Publications by authors named "David E Newby"

538 Publications

Response by Bing et al to Letter Regarding Article, "Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial".

Circulation 2021 Nov 29;144(22):e335. Epub 2021 Nov 29.

BHF Centre for Cardiovascular Science (R.B., D.E.N., M.R.D.), University of Edinburgh, UK.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.057127DOI Listing
November 2021

Prognostic value of fractional flow reserve from computed tomography.

Heart 2021 Nov 15. Epub 2021 Nov 15.

Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1136/heartjnl-2021-320375DOI Listing
November 2021

Response to: Correspondence on "Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure" by Yalta .

Heart 2021 12 16;107(23):1922-1923. Epub 2021 Oct 16.

Centre for Cardiovascular Science, University of Edinburgh Division of Clinical and Surgical Sciences, Edinburgh, UK.

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http://dx.doi.org/10.1136/heartjnl-2021-320174DOI Listing
December 2021

A novel cardiovascular magnetic resonance risk score for predicting mortality following surgical aortic valve replacement.

Sci Rep 2021 Oct 12;11(1):20183. Epub 2021 Oct 12.

CMR Unit, Department of CMR, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College, Sydney Street, London, SW3 6NP, UK.

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care.Trial Registration ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936.
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http://dx.doi.org/10.1038/s41598-021-99788-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511276PMC
October 2021

Major adverse cardiac events in symptomatic women with non-obstructive CAD on coronary CTA: pooled analysis from PROMISE and SCOT-HEART.

Int J Cardiovasc Imaging 2021 Oct 10. Epub 2021 Oct 10.

Division of Cardiology, Department of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham St, Little Rock, AR, 72205, USA.

The presence of non-obstructive coronary artery disease (CAD) on coronary computed tomography angiography (CTA) has been associated with the occurrence of major adverse cardiac events (MACE). However, factors associated with the development of MACE in symptomatic women with non-obstructive CAD on coronary CTA have not been fully elucidated. We sought to examine the influence of risk factors and coronary artery calcification on MACE in symptomatic women with non-obstructive CAD on coronary CTA. Women from PROMISE and SCOT-HEART trials with none or non-obstructive CAD on coronary CTA comprised the study cohort. Baseline characteristics and clinical presentation were assessed. Survival analysis using Kaplan-Meier curves was done to compare outcomes stratified by the atherosclerotic cardiovascular disease (ASCVD) risk score and the Agatston score. The primary endpoint was a composite of all-cause mortality, myocardial infarction, and revascularization. 2597 women had non-obstructive CAD or normal coronary CTA, with a median follow-up of 32 months. Compared to women without MACE, women with MACE had lower high-density lipoprotein cholesterol (HDL-C) levels and higher mean ASCVD risk scores. Further, women with non-obstructive CAD and ASCVD ≥ 7.5% had higher risk of MACE than those with ASCVD < 7.5% [3.2% vs. 1.1%, adjusted HR (aHR) of 3.1 (95% CI 1.32, 7.23), P-value 0.009]. The Agatston calcium score, on the other hand, was not independently associated with MACE among this population of symptomatic women. Symptomatic women with non-obstructive CAD on coronary CTA are at higher risk for MACE, with the ASCVD risk score being independently associated with the occurrence of adverse events.
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http://dx.doi.org/10.1007/s10554-021-02429-3DOI Listing
October 2021

MRI and CT coronary angiography in survivors of COVID-19.

Heart 2021 Oct 6. Epub 2021 Oct 6.

Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.

Objectives: To determine the contribution of comorbidities on the reported widespread myocardial abnormalities in patients with recent COVID-19.

Methods: In a prospective two-centre observational study, patients hospitalised with confirmed COVID-19 underwent gadolinium and manganese-enhanced MRI and CT coronary angiography (CTCA). They were compared with healthy and comorbidity-matched volunteers after blinded analysis.

Results: In 52 patients (median age: 54 (IQR 51-57) years, 39 males) who recovered from COVID-19, one-third (n=15, 29%) were admitted to intensive care and a fifth (n=11, 21%) were ventilated. Twenty-three patients underwent CTCA, with one-third having underlying coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), patients demonstrated reduced left (ejection fraction (EF): 57.4±11.1 (95% CI 54.0 to 60.1) versus 66.3±5 (95 CI 62.4 to 69.8)%; p=0.02) and right (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 60.5±4.9 (95% CI 57.1 to 63.2)%; p≤0.0001) ventricular systolic function with elevated native T1 values (1225±46 (95% CI 1205 to 1240) vs 1197±30 (95% CI 1178 to 1216) ms;p=0.04) and extracellular volume fraction (ECV) (31±4 (95% CI 29.6 to 32.1) vs 24±3 (95% CI 22.4 to 26.4)%; p<0.0003) but reduced myocardial manganese uptake (6.9±0.9 (95% CI 6.5 to 7.3) vs 7.9±1.2 (95% CI 7.4 to 8.5) mL/100 g/min; p=0.01). Compared with comorbidity-matched volunteers (n=26), patients had preserved left ventricular function but reduced right ventricular systolic function (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 59.3±4.9 (95% CI 51.0 to 66.5)%; p=0.0005) with comparable native T1 values (1225±46 (95% CI 1205 to 1240) vs 1227±51 (95% CI 1208 to 1246) ms; p=0.99), ECV (31±4 (95% CI 29.6 to 32.1) vs 29±5 (95% CI 27.0 to 31.2)%; p=0.35), presence of late gadolinium enhancement and manganese uptake. These findings remained irrespective of COVID-19 disease severity, presence of myocardial injury or ongoing symptoms.

Conclusions: Patients demonstrate right but not left ventricular dysfunction. Previous reports of left ventricular myocardial abnormalities following COVID-19 may reflect pre-existing comorbidities.

Trial Registration Number: NCT04625075.
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http://dx.doi.org/10.1136/heartjnl-2021-319926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503921PMC
October 2021

Troponin-Guided Coronary Computed Tomographic Angiography After Exclusion of Myocardial Infarction.

J Am Coll Cardiol 2021 Oct;78(14):1407-1417

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom. Electronic address:

Background: Patients with suspected acute coronary syndrome in whom myocardial infarction has been excluded are at risk of future adverse cardiac events.

Objectives: This study evaluated the usefulness of high-sensitivity cardiac troponin I (hs-cTnI) to select patients for further investigation after myocardial infarction has been excluded.

Methods: This is a prospective cohort study of patients presenting to the emergency department with suspected acute coronary syndrome and hs-cTnI concentrations below the sex-specific 99th percentile. Patients were recruited in a 2:1 fashion, stratified by peak hs-cTnI concentration above and below the risk stratification threshold of 5 ng/L. All patients underwent coronary computed tomography angiography (CCTA) after hospital discharge.

Results: Overall, 250 patients were recruited (61.4 ± 12.2 years 31% women) in whom 62.4% (156 of 250 patients) had coronary artery disease (CAD). Patients with intermediate hs-cTnI concentrations (between 5 ng/L and the sex-specific 99th percentile) were more likely to have CAD than those with hs-cTnI concentrations <5 ng/L (71.9% [120 of 167 patients] vs 43.4% [36 of 83 patients]; odds ratio: 3.33; 95% CI: 1.92-5.78). Conversely, there was no association between anginal symptoms and CAD (63.2% [67 of 106 patients] vs 61.8% [89 of 144 patients]; odds ratio: 0.92; 95% CI: 0.48-1.76). Most patients with CAD did not have a previous diagnosis (53.2%; 83 of 156 patients) and were not on antiplatelet and statin therapies (63.5%; 99 of 156 patients) before they underwent CCTA.

Conclusions: In patients who had myocardial infarction excluded, CAD was 3× more likely in those with intermediate hs-cTnI concentrations compared with low hs-cTnI concentrations. In such patients, CCTA could help to identify those with occult CAD and to target preventative treatments, thereby improving clinical outcomes.
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http://dx.doi.org/10.1016/j.jacc.2021.07.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482793PMC
October 2021

Early computed tomography coronary angiography in patients with suspected acute coronary syndrome: randomised controlled trial.

BMJ 2021 09 29;374:n2106. Epub 2021 Sep 29.

University of Edinburgh, Edinburgh, UK.

Objectives: To establish if the use of early computed tomography (CT) coronary angiography improves one year clinical outcomes in patients presenting to the emergency department with acute chest pain and at intermediate risk of acute coronary syndrome and subsequent clinical events.

Design: Randomised controlled trial.

Setting: 37 hospitals in the UK.

Participants: Adults with suspected or a provisional diagnosis of acute coronary syndrome and one or more of previous coronary heart disease, raised levels of cardiac troponin, or abnormal electrocardiogram.

Interventions: Early CT coronary angiography and standard of care compared with standard of care only.

Main Outcome Measures: Primary endpoint was all cause death or subsequent type 1 or 4b myocardial infarction at one year.

Results: Between 23 March 2015 and 27 June 2019, 1748 participants (mean age 62 years (standard deviation 13), 64% men, mean global registry of acute coronary events (GRACE) score 115 (standard deviation 35)) were randomised to receive early CT coronary angiography (n=877) or standard of care only (n=871). Median time from randomisation to CT coronary angiography was 4.2 (interquartile range 1.6-21.6) hours. The primary endpoint occurred in 51 (5.8%) participants randomised to CT coronary angiography and 53 (6.1%) participants who received standard of care only (adjusted hazard ratio 0.91 (95% confidence interval 0.62 to 1.35), P=0.65). Invasive coronary angiography was performed in 474 (54.0%) participants randomised to CT coronary angiography and 530 (60.8%) participants who received standard of care only (adjusted hazard ratio 0.81 (0.72 to 0.92), P=0.001). There were no overall differences in coronary revascularisation, use of drug treatment for acute coronary syndrome, or subsequent preventive treatments between the two groups. Early CT coronary angiography was associated with a slightly longer time in hospital (median increase 0.21 (95% confidence interval 0.05 to 0.40) days from a median hospital stay of 2.0 to 2.2 days).

Conclusions: In intermediate risk patients with acute chest pain and suspected acute coronary syndrome, early CT coronary angiography did not alter overall coronary therapeutic interventions or one year clinical outcomes, but reduced rates of invasive angiography while modestly increasing length of hospital stay. These findings do not support the routine use of early CT coronary angiography in intermediate risk patients with acute chest pain and suspected acute coronary syndrome.

Trial Registration: ISRCTN19102565, NCT02284191.
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http://dx.doi.org/10.1136/bmj.n2106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479591PMC
September 2021

Forget Ischemia: It's All About the Plaque.

Circulation 2021 Sep 27;144(13):1039-1041. Epub 2021 Sep 27.

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, United Kingdom.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054102DOI Listing
September 2021

Transcatheter Valve Replacement for Bicuspid Aortic Stenosis.

JAMA 2021 09;326(11):1009-1010

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

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http://dx.doi.org/10.1001/jama.2021.13229DOI Listing
September 2021

Association of coronary artery calcium score with qualitatively and quantitatively assessed adverse plaque on coronary CT angiography in the SCOT-HEART trial.

Eur Heart J Cardiovasc Imaging 2021 Sep 16. Epub 2021 Sep 16.

BHF Centre for Cardiovascular Science, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH164SB, UK.

Aims: Coronary artery calcification is a marker of cardiovascular risk, but its association with qualitatively and quantitatively assessed plaque subtypes is unknown.

Methods And Results: In this post-hoc analysis, computed tomography (CT) images and 5-year clinical outcomes were assessed in SCOT-HEART trial participants. Agatston coronary artery calcium score (CACS) was measured on non-contrast CT and was stratified as zero (0 Agatston units, AU), minimal (1-9 AU), low (10-99 AU), moderate (100-399 AU), high (400-999 AU), and very high (≥1000 AU). Adverse plaques were investigated by qualitative (visual categorization of positive remodelling, low-attenuation plaque, spotty calcification, and napkin ring sign) and quantitative (calcified, non-calcified, low-attenuation, and total plaque burden; Autoplaque) assessments. Of 1769 patients, 36% had a zero, 9% minimal, 20% low, 17% moderate, 10% high, and 8% very high CACS. Amongst patients with a zero CACS, 14% had non-obstructive disease, 2% had obstructive disease, 2% had visually assessed adverse plaques, and 13% had low-attenuation plaque burden >4%. Non-calcified and low-attenuation plaque burden increased between patients with zero, minimal, and low CACS (P < 0.001), but there was no statistically significant difference between those with medium, high, and very high CACS. Myocardial infarction occurred in 41 patients, 10% of whom had zero CACS. CACS >1000 AU and low-attenuation plaque burden were the only predictors of myocardial infarction, independent of obstructive disease, and 10-year cardiovascular risk score.

Conclusion: In patients with stable chest pain, zero CACS is associated with a good but not perfect prognosis, and CACS cannot rule out obstructive coronary artery disease, non-obstructive plaque, or adverse plaque phenotypes, including low-attenuation plaque.
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http://dx.doi.org/10.1093/ehjci/jeab135DOI Listing
September 2021

Native Aortic Valve Disease Progression and Bioprosthetic Valve Degeneration in Patients With Transcatheter Aortic Valve Implantation.

Circulation 2021 Oct 29;144(17):1396-1408. Epub 2021 Aug 29.

Centre for Cardiovascular Science (E.T., T.R.G.C., A.F., M.K.D., R.B., N.L.C., A.K.B., N.G.U., M.C.W., E.J.R.v.B., D.E.N., M.R.D.), University of Edinburgh, UK.

Background: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR).

Methods: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and F-sodium fluoride (F-NaF) positron emission tomography. Participants (n=47) were imaged once with F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol.

Results: In patients with TAVI, native aortic valves demonstrated F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (=0.36, =0.023). F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; =0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; =0.78), computed tomography (15% versus 14%, respectively; =0.87), and positron emission tomography (15% versus 29%, respectively; =0.09). Baseline F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (=0.7, <0.001) and SAVR (=0.7, <0.001). On multivariable analysis, F-NaF uptake was the only predictor of peak velocity progression (<0.001).

Conclusions: In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542078PMC
October 2021

Clinical burden, risk factor impact and outcomes following myocardial infarction and stroke: A 25-year individual patient level linkage study.

Lancet Reg Health Eur 2021 Aug;7:100141

Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom.

Background: Understanding trends in the incidence and outcomes of myocardial infarction and stroke, and how these are influenced by changes in cardiovascular risk factors can inform health policy and healthcare provision.

Methods: We identified all patients 30 years or older with myocardial infarction or stroke in Scotland. Risk factor levels were determined from national health surveys. Incidence, potential impact fractions and burden attributable to risk factor changes were calculated. Risk of subsequent fatal and non-fatal events (myocardial infarction, stroke, bleeding and heart failure hospitalization) were calculated with multi-state models.

Findings: From 1990 to 2014, there were 372,873 (71±13 years) myocardial infarctions and 290,927 (74±13 years) ischemic or hemorrhagic strokes. Age-standardized incidence per 100,000 fell from 1,069 (95% confidence interval, 1,024-1,116) to 276 (263-290) for myocardial infarction and from 608 (581-636) to 188 (178-197) for ischemic stroke. Systolic blood pressure, smoking and cholesterol decreased, but body-mass index increased, and diabetes prevalence doubled. Changes in risk factors accounted for a 74% (57-91%) reduction in myocardial infarction and 68% (55-83%) reduction in ischemic stroke. Following myocardial infarction, the risk of death decreased (30% to 20%), but non-fatal events increased (20% to 24%) whereas the risk of both death (47% to 34%) and non-fatal events (22% to 17%) decreased following stroke.

Interpretation: Over the last 25 years, substantial reductions in myocardial infarction and ischemic stroke incidence are attributable to major shifts in risk factor levels. Deaths following the index event decreased for both myocardial infarction and stroke, but rates remained substantially higher for stroke.

Funding: British heart foundation.
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http://dx.doi.org/10.1016/j.lanepe.2021.100141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351196PMC
August 2021

The therapeutic potential of apelin in kidney disease.

Nat Rev Nephrol 2021 12 13;17(12):840-853. Epub 2021 Aug 13.

BHF/University Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh, UK.

Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. The mainstay of treatment for CKD is blockade of the renin-angiotensin-aldosterone system (RAAS), which reduces blood pressure and proteinuria and slows kidney function decline. Despite this treatment, many patients progress to kidney failure, which requires dialysis or kidney transplantation, and/or die as a result of cardiovascular disease. The apelin system is an endogenous physiological regulator that is emerging as a potential therapeutic target for many diseases. This system comprises the apelin receptor and its two families of endogenous ligands, apelin and elabela/toddler. Preclinical and clinical studies show that apelin receptor ligands are endothelium-dependent vasodilators and potent inotropes, and the apelin system has a reciprocal relationship with the RAAS. In preclinical studies, apelin regulates glomerular haemodynamics and acts on the tubule to promote aquaresis. In addition, apelin is protective in several kidney injury models. Although the apelin system has not yet been studied in patients with CKD, the available data suggest that apelin is a promising potential therapeutic target for kidney disease.
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http://dx.doi.org/10.1038/s41581-021-00461-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361827PMC
December 2021

Categorising myocardial infarction with advanced cardiovascular imaging.

Lancet 2021 Aug;398(10299):e9

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)01329-5DOI Listing
August 2021

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

J Am Coll Cardiol 2021 Aug;78(6):545-558

Department of Radiology and Nuclear Medicine, German Heart Center Munich, Munich, Germany.

Background: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined.

Objectives: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality.

Methods: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome.

Results: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m) and small (LVEDVi ≤55 mL/m) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort.

Conclusions: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.
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http://dx.doi.org/10.1016/j.jacc.2021.05.047DOI Listing
August 2021

Duration of dual antiplatelet therapy and stability of coronary heart disease: a 60 000-patient meta-analysis of randomised controlled trials.

Open Heart 2021 07;8(2)

BHF Centre for Cardiovascular Science, University of Edinburgh Division of Clinical and Surgical Sciences, Edinburgh, UK.

Background: Dual antiplatelet therapy (DAPT) has important implications for clinical outcomes in coronary disease. However, the optimal DAPT duration remains uncertain.

Methods And Results: We searched four major databases for randomised controlled trials comparing long-term (≥12 months) with short-term (≤6 months) or shorter (≤3 months) DAPT in patients with coronary syndromes. The primary outcome was all-cause mortality. Secondary outcomes were any bleeding and major bleeding (safety), cardiac death, myocardial infarction, stent thrombosis, revascularisation and stroke (efficacy). Nineteen randomised controlled trials (n=60 111) satisfied inclusion criteria, 8 assessed ≤3 months DAPT. Compared with long-term (≥12 months), short-term DAPT (≤6 months) was associated with a trend towards reduced all-cause mortality (RR: 0.90, 95% CI: 0.80 to 1.01) and significant bleeding reduction (RR: 0.68, 95% CI: 0.55 to 0.83 and RR: 0.66, 95% CI: 0.56 to 0.77 for major and any bleeding, respectively). There were no significant differences in efficacy outcomes. These associations persisted in sensitivity analysis comparing shorter duration DAPT (≤3 months) to long-term DAPT (≥12 months) for all-cause mortality (RR: 0.91, 95% CI: 0.79 to 1.05). In subgroup analysis, short-term DAPT was associated with lower risk of bleeding in patients with acute or chronic coronary syndromes (RR: 0.66, 95% CI: 0.54 to 0.81 and RR: 0.53, 95% CI: 0.33 to 0.65, respectively), but higher risk of stent thrombosis in acute coronary syndrome (RR: 1.49, 95% CI: 1.02 to 2.17 vs RR: 1.25, 95% CI 0.44 to 3.58).

Conclusion: Our meta-analysis suggests that short (≤6 months) and shorter (≤3 months) durations DAPT are associated with lower risk of bleeding, equivalent efficacy and a trend towards lower all-cause mortality irrespective of coronary artery disease stability.
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http://dx.doi.org/10.1136/openhrt-2021-001707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330558PMC
July 2021

Modelling [F]LW223 PET data using simplified imaging protocols for quantification of TSPO expression in the rat heart and brain.

Eur J Nucl Med Mol Imaging 2021 Aug 2. Epub 2021 Aug 2.

University/ BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Purpose: To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [F]LW223, kinetics in the heart and brain when using a simplified imaging approach.

Methods: Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (V) and binding potential transfer corrected (BP) using arterial or image-derived input function (IDIF). Quantitative bias of simplified protocols using IDIF versus arterial input function (AIF) and stability of kinetic parameters for PET imaging data of different length (40-120 min) were estimated.

Results: PET outcome measures estimated using IDIF significantly correlated with those derived with invasive AIF, albeit with an inherent systematic bias. Truncation of the dynamic PET scan duration to less than 100 min reduced the stability of the kinetic modelling outputs. Quantification of [F]LW223 uptake kinetics in the brain and heart required the use of different outcome measures, with BP more stable in the heart and V more stable in the brain.

Conclusion: Modelling of [F]LW223 PET showed the use of simplified IDIF is acceptable in the rat and the minimum scan duration for quantification of TSPO expression in rats using kinetic modelling with this radiotracer is 100 min. Carefully assessing kinetic outcome measures when conducting a systems level as oppose to single-organ centric analyses is crucial. This should be taken into account when assessing the emerging role of the TSPO heart-brain axis in the field of PET imaging.
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http://dx.doi.org/10.1007/s00259-021-05482-1DOI Listing
August 2021

Challenging the obesity paradox: extreme obesity and COPD mortality in the SUMMIT trial.

ERJ Open Res 2021 Jul 26;7(3). Epub 2021 Jul 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medicine, Baltimore, MD, USA.

Populations with COPD demonstrate higher survival in overweight and obese compared with normal weight; the "obesity paradox". Relationships in less-severe COPD are unclear, as is the impact of cardiovascular risk, and few studies include individuals at extremes of obesity.  We examined the relationship between body mass index (BMI; defined as underweight: <20 kg·m, normal: 20-25 kg·m, overweight: 25- <30 kg·m, obese class I: 30- <35 kg·m, class II: 35- <40 kg·m and class III: ≥40 kg·m), morbidity, and mortality in the SUMMIT trial population (n=16 485), characterised by moderate COPD and heightened cardiovascular risk with a substantial proportion with class III obesity. The association between BMI category and time to event was modelled proportional hazards (reference normal weight) adjusted for demographics and cardiorespiratory disease.  Consistent with the paradox, underweight individuals demonstrated higher mortality (hazard ratio (HR) 1.31 (95% CI 1.04-1.64)), with lower mortality among overweight (HR 0.62 (95% CI 0.52-0.73)) and obese class I (HR 0.75 (95% CI 0.62-0.90)). However, mortality increased in obese class III (HR 1.36 (95% CI 1.00-1.86)). Death was primarily attributable to cardiovascular causes.  Within a large, multinational cohort with moderate COPD and increased cardiovascular risk, the phenomenon of reduced mortality with obesity did not persist at BMI >40 kg·m, suggesting that obesity may not remain protective at the extremes in this population.
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http://dx.doi.org/10.1183/23120541.00902-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311131PMC
July 2021

Effect of hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with and without type 1 diabetes: A prospective, randomised, open-label, blinded endpoint, cross-over study.

Endocrinol Diabetes Metab 2021 Jul 7;4(3):e00258. Epub 2021 May 7.

Department of Diabetes Royal Infirmary of Edinburgh Edinburgh UK.

Aims: This study examined the effect of experimentally-induced hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with, and without, type 1 diabetes.

Methods: In a prospective, randomised, open-label, blinded, endpoint cross-over study, 17 young adults with type 1 diabetes with no cardiovascular risk factors, and 10 healthy non-diabetic volunteers, underwent hyperinsulinaemic-euglycaemic (blood glucose 4.5-5.5 mmol/L) and hypoglycaemic (2.2-2.5 mmol/L) clamps. Myocardial blood flow was assessed using transthoracic echocardiography Doppler coronary flow reserve (CFR) and myocardial injury using plasma high-sensitivity cardiac troponin I (hs-cTnI) concentration.

Results: During hypoglycaemia, coronary flow reserve trended non-significantly lower in those with type 1 diabetes than in the non-diabetic participants (3.54 ± 0.47 vs. 3.89 ± 0.89). A generalised linear mixed-model analysis examined diabetes status and euglycaemia or hypoglycaemia as factors affecting CFR. No statistically significant difference in CFR was observed for diabetes status ( = .23) or between euglycaemia and hypoglycaemia ( = .31). No changes in hs-cTnI occurred during hypoglycaemia or in the recovery period ( = .86).

Conclusions: A small change in CFR was not statistically significant in this study, implying hypoglycaemia may require more than coronary vasomotor dysfunction to cause harm. Further larger studies are required to investigate this putative problem.
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http://dx.doi.org/10.1002/edm2.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279606PMC
July 2021

Latin American guideline shows the way.

Heart 2021 09 5;107(18):1442-1443. Epub 2021 Jul 5.

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1136/heartjnl-2021-319724DOI Listing
September 2021

Acute cardiovascular effects of controlled exposure to dilute Petrodiesel and biodiesel exhaust in healthy volunteers: a crossover study.

Part Fibre Toxicol 2021 06 14;18(1):22. Epub 2021 Jun 14.

Department of Public Health and Clinical Medicine, Section of Medicine, Umeå University, Umeå, Sweden.

Background: Air pollution derived from combustion is associated with considerable cardiorespiratory morbidity and mortality in addition to environmental effects. Replacing petrodiesel with biodiesel may have ecological benefits, but impacts on human health remain unquantified. The objective was to compare acute cardiovascular effects of blended and pure biodiesel exhaust exposure against known adverse effects of petrodiesel exhaust (PDE) exposure in human subjects. In two randomized controlled double-blind crossover studies, healthy volunteers were exposed to PDE or biodiesel exhaust for one hour. In study one, 16 subjects were exposed, on separate occasions, to PDE and 30% rapeseed methyl ester biodiesel blend (RME30) exhaust, aiming at PM 300 μg/m. In study two, 19 male subjects were separately exposed to PDE and exhaust from a 100% RME fuel (RME100) using similar engine load and exhaust dilution. Generated exhaust was analyzed for physicochemical composition and oxidative potential. Following exposure, vascular endothelial function was assessed using forearm venous occlusion plethysmography and ex vivo thrombus formation was assessed using a Badimon chamber model of acute arterial injury. Biomarkers of inflammation, platelet activation and fibrinolysis were measured in the blood.

Results: In study 1, PDE and RME30 exposures were at comparable PM levels (314 ± 27 μg/m; (PM ± SD) and 309 ± 30 μg/m respectively), whereas in study 2, the PDE exposure concentrations remained similar (310 ± 34 μg/m), but RME100 levels were lower in PM (165 ± 16 μg/m) and PAHs, but higher in particle number concentration. Compared to PDE, PM from RME had less oxidative potential. Forearm infusion of the vasodilators acetylcholine, bradykinin, sodium nitroprusside and verapamil resulted in dose-dependent increases in blood flow after all exposures. Vasodilatation and ex vivo thrombus formation were similar following exposure to exhaust from petrodiesel and the two biodiesel formulations (RME30 and RME100). There were no significant differences in blood biomarkers or exhaled nitric oxide levels between exposures.

Conclusions: Despite differences in PM composition and particle reactivity, controlled exposure to biodiesel exhaust was associated with similar cardiovascular effects to PDE. We suggest that the potential adverse health effects of biodiesel fuel emissions should be taken into account when evaluating future fuel policies.

Trial Registration: ClinicalTrials.gov, NCT01337882 /NCT01883466. Date of first enrollment March 11, 2011, registered April 19, 2011, i.e. retrospectively registered.
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http://dx.doi.org/10.1186/s12989-021-00412-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204543PMC
June 2021

First-phase ejection fraction by cardiovascular magnetic resonance predicts outcomes in aortic stenosis.

J Cardiovasc Magn Reson 2021 06 10;23(1):73. Epub 2021 Jun 10.

British Heart Foundation Centre of Research Excellence, King's College London, London, UK.

Background: First-phase ejection fraction (EF1; the ejection fraction measured during active systole up to the time of maximal aortic flow) measured by transthoracic echocardiography (TTE) is a powerful predictor of outcomes in patients with aortic stenosis. We aimed to assess whether cardiovascular magnetic resonance (CMR) might provide more precise measurements of EF1 than TTE and to examine the correlation of CMR EF1 with measures of fibrosis.

Methods: In 141 patients with at least mild aortic stenosis, we measured CMR EF1 from a short-axis 3D stack and compared its variability with TTE EF1, and its associations with myocardial fibrosis and clinical outcome (aortic valve replacement (AVR) or death).

Results: Intra- and inter-observer variation of CMR EF1 (standard deviations of differences within and between observers of 2.3% and 2.5% units respectively) was approximately 50% that of TTE EF1. CMR EF1 was strongly predictive of AVR or death. On multivariable Cox proportional hazards analysis, the hazard ratio for CMR EF1 was 0.93 (95% confidence interval 0.89-0.97, p = 0.001) per % change in EF1 and, apart from aortic valve gradient, CMR EF1 was the only imaging or biochemical measure independently predictive of outcome. Indexed extracellular volume was associated with AVR or death, but not after adjusting for EF1.

Conclusions: EF1 is a simple robust marker of early left ventricular impairment that can be precisely measured by CMR and predicts outcome in aortic stenosis. Its measurement by CMR is more reproducible than that by TTE and may facilitate left ventricular structure-function analysis.
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http://dx.doi.org/10.1186/s12968-021-00756-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191208PMC
June 2021

Assessment of stunned and viable myocardium using manganese-enhanced MRI.

Open Heart 2021 06;8(1)

Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.

Objective: In a proof-of-concept study, to quantify myocardial viability in patients with acute myocardial infarction using manganese-enhanced MRI (MEMRI), a measure of intracellular calcium handling.

Methods: Healthy volunteers (n=20) and patients with ST-elevation myocardial infarction (n=20) underwent late gadolinium enhancement (LGE) using gadobutrol and MEMRI using manganese dipyridoxyl diphosphate. Patients were scanned ≤7 days after reperfusion and rescanned after 3 months. Differential manganese uptake was described using a two-compartment model.

Results: After manganese administration, healthy control and remote non-infarcted myocardium showed a sustained 25% reduction in T1 values (mean reductions, 288±34 and 281±12 ms). Infarcted myocardium demonstrated less T1 shortening than healthy control or remote myocardium (1157±74 vs 859±36 and 835±28 ms; both p<0.0001) with intermediate T1 values (1007±31 ms) in peri-infarct regions. Compared with LGE, MEMRI was more sensitive in detecting dysfunctional myocardium (dysfunctional fraction 40.5±11.9 vs 34.9%±13.9%; p=0.02) and tracked more closely with abnormal wall motion (r=0.72 vs 0.55; p<0.0001). Kinetic modelling showed reduced myocardial manganese influx between remote, peri-infarct and infarct regions, enabling absolute discrimination of infarcted myocardium. After 3 months, manganese uptake increased in peri-infarct regions (16.5±3.5 vs 22.8±3.5 mL/100 g/min, p<0.0001), but not the remote (23.3±2.8 vs 23.0±3.2 mL/100 g/min, p=0.8) or infarcted (11.5±3.7 vs 14.0±1.2 mL/100 g/min, p>0.1) myocardium.

Conclusions: Through visualisation of intracellular calcium handling, MEMRI accurately differentiates infarcted, stunned and viable myocardium, and correlates with myocardial dysfunction better than LGE. MEMRI holds major promise in directly assessing myocardial viability, function and calcium handling across a range of cardiac diseases.

Trial Registration Numbers: NCT03607669; EudraCT number 2016-003782-25.
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http://dx.doi.org/10.1136/openhrt-2021-001646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186753PMC
June 2021

A Machine-Learning Framework to Identify Distinct Phenotypes of Aortic Stenosis Severity.

JACC Cardiovasc Imaging 2021 09 19;14(9):1707-1720. Epub 2021 May 19.

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Objectives: The authors explored the development and validation of machine-learning models for augmenting the echocardiographic grading of aortic stenosis (AS) severity.

Background: In AS, symptoms and adverse events develop secondarily to valvular obstruction and left ventricular decompensation. The current echocardiographic grading of AS severity focuses on the valve and is limited by diagnostic uncertainty.

Methods: Using echocardiography (ECHO) measurements (ECHO cohort, n = 1,052), we performed patient similarity analysis to derive high-severity and low-severity phenogroups of AS. We subsequently developed a supervised machine-learning classifier and validated its performance with independent markers of disease severity obtained using computed tomography (CT) (CT cohort, n = 752) and cardiovascular magnetic resonance (CMR) imaging (CMR cohort, n = 160). The classifier's prognostic value was further validated using clinical outcomes (aortic valve replacement [AVR] and death) observed in the ECHO and CMR cohorts.

Results: In 1,964 patients from the 3 multi-institutional cohorts, 1,346 (68%) subjects had either nonsevere or discordant AS severity. Machine learning identified 1,117 (57%) patients as having high-severity and 847 (43%) as having low-severity AS. High-severity patients in CT and CMR cohorts had higher valve calcium scores and left ventricular mass and fibrosis, respectively than the low-severity group. In the ECHO cohort, progression to AVR and progression to death in patients who did not receive AVR was faster in the high-severity group. Compared with the conventional classification of disease severity, machine-learning-based severity classification improved discrimination (integrated discrimination improvement: 0.07; 95% confidence interval: 0.02 to 0.12) and reclassification (net reclassification improvement: 0.17; 95% confidence interval: 0.11 to 0.23) for the outcome of AVR at 5 years. For both ECHO and CMR cohorts, we observed prognostic value of the machine-learning classifications for subgroups with asymptomatic, nonsevere or discordant AS.

Conclusions: Machine learning can integrate ECHO measurements to augment the classification of disease severity in most patients with AS, with major potential to optimize the timing of AVR.
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http://dx.doi.org/10.1016/j.jcmg.2021.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434951PMC
September 2021

Improved identification of abdominal aortic aneurysm using the Kernelized Expectation Maximization algorithm.

Philos Trans A Math Phys Eng Sci 2021 Jun 10;379(2200):20200201. Epub 2021 May 10.

Biomedical Imaging Science Department, University of Leeds, Leeds, UK.

Abdominal aortic aneurysm (AAA) monitoring and risk of rupture is currently assumed to be correlated with the aneurysm diameter. Aneurysm growth, however, has been demonstrated to be unpredictable. Using PET to measure uptake of [F]-NaF in calcified lesions of the abdominal aorta has been shown to be useful for identifying AAA and to predict its growth. The PET low spatial resolution, however, can affect the accuracy of the diagnosis. Advanced edge-preserving reconstruction algorithms can overcome this issue. The kernel method has been demonstrated to provide noise suppression while retaining emission and edge information. Nevertheless, these findings were obtained using simulations, phantoms and a limited amount of patient data. In this study, the authors aim to investigate the usefulness of the anatomically guided kernelized expectation maximization (KEM) and the hybrid KEM (HKEM) methods and to judge the statistical significance of the related improvements. Sixty-one datasets of patients with AAA and 11 from control patients were reconstructed with ordered subsets expectation maximization (OSEM), HKEM and KEM and the analysis was carried out using the target-to-blood-pool ratio, and a series of statistical tests. The results show that all algorithms have similar diagnostic power, but HKEM and KEM can significantly recover uptake of lesions and improve the accuracy of the diagnosis by up to 22% compared to OSEM. The same improvements are likely to be obtained in clinical applications based on the quantification of small lesions, like for example cancer. This article is part of the theme issue 'Synergistic tomographic image reconstruction: part 1'.
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http://dx.doi.org/10.1098/rsta.2020.0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107650PMC
June 2021

Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.

Circulation 2021 Jun 29;143(25):2418-2427. Epub 2021 Apr 29.

British Heart Foundation Centre for Cardiovascular Science (T.A.P., M.K.D., R.B., A.C.W., M.C.W., P.D.A., J.P.M.A., T.R.G.C., W.S.A.J., M.S., T.F., N.B., D.E.N., M.R.D.), University of Edinburgh, United Kingdom.

Background: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis.

Methods: In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score.

Results: A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; =0.49). Similarly, there were no differences in change in peak aortic jet velocity or F-sodium fluoride aortic valve uptake.

Conclusions: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212878PMC
June 2021

Machine-learning with F-sodium fluoride PET and quantitative plaque analysis on CT angiography for the future risk of myocardial infarction.

J Nucl Med 2021 Apr 23. Epub 2021 Apr 23.

Cedars-Sinai Medical Center, United States.

Coronary F-sodium fluoride (F-NaF) positron emission tomography (PET) and computed tomography (CT) angiography-based quantitative plaque analysis have shown promise in refining risk stratification in patients with coronary artery disease. We combined both of these novel imaging approaches to develop an optimal machine-learning model for the future risk of myocardial infarction in patients with stable coronary disease. Patients with known coronary artery disease underwent coronary F-NaF PET and CT angiography on a hybrid PET/CT scanner. Machine-learning by extreme gradient boosting was trained using clinical data, CT quantitative plaque analysis measures and F-NaF PET, and it was tested using repeated 10-fold hold-out testing. Among 293 study participants (65±9 years; 84% male), 22 subjects experienced a myocardial infarction over the 53 [40-59] months of follow-up. On univariable receiver-operator-curve analysis, only F-NaF coronary uptake emerged as a predictor of myocardial infarction (c-statistic 0.76, 95% confidence interval [CI] 0.68-0.83). When incorporated into machine-learning models, clinical characteristics showed limited predictive performance (c-statistic 0.64, 95% CI 0.53-0.76;) and were outperformed by a quantitative plaque analysis-based machine-learning model (c-statistic 0.72, 95% CI 0.60-0.84). After inclusion of all available data (clinical, quantitative plaque and F-NaF PET), we achieved a substantial improvement ( = 0.008 versus F-NaF PET alone) in the model performance (c-statistic 0.85, 95% CI 0.79-0.91). Both F-NaF uptake and quantitative plaque analysis measures are additive and strong predictors of outcome in patients with established coronary artery disease. Optimal risk stratification can be achieved by combining clinical data with these approaches in a machine-learning model.
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http://dx.doi.org/10.2967/jnumed.121.262283DOI Listing
April 2021

Response by Meah et al to Letter Regarding Article, "Coronary F-Fluoride Uptake and Progression of Coronary Artery Calcification".

Circ Cardiovasc Imaging 2021 Apr 20:CIRCIMAGING121012514. Epub 2021 Apr 20.

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, United Kingdom. (M.N.M., M.K.D., D.E.N., P.A.).

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http://dx.doi.org/10.1161/CIRCIMAGING.121.012514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611719PMC
April 2021
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