Publications by authors named "Nicholas L Mills"

246 Publications

Biomarker-based risk scores in atrial fibrillation.

Eur Heart J Acute Cardiovasc Care 2021 Oct 26. Epub 2021 Oct 26.

Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1093/ehjacc/zuab088DOI Listing
October 2021

Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility.

Hepatology 2021 Oct 15. Epub 2021 Oct 15.

Centre for Medical Informatics, Usher Institute, University of Edinburgh.

Background & Aims: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.

Approach & Results: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases,506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P < 5 * 10 ), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.

Conclusions: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
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http://dx.doi.org/10.1002/hep.32199DOI Listing
October 2021

Cardiac myosin-binding protein C as a biomarker of acute myocardial infarction.

Eur Heart J Acute Cardiovasc Care 2021 Oct 11. Epub 2021 Oct 11.

Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1093/ehjacc/zuab086DOI Listing
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

Infective Endocarditis Hospitalizations and Outcomes in Patients With End-Stage Kidney Disease: A Nationwide Data-Linkage Study.

J Am Heart Assoc 2021 Oct 28;10(19):e022002. Epub 2021 Sep 28.

BHF/University Centre for Cardiovascular ScienceUniversity of Edinburgh United Kingdom.

Background We investigated the clinical features, microbiology, and short- and long-term outcomes of incident infective endocarditis (IE) hospitalizations in patients with end-stage kidney disease (ESKD) requiring dialysis or with a kidney transplant over 25 years in Scotland. Methods and Results In this retrospective, population-based cohort study linking national hospitalization and mortality data, we identified patients with a history of ESKD and hospitalized with IE in Scotland between January 1, 1990 and December 31, 2014. From January 1, 2008, individual IE hospitalizations were additionally linked to national microbiology data. Multivariable logistic regression, adjusting for patient demographics and comorbidities, evaluated the association between ESKD and all-cause death at 1 and 3 years. Of 7638 incident IE hospitalizations between 1990 and 2014, 2.8% (216/7638) occurred in 210 patients with ESKD and 97.2% (7422/7638) occurred in 7303 patients without ESKD. Positive findings from blood cultures were identified in 42% (950/2267) of incident IE hospitalizations from 2008. was isolated in 25.9% (21/81) and 12.8% (280/2186) of patients with and without ESKD, respectively (=0.002). ESKD was associated with an increased odds of death at 1 (44.9% versus 31.4%; adjusted odds ratio [aOR], 2.47, 95% CI, 1.85-3.30;, <0.001) and 3 years (63.9% versus 42.8%; aOR, 3.77; 95% CI, 2.79-5.12; <0.001). Conclusions IE is associated with a poor prognosis in patients with ESKD, especially in the longer term. Compared with patients without ESKD, patients with ESKD were twice as likely to die within 1 year, and 3 times as likely to die within 3 years of IE hospitalization.
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http://dx.doi.org/10.1161/JAHA.121.022002DOI Listing
October 2021

Population Screening With Coronary Computed Tomography Angiography and the Prevention of Coronary Events.

Circulation 2021 09 20;144(12):930-933. Epub 2021 Sep 20.

British Heart Foundation/Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (K.K.L., R.W., M.C.W., N.L.M.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055784DOI Listing
September 2021

Genome-Wide Association Study of NAFLD Using Electronic Health Records.

Hepatol Commun 2021 Sep 17. Epub 2021 Sep 17.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edingburgh, Scotland.

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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http://dx.doi.org/10.1002/hep4.1805DOI 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

Implementing an early rule-out pathway for acute myocardial infarction in clinical practice.

Heart 2021 Sep 3. Epub 2021 Sep 3.

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

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http://dx.doi.org/10.1136/heartjnl-2019-316242DOI Listing
September 2021

Risk factors for type 1 and type 2 myocardial infarction.

Eur Heart J 2021 Aug 25. Epub 2021 Aug 25.

BHF Centre for Cardiovascular Science, University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SA, UK.

Aims: Whilst the risk factors for type 1 myocardial infarction due to atherosclerotic plaque rupture and thrombosis are established, our understanding of the factors that predispose to type 2 myocardial infarction during acute illness is still emerging. Our aim was to evaluate and compare the risk factors for type 1 and type 2 myocardial infarction.

Methods And Results: We conducted a secondary analysis of a multi-centre randomized trial population of 48 282 consecutive patients attending hospital with suspected acute coronary syndrome. The diagnosis of myocardial infarction during the index presentation and all subsequent reattendances was adjudicated according to the Universal Definition of Myocardial Infarction. Cox regression was used to identify predictors of future type 1 and type 2 myocardial infarction during a 1-year follow-up period. Within 1 year, 1331 patients had a subsequent myocardial infarction, with 924 and 407 adjudicated as type 1 and type 2 myocardial infarction, respectively. Risk factors for type 1 and type 2 myocardial infarction were similar, with age, hyperlipidaemia, diabetes, abnormal renal function, and known coronary disease predictors for both (P < 0.05 for all). Whilst women accounted for a greater proportion of patients with type 2 as compared to type 1 myocardial infarction, after adjustment for other risk factors, sex was not a predictor of type 2 myocardial events [adjusted hazard ratio (aHR) 0.82, 95% confidence interval (CI) 0.66-1.01]. The strongest predictor of type 2 myocardial infarction was a prior history of type 2 events (aHR 6.18, 95% CI 4.70-8.12).

Conclusions: Risk factors for coronary disease that are associated with type 1 myocardial infarction are also important predictors of type 2 events during acute illness. Treatment of these risk factors may reduce future risk of both type 1 and type 2 myocardial infarction.
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http://dx.doi.org/10.1093/eurheartj/ehab581DOI Listing
August 2021

Rapid diagnostic algorithms for non-ST-segment elevation myocardial infarction.

Eur Heart J Acute Cardiovasc Care 2021 Oct;10(7):825-827

Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1093/ehjacc/zuab059DOI Listing
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

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

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

High-Sensitivity Cardiac Troponin is not Associated with Acute Cellular Rejection after Heart Transplantation.

Transplantation 2021 Jun 29. Epub 2021 Jun 29.

1Transplant Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK 2Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 3Department of Pathology, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK 4BHF Center for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK 5Usher Institute, University of Edinburgh, Edinburgh, UK.

Background: Acute cellular rejection (ACR) is common in the first year after cardiac transplantation and regular surveillance endomyocardial biopsy (EMB) is required. An inexpensive, simple non-invasive diagnostic test would be useful. Prior studies suggest Cardiac troponin (cTn) has potential as a 'rule-out' test to minimize the use of EMB. Our aim was to determine whether a new high-sensitivity cardiac troponin I (hs-cTnI) assay would have utility as a 'rule-out' test for ACR after heart transplantation.

Methods: Blood samples at patient follow up visits were collected and stored over a period of five years. Serum cTnI concentrations were measured using the ARCHITECTSTAT hs-cTnI assay and compared with an EMB performed on the same day. Receiver-operator curve (ROC) analysis based on mixed effects logistic regression models that account for repeated measurements in individuals was performed to determine a serum troponin level below which ACR could be reliably excluded.

Results: 170 patients had 883 serum hs-cTnI results paired to a routine surveillance EMB. 51 (6%) EMB showed significant ACR (grade ≥2R). ROC analysis approximated the null hypothesis AUC 0.509 (95% CI 0.428 -0.591). Sub-analysis including repeated hs-cTnI levels in a single individual and early (<3 month) EMB also showed no diagnostic utility of hs-cTnI measurement (AUC 0.512).

Conclusions: In the largest published study to date, we found no association between hs-cTnI concentration and the presence of significant ACR on surveillance EMB. Measurement of hs-cTnI may not be a useful technique for diagnosis or exclusion of ACR after heart transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003876DOI Listing
June 2021

Sex Differences in Cardiac Troponin I and T and the Prediction of Cardiovascular Events in the General Population.

Clin Chem 2021 Oct;67(10):1351-1360

Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Cardiac troponin concentrations differ in women and men, but how this influences risk prediction and whether a sex-specific approach is required is unclear. We evaluated whether sex influences the predictive ability of cardiac troponin I and T for cardiovascular events in the general population.

Methods: High-sensitivity cardiac troponin (hs-cTn) I and T were measured in the Generation Scotland Scottish Family Health Study of randomly selected volunteers drawn from the general population between 2006 and 2011. Cox-regression models evaluated associations between hs-cTnI and hs-cTnT and the primary outcome of cardiovascular death, myocardial infarction, or stroke.

Results: In 19 501 (58% women, mean age 47 years) participants, the primary outcome occurred in 2.7% (306/11 375) of women and 5.1% (411/8126) of men during the median follow-up period of 7.9 (IQR, 7.1-9.2) years. Cardiac troponin I and T concentrations were lower in women than men (P < 0.001 for both), and both were more strongly associated with cardiovascular events in women than men. For example, at a hs-cTnI concentration of 10 ng/L, the hazard ratio relative to the limit of blank was 9.7 (95% CI 7.6-12.4) and 5.6 (95% CI 4.7-6.6) for women and men, respectively. The hazard ratio for hs-cTnT at a concentration of 10 ng/L relative to the limit of blank was 3.7 (95% CI 3.1-4.3) and 2.2 (95% CI 2.0-2.5) for women and men, respectively.

Conclusions: Cardiac troponin concentrations differ in women and men and are stronger predictors of cardiovascular events in women. Sex-specific approaches are required to provide equivalent risk prediction.
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http://dx.doi.org/10.1093/clinchem/hvab109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486023PMC
October 2021

Latin American guideline shows the way.

Heart 2021 Sep 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

Cardiac Troponin Thresholds and Kinetics to Differentiate Myocardial Injury and Myocardial Infarction.

Circulation 2021 Aug 25;144(7):528-538. Epub 2021 Jun 25.

British Heart Foundation Centre for Cardiovascular Science (R.W., C.T., D.D., K.K.L., M.T.H.L., A.B., T.F., A.A., A.R.C., N.L.M.), University of Edinburgh, UK.

Background: Although the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It is unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice.

Methods: In a secondary analysis of a multicenter randomized controlled trial, we identified 46 092 consecutive patients presenting with suspected acute coronary syndrome without ST-segment-elevation myocardial infarction. High-sensitivity cardiac troponin I concentrations at presentation and on serial testing were compared between patients with myocardial injury and infarction. The positive predictive value and specificity were determined at the sex-specific 99th percentile upper reference limit and rule-in thresholds of 64 ng/L and 5-fold of the upper reference limit for a diagnosis of type 1 myocardial infarction.

Results: Troponin was above the 99th percentile in 8188 patients (18%). The diagnosis was type 1 or type 2 myocardial infarction in 50% and 14% and acute or chronic myocardial injury in 20% and 16%, respectively. Troponin concentrations were similar at presentation in type 1 (median [25th-75th percentile] 91 [30-493] ng/L) and type 2 (50 [22-147] ng/L) myocardial infarction and in acute (50 [26-134] ng/L) and chronic (51 [31-130] ng/L) myocardial injury. The 99th percentile and rule-in thresholds of 64 ng/L and 5-fold upper reference limit gave a positive predictive value of 57% (95% CI, 56%-58%), 59% (58%-61%), and 62% (60%-64%) and a specificity of 96% (96%-96%), 96% (96%-96%), and 98% (97%-98%), respectively. The absolute, relative, and rate of change in troponin concentration were highest in patients with type 1 myocardial infarction (<0.001 for all). Discrimination improved when troponin concentration and change in troponin were combined compared with troponin concentration at presentation alone (area under the curve, 0.661 [0.642-0.680] versus 0.613 [0.594-0.633]).

Conclusions: Although we observed important differences in the kinetics, cardiac troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction in practice and should not guide management decisions in isolation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01852123.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360674PMC
August 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

Cardiovascular biomarkers in COVID-19.

Eur Heart J Acute Cardiovasc Care 2021 Jun;10(5):473-474

Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1093/ehjacc/zuab037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245137PMC
June 2021

Mechanisms of Myocardial Injury in COVID-19.

Clin Chem 2021 08;67(8):1044-1046

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

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http://dx.doi.org/10.1093/clinchem/hvab111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341006PMC
August 2021

Diagnosis, Investigation and Management of Patients with Acute and Chronic Myocardial Injury.

J Clin Med 2021 May 26;10(11). Epub 2021 May 26.

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4SA, UK.

The application of high-sensitivity cardiac troponins in clinical practice has led to an increase in the recognition of elevated concentrations in patients without myocardial ischaemia. The Fourth Universal Definition of Myocardial Infarction encourages clinicians to classify such patients as having an acute or chronic myocardial injury based on the presence or absence of a rise or a fall in cardiac troponin concentrations. Both conditions may be caused by a variety of cardiac and non-cardiac conditions, and evidence suggests that clinical outcomes are worse than patients with myocardial infarction due to atherosclerotic plaque rupture, with as few as one-third of patients alive at 5 years. Major adverse cardiovascular events are comparable between populations, and up to three-fold higher than healthy individuals. Despite this, no evidence-based strategies exist to guide clinicians in the investigation of non-ischaemic myocardial injury. This review explores the aetiology of myocardial injury and proposes a simple framework to guide clinicians in early assessment to identify those who may benefit from further investigation and treatment for those with cardiovascular disease.
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http://dx.doi.org/10.3390/jcm10112331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199345PMC
May 2021

The Ambulance Cardiac Chest Pain Evaluation in Scotland Study (ACCESS): A Prospective Cohort Study.

Ann Emerg Med 2021 06 27;77(6):575-588. Epub 2021 Apr 27.

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; BHF Cardiovascular Biomarker Laboratory, University of Edinburgh, Edinburgh, United Kingdom; Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

Study Objective: To determine whether risk stratification in the out-of-hospital setting could identify patients with chest pain who are at low and high risk to avoid admission or aid direct transfer to cardiac centers.

Methods: Paramedics prospectively enrolled patients with suspected acute coronary syndrome without diagnostic ST-segment elevation on the ECG. The History, ECG, Age and Risk Factors (HEAR) score was recorded contemporaneously, and out-of-hospital samples were obtained to measure cardiac Troponin I (cTnI) level on a point-of-care device, to allow calculation of the History, ECG, Age, Risk Factors, and Troponin (HEART) score. HEAR and HEART scores less than or equal to 3 and greater than or equal to 7 were defined as low and high risk for major adverse cardiac events at 30 days.

Results: Of 1,054 patients (64 years [SD 15 years]; 42% women), 284 (27%) experienced a major adverse cardiac event at 30 days. The HEAR score was calculated in all patients, with point-of-care cTnI testing available in 357 (34%). A HEAR score less than or equal to 3 identified 32% of patients (334/1,054) as low risk, with a sensitivity of 84.9% (95% confidence interval [CI] 80.7% to 89%), whereas a score greater than or equal to 7 identified just 3% of patients (30/1,054) as high risk, with a specificity of 98.7% (95% CI 97.9% to 99.5%). A point-of-care HEART score less than or equal to 3 identified a similar proportion as low risk (30%), with a sensitivity of 87.0% (95% CI 80.7% to 93.4%), whereas a score greater than or equal to 7 identified 14% as high risk, with a specificity of 94.8% (95% CI 92.0% to 97.5%).

Conclusion: Paramedics can use the HEAR score to discriminate risk, but even when used in combination with out-of-hospital point-of-care cTnI testing, the HEART score does not safely rule out major adverse cardiac events, and only a small proportion of patients are identified as high risk.
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http://dx.doi.org/10.1016/j.annemergmed.2021.01.012DOI Listing
June 2021

Sex differences in investigations and outcomes among patients with type 2 myocardial infarction.

Heart 2021 Sep 20;107(18):1480-1486. Epub 2021 Apr 20.

Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.

Objectives: Type 2 myocardial infarction (MI) is a heterogenous condition and whether there are differences between women and men is unknown. We evaluated sex differences in clinical characteristics, investigations and outcomes in patients with type 2 MI.

Methods: In the Swedish Web based system for Enhancement and Development of Evidence based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, we compared patients admitted to coronary care units with a diagnosis of type 1 or type 2 MI. Sex-stratified Cox regression models evaluated the association with all-cause death in men and women separately.

Results: We included 57 264 (median age 73 years, 65% men) and 6485 (median age 78 years, 50% men) patients with type 1 and type 2 MI, respectively. No differences were observed in the proportion of men and women with type 2 MI who underwent echocardiography and coronary angiography, but women were less likely than men to have left ventricular (LV) impairment and obstructive coronary artery disease (CAD). Compared with type 1 MI, patients with type 2 MI had higher risk of death regardless of sex (men: adjusted HR 1.55 (95% CI 1.44 to 1.67); women: adjusted HR 1.34 (95% CI 1.24 to 1.45)). In those with type 2 MI, the risk of death was lower for women than men (adjusted HR 0.85 (95% CI 0.76 to 0.92) (men, reference)).

Conclusions: Type 2 MI occurred in men and women equally and we found no evidence of sex bias in the selection of patients for cardiac investigations. Patients with type 2 MI had worse outcomes, but women were less likely to have obstructive CAD or severe LV impairment and were more likely to survive than men.
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http://dx.doi.org/10.1136/heartjnl-2021-319118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408584PMC
September 2021

Sex-Specific Computed Tomography Coronary Plaque Characterization and Risk of Myocardial Infarction.

JACC Cardiovasc Imaging 2021 09 14;14(9):1804-1814. Epub 2021 Apr 14.

Cedars-Sinai Medical Center, Los Angeles, California, USA.

Objectives: This study was designed to investigate whether coronary computed tomography angiography assessments of coronary plaque might explain differences in the prognosis of men and women presenting with chest pain.

Background: Important sex differences exist in coronary artery disease. Women presenting with chest pain have different risk factors, symptoms, prevalence of coronary artery disease and prognosis compared to men.

Methods: Within a multicenter randomized controlled trial, we explored sex differences in stenosis, adverse plaque characteristics (positive remodeling, low-attenuation plaque, spotty calcification, or napkin ring sign) and quantitative assessment of total, calcified, noncalcified and low-attenuation plaque burden.

Results: Of the 1,769 participants who underwent coronary computed tomography angiography, 772 (43%) were female. Women were more likely to have normal coronary arteries and less likely to have adverse plaque characteristics (p < 0.001 for all). They had lower total, calcified, noncalcified, and low-attenuation plaque burdens (p < 0.001 for all) and were less likely to have a low-attenuation plaque burden >4% (41% vs. 59%; p < 0.001). Over a median follow-up of 4.7 years, myocardial infarction (MI) occurred in 11 women (1.4%) and 30 men (3%). In those who had MI, women had similar total, noncalcified, and low-attenuation plaque burdens as men, but men had higher calcified plaque burden. Low-attenuation plaque burden predicted MI (hazard ratio: 1.60; 95% confidence interval: 1.10 to 2.34; p = 0.015), independent of calcium score, obstructive disease, cardiovascular risk score, and sex.

Conclusions: Women presenting with stable chest pain have less atherosclerotic plaque of all subtypes compared to men and a lower risk of subsequent MI. However, quantitative low-attenuation plaque is as strong a predictor of subsequent MI in women as in men. (Scottish Computed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).
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http://dx.doi.org/10.1016/j.jcmg.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435010PMC
September 2021

Diagnostic performance of the combined nasal and throat swab in patients admitted to hospital with suspected COVID-19.

BMC Infect Dis 2021 Apr 6;21(1):318. Epub 2021 Apr 6.

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4SA, UK.

Background: Accurate diagnosis in patients with suspected coronavirus disease 2019 (COVID-19) is essential to guide treatment and limit spread of the virus. The combined nasal and throat swab is used widely, but its diagnostic performance is uncertain.

Methods: In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, we evaluated the combined nasal and throat swab with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in consecutive patients admitted to hospital with suspected COVID-19. Diagnostic performance of the index and serial tests was evaluated for a primary outcome of confirmed or probable COVID-19, and a secondary outcome of confirmed COVID-19 on serial testing. The diagnosis was adjudicated by a panel, who recorded clinical, laboratory and radiological features blinded to the test results.

Results: We enrolled 1368 consecutive patients (median age 68 [interquartile range, IQR 53-80] years, 47% women) who underwent a total of 3822 tests (median 2 [IQR 1-3] tests per patient). The primary outcome occurred in 36% (496/1368), of whom 65% (323/496) and 35% (173/496) had confirmed and probable COVID-19, respectively. The index test was positive in 255/496 (51%) patients with the primary outcome, giving a sensitivity and specificity of 51.4% (95% confidence interval [CI] 48.8 to 54.1%) and 99.5% (95% CI 99.0 to 99.8%). Sensitivity increased in those undergoing 2, 3 or 4 tests to 60.1% (95% CI 56.7 to 63.4%), 68.3% (95% CI 64.0 to 72.3%) and 77.6% (95% CI 72.7 to 81.9%), respectively. The sensitivity of the index test was 78.9% (95% CI 74.4 to 83.2%) for the secondary outcome of confirmed COVID-19 on serial testing.

Conclusions: In patients admitted to hospital, a single combined nasal and throat swab with RT-PCR for SARS-CoV-2 has excellent specificity, but limited diagnostic sensitivity for COVID-19. Diagnostic performance is significantly improved by repeated testing.
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http://dx.doi.org/10.1186/s12879-021-05976-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022129PMC
April 2021

Chest pain presentations to hospital during the COVID-19 lockdown: Lessons for public health media campaigns.

PLoS One 2021 1;16(4):e0249389. Epub 2021 Apr 1.

BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Objective: Emergency Department (ED) attendances with chest pain reduced during the COVID-19 lockdown. We performed a service evaluation project in NHS Lothian to explore how and why the COVID-19 pandemic and public health advice had affected chest pain presentations and help-seeking behaviour at an individual patient level using a qualitative interview approach.

Methods: We carried out 28 semi-structured telephone interviews with a convenience sample of patients who presented with chest pain during lockdown and in patients with known coronary heart disease under the outpatient care of a cardiologist in April and May 2020. Interviews were audio recorded and voice files listened to while making detailed notes. Salient themes and issues were documented as verbatim extracts. Interviews were analysed thematically.

Results: Patient interviews revealed three main themes. 1) pandemic help-seeking behaviour; describing how participants made the decision to seek professional healthcare assessment. 2) COVID-19 exposure concerns; describing how the subthemes of perceived vulnerability, wishing to protect others and adding pressure to the health service shaped their decision making for an episode of acute chest pain. 3) hospital experience; describing the difference between the imagined and actual experience in hospital.

Conclusions: Qualitative interviews revealed how the pandemic shaped help-seeking practices, how patients interpreted their personal vulnerability to the virus, and described patient experience of attending hospital for assessment during this time. As patient numbers presenting to hospital appeared to mirror public health messaging, dynamic monitoring of this messaging should evaluate public response to healthcare campaigns to ensure the net impact on health, pandemic and non-pandemic related, is optimised.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249389PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016249PMC
April 2021

Serum transthyretin and risk of cognitive decline and dementia: 22-year longitudinal study.

Neurol Sci 2021 Mar 26. Epub 2021 Mar 26.

Department of Epidemiology and Public Health, Institute of Epidemiology and Health Care, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK.

Serum transthyretin (TTR) may be an early biomarker for Alzheimer's disease and related disorders (ADRD). We investigated associations of TTR measured at baseline with cognitive decline and incident ADRD and whether TTR trajectories differ between ADRD cases and non-cases, over 22 years before diagnosis. A total of 6024 adults aged 45-69 in 1997-1999 were followed up until 2019. TTR was assessed three times, and 297 cases of dementia were recorded. Higher TTR was associated with higher cognitive function at baseline; however, TTR was unrelated to subsequent change in cognitive function. TTR at baseline did not predict ADRD risk (hazard ratio per SD TTR (4.8 mg/dL) = 0.97; 95% confidence interval: 0.94-1.00). Among those later diagnosed with ADRD, there was a marginally steeper downward TTR trajectory than those free of ADRD over follow-up (P=0.050). Our findings suggest TTR is not neuroprotective. The relative decline in TTR level in the preclinical stage of ADRD is likely to be a consequence of disease processes.
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http://dx.doi.org/10.1007/s10072-021-05191-5DOI Listing
March 2021

Predicting readmission and death after hospital discharge: a comparison of conventional frailty measurement with an electronic health record-based score.

Age Ageing 2021 09;50(5):1641-1648

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

Background: frailty measurement may identify patients at risk of decline after hospital discharge, but many measures require specialist review and/or additional testing.

Objective: to compare validated frailty tools with routine electronic health record (EHR) data at hospital discharge, for associations with readmission or death.

Design: observational cohort study.

Setting: hospital ward.

Subjects: consented cardiology inpatients ≥70 years old within 24 hours of discharge.

Methods: patients underwent Fried, Short Physical Performance Battery (SPPB), PRISMA-7 and Clinical Frailty Scale (CFS) assessments. An EHR risk score was derived from the proportion of 31 possible frailty markers present. Electronic follow-up was completed for a primary outcome of 90-day readmission or death. Secondary outcomes were mortality and days alive at home ('home time') at 12 months.

Results: in total, 186 patients were included (79 ± 6 years old, 64% males). The primary outcome occurred in 55 (30%) patients. Fried (hazard ratio [HR] 1.47 per standard deviation [SD] increase, 95% confidence interval [CI] 1.18-1.81, P < 0.001), CFS (HR 1.24 per SD increase, 95% CI 1.01-1.51, P = 0.04) and EHR risk scores (HR 1.35 per SD increase, 95% CI 1.02-1.78, P = 0.04) were independently associated with the primary outcome after adjustment for age, sex and co-morbidity, but the SPPB and PRISMA-7 were not. The EHR risk score was independently associated with mortality and home time at 12 months.

Conclusions: frailty measurement at hospital discharge identifies patients at risk of poorer outcomes. An EHR-based risk score appeared equivalent to validated frailty tools and may be automated to screen patients at scale, but this requires further validation.
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http://dx.doi.org/10.1093/ageing/afab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437069PMC
September 2021
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