Background Systemic right ventricle (sRV) patients are at an increased risk of developing heart failure. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) could be a valuable treatment option. This study investigated the changes in ventricular function in sRV failure patients in the first year after starting SGLT2i.Methods Adult sRV patients from the international, real-world ACHIEVE-SGLT2i registry were included if they had a clinical diagnosis of sRV failure, a transthoracic echocardiogram before starting SGLT2i, and at least one in the first year after starting available for analysis. The primary outcomes were changes in sRV global longitudinal strain (GLS) and fractional area change (FAC). Longitudinal changes were evaluated using linear mixed models.Results Thirty-nine sRV failure patients (46±9.3 years old, 41% female) were included. Twenty-five (64%) had transposition of the great arteries after an atrial switch procedure and 14 (36%) had congenitally corrected transposition. sRV GLS improved significantly in the first 50 days (−1.4%-point per month, p<0.001) and stabilised afterwards (<0.1%-point per month, p=0.520). Though age had a significant overall negative effect on sRV GLS (0.1%-point per year of age, p=0.049), it did not influence the longitudinal changes after starting SGLT2i. sRV FAC also improved in the first 50 days (3.2%-point per month, p=0.002), after which sRV FAC deteriorated in patients with subpulmonary left ventricular pacing (−0.9%-point per month, p=0.012) while it stabilised in patients without pacing (0.1%-point per month, p=0.573). In the first 50 days, tricuspid annular plane systolic excursion also improved significantly in all patients (1.2 mm per month, p=0.006), and stabilised afterwards (p=0.721).Conclusions SGLT2i therapy is associated with improvements in systolic ventricular function in sRV failure patients. Despite early improvement in sRV FAC, there was a negative longer term correlation with subpulmonary left ventricular pacing, potentially reflecting adverse effects of subpulmonary ventricular pacing on sRV function.

Background:Single ventricle patients are at high risk of developing circulatory failure. There is limited evidence for pharmacological treatment. This study assessed the echocardiographic changes in ventricular function during sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy in patients with single ventricle failure (SVF). Methods:SVF patients with a baseline transthoracic echocardiogram within six months before starting SGLT2i and at least one echocardiographic examination within twelve months follow-up were included from a real-world international registry of adult congenital heart disease patients on SGLT2i. Mixed models were used to evaluate longitudinal changes in ventricular function and differences between patients with SVF with ≥ moderately reduced systolic function (SVFrEF) and with ≤ mildly reduced function (SVFpEF). Results:Thirteen patients were included. The median age was 21 [20-42] years, 8 (61.5 %) were female, 10 (76.9 %) had a Fontan circulation, 8 (61.5 %) had SVFrEF, and 5 (38.5 %) SVFpEF at the start of SGLT2i. The mean follow-up was 7.6 ± 3.3 months. End-systolic area decreased significantly in all patients (-1.6 cm2 per month, p = 0.007) in the first 100 days. Fractional area change improved in the first 100 days in SVFrEF patients (3.5 %-point per month, p < 0.001), while SVFpEF patients remained stable. There was a significant improvement in the free wall strain in all patients (-0.3 %-point per month, p = 0.036) but not in global longitudinal strain (p = 0.087). Isovolumic acceleration also improved in the first 100 days (0.5 m/s2 per month, p = 0.010). Conclusions:Echocardiographic signals of improved ventricular function were observed in the first year of SGLT2i therapy in patients with SVF.

BACKGROUND:Heart failure (HF) is the principal cause of morbidity and mortality in adults with congenital heart disease (ACHD). Robust evidence-based treatment options are lacking. OBJECTIVES:This study aims to evaluate the safety, tolerability, and short-term HF-related effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a real-world ACHD population. METHODS:All patients with ACHD treated with SGLT2i in 4 European ACHD centers were included in this retrospective study. Data were collected from 1 year before starting SGLT2i to the most recent follow-up. Data on side effects, discontinuation, mortality, and hospitalizations were collected. RESULTS:In total, 174 patients with ACHD were treated with SGLT2i from April 2016 to July 2023. The mean age was 48.7 ± 15.3 years, 72 (41.4%) were female, and 29 (16.7%) had type 2 diabetes mellitus. Ten (5.7%) patients had mild, 75 (43.1%) moderate, and 89 (51.1%) severe congenital heart disease. HF was the most frequent starting indication (n = 162, 93.1%), followed by type 2 diabetes (n = 11, 6.3%) and chronic kidney disease (n = 1, 0.6%). At median follow-up of 7.7 months (Q1-Q3: 3.9-13.2 months), 18 patients (10.3%) reported side effects, 12 (6.9%) permanently discontinued SGLT2i, and 4 (2.3%) died of SGLT2i-unrelated causes. A significant reduction in the HF hospitalization rate was observed from 6 months before to 6 months after starting SGLT2i (relative rate = 0.30; 95% CI: 0.14-0.62; P = 0.001). CONCLUSIONS:SGLT2i generally seem safe, well-tolerated, and potentially beneficial in patients with ACHD. SGLT2i was associated with a 3-fold reduction in the 6-month HF hospitalization rate. These results warrant prospective randomized investigation of the potential benefits of SGLT2i for patients with ACHD.

Background: We present our early experience of introducing state-of-the-art endoscopic vessel harvesting (EVH) into a hospital in Scotland. Coronary arteries bypass grafting (CABG) is the most frequently performed adult cardiac surgical operation and circa. 1200 cases were performed across Scotland in 2019/20, prior to the COVID-19 pandemic. Although internal thoracic artery (ITA) is the preferred conduit, most CABG operations require long saphenous vein (LSV) to be harvested from one or both legs. The radial artery (RA) is also used less frequently. Conduits are currently harvested by open technique, representing one of the longest incisions in surgery. Even when expertly performed, this is a major source of morbidity and delayed hospital discharge. Known risk factors for wound complications include age > 75 years, female sex, BMI > 28, history of smoking, diabetes mellitus and peripheral vascular disease. Both LSV and RA can be successfully harvested endoscopically via 2 cm incision with expected reduction in post-operative morbidity. In our quest to make CABG less invasive, we decided to embark upon a programme of EVH and hereby present our early clinical experience and vision for future roll-out across centres routinely performing cardiac surgery in Scotland. Methods: Consecutive patients undergoing isolated elective CABG surgery at one institution were consented for endoscopic vessel harvesting (EVH). We used a novel on-screen imaging (CoreVista, CardioPrecision), along with latest EVH harvesting tools (HemoPro 2, Getinge) and standard imaging/CO2 insufflation (Stryker). Data on risk factors, wound complications, patient satisfaction and length of stay were collected. Results: A short video will be used to demonstrate key steps of the procedure. Nine patients were recruited into the study. The mean age was 61 years [95% CI 53-69 years]. Six out of 9 (66%) patients had one or more risk factors for post-operative wound complications. LSV was harvested endoscopically in 6 patients (66%) and RA in 3 (33%) patients. The median number of grafts was 3 [range 2-5]. There were no immediate wound complications. All patients expressed a high level of satisfaction with the surgical result. Median post-operative length of stay was 5 days [range 5-6 days]. At a median follow-up of 2 months there were no late wound complication or adverse events reported. Conclusions: EVH was successfully delivered without complications in our series with high degree of patient satisfaction and consistently short length of stay. The combination of devices was easy to use and integrate into the standard CABG theatre footprint and procedure. Plans are now being made to implement EVH more widely across Scotland.

Purpose:To assess the association between nonalcoholic fatty liver disease (NAFLD) and quantitative atherosclerotic plaque at CT.Materials and Methods:In this post hoc analysis of the prospective Scottish Computed Tomography of the HEART trial (November 2010 to September 2014), hepatosteatosis and coronary artery calcium score were measured at noncontrast CT. Presence of stenoses, visually assessed high-risk plaque, and quantitative plaque burden were assessed at coronary CT angiography. Multivariable models were constructed to assess the impact of hepatosteatosis and cardiovascular risk factors on coronary artery disease.Results:Images from 1726 participants (mean age, 58 years ± 9 [SD]; 974 men) were included. Participants with hepatosteatosis (155 of 1726, 9%) had a higher body mass index, more hypertension and diabetes mellitus, and higher cardiovascular risk scores (P < .001 for all) compared with those without hepatosteatosis. They had increased coronary artery calcium scores (median, 43 Agatston units [AU] [interquartile range, 0-273] vs 19 AU [0-225], P = .046), more nonobstructive disease (48% vs 37%, P = .02), and higher low-attenuation plaque burden (5.11% [0-7.16] vs 4.07% [0-6.84], P = .04). However, these associations were not independent of cardiovascular risk factors. Over a median of 4.7 years, there was no evidence of a difference in myocardial infarction between those with and without hepatosteatosis (1.9% vs 2.4%, P = .92).Conclusion:Hepatosteatosis at CT was associated with an increased prevalence of coronary artery disease at CT, but this was not independent of the presence of cardiovascular risk factors.Keywords: CT, Cardiac, Nonalcoholic Fatty Liver Disease, Coronary Artery Disease, Hepatosteatosis, Plaque QuantificationClinical trial registration no. NCT01149590 Supplemental material is available for this article. © RSNA, 2022See also commentary by Abohashem and Blankstein in this issue.

Background: Databases for Congenital Heart Disease (CHD) are effective in delivering accessible datasets ready for statistical inference. Data collection hitherto has, however, been labour and time intensive and has required substantial financial support to ensure sustainability. We propose here creation and piloting of a semi-automated technique for data extraction from clinic letters to populate a clinical database. Methods: PDF formatted clinic letters stored in a local folder, through a series of algorithms, underwent data extraction, preprocessing, and analysis. Specific patient information (diagnoses, diagnostic complexity, interventions, arrhythmia, medications, and demographic data) was processed into text files and structured data tables, used to populate a database. A specific data validation schema was predefined to verify and accommodate the information populating the database. Unsupervised learning in the form of a dimensionality reduction technique was used to project data into 2 dimensions and visualize their intrinsic structure in relation to the diagnosis, medication, intervention, and European Society of Cardiology classification lists of disease complexity. Ninety-three randomly selected letters were reviewed manually for accuracy. Results: There were 1409 consecutive outpatient clinic letters used to populate the Scottish Adult Congenital Cardiac Database. Mean patient age was 35.4 years; 47.6% female; with 698 (49.5%) having moderately complex, 369 (26.1%) greatly complex, and 284 (20.1%) mildly complex lesions. Individual diagnoses were successfully extracted in 96.95%, and demographic data were extracted in 100% of letters. Data extraction, database upload, data analysis and visualization took 571 seconds (9.51 minutes). Manual data extraction in the categories of diagnoses, intervention, and medications yielded accuracy of the computer algorithm in 94%, 93%, and 93%, respectively. Conclusions: Semiautomated data extraction from clinic letters into a database can be achieved successfully with a high degree of accuracy and efficiency.

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. Lowattenuation 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. (C) 2021 by the American College of Cardiology Foundation.

Aims Valvular heart disease can be identified by calcification on coronary computed tomography angiography (CCTA) and has been associated with adverse clinical outcomes. We assessed aortic and mitral valve calcification in patients presenting with stable chest pain and their association with cardiovascular risk factors, coronary artery disease, and cardiovascular outcomes. Methods and results In 1769 patients (58 +/- 9 years, 56% male) undergoing CCTA for stable chest pain, aortic and mitral valve calcification were quantified using Agatston score. Aortic valve calcification was present in 241 (14%) and mitral calcification in 64 (4%). Independent predictors of aortic valve calcification were age, male sex, hypertension, diabetes mellitus, and cerebrovascular disease, whereas the only predictor of mitral valve calcification was age. Patients with aortic and mitral valve calcification had higher coronary artery calcium scores and more obstructive coronary artery disease. The composite endpoint of cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke was higher in those with aortic [hazard ratio (HR) 2.87; 95% confidence interval (CI) 1.60-5.17; P< 0.001] or mitral (HR 3.50; 95% CI 1.47-8.07; P = 0.004) valve calcification, but this was not independent of coronary artery calcification or obstructive coronary artery disease. Conclusion Aortic and mitral valve calcification occurs in one in six patients with stable chest pain undergoing CCTA and is associated with concomitant coronary atherosclerosis. Whilst valvular calcification is associated with a higher risk of cardiovascular events, this was not independent of the burden of coronary artery disease.

Introduction This post-hoc analysis of the SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) assessed the frequency and implications of coronary artery disease (CAD) in patients with a zero coronary artery calcium score (CACS). Methods Agatston CACS was assessed on non-contrast and CAD on contrast CT coronary angiography. Adverse plaque characteristics (APC) were visually identified as positive remodelling or low attenuation plaque and quantitative plaque burden was measured. Results Of 642 patients with zero CACS, CAD was present in 105 (16%). Compared to patients with normal coronary arteries, those with zero CACS and CAD were older (55±9 vs 53±10 years, p=0.016) and had higher cardiovascular risk scores (14±9 vs 12±8, p=0.013). On CTCA 92 (14%) had non-obstructive CAD, 13 (2%) obstructive CAD, 14 (2%) APC and 85 (13%) low attenuation plaque burden >4%. Compared to patients with normal coronary arteries, those with zero CACS and CAD were more likely to receive statins (67% vs 17%, p<0.001), antiplatelet therapy (74% vs 28%, p<0.001), angiography (18% vs 2%, p<0.001) and revascularisation (7% vs 0%, p<0.001). Quality-of-life and symptoms were similar in patients with normal coronary arteries and those with zero CACS and CAD (p>0.05). Over 5 years of follow-up, 1 event (1%, myocardial infarction) occurred in patients with zero CACS and CAD compared to 3 events (1%, 2 myocardial infarction and 1 coronary heart disease death) in patients with normal coronary arteries. Conclusion CAD occurs in 16% of patients with zero CACS, with prognostically significant plaque subtypes occurring in some patients, although the overall event-rate is low.

The Coronary Artery Disease Reporting And Data System (CAD-RADS) and Coronary Artery Calcium Data and Reporting System (CAC-DRS) aim to improve communication of results.Images from 1,769 patients from the Scottish Computed Tomography of the HEART (SCOT-HEART) trial were assessed.Patients classifi ed as CAC-DRS 3 were at an increased risk of fatal or non-fatal myocardial infarction.Patients with higher CAD-RADS categories were at an increased risk of fatal or non-fatal myocardial infarction, with patients classifi ed as CAD-RADS 4B at the highest risk .This confi rms that the classifi cation provides additional prognostic discrimination for future coronary heart disease events.

Abstract Aims The relative benefits of computed tomography coronary angiography (CTCA)-guided management in women and men with suspected angina due to coronary heart disease (CHD) are uncertain. Methods and results In this post hoc analysis of an open-label parallel-group multicentre trial, we recruited 4146 patients referred for assessment of suspected angina from 12 cardiology clinics across the UK. We randomly assigned (1:1) participants to standard care alone or standard care plus CTCA. Fewer women had typical chest pain symptoms (n = 582, 32.0%) when compared with men (n = 880, 37.9%; P < 0.001). Amongst the CTCA-guided group, more women had normal coronary arteries [386 (49.6%) vs. 263 (26.2%)] and less obstructive CHD [105 (11.5%) vs. 347 (29.8%)]. A CTCA-guided strategy resulted in more women than men being reclassified as not having CHD {19.2% vs. 13.1%; absolute risk difference, 5.7 [95% confidence interval (CI): 2.7–8.7, P < 0.001]} or having angina due to CHD [15.0% vs. 9.0%; absolute risk difference, 5.6 (2.3–8.9, P = 0.001)]. After a median of 4.8 years follow-up, CTCA-guided management was associated with similar reductions in the risk of CHD death or non-fatal myocardial infarction in women [hazard ratio (HR) 0.50, 95% CI 0.24–1.04], and men (HR 0.63, 95% CI 0.42–0.95; Pinteraction = 0.572). Conclusion Following the addition of CTCA, women were more likely to be found to have normal coronary arteries than men. This led to more women being reclassified as not having CHD, resulting in more downstream tests and treatments being cancelled. There were similar prognostic benefits of CTCA for women and men.

Objectives: To assess the prognostic implications of standardized reporting systems for coronary computed tomography angiography (CCTA) and coronary artery calcium scores (CACS) in patients with stable chest pain. Background: The Coronary Artery Disease Reporting And Data System (CAD-RADS) and Coronary Artery Calcium - Data and Reporting System (CAC-DRS) aim to improve communication of CACS and CCTA results, but its influence on prognostication is unknown. Methods: Images from 1769 patients who underwent CCTA as part of the Scottish Computed Tomography of the HEART (SCOT-HEART) multi-center randomized controlled trial were assessed. CACS were classified as CAC-DRS 0 to 3 based on Agatston scores. CCTA were classified as CAD-RADS 0 to 5 based on the most clinically relevant finding per patient. The primary outcome was the five-year events of fatal and non-fatal myocardial infarction. Results: Patients had a mean age of 58 +/- 10 years and 56% were male. CAC-DRS 0, 1, 2 and 3 occurred in 642 (36%), 510 (29%), 239 (14%) and 379 (21%) patients respectively. CAD-RADS 0, 1, 2, 3, 4A, 4B and 5 occurred in 622 (35%), 327 (18%), 211 (12%), 165 (9%), 221 (12%), 42 (2%) and 181 (10%) patients respectively. Patients classified as CAC-DRS 3 were at an increased risk of fatal or non-fatal myocardial infarction compared to CAC-DRS 0 patients (hazard ratio (HR) 9.41; 95% confidence interval (CI) 3.24, 27.31; p < 0.001). Patients with higher CAD-RADS categories were at an increased risk of fatal or non-fatal myocardial infarction, with patients classified as CAD-RADS 4B at the highest risk compared to CAD-RADS 0 patients (HR 19.14; 95% CI 4.28, 85.53; p < 0.001). Conclusion: Patients with higher CAC-DRS and CAD-PADS scores were at increased risk of subsequent fatal and non-fatal myocardial infarction. This confirms that the classification provides additional prognostic discrimination for future coronary heart disease events.

We assessed whether non-calcific low-density plaque on coronary CT angiography (CCTA) might improve risk stratification independent of classic risk markers. In the multicenter SCOT-HEART randomized controlled trial, we investigated associations between the risk of fatal or non-fatal myocardial

BACKGROUND Unlike most noninvasive imaging modalities, coronary computed tomography angiography can characterize subtypes of atherosclerotic plaque. OBJECTIVES The purpose of this study was to investigate the prognostic implications of adverse coronary plaque characteristics in patients with suspected coronary artery disease. METHODS In this SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) post hoc analysis, the presence of adverse plaque (positive remodeling or low attenuation plaque), obstructive disease, and coronary artery calcification within 15 coronary segments was assessed on coronary computed tomography angiography of 1,769 patients who were followed-up for 5 years. RESULTS Among study participants (mean age 58 +/- 10 years; 56% male), 608 (34%) patients had 1 or more adverse plaque features. Coronary heart disease death or nonfatal myocardial infarction was 3 times more frequent in patients with adverse plaque (n = 25 of 608 [4.1%] vs. n = 16 of 1,161 [1.4%]; p < 0.001; hazard ratio [HR]: 3.01; 95% confidence interval (CI): 1.61 to 5.63; p = 0.001) and was twice as frequent in those with obstructive disease (n = 22 of 452 [4.9%] vs. n = 16 of 671 [2.4%]; p = 0.024; HR: 1.99; 95% CI: 1.05 to 3.79; p = 0.036). Patients with both obstructive disease and adverse plaque had the highest event rate, with a 10-fold increase in coronary heart disease death or nonfatal myocardial infarction compared with patients with normal coronary arteries (HR: 11.50; 95% CI: 3.39 to 39.04; p < 0.001). However, these associations were not independent of coronary artery calcium score, a surrogate measure of coronary plaque burden. CONCLUSIONS Adverse coronary plaque characteristics and overall calcified plaque burden confer an increased risk of coronary heart disease death or nonfatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590) (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND:Within the SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) trial of patients with stable chest pain, the use of coronary computed tomography angiography (CTA) reduced the rate of death from coronary heart disease or nonfatal myocardial infarction (primary endpoint). OBJECTIVES:This study sought to assess the consistency and mechanisms of the 5-year reduction in this endpoint. METHODS:In this open-label trial, 4,146 participants were randomized to standard care alone or standard care plus coronary CTA. This study explored the primary endpoint by symptoms, diagnosis, coronary revascularizations, and preventative therapies. RESULTS:Event reductions were consistent across symptom and risk categories (p = NS for interactions). In patients who were not diagnosed with angina due to coronary heart disease, coronary CTA was associated with a lower primary endpoint incidence rate (0.23; 95% confidence interval [CI]: 0.13 to 0.35 vs. 0.59; 95% CI: 0.42 to 0.80 per 100 patient-years; p < 0.001). In those who had undergone coronary CTA, rates of coronary revascularization were higher in the first year (hazard ratio [HR]: 1.21; 95% CI: 1.01 to 1.46; p = 0.042) but lower beyond 1 year (HR: 0.59; 95% CI: 0.38 to 0.90; p = 0.015). Patients assigned to coronary CTA had higher rates of preventative therapies throughout follow-up (p < 0.001 for all), with rates highest in those with CT-defined coronary artery disease. Modeling studies demonstrated the plausibility of the observed effect size. CONCLUSIONS:The beneficial effect of coronary CTA on outcomes is consistent across subgroups with plausible underlying mechanisms. Coronary CTA improves coronary heart disease outcomes by enabling better targeting of preventative treatments to those with coronary artery disease. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

ObjectiveTroponin and B-type natriuretic peptide (BNP) concentrations are associated with cardiovascular risk in stable patients. Understanding their determinants and identifying modifiable clinical targets may improve outcomes. We aimed to establish clinical and cardiac determinants of these biomarkers.MethodsThis was a prespecified substudy from the randomised Scottish Computed Tomography of the Heart trial, which enrolled patients 18–75 years with suspected stable angina between 2010 and 2014 (NCT01149590). We included patients from six centres in whom high-sensitivity troponin I and BNP were measured (Singulex Erenna). Patients with troponin >99th centile upper reference limit (10.2 ng/L) or BNP ≥400 ng/L were excluded to avoid inclusion of patients with myocardial injury or heart failure. Multivariable linear regression models were constructed with troponin and BNP as dependent variables.ResultsIn total, 885 patients were included; 881 (99%) and 847 (96%) had troponin and BNP concentrations above the limit of detection, respectively. Participants had a slight male preponderance (n=513; 56.1%), and the median age was 59.0 (IQR 51.0–65.0) years. The median troponin and BNP concentrations were 1.4 (IQR 0.90–2.1) ng/L and 29.1 (IQR 14.0–54.0) ng/L, respectively. Age and atherosclerotic burden were independent predictors of both biomarkers. Male sex, left ventricular mass and systolic blood pressure were independent predictors of increased troponin. In contrast, female sex and left ventricular volume were independent predictors of increased BNP.ConclusionsTroponin and BNP are associated with coronary atherosclerosis but have important sex differences and distinct and contrasting associations with CT-determined left ventricular mass and volume.Clinical Trial registrationNCT01149590; Post-results.

OBJECTIVES This study sought to compare the performance of history-based risk scores in predicting obstructive coronary artery disease (CAD) among patients with stable chest pain from the SCOT-HEART study. BACKGROUND Risk scores for estimating pre-test probability of CAD are derived from referral-based populations with a high prevalence of disease. The generalizability of these scores to lower prevalence populations in the initial patient encounter for chest pain is uncertain. METHODS We compared 3 scores among patients with suspected CAD in the coronary computed tomographic angiography (CTA) randomized arm of the SCOT-HEART study for the outcome of obstructive CAD by coronary CTA: the updated Diamond-Forrester score (UDF), CAD Consortium clinical score (CAD2), and CONFIRM risk score (CRS). We tested calibration with goodness-of-fit, discrimination with area under the receiver-operating curve (AUC), and reclassification with net reclassification improvement (NRI) to identify low-risk patients. RESULTS In 1,738 patients (age 58 +/- 10 years and 44.0% women), overall calibration was best for UDF, with under-estimation by CRS and CAD2. Discrimination by AUC was highest for CAD2 at 0.79 (95% confidence interval [CI]: 0.77 to 0.81) than for UDF (0.77 [95% CI: 0.74 to 0.79]) or CRS (0.75 [95% CI: 0.73 to 0.77]) (p < 0.001 for both comparisons). Reclassification of low-risk patients at the 10% probability threshold was best for CAD2 (NRI 0.31, 95% CI: 0.27 to 0.35) followed by CRS (NRI 0.21, 95% CI: 0.17 to 0.25) compared with UDF (p < 0.001 for all comparisons), with a consistent trend at the 15% threshold. CONCLUSIONS In this multicenter clinic-based cohort of patients with suspected CAD and uniform CAD evaluation by coronary CTA, CAD2 provided the best discrimination and classification, despite overestimation of obstructive CAD as evaluated by coronary CTA. CRS exhibited intermediate performance followed by UDF for discrimination and reclassification. (C) 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation.

HomeCirculationVol. 140, No. 18Endothelial Progenitor Cells Do Not Originate From the Bone Marrow Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBEndothelial Progenitor Cells Do Not Originate From the Bone Marrow Takeshi Fujisawa, BSc, PhD, Olga Tura-Ceide, BSc, PhD, Amanda Hunter, MBChB, Andrew Mitchell, MBChB, Alex Vesey, MBChB, Claire Medine, BSc, PhD, Susan Gallogly, BSc, PhD, Patrick W.F. Hadoke, BSc, PhD, Charlotte Keith, BSc, Anne Sproul, MI BIOL, Huw Roddie, MBChB, PhD, Grant McQuaker, DM, Ian Wilmut, BSc, PhD, Nicholas L. Mills, MBChB, PhD and Mairi Brittan, BSc, PhD Takeshi FujisawaTakeshi Fujisawa British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Search for more papers by this author , Olga Tura-CeideOlga Tura-Ceide Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain (O.T.-C.). Search for more papers by this author , Amanda HunterAmanda Hunter British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Search for more papers by this author , Andrew MitchellAndrew Mitchell British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Search for more papers by this author , Alex VeseyAlex Vesey British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Search for more papers by this author , Claire MedineClaire Medine British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Search for more papers by this author , Susan GalloglySusan Gallogly British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Search for more papers by this author , Patrick W.F. HadokePatrick W.F. Hadoke British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Search for more papers by this author , Charlotte KeithCharlotte Keith South East Scotland Cytogenetics Service (C.K.), Western General Hospital, Edinburgh, United Kingdom. Search for more papers by this author , Anne SproulAnne Sproul Department of Haematology (A.S., H.R.), Western General Hospital, Edinburgh, United Kingdom. Search for more papers by this author , Huw RoddieHuw Roddie Department of Haematology (A.S., H.R.), Western General Hospital, Edinburgh, United Kingdom. Search for more papers by this author , Grant McQuakerGrant McQuaker Bone Marrow Transplant Unit, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom (G.M.). Search for more papers by this author , Ian WilmutIan Wilmut MRC Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine (I.W.), University of Edinburgh, United Kingdom. Search for more papers by this author , Nicholas L. MillsNicholas L. Mills Nicholas L. Mills, MBChB, PhD, British Heart Foundation Centre for Cardiovascular Science, Chancellor’s Building, Royal Infirmary of Edinburgh, Edinburgh EH16 4SB, United Kingdom. Email E-mail Address: [email protected] British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. Usher Institute for Population Health Sciences & Informatics (N.L.M.), University of Edinburgh, United Kingdom. *Drs Mills and Brittan contributed equally. Search for more papers by this author and Mairi BrittanMairi Brittan British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom. *Drs Mills and Brittan contributed equally. Search for more papers by this author Originally published28 Oct 2019https://doi.org/10.1161/CIRCULATIONAHA.119.042351Circulation. 2019;140:1524–1526Endothelial progenitor cells (EPCs) are thought to originate from the bone marrow, mobilize in response to ischemia, and home to sites of vascular injury. Despite uncertainty regarding their origin, phenotype, and therapeutic viability, there remains great interest in harnessing EPCs to promote vascular regeneration. Autologous bone marrow cells have been delivered to thousands of patients, on the premise that these populations contain functional EPCs, with conflicting results.1 One potential explanation for the lack of consistent benefit is that bone marrow is not the origin of circulating EPCs. Indeed, although late-outgrowth endothelial cells can be readily isolated from cord and peripheral blood,2,3 we have not been able to obtain endothelial cells from the culture of bone marrow.3 These findings suggest that circulating EPCs arise from an alternative niche in the vessel wall.To define EPC origin, we recruited 5 male participants (46±7 years) who had undergone allogeneic bone marrow transplant from female donors for the treatment of hematological malignancy 12 to 120 months previously. The study was performed with approval from our research ethics committee and with written informed consent. Complete donor chimerism was demonstrated in all participants at the time of enrollment. Early- and late-outgrowth endothelial cells were isolated from whole blood,2,3 and vessel wall endothelial cells were harvested from forearm veins using a J-shaped guidewire and expanded in culture. The contribution of bone marrow cells to each lineage was assessed by using fluorescence in situ hybridization to detect the X and Y chromosomes, and supported by live cell imaging, flow cytometry, and immunofluorescence staining. Genotype was further analyzed by short tandem repeat analysis using multiplex polymerase chain reaction amplification and detection of DNA sequences of loci that frequently contain polymorphisms. Clonogenic potential at the single-cell level was quantified in each lineage, and the origin of clonogenic progenitors was assessed by fluorescence in situ hybridization.All early-outgrowth cells had an XX genotype consistent with bone marrow origin, formed clusters of spindle-shaped cells expressing high levels of the pan-leukocyte antigen CD45 rather than endothelial antigens, and did not undergo proliferation or clonogenic expansion (Figure, A and B). Therefore, early-outgrowth cells, previously described as endothelial cell colony-forming units, are hematopoietic and not the progeny of circulating EPCs. In contrast, all vessel wall endothelial cells had an XY genotype, confirming that they were not derived from bone marrow. These cells proliferated in culture to form a cobblestone monolayer with ubiquitous expression of CD31. During early passages, late-outgrowth endothelial cells had a mixed genotype with both XX and XY cells, although the proportion of cells with an XX genotype decreased from 24.8±4.4% to 0.8±0.5% by the third passage (P<0.01) (Figure, B). It is important to note that, of those expressing CD31, 99.3±0.7% had an XY genotype at the third passage and therefore did not arise from bone marrow (Figure, C). In contrast, those that did not express CD31 had an XX genotype and were likely contaminating hematopoietic cells commonly found by using this isolation protocol (Figure, D).2 These cells expressed CD45, were observed overlying the endothelial monolayer in 3-dimensional confocal z-stacks (Figure, E), and were diminished from passage 1 to 3 (16.5±9.1% versus 1.8±0.9%; P<0.05), presumably because of their lack of proliferative capacity and inability to survive in endothelial-specific growth conditions.Download figureDownload PowerPointFigure. The origin of endothelial progenitor cells.A, Flow cytometric analysis of early-outgrowth cells, late-outgrowth endothelial cells, and vessel wall endothelial cells with antibodies to CD45, CD31, CD34, KDR, and CD146. Immunofluorescence staining for viable nuclei (DRAQ5, yellow), CD45 (blue), CD146 (magenta), and CD31 (green). Scale bar: 500 µm. B, Fluorescence in situ hybridization (FISH) for the X and Y chromosomes combined with CD31 staining of early-outgrowth cells (day 5), late-outgrowth endothelial cells (passage 1), and vessel wall endothelial cells (passage 1) in male patients with sex-mismatched bone marrow transplants. Representative images show Y chromosome (green), X chromosome (red), CD31 (yellow), and nuclei (DAPI, blue). Examples of CD31-negative cells with an XX genotype (white arrows) and CD31-positive cells with an XY genotype (yellow arrows) are shown. Scale bar: 20 μm. *P<0.001, one-way ANOVA. Genotype of early-outgrowth cells, late-outgrowth endothelial cells, and vessel wall endothelial cells with (C) and without (D) CD31 expression. E, Immunofluorescence for CD45 (blue) and CD31 (yellow) in late-outgrowth endothelial cells. Scale bar: 50 μm. F, Short tandem repeat analysis for the sex-specific locus, amelogenin. The proportion of cells with XX and XY genotype was calculated from polymerase chain reaction products of 104 and 110 base pairs corresponding to the X and Y chromosomes, respectively. *P<0.05, one-way ANOVA. G, Images showing expansion of a colony of late-outgrowth endothelial cells from a single endothelial progenitor cell of recipient origin (XY genotype). Y chromosome (green), X chromosome (red), CD31 (yellow), and nuclei (DAPI, blue). Scale bar: 100 μm. DAPI indicates 4′,6-diamidino-2-phenylindole; and STR, short tandem repeat.Short tandem repeat analysis of the sex-specific amelogenin gene locus was consistent with fluorescence in situ hybridization (Figure, F), confirming the XX genotype of early-outgrowth cells, the XY genotype of vessel wall endothelial cells, and that late-outgrowth endothelial cells were initially of mixed genotype with a declining fraction of contaminating XX cells between passages 1 and 3 (36.3±2.2% to 5.9±3.6%, P<0.05). Clonogenic colonies expanded from single cells were only obtained for late-outgrowth endothelial cells (4/5 participants, 8.8±4.0% efficiency) (Figure, G). All clones expressed CD31 and were entirely XY in genotype.Although our study includes a small number of participants, we have systematically studied the origin of EPCs in people with sex-mismatched bone marrow transplantation by using 2 distinct but complementary methods. Although endothelial cells can be obtained from a circulating progenitor and are capable of clonal expansion, these cells do not share the genotype of the transplanted bone marrow. We conclude that EPCs in circulation do not originate from the bone marrow.Our findings contrast those of Lin and colleagues.4 They recognized that single-cell culture would be necessary to definitively address whether endothelial cells capable of clonal expansion derive from bone marrow. These methods were used in our analysis demonstrating that all clones formed from single cells were derived from the recipient rather than from donor bone marrow. Our findings were internally consistent and clear, and in agreement with recent evidence showing that endogenous neovascularization in the heart is driven by tissue-resident EPCs without a direct contribution from bone marrow cells.5 This represents a paradigm shift that requires a reevaluation of our approach to harness EPCs for therapeutic vascular regeneration.AcknowledgmentsThe authors acknowledge the imaging facility and the flow cytometry facility at the MRC Centre for Regenerative Medicine at the University of Edinburgh for technical support. Prof Kuramoto at Kitasato University in Japan is gratefully acknowledged for support to Dr Fujisawa.Sources of FundingThis research was supported by the Chief Scientist Office (CZB/4/812), and the British Heart Foundation through Intermediate (FS/16/4/31831) and Senior (FS/16/14/32023) Research Fellowships and through a Cardiovascular Regenerative Medicine Centre Award (RE/18/5/34216) and Research Excellence Award (RE/18/5/34216).DisclosuresNone.Footnotes*Drs Mills and Brittan contributed equally.https://www.ahajournals.org/journal/circData sharing: Data and supporting materials can be made available upon request from the corresponding author.Nicholas L. Mills, MBChB, PhD, British Heart Foundation Centre for Cardiovascular Science, Chancellor’s Building, Royal Infirmary of Edinburgh, Edinburgh EH16 4SB, United Kingdom. Email nick.[email protected]ac.ukReferences1. Nowbar AN, Mielewczik M, Karavassilis M, Dehbi HM, Shun-Shin MJ, Jones S, Howard JP, Cole GD, Francis DP; DAMASCENE writing group. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis.BMJ. 2014; 348:g2688. doi: 10.1136/bmj.g2688CrossrefMedlineGoogle Scholar2. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals.Blood. 2007; 109:1801–1809. doi: 10.1182/blood-2006-08-043471CrossrefMedlineGoogle Scholar3. Tura O, Skinner EM, Barclay GR, Samuel K, Gallagher RC, Brittan M, Hadoke PW, Newby DE, Turner ML, Mills NL. Late outgrowth endothelial cells resemble mature endothelial cells and are not derived from bone marrow.Stem Cells. 2013; 31:338–348. doi: 10.1002/stem.1280CrossrefMedlineGoogle Scholar4. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood.J Clin Invest. 2000; 105:71–77. doi: 10.1172/JCI8071CrossrefMedlineGoogle Scholar5. Li Z, Solomonidis EG, Meloni M, Taylor RS, Duffin R, Dobie R, Magalhaes MS, Henderson BEP, Louwe PA, D’Amico G, et al. Single-cell transcriptome analyses reveal novel targets modulating cardiac neovascularization by resident endothelial cells following myocardial infarction.Eur Heart J. 2019; 40:2507–2520. doi: 10.1093/eurheartj/ehz305CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Pelliccia F, Zimarino M, De Luca G, Viceconte N, Tanzilli G and De Caterina R (2022) Endothelial Progenitor Cells in Coronary Artery Disease: From Bench to Bedside, Stem Cells Translational Medicine, 10.1093/stcltm/szac010, 11:5, (451-460), Online publication date: 27-May-2022. 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Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.119.042351PMID: 31657952 Originally publishedOctober 28, 2019 Keywordsendothelial progenitor cellscell- and tissue-based therapybone marrow cellsPDF download Advertisement SubjectsAngiogenesisBasic Science ResearchCell Therapy

Introduction: Valvular heart disease can be identified by the presence of calcification on coronary computed tomography angiography (CCTA). This sub-study of the SCOT-HEART trial assesses the presence and quantification of aortic and mitral valve calcification.