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2.
Open Heart ; 10(2)2023 09.
Article in English | MEDLINE | ID: mdl-37666643

ABSTRACT

INTRODUCTION: Severe aortic stenosis is a major cause of morbidity and mortality. The existing treatment pathway for transcatheter aortic valve implantation (TAVI) traditionally relies on tertiary Heart Valve Centre workup. However, this has been associated with delays to treatment, in breach of British Cardiovascular Intervention Society targets. A novel pathway with emphasis on comprehensive patient workup at a local centre, alongside close collaboration with a Heart Valve Centre, may help reduce the time to TAVI. METHODS: The centre performing local workup implemented a novel TAVI referral pathway. Data were collected retrospectively for all outpatients referred for consideration of TAVI to a Heart Valve Centre from November 2020 to November 2021. The main outcome of time to TAVI was calculated as the time from Heart Valve Centre referral to TAVI, or alternative intervention, expressed in days. For the centre performing local workup, referral was defined as the date of multidisciplinary team discussion. For this centre, a total pathway time from echocardiographic diagnosis to TAVI was also evaluated. A secondary outcome of the proportion of referrals proceeding to TAVI at the Heart Valve Centre was analysed. RESULTS: Mean±SD time from referral to TAVI was significantly lower at the centre performing local workup, when compared with centres with traditional referral pathways (32.4±64 to 126±257 days, p<0.00001). The total pathway time from echocardiographic diagnosis to TAVI for the centre performing local workup was 89.9±67.6 days, which was also significantly shorter than referral to TAVI time from all other centres (p<0.003). Centres without local workup had a significantly lower percentage of patients accepted for TAVI (49.5% vs 97.8%, p<0.00001). DISCUSSION: A novel TAVI pathway with emphasis on local workup within a non-surgical centre significantly reduced both the time to TAVI and rejection rates from a Heart Valve Centre. If adopted across the other centres, this approach may help improve access to TAVI.


Subject(s)
Transcatheter Aortic Valve Replacement , Humans , Retrospective Studies , Transcatheter Aortic Valve Replacement/adverse effects , Echocardiography , Outpatients , Referral and Consultation
3.
Sci Rep ; 13(1): 11478, 2023 07 16.
Article in English | MEDLINE | ID: mdl-37455284

ABSTRACT

Diabetes is a heterogenous, multimorbid disorder with a large variation in manifestations, trajectories, and outcomes. The aim of this study is to validate a novel machine learning method for the phenotyping of diabetes in the context of comorbidities. Data from 9967 multimorbid patients with a new diagnosis of diabetes were extracted from Clinical Practice Research Datalink. First, using BEHRT (a transformer-based deep learning architecture), the embeddings corresponding to diabetes were learned. Next, topological data analysis (TDA) was carried out to test how different areas in high-dimensional manifold correspond to different risk profiles. The following endpoints were considered when profiling risk trajectories: major adverse cardiovascular events (MACE), coronary artery disease (CAD), stroke (CVA), heart failure (HF), renal failure (RF), diabetic neuropathy, peripheral arterial disease, reduced visual acuity and all-cause mortality. Kaplan Meier curves were plotted for each derived phenotype. Finally, we tested the performance of an established risk prediction model (QRISK) by adding TDA-derived features. We identified four subgroups of patients with diabetes and divergent comorbidity patterns differing in their risk of future cardiovascular, renal, and other microvascular outcomes. Phenotype 1 (young with chronic inflammatory conditions) and phenotype 2 (young with CAD) included relatively younger patients with diabetes compared to phenotypes 3 (older with hypertension and renal disease) and 4 (older with previous CVA), and those subgroups had a higher frequency of pre-existing cardio-renal diseases. Within ten years of follow-up, 2592 patients (26%) experienced MACE, 2515 patients (25%) died, and 2020 patients (20%) suffered RF. QRISK3 model's AUC was augmented from 67.26% (CI 67.25-67.28%) to 67.67% (CI 67.66-67.69%) by adding specific TDA-derived phenotype and the distances to both extremities of the TDA graph improving its performance in the prediction of CV outcomes. We confirmed the importance of accounting for multimorbidity when risk stratifying heterogenous cohort of patients with new diagnosis of diabetes. Our unsupervised machine learning method improved the prediction of clinical outcomes.


Subject(s)
Diabetes Mellitus , Unsupervised Machine Learning , Humans , Diabetes Mellitus/epidemiology , Comorbidity , Data Analysis , Cardiovascular Diseases/epidemiology , Risk Assessment , Kidney Diseases/epidemiology , Male , Female , Middle Aged , Aged , Phenotype
4.
Open Heart ; 10(1)2023 02.
Article in English | MEDLINE | ID: mdl-36822818

ABSTRACT

BACKGROUND: Long COVID is associated with multiple symptoms and impairment in multiple organs. Cross-sectional studies have reported cardiac impairment to varying degrees by varying methodologies. Using cardiac MR (CMR), we investigated a 12-month trajectory of abnormalities in Long COVID. OBJECTIVES: To investigate cardiac abnormalities 1-year post-SARS-CoV-2 infection. METHODS: 534 individuals with Long COVID underwent CMR (T1/T2 mapping, cardiac mass, volumes, function and strain) and multiorgan MRI at 6 months (IQR 4.3-7.3) since first post-COVID-19 symptoms. 330 were rescanned at 12.6 (IQR 11.4-14.2) months if abnormal baseline findings were reported. Symptoms, questionnaires and blood samples were collected at both time points. CMR abnormalities were defined as ≥1 of low left or right ventricular ejection fraction (LVEF), high left or right ventricular end diastolic volume, low 3D left ventricular global longitudinal strain (GLS), or elevated native T1 in ≥3 cardiac segments. Significant change over time was reported by comparison with 92 healthy controls. RESULTS: Technical success of multiorgan and CMR assessment in non-acute settings was 99.1% and 99.6% at baseline, and 98.3% and 98.8% at follow-up. Of individuals with Long COVID, 102/534 (19%) had CMR abnormalities at baseline; 71/102 had complete paired data at 12 months. Of those, 58% presented with ongoing CMR abnormalities at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms or clinical outcomes. At baseline, low LVEF was associated with persistent CMR abnormality, abnormal GLS associated with low quality of life and abnormal T1 in at least three segments was associated with better clinical outcomes at 12 months. CONCLUSION: CMR abnormalities (left entricular or right ventricular dysfunction/dilatation and/or abnormal T1mapping), occurred in one in five individuals with Long COVID at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers could not identify CMR abnormalities in Long COVID. TRIAL REGISTRATION NUMBER: NCT04369807.


Subject(s)
COVID-19 , Humans , Stroke Volume , Post-Acute COVID-19 Syndrome , Cross-Sectional Studies , Quality of Life , Predictive Value of Tests , SARS-CoV-2 , Ventricular Function, Right
5.
Front Cardiovasc Med ; 9: 1043711, 2022.
Article in English | MEDLINE | ID: mdl-36407437

ABSTRACT

Diabetic heart disease is a major healthcare problem. Patients with diabetes show an excess of death from cardiovascular causes, twice as high as the general population and those with diabetes type 1 and longer duration of the disease present with more severe cardiovascular complications. Premature coronary artery disease and heart failure are leading causes of morbidity and reduced life expectancy. Multimodality cardiac imaging, including echocardiography, cardiac computed tomography, nuclear medicine, and cardiac magnetic resonance play crucial role in the diagnosis and management of different pathologies included in the definition of diabetic heart disease. In this review we summarise the utility of multi-modality cardiac imaging in characterising ischaemic and non-ischaemic causes of diabetic heart disease and give an overview of the current clinical practice. We also describe emerging imaging techniques enabling early detection of coronary artery inflammation and the non-invasive characterisation of the atherosclerotic plaque disease. Furthermore, we discuss the role of MRI-derived techniques in studying altered myocardial metabolism linking diabetes with the development of diabetic cardiomyopathy. Finally, we discuss recent data regarding the use of artificial intelligence applied to large imaging databases and how those efforts can be utilised in the future in screening of patients with diabetes for early signs of disease.

6.
Lancet Diabetes Endocrinol ; 10(9): 645-654, 2022 09.
Article in English | MEDLINE | ID: mdl-35878651

ABSTRACT

BACKGROUND: Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. METHODS: We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, ß blockers, calcium channel blockers, and thiazide diuretics, was estimated using a network meta-analysis framework. This study is registered with PROSPERO, CRD42018099283. FINDINGS: We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0-5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91-0·98]) compared with those without type 2 diabetes (0·89 [0·87-0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated. INTERPRETATION: Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted. FUNDING: British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Heart Failure , Hypertension , Antihypertensive Agents , Blood Pressure , Female , Humans , Male
8.
Lancet ; 398(10313): 1803-1810, 2021 11 13.
Article in English | MEDLINE | ID: mdl-34774144

ABSTRACT

BACKGROUND: Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials. METHODS: We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons. FINDINGS: 145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84-0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76-0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76-0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of ß blockers (RR 1·48 [1·27-1·72]) and thiazide diuretics (RR 1·20 [1·07-1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92-1·13]). INTERPRETATION: Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes. FUNDING: British Heart Foundation, National Institute for Health Research, and Oxford Martin School.


Subject(s)
Antihypertensive Agents/therapeutic use , Diabetes Mellitus, Type 2/prevention & control , Hypertension/drug therapy , Adrenergic beta-Antagonists/therapeutic use , Aged , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Blood Pressure/drug effects , Calcium Channel Blockers/therapeutic use , Diabetes Mellitus, Type 2/epidemiology , Female , Humans , Male , Middle Aged , Sodium Chloride Symporter Inhibitors/therapeutic use
9.
Diabetes Care ; 44(8): 1877-1884, 2021 08.
Article in English | MEDLINE | ID: mdl-34162666

ABSTRACT

OBJECTIVE: Insulin resistance (IR) may mediate heart failure (HF) development. We examined whether IR in people with newly diagnosed type 2 diabetes (T2D) increased their risk of a composite outcome of HF or death or of HF alone. RESEARCH DESIGN AND METHODS: Insulin resistance (HOMA2-IR) values for UKPDS participants were derived from paired fasting plasma glucose (FPG) and insulin measures. Kaplan-Meier survival curves and multivariable survival models were used to evaluate associations between HOMA2-IR and HF/death or HF alone. We adjusted for potential confounders by including variables with univariate associations (P < 0.1) and by requiring a multivariable P < 0.05. RESULTS: Of 5,102 UKPDS participants with newly diagnosed T2D, 4,344 had HOMA2-IR measurements. At enrollment, mean (SD) age was 52.5 (8.7) years, with HbA1c 7.2% (1.8%), and BMI 28.8 (5.5) kg/m2, and median (interquartile range) HOMA2-IR was 1.6 (1.1-2.2). HF/death occurred in 1,974 (45.4%) participants (235 first HF events, 1,739 deaths) over a median follow-up of 16.4 years. Multivariable independent associations with HF/death were older age and higher BMI, HOMA2-IR, FPG, waist-to-hip ratio, systolic blood pressure, LDL cholesterol, and heart rate as well as sex, race, smoking status, prior atrial fibrillation, and prior microalbuminuria. A doubling of HOMA2-IR was associated with a 5% greater risk of HF/death (relative risk [RR] 1.05 [95% CI 1.01-1.12], P = 0.0029) and a 14% greater risk of HF (RR 1.14, [95% CI 1.02-1.27], P = 0.017). CONCLUSIONS: Patients with newly diagnosed T2D and insulin resistance were more likely to develop HF or die than those more sensitive to insulin.


Subject(s)
Diabetes Mellitus, Type 2 , Heart Failure , Insulin Resistance , Aged , Blood Glucose , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Heart Failure/epidemiology , Humans , Insulin , Middle Aged , Risk Factors
10.
BMJ Open ; 11(3): e048391, 2021 03 30.
Article in English | MEDLINE | ID: mdl-33785495

ABSTRACT

OBJECTIVE: To assess medium-term organ impairment in symptomatic individuals following recovery from acute SARS-CoV-2 infection. DESIGN: Baseline findings from a prospective, observational cohort study. SETTING: Community-based individuals from two UK centres between 1 April and 14 September 2020. PARTICIPANTS: Individuals ≥18 years with persistent symptoms following recovery from acute SARS-CoV-2 infection and age-matched healthy controls. INTERVENTION: Assessment of symptoms by standardised questionnaires (EQ-5D-5L, Dyspnoea-12) and organ-specific metrics by biochemical assessment and quantitative MRI. MAIN OUTCOME MEASURES: Severe post-COVID-19 syndrome defined as ongoing respiratory symptoms and/or moderate functional impairment in activities of daily living; single-organ and multiorgan impairment (heart, lungs, kidneys, liver, pancreas, spleen) by consensus definitions at baseline investigation. RESULTS: 201 individuals (mean age 45, range 21-71 years, 71% female, 88% white, 32% healthcare workers) completed the baseline assessment (median of 141 days following SARS-CoV-2 infection, IQR 110-162). The study population was at low risk of COVID-19 mortality (obesity 20%, hypertension 7%, type 2 diabetes 2%, heart disease 5%), with only 19% hospitalised with COVID-19. 42% of individuals had 10 or more symptoms and 60% had severe post-COVID-19 syndrome. Fatigue (98%), muscle aches (87%), breathlessness (88%) and headaches (83%) were most frequently reported. Mild organ impairment was present in the heart (26%), lungs (11%), kidneys (4%), liver (28%), pancreas (40%) and spleen (4%), with single-organ and multiorgan impairment in 70% and 29%, respectively. Hospitalisation was associated with older age (p=0.001), non-white ethnicity (p=0.016), increased liver volume (p<0.0001), pancreatic inflammation (p<0.01), and fat accumulation in the liver (p<0.05) and pancreas (p<0.01). Severe post-COVID-19 syndrome was associated with radiological evidence of cardiac damage (myocarditis) (p<0.05). CONCLUSIONS: In individuals at low risk of COVID-19 mortality with ongoing symptoms, 70% have impairment in one or more organs 4 months after initial COVID-19 symptoms, with implications for healthcare and public health, which have assumed low risk in young people with no comorbidities. TRIAL REGISTRATION NUMBER: NCT04369807; Pre-results.


Subject(s)
COVID-19/complications , Hospitalization/statistics & numerical data , SARS-CoV-2 , Activities of Daily Living , Adult , Aged , COVID-19/epidemiology , COVID-19/physiopathology , Case-Control Studies , Community-Based Participatory Research , Diabetes Mellitus, Type 2/complications , Female , Humans , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Post-Acute COVID-19 Syndrome
11.
Diabetes Res Clin Pract ; 170: 108488, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33035598

ABSTRACT

AIMS: Heart failure is a fatal complication of type 2 diabetes but little is known about its incidence in people with impaired glucose tolerance (IGT). We used Acarbose Cardiovascular Evaluation (ACE) trial data to identify predictors of hospitalisation for heart failure (hHF) or cardiovascular (CV) death in patients with coronary heart disease (CHD) and IGT randomised to acarbose or placebo. METHODS: Independent hHF/CV death risk factors were determined using Cox proportional hazards models, with participants censored at first hHF event, CV death, or end of follow-up. RESULTS: During median 5-year follow-up, the composite outcome of hHF/CV death occurred in 393 (6.0%) participants. Significant hHF/CV death multivariate predictors were higher age and plasma creatinine, and prior heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF) and stroke. Acarbose, compared with placebo, did not reduce hHF/CV death (hazard ratio [HR] 0.89, 95% CI 0.64-1.24, P = 0.48) or hHF (HR 0.90, 95% CI 0.74-1.10, P = 0.32). CONCLUSIONS: Patients with CHD and IGT at greater risk of hHF/CV death were older with higher plasma creatinine, prior HF, MI, AF or stroke. Addition of acarbose to optimised CV therapy to reduce post-prandial glucose excursions did not reduce the risk of hHF/CV death or hHF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513.


Subject(s)
Acarbose/therapeutic use , Coronary Disease/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Glucose Intolerance/epidemiology , Heart Failure/epidemiology , Aged , Coronary Disease/mortality , Creatinine/blood , Diabetes Mellitus, Type 2/blood , Double-Blind Method , Female , Glycoside Hydrolase Inhibitors/therapeutic use , Heart Failure/mortality , Humans , Incidence , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Infarction/mortality , Proportional Hazards Models , Risk Factors , Treatment Outcome
12.
Am Heart J ; 220: 82-88, 2020 02.
Article in English | MEDLINE | ID: mdl-31790905

ABSTRACT

BACKGROUND: Type 2 diabetes (T2D) patients are at increased risk for cardiovascular (CV) events. Most guidelines recommend treating low-density lipoprotein cholesterol (LDL-C) levels to ≤70 mg/dL (1.8 mM) for patients with T2D and established atherosclerotic CV disease, and some a more aggressive target of ≤55 mg/dL (1.4 mM). Our objective was to assess the degree to which these LDL-C targets are achieved in routine practice. METHODS: Using data from TECOS, an international pragmatic CV outcomes trial of sitagliptin vs placebo, we assessed lipid-lowering treatment among patients with T2D and CV disease, baseline lipid values, and the association between baseline LDL-C and 5-year risk for major adverse cardiac events (MACE; ie, CV death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 11,066 of 14,671 TECOS participants (75.4%) had LDL-C measured at baseline. Median age was 65 years, 72% were male, and median T2D duration was 10 years. Overall, 82.5% of patients were on statins; only 5.8% were on ezetimibe. At baseline, 14.3% had LDL-C ≤55 mg/dL, 18.4% between 55.1 and 70 mg/dL, 35% between 70.1 and 100 mg/dL, and 32.3% >100 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a higher risk of MACE (HR 1.05, 95% CI 1.03-1.07) or CV death (HR 1.06, 95% CI 1.04-1.09). CONCLUSIONS: Although most high-risk patients with T2D and CV disease were on lipid-lowering therapy, only 1:3 had LDL-C <70 mg/dL and 1:6 had LDL-C <55 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a 5% and 6% higher 5-year incidence of MACE and CV death, respectively. (TECOS, NCT00790205).


Subject(s)
Atherosclerosis/blood , Cholesterol, LDL/blood , Diabetes Mellitus, Type 2/blood , Aged , Atherosclerosis/prevention & control , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/drug therapy , Double-Blind Method , Ezetimibe/therapeutic use , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Myocardial Infarction/epidemiology , Reference Values , Sitagliptin Phosphate/therapeutic use , Stroke/epidemiology
13.
Int J Cardiovasc Imaging ; 35(7): 1297-1308, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30778713

ABSTRACT

Early risk stratification after ST-segment-elevation myocardial infarction (STEMI) is of major clinical importance. Strain quantifies myocardial deformation and can demonstrate abnormal global and segmental myocardial function in acute ischaemia. Native T1-mapping allows assessment of the severity of acute ischemic injury, however its clinical applicability early post MI is limited by the complex dynamic changes happening in the myocardium post MI. We aimed to explore relationship between T1-mapping and feature tracking imaging, to establish whether combined analysis of these parameters could predict recovery after STEMI. 96 STEMI patients (aged 60 ± 11) prospectively recruited in the Oxford Acute Myocardial Infarction (OxAMI) study underwent 3T-CMR scans acutely (within 53 ± 32 h from primary percutaneous coronary intervention) and at 6 months (6M). The imaging protocol included: cine, ShMOLLI T1-mapping and late gadolinium enhancement (LGE). Segments were divided in the infarct, adjacent and remote zones based on the presence of LGE. Peak circumferential (Ecc) and radial (Err) strain was assessed using cvi42 software. Acute segmental strain correlated with segmental T1-mapping values (T1 vs. Err - 0.75 ± 0.25, p < 0.01; T1 vs. Ecc 0.72 ± 0.32, p < 0.01) and with LGE segmental injury (LGE vs. Err - 0.56 ± 0.29, p < 0.01; LGE vs. Ecc 0.54 ± 0.35, p < 0.01). Moreover, acute segmental T1 and strain predicted segmental LGE transmurality on 6M scans (p < 0.001, r = 0.5). Multiple regression analysis confirmed combined analysis of global Ecc and T1-mapping was significantly better than either method alone in predicting final infarct size at 6M (r = 0.556 vs r = 0.473 for global T1 only and r = 0.476 for global Ecc only, p < 0.001). This novel CMR method combining T1-mapping and feature tracking analysis of acute CMR scans predicts LGE transmurality and infarct size at 6M following STEMI.


Subject(s)
Magnetic Resonance Imaging, Cine , Myocardium/pathology , ST Elevation Myocardial Infarction/diagnostic imaging , Aged , Contrast Media/administration & dosage , Female , Humans , Image Interpretation, Computer-Assisted , Male , Middle Aged , Percutaneous Coronary Intervention , Predictive Value of Tests , Prospective Studies , ST Elevation Myocardial Infarction/pathology , ST Elevation Myocardial Infarction/physiopathology , ST Elevation Myocardial Infarction/surgery , Severity of Illness Index , Time Factors , Treatment Outcome
14.
Echo Res Pract ; 4(1): R1-R13, 2017 Mar 01.
Article in English | MEDLINE | ID: mdl-28096184

ABSTRACT

Despite significant advancements in the field of cardiovascular imaging, transoesophageal echocardiography remains the key imaging modality in the management of valvular pathologies. This paper provides echocardiographers with an overview of the modern role of TOE in the diagnosis and management of valvular disease. We describe how the introduction of 3D techniques has changed the detection and grading of valvular pathologies and concentrate on its role as a monitoring tool in interventional cardiology. In addition, we focus on the echocardiographic and Doppler techniques used in the assessment of prosthetic valves and provide guidance for the evaluation of prosthetic valves. Finally, we summarise quantitative methods used for the assessment of valvular stenosis and regurgitation and highlight the key areas where echocardiography remains superior over other novel imaging modalities.

16.
Arterioscler Thromb Vasc Biol ; 32(3): 669-76, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22267479

ABSTRACT

OBJECTIVE: Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. METHODS AND RESULTS: In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-α (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (P<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-α (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (P<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKKß by 42±2% (P<0.001) IKB-α by 54±14% (P<0.01). Accumulation of nuclear p65 NF-κB in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4; P<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%; P<0.001). CONCLUSION: NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Inflammation/metabolism , Monocytes/drug effects , Niacin/pharmacology , Receptors, G-Protein-Coupled/drug effects , Receptors, Nicotinic/drug effects , Cell Adhesion/drug effects , Cells, Cultured , Chemokine CCL2/metabolism , Chemotaxis, Leukocyte/drug effects , Cyclooxygenase 2 Inhibitors/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/immunology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , I-kappa B Kinase/metabolism , Inflammation/genetics , Inflammation/immunology , Inflammation Mediators/metabolism , Integrin alpha4beta1/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Monocytes/immunology , Monocytes/metabolism , Phosphorylation , Pyrazines/pharmacology , RNA Interference , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/metabolism , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/agonists , Toll-Like Receptor 4/metabolism , Transcription Factor RelA/metabolism , Transfection , Tumor Necrosis Factor-alpha/metabolism , Vascular Cell Adhesion Molecule-1/metabolism
17.
Diabetes ; 60(4): 1158-67, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21350084

ABSTRACT

OBJECTIVE: The study objective was to determine the key early mechanisms underlying the beneficial redistribution, function, and inflammatory profile of adipose tissue in 11ß-hydroxysteroid dehydrogenase type 1 knockout (11ß-HSD1(-/-)) mice fed a high-fat (HF) diet. RESEARCH DESIGN AND METHODS: By focusing on the earliest divergence in visceral adiposity, subcutaneous and visceral fat depots from 11ß-HSD1(-/-) and C57Bl/6J control mice fed an HF diet for 4 weeks were used for comparative microarray analysis of gene expression, and differences were validated with real-time PCR. Key changes in metabolic signaling pathways were confirmed using Western blotting/immunoprecipitation, and fat cell size was compared with the respective chow-fed control groups. Altered adipose inflammatory cell content and function after 4 weeks (early) and 18 weeks (chronic) of HF feeding was investigated using fluorescence (and magnetic)-activated cell sorting analysis, immunohistochemistry, and in situ hybridization. RESULTS: In subcutaneous fat, HF-fed 11ß-HSD1(-/-) mice showed evidence of enhanced insulin and ß-adrenergic signaling associated with accretion of smaller metabolically active adipocytes. In contrast, reduced 11ß-HSD1(-/-) visceral fat accumulation was characterized by maintained AMP kinase activation, not insulin sensitization, and higher adipocyte interleukin-6 release. Intracellular glucocorticoid deficiency was unexpectedly associated with suppressed inflammatory signaling and lower adipocyte monocyte chemoattractant protein-1 secretion with strikingly reduced cytotoxic T-cell and macrophage infiltration, predominantly in visceral fat. CONCLUSIONS: Our data define for the first time the novel and distinct depot-specific mechanisms driving healthier fat patterning and function as a result of reduced intra-adipose glucocorticoid levels.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Inflammation/metabolism , Obesity, Abdominal/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 3T3-L1 Cells , AMP-Activated Protein Kinases/metabolism , Adipocytes/drug effects , Adipocytes/metabolism , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Blotting, Western , Dietary Fats/adverse effects , Enzyme Activation/drug effects , Flow Cytometry , Glucocorticoids/pharmacology , Immunohistochemistry , In Situ Hybridization , Inflammation/genetics , Interleukin-6/pharmacology , Intra-Abdominal Fat/metabolism , Male , Mice , Mice, Mutant Strains , Obesity, Abdominal/chemically induced , Obesity, Abdominal/genetics , Reverse Transcriptase Polymerase Chain Reaction
18.
Endocrinology ; 149(12): 5909-18, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18755798

ABSTRACT

Obesity is associated with an increased risk of diabetes type 2, dyslipidemia, and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by excessive dietary fat, particularly cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11beta-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7beta-HC). Here, we report that 11beta-HSD1 catalyzes the reduction of 7KC to 7beta-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7beta-HC. Approximately 73% of added 7KC was reduced to 7beta-HC within 24 h; this conversion was prevented by selective inhibition of 11beta-HSD1. Oxysterol and glucocorticoid conversion by 11beta-HSD1 was competitive and occurred with a physiologically relevant IC(50) range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11beta-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7beta-HC did not activate liver X receptor in a transactivation assay, nor did they display intrinsic activation of the glucocorticoid receptor. However, when coincubated with glucocorticoid (10 nm), 7KC repressed, and 7beta-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11beta-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11beta-HSD1. Thus, the activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adipocytes/metabolism , Glucocorticoids/metabolism , Hydroxycholesterols/metabolism , Ketocholesterols/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 3T3-L1 Cells , Adipocytes/cytology , Animals , Cell Line , DNA-Binding Proteins/metabolism , Humans , Liver X Receptors , Mice , Models, Biological , Obesity/metabolism , Orphan Nuclear Receptors , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Glucocorticoid/metabolism , Reverse Transcriptase Polymerase Chain Reaction
19.
Drug Discov Today ; 12(13-14): 504-20, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17631244

ABSTRACT

Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders and memory impairments. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose and brain, amplifying local action. Obese humans and rodents show increased 11beta-HSD1 in adipose tissue. Transgenic mice overexpressing 11beta-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome. Conversely, 11beta-HSD1 knockout mice have a 'cardioprotective' phenotype, whose effects are also seen with 11beta-HSD1 inhibitors in rodents. However, any major metabolic effects of 11beta-HSD1 inhibition in humans are, as yet, unreported. 11beta-HSD1 null mice also resist cognitive decline with ageing, and this is seen in humans with a prototypic inhibitor. Thus 11beta-HSD1 inhibition is an emerging pleiotropic therapeutic target.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adipose Tissue/enzymology , Animals , Drug Delivery Systems , Glucocorticoids/metabolism , Humans , Inflammation/enzymology , Metabolic Syndrome/drug therapy , Metabolic Syndrome/enzymology , Obesity/drug therapy , Obesity/enzymology
20.
Diabetes ; 54(12): 3371-8, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16306351

ABSTRACT

Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). Indeed, 11beta-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11beta-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11beta-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11beta-HSD-1.


Subject(s)
Blood Glucose/metabolism , Glucocorticoids/blood , Metabolic Syndrome/genetics , Adipose Tissue/anatomy & histology , Adipose Tissue/pathology , Animals , Corticosterone/blood , Crosses, Genetic , Cushing Syndrome/blood , Epididymis , Insulin/blood , Leptin/blood , Liver/metabolism , Male , Mice , Mice, Obese , Models, Genetic , Obesity/genetics , Obesity/pathology , RNA/genetics , RNA/isolation & purification , Skin , Triglycerides/metabolism
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