted hazard ratios of 0.56 (95% confidence interval [CI]: 0.64 to 0.89; p < 0.01) for all-cause mortality, 0.77 (95% CI: 0.67 to 0.89; p < 0.01) for CV events, and 0.68 (95% CI: 0.54 to 0.87; p < 0.01) for AR events.

Conclusions: This large retrospective study shows that the prescription of ACE inhibitors or ARBs in patients with moderate to severe AR was associated with significantly reduced all-cause mortality and CV and AR events. These data need to be confirmed by a prospective randomized controlled outcome trial.
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http://dx.doi.org/10.1016/j.jacc.2011.07.043DOI Listing
November 2011

Does subclinical atherosclerosis burden identify the increased risk of cardiovascular disease mortality among United Kingdom Indian Asians? A population study.

Am Heart J 2011 Sep 9;162(3):460-6. Epub 2011 Aug 9.

Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, UK.

Background: Indian Asians living in the United Kingdom have a >50% higher risk of cardiovascular disease (CVD) death compared with native European whites. The mechanisms underlying their excess mortality are not clear, and there are no validated tools capable of identifying this increased risk. The burden of subclinical atherosclerosis detected in the carotid arteries is an established prognosticator for major CVD events. We hypothesized that the increased prevalence of CVD among Indian Asians would be reflected by their having a greater burden of subclinical carotid artery atherosclerosis compared with European whites.

Methods: We studied 2,288 healthy subjects and 148 patients with known CVD from the London Life Sciences Prospective Population study who underwent carotid ultrasonography for assessment of intima-media thickness (IMT), plaque prevalence, and plaque echogenicity.

Results: The prevalence of CVD was significantly higher among Indian Asians compared with European whites (odds ratio 1.72, 95% CI 1.2-2.3). Intima-media thickness was slightly higher in European whites compared with that of Indian Asians (0.66 vs 0.65 mm, P = .06), reflecting their higher Framingham Risk Score. After adjustment for cardiovascular risk factors, there were no significant differences in IMT, plaque prevalence, or plaque echogenicity between the 2 ethnic groups regardless of CVD status.

Conclusion: The burden of carotid atherosclerosis does not identify the markedly increased risk of CVD among United Kingdom Indian Asians. Other markers and mechanisms of disease require investigation in this high-risk group.
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http://dx.doi.org/10.1016/j.ahj.2011.06.018DOI Listing
September 2011

Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis.

J Am Coll Cardiol 2011 Aug;58(6):570-6

Centre for Cardiovascular and Lung Biology, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.

Objectives: The purpose of this study was to investigate the impact of renin-angiotensin system blockade therapy on outcomes in aortic stenosis (AS).

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are perceived to be relatively contraindicated in AS. However, inhibitors of the renin-angiotensin system may be beneficial in AS through their cardioprotective and beneficial effects on left ventricular remodeling.

Methods: The Health Informatics dispensed prescribing, morbidity, and mortality database for the population of Tayside, Scotland, was linked through a unique patient identifier to the Tayside echocardiography database (>110,000 scans). Patients with a diagnosis of AS from 1993 to 2008 were identified. Cox regression model (adjusted for confounding variables) and propensity score analysis were used to assess the impact of ACEIs or ARBs on all-cause mortality and cardiovascular (CV) events (CV death or hospitalizations).

Results: A total of 2,117 patients with AS (mean age 73 ± 12 years, 46% men) were identified and 699 (33%) were on ACEI or ARB therapy. Over a mean follow-up of 4.2 years, there were 1,087 (51%) all-cause deaths and 1,018 (48%) CV events. Those treated with ACEIs or ARBs had a significantly lower all-cause mortality with an adjusted hazard ratio of 0.76 (95% confidence interval: 0.62 to 0.92, p < 0.0001) and fewer CV events with an adjusted hazard ratio of 0.77 (95% confidence interval: 0.65 to 0.92, p < 0.0001). The outcome benefits of ACEIs/ARBs were further supported by propensity score analysis.

Conclusions: This large observational study suggests that ACEI/ARB therapy is associated with an improved survival and a lower risk of CV events in patients with AS.
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http://dx.doi.org/10.1016/j.jacc.2011.01.063DOI Listing
August 2011

The distinct relationships of carotid plaque disease and carotid intima-media thickness with left ventricular function.

J Am Soc Echocardiogr 2010 Dec;23(12):1303-9

Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, UK.

Background: Subclinical carotid atherosclerosis has been associated with impaired left ventricular (LV) function and the development of heart failure. Whether impaired LV function is related primarily to increased intima-media thickness (IMT) or burden of plaque disease or both remains to be determined.

Methods: A total of 2,279 subjects without clinical cardiovascular disease recruited from the London Life Sciences Prospective Population cohort study were studied. Carotid ultrasonography and transthoracic echocardiography were performed on all subjects. Carotid IMT and plaque scores were measured, and their relationships with LV volumes, LV ejection fraction, myocardial LV longitudinal function (Sa and Ea velocities), and LV filling pressure (E/Ea ratio) were assessed before and after adjustment for covariates.

Results: Compared with those without carotid artery disease, subjects with either increased IMT and/or presence of plaque disease had identical Sa velocities (both 9.0 cm/sec), lower Ea velocities (8.7 vs 9.9 cm/sec, P < .001) and higher E/Ea ratios (8.4 vs 7.6, P < .001). After multiple linear regression analysis, increasing IMT remained independently related to reduced Ea velocity (P < .001) but not LV ejection fraction, Sa velocity, or E/Ea ratio. In a separate adjusted analysis, subjects with severe burdens of carotid plaque disease (more than five plaques) had reduced LV ejection fractions (β = -2.9; 95% confidence interval [CI], 1.0 to 4.8, P = .003), attenuated Sa velocities (β = -0.79; 95% CI, -1.2 to -0.3, P = .003), attenuated Ea velocities 2 (β = -0.79; 95% CI, -1.3 to -0.2, P = .007), and increased E/Ea ratios (β = 0.84; 95% CI, 0.2 to 1.5, P = .009) compared to individuals without carotid plaques.

Conclusion: These findings demonstrate that subclinical carotid plaque disease rather than IMT is more closely related to LV systolic function and LV filling pressure. These data support the application of carotid ultrasonography beyond cardiovascular disease risk prediction, while providing insight into potential mechanisms underlying the development of subclinical LV dysfunction.
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http://dx.doi.org/10.1016/j.echo.2010.08.021DOI Listing
December 2010

New insights into the relationship of left ventricular geometry and left ventricular mass with cardiac function: A population study of hypertensive subjects.

Eur Heart J 2010 Mar 19;31(5):588-94. Epub 2009 Nov 19.

Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, UK.

Aims: Remodelling of the left ventricle (LV) is associated with adverse cardiovascular events, but the mechanisms of these effects remain undefined. We investigated the relationship of LV mass and geometry to LV function in a large cohort of hypertensive subjects.

Methods And Results: We studied 1074 hypertensive individuals without cardiovascular disease recruited from the London Life Sciences Prospective Population (LOLIPOP) study. All subjects underwent echocardiography for derivation of LV mass index (LVMI), measurement of transmitral filling pattern, and LV ejection fraction (EF). The tissue Doppler parameters of peak myocardial systolic velocity (Sa), diastolic velocity (Ea), and of LV filling pressure (E/Ea) were measured. Left ventricular function was correlated with degree of concentric remodelling, determined by relative wall thickness, and with LV geometric pattern. The presence of LV hypertrophy was independently associated with significantly worse systolic function, diastolic function, and higher LV filling pressure when compared with subjects with normal LV geometry or non-hypertrophic concentric remodelling. After adjustment for covariates including LVMI, peak Sa velocity and EF increased (P < 0.001), whereas peak Ea velocity decreased significantly (P < 0.001) with increasing degrees of concentric remodelling.

Conclusion: In hypertensives, hypertrophic remodelling is independently associated with impaired LV function and increased LV filling pressure. Increasing degrees of non-hypertrophic concentric remodelling are associated with attenuated diastolic function, but augmented systolic function, possibly representing an adaptive response to pressure overload physiology.
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http://dx.doi.org/10.1093/eurheartj/ehp490DOI Listing
March 2010

Normative reference values for the tissue Doppler imaging parameters of left ventricular function: a population-based study.

Eur J Echocardiogr 2010 Jan 12;11(1):51-6. Epub 2009 Nov 12.

Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow HA1 3UJ, UK.

Objective: Tissue Doppler imaging (TDI) is used routinely to quantify left ventricular function and filling pressure. However, there remains a lack of percentile-based normative reference values for these clinically important parameters.

Methods: Four hundred and fifty-three healthy subjects aged 35-75 years were included for analysis from the London Life Sciences Prospective Population (LOLIPOP) study. Subjects were free of manifest cardiovascular disease, cardiovascular risk factors, and significant coronary artery disease as determined by electron-beam computed tomography. They underwent 2D and Doppler echocardiography for assessment of left heart structure and function. TDI was performed at the septal and lateral mitral annular sites enabling on-line derivation of myocardial systolic velocity (Sa), diastolic velocity (Ea), and the ratio of Ea to transmitral E-wave (E/Ea).

Results: Reference ranges (5th and 95th percentile values) for septal, lateral, and average mitral annular Sa velocity, Ea velocity, and E/Ea ratio were derived for the whole cohort and for each of the four age groups (35-44, 45-54, 55-64, 65-75). Increasing age was associated with a significant attenuation in myocardial velocity when averaged from both the septal and lateral mitral annulus, exerting a greater influence upon average Ea velocity (P < 0.001) compared with average Sa velocity (P = 0.04). Average E/Ea ratio increased significantly with advancing age (P < 0.001).

Conclusion: The reference ranges presented for the TDI parameters of Sa velocity, Ea velocity, and E/Ea ratio will help to standardize the assessment of LV function by tissue Doppler echocardiography.
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http://dx.doi.org/10.1093/ejechocard/jep164DOI Listing
January 2010

Comparison between myocardial contrast echocardiography and (99m)technetium sestamibi single photon emission computed tomography determined myocardial viability in predicting hard cardiac events following acute myocardial infarction.

Am J Cardiol 2009 Nov;104(9):1184-8

Department of Cardiovascular Medicine, Northwick Park Institute of Medical Research, Northwick Park Hospital, Harrow, Middlesex, United Kingdom.

The extent of residual myocardial viability (MV) after acute myocardial infarction (AMI) is an important determinant of the outcome. Single photon emission computed tomography (SPECT) is widely used to assess MV after an AMI. However, myocardial contrast echocardiography (MCE), a relatively new technique for the assessment of MV, has better spatial and temporal resolution than SPECT. The present study evaluated whether MV determined by MCE is comparable to that determined using SPECT for the prediction of hard cardiac events after an AMI. Accordingly, 99 patients who had undergone simultaneous rest low-power MCE and nitrate-enhanced SPECT 7 days after an AMI were followed up for cardiac death and AMIs. Both MCE perfusion (1 = normal; 2 = reduced; and 3 = absent) and SPECT tracer uptake (0 = normal; 1 = mildly reduced; 2 = moderately reduced; 3 = severely reduced; and 4 = absent) were scored on a 16-segment left ventricular model. The contrast perfusion index and SPECT perfusion index were calculated by adding the respective scores in the 16 segments and dividing by 16. The contrast perfusion index and SPECT perfusion index were used as a measure of the residual MV on MCE and SPECT, respectively. Of the 99 patients recruited, 95 were available for the follow-up examination (follow-up 46 +/- 16 months). A total of 15 events (16%) occurred (8 cardiac deaths and 7 AMIs). Of the clinical, biochemical, echocardiographic, and SPECT markers of prognosis, the only independent predictors of cardiac death and cardiac death or AMI were age and MV as determined by MCE (p = 0.01 and p = 0.002, respectively). In conclusion, MV determined by MCE at rest was superior to nitrate-enhanced SPECT for the prediction of hard cardiac events after AMI.
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http://dx.doi.org/10.1016/j.amjcard.2009.06.026DOI Listing
November 2009

Peak cardiac power output, measured noninvasively, is a powerful predictor of outcome in chronic heart failure.

Circ Heart Fail 2009 Jan;2(1):33-8

Division of Cardiology, Columbia University, New York, NY, USA.

Background: The cardiac output (CO) response to exercise and other invasively derived hemodynamic variables has been variably described to provide better prognostication than peak V(O(2)) in patients with chronic heart failure. Using noninvasive measurements of CO during exercise, we compared the prognostic value of peak CO and cardiac power to peak V(O(2)) in chronic heart failure patients.

Method And Results: One hundred seventy-one consecutive patients with chronic heart failure underwent symptom limited bicycle exercise with noninvasive estimation of CO using an inert gas rebreathing method. An accurate measure of peak CO was obtained in 148 patients (85% of patients; mean age, 53+/-14 years; 80% male; left ventricular ejection fraction, 24+/-12%; ischemic etiology, 34%). Peak cardiac power was derived from the product of the peak mean arterial blood pressure and CO divided by 451. End points consisted of death, urgent heart transplant, or left ventricular assist device implantation. Duration of follow-up averaged 337+/-252 days (median, 295 days). Univariate and multivariate analysis were performed. The variables analyzed included peak V(O(2)), peak CO, peak cardiac power, V(E)/V(CO(2)) slope, and V(O(2)) at anaerobic threshold. Event-free survival for the entire cohort was 83% with 5 deaths, 4 left ventricular assist device implants, and 16 urgent transplants. Peak V(O(2)) was 12.9+/-4.5 mL/kg per min, and peak cardiac power was 1.7+/-0.9 W. Peak V(O(2)), peak CO, peak cardiac power, V(E)/V(CO(2)) slope, and V(O(2)) at anaerobic threshold were predictive of outcome on univariate analysis. On multivariate analysis, peak cardiac power and peak CO were predictive of outcome with peak cardiac power being the most powerful independent predictor of outcome (P=0.01).

Conclusions: Peak cardiac power, measured noninvasively, is an independent predictor of outcome that can enhance the prognostic power of peak V(O(2)) in the evaluation of patients with heart failure.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.108.798611DOI Listing
January 2009

Improved prediction of outcome by contrast echocardiography determined left ventricular remodelling parameters compared to unenhanced echocardiography in patients following acute myocardial infarction.

Eur J Echocardiogr 2009 Dec 4;10(8):933-40. Epub 2009 Aug 4.

Department of Cardiovascular Medicine, Northwick Park Hospital, Northwick Park Institute of Medical Research, Harrow, UK.

Aims: Contrast echocardiography has been shown to be a more accurate method of assessing left ventricular (LV) remodelling compared with unenhanced echocardiography after acute myocardial infarction (AMI). However, whether this translated into improved prediction of outcome is not known.

Methods And Results: Accordingly, a total of 89 consecutive patients undergoing contrast echocardiography and unenhanced echocardiography 7 to 10 days after AMI and reperfusion therapy were followed up for cardiac death (CD) and AMI. LV ejection fraction (LVEF), LV end-systolic volume (ESV), and LV end-diastolic volume were assessed by the two methods independently. Outcome data were obtained (mean 46 +/- 16 months).There were 15 (17%) events (eight CDs and seven AMIs). LVEF and ESV with contrast echocardiography were found to be independent multivariable predictors of CD (P = 0.04 and P = 0.02, respectively) and CD or AMI (P = 0.02 and P = 0.01, respectively). Furthermore, LVEF and ESV with contrast echocardiography provided incremental information for the prediction of CD (P = 0.004 and P = 0.004, respectively) and CD or AMI (P = 0.02 and P = 0.03, respectively).

Conclusion: Contrast echocardiography provided improved prediction of outcome compared with unenhanced echocardiography following AMI.
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http://dx.doi.org/10.1093/ejechocard/jep099DOI Listing
December 2009

Ethnicity-related differences in left ventricular function, structure and geometry: a population study of UK Indian Asian and European white subjects.

Heart 2010 Mar 2;96(6):466-71. Epub 2009 Jul 2.

Department of Cardiovascular Medicine, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK.

Objectives: The authors studied healthy UK Indian Asian and European white subjects to assess whether functional, structural and geometrical properties of the left heart are intrinsically related to ethnicity.

Background: Quantitative assessment of cardiac function and structure is necessary to diagnose heart failure syndromes and is validated to refine risk prediction. A better understanding of the demographic factors that influence these variables is required.

Methods: 458 healthy subjects were recruited from the London Life Sciences Prospective Population (LOLIPOP) study. They underwent 2-D and tissue Doppler echocardiography for quantification of left ventricular (LV) function, LV volumes, left atrial volume index (LAVI), left ventricular mass index (LVMI) and relative wall thickness (RWT).

Results: Indian Asians had attenuated mitral annular systolic velocity (8.9 cm/s vs 9.5 cm/s, p<0.001), lower mitral annular early diastolic velocity (10.3 cm/s vs 11.0 cm/s, p<0.001) and higher E/Ea ratio (7.9 vs 7.0, p<0.001) compared to European white subjects. Although Indian Asians had significantly smaller left heart volumes and LVMI, they had a significantly higher RWT (0.37 vs 0.35, p<0.001). After adjustment for covariates, these ethnicity-related differences remained highly significant (p<0.001).

Conclusion: Compared to European white people, Indian Asians had attenuated longitudinal LV function, higher LV filling pressure and demonstrated a greater degree of concentric remodelling independent of other demographic and clinical parameters.
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http://dx.doi.org/10.1136/hrt.2009.173153DOI Listing
March 2010

Therapeutic development in cardiac syndrome X: a need to target the underlying pathophysiology.

Cardiovasc Ther 2009 ;27(1):49-58

Division of Medicine and Therapeutics, University of Dundee, Dundee, UK.

Morbidity of patients with cardiac syndrome X (typical anginal-like chest pain and normal coronary arteriogram) is high with continuing episodes of chest pain and frequent hospital readmissions. Management of this syndrome represents a major challenge for the treating physician. Conventional therapies with antianginal agents such as nitrates, calcium channel antagonists, classic beta-adrenoceptor blockers and nicorandil have been tried, with variable success. However, this might be related to a failure to target the underlying pathophysiology and, clearly, more effective therapies are needed. Supporting evidence for the important role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has come from the recent observation that basal superoxide production predicts future cardiovascular events in this patient group. This review will discuss the pathophysiology, current medical management and potential new pharmacological treatment for patients with cardiac syndrome X which target endothelial dysfunction and oxidative stress. What's already known about this topic? Morbidity of patients with cardiac syndrome X is high. The important role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X. What does this article add? This review will discuss the pathophysiology, current medical management and potential new pharmacological treatment for patients with cardiac syndrome X which target endothelial dysfunction and oxidative stress.
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http://dx.doi.org/10.1111/j.1755-5922.2008.00070.xDOI Listing
March 2009

Relationship between myocardial perfusion with myocardial contrast echocardiography and function early after acute myocardial infarction for the prediction of late recovery of function.

Int J Cardiol 2010 Apr 14;140(2):169-74. Epub 2008 Dec 14.

Northwick Park Hospital, UK.

Background: Following ST elevation acute myocardial infarction (STEMI) and reperfusion therapy, there are often persistent wall thickening (WT) abnormalities and perfusion defects due to variable degree of myocardial stunning and necrosis. We hypothesised that following STEMI and reperfusion therapy, the extent of residual perfusion assessed by myocardial contrast echocardiography (MCE) and not the extent of WT abnormalities would predict subsequent global recovery of left ventricular (LV) function.

Methods: Accordingly, 112 patients with STEMI underwent simultaneous assessment of WT abnormality and perfusion using MCE 7+/-2 days after AMI and reperfusion therapy. Both WT and perfusion were scored on a 16 segment LV model. Contrast perfusion index (CPI), and global LV function were calculated. Echocardiography was repeated 12 weeks after reperfusion to assess recovery of LV function.

Results: Of the 112 patients recruited, follow up echocardiography 12 weeks after reperfusion was available in 98 patients. CPI was significantly higher (p<0.0001) in the 66 patients, who showed late recovery of LV function (1.67+/-0.27) compared to those who did not show recovery of function (1.25+/-0.04). No significant difference was noted in the indices of baseline LV function in patients with (1.67+/-0.32) and without (1.80+/-0.36) recovery of LV function. The multivariable predictors of late recovery of function were MCE (p=0.02), absence of diabetes (p=0.02) and lower peak creatine kinase (p=0.01).

Conclusion: The extent of residual contrast perfusion and not WT abnormalities predicts late recovery of global LV function after acute myocardial infarction and reperfusion therapy.
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http://dx.doi.org/10.1016/j.ijcard.2008.11.052DOI Listing
April 2010

Normal value of carotid intima-media thickness--a surrogate marker of atherosclerosis: quantitative assessment by B-mode carotid ultrasound.

J Am Soc Echocardiogr 2008 Feb 30;21(2):112-6. Epub 2007 Aug 30.

Northwick Park Hospital and Institute of Post Graduate Medicine and Research, London, United Kingdom.

Background: Carotid intima-media thickness (IMT) is a surrogate marker of atherosclerosis and imparts prognostic information independent of traditional cardiovascular risk factors. Quantitative assessment of IMT using semiautomated border detection software is a new and easy technique that has been previously shown to be accurate, effective, and reproducible. The study is aimed to define the upper limit of carotid IMT at the common carotid artery (CCA) and its bifurcation among a healthy population in the United Kingdom.

Methods: Asymptomatic men and women aged 35 to 75 years, without evidence of clinical atherosclerosis, underwent B-mode carotid duplex ultrasound (Sonos 7500, Philips, Best, The Netherlands). Mean carotid IMT at the far wall of both left and right CCA were quantitatively determined using a semiautomated edge-detection algorithm (Q-lab 4, Philips). Healthy population was defined as participants with no cardiovascular disease and no evidence of diabetes mellitus or hypertension with a body mass index less than 30 kg/m2, serum cholesterol less than 6 mmol/L, and absence of carotid plaque on ultrasound.

Results: Of the 453 participants, 137 were found to be healthy. IMT measured at the bifurcation was found to be significantly higher compared with that at the CCA. Carotid IMT in both CCA and its bifurcation increased significantly with age. The upper limits (97.5 percentile) of IMT at CCA for participants age 35 to 39, 40 to 49, 50 to 59, and 60 years or older were 0.60, 0.64, 0.71, and 0.81 mm, respectively, whereas for that at bifurcation were 0.83, 0.77, 0.85, and 1.05 mm, respectively.

Conclusion: This study demonstrated the value of IMT at CCA and its bifurcation in a healthy population in the United Kingdom using a semiautomated edge-detection software, which is easy to use and reproducible.
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http://dx.doi.org/10.1016/j.echo.2007.05.002DOI Listing
February 2008
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