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ObjectiveIn patients with acute chest pain who have had myocardial infarction excluded, plasma cardiac troponin I concentrations ≥5 ng/L are associated with risk of future adverse cardiovascular events. We aim to evaluate the association between cardiac troponin and coronary plaque composition in such patients.MethodsIn a prespecified secondary analysis of a prospective cohort study, blinded quantitative plaque analysis was performed on 242 CT coronary angiograms of patients with acute chest pain in whom myocardial infarction was excluded. Patients were stratified by peak plasma cardiac troponin I concentration ≥5 ng/L or ResultsThe cohort was predominantly middle-aged (62±12 years) men (69%). Patients with plasma cardiac troponin I concentration ≥5 ng/L (n=161) had a higher total (median 33% (IQR 0–47) vs 0% (IQR 0–33)), non-calcified (27% (IQR 0–37) vs 0% (IQR 0–28)), calcified (2% (IQR 0–8) vs 0% (IQR 0–3)) and low-attenuation (1% (IQR 0–3) vs 0% (IQR 0–1)) coronary plaque burden compared with those with concentrations ConclusionIn patients with acute chest pain but without myocardial infarction, plasma cardiac troponin I concentrations ≥5 ng/L are associated with greater burden of low-attenuation coronary plaque.

Background: Computational tomography coronary angiography (CTCA) is increasingly the diagnostic test of choice for investigating patients with stable anginal symptoms. Objectives: We sought to conduct a systematic review and meta-analysis comparing CTCA with invasive coronary angiography (ICA) with regards to major adverse cardiovascular events (MACE), procedural complications and rates of revascularisation. Methods: We conducted a systematic review and meta-analysis in line with the PRISMA statement. A literature search was conducted using PubMed, MEDLINE Ovid and Embase, with three studies included in meta-analysis. Statistical analysis was undertaken using Review Manager 5.3 for MacOS software and outcomes expressed as odds ratio, with 95% confidence intervals and sensitivity analysis was conducted. Results: A total of 5662 patients were included in this study level meta-analysis. There was no difference in MACE between CT and angiography [2.97% v 3.45%, fixed-effect model, OR: 0.84 (0.62–1.14), p = 0.26, I2 0%] and no difference found in rates of myocardial infarction, death or stroke. CTCA was associated with a reduced rate of revascularisation [12.6% v 18.3%, fixed-effects model, OR: 0.64 (0.55–0.75), p

The identification of intracoronary thrombus and atherothrombosis is central to the diagnosis of acute myocardial infarction, with the differentiation between type 1 and type 2 myocardial infarction being crucial for immediate patient management. Invasive coronary angiography has remained the principal imaging modality used in the investigation of patients with myocardial infarction. More recently developed invasive intravascular imaging approaches, such as angioscopy, intravascular ultrasound and optical coherence tomography, can be used as adjunctive imaging modalities to provide more direct visualisation of coronary atheroma and the causes of myocardial infarction as well as to improve the sensitivity of thrombus detection. However, these invasive approaches have practical and logistic constraints that limit their widespread and routine application. Non-invasive angiographic techniques, such as computed tomography and magnetic resonance imaging, have become more widely available and have improved the non-invasive visualisation of coronary artery disease. Although they also have a limited ability to reliably identify intracoronary thrombus, this can be overcome by combining their anatomical and structural characterisation of coronary anatomy with positron emission tomography. Specific radiotracers which bind with high specificity and sensitivity to components of thrombus, such as activated platelets, fibrin and factor XIIIa, hold promise for the non-invasive detection of intracoronary thrombus. The development of these novel non-invasive approaches has the potential to inform clinical decision making and patient management as well as to provide a non-invasive technique to assess the efficacy of novel antithrombotic therapies or interventional strategies. However, these have yet to be realised in routine clinical practice.

Background: Takotsubo syndrome is an acute cardiac emergency characterized by transient left ventricular systolic dysfunction typically following a stressful event. Despite its rapidly rising incidence, its pathophysiology remains poorly understood. Takotsubo syndrome may pass unrecognized, especially if timely diagnostic imaging is not performed. Defective myocardial calcium homeostasis is a central cause of contractile dysfunction and has not been explored in takotsubo syndrome. We aimed to investigate myocardial calcium handling using manganese-enhanced magnetic resonance imaging during the acute and recovery phases of takotsubo syndrome. Methods: Twenty patients with takotsubo syndrome (63±12 years of age; 90% female) and 20 volunteers matched on age, sex, and cardiovascular risk factors (59±11 years of age; 70% female) were recruited from the Edinburgh Heart Centre between March 2020 and October 2021. Patients underwent gadolinium and manganese-enhanced magnetic resonance imaging during index hospitalization with repeat manganese-enhanced magnetic resonance imaging performed after at least 3 months. Results: Compared with matched control volunteers, patients had a reduced left ventricular ejection fraction (51±11 versus 67±8%; P 2 ; P P P P P Conclusions: In patients with takotsubo syndrome, there is a profound perturbation of myocardial manganese uptake, which is most marked in the acute phase but persists for at least 3 months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema, suggesting abnormal myocardial calcium handling may be implicated in the pathophysiology of takotsubo syndrome. Manganese-enhanced magnetic resonance imaging has major potential to assist in the diagnosis, characterization, and risk stratification of patients with takotsubo syndrome. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04623788.

Fluorine 18–labeled sodium fluoride PET/MRI characteristics were associated with the culprit atherosclerotic plaques in the carotid circulation of study participants with acute neurovascular syndrome; PET/MRI was also usable in the assessment of carotid stenosis, high-risk plaque features, and plaque biologic activity.BackgroundMRI and fluorine 18–labeled sodium fluoride (18F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed.PurposeTo evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome.Materials and MethodsIn this prospective observational cohort study (October 2017 to January 2020), participants underwent 18F-NaF PET/MRI. An experienced clinician determined the culprit carotid artery based on symptoms and record review. 18F-NaF uptake was quantified using standardized uptake values and tissue-to-background ratios. Statistical significance was assessed with the Welch, χ2, Wilcoxon, or Fisher test. Multivariable models were used to evaluate the relationship between the imaging markers and the culprit versus nonculprit vessel.ResultsA total of 110 participants were evaluated (mean age, 68 years ± 10 [SD]; 70 men and 40 women). Of the 110, 34 (32%) had prior cerebrovascular disease, and 26 (24%) presented with amaurosis fugax, 54 (49%) with transient ischemic attack, and 30 (27%) with stroke. Compared with nonculprit carotids, culprit carotids had greater stenoses (≥50% stenosis: 30% vs 15% [P = .02]; ≥70% stenosis: 25% vs 4.5% [P < .001]) and had increased prevalence of MRI-derived adverse plaque features, including intraplaque hemorrhage (42% vs 23%; P = .004), necrotic core (36% vs 18%; P = .004), thrombus (7.3% vs 0%; P = .01), ulceration (18% vs 3.6%; P = .001), and higher 18F-NaF uptake (maximum tissue-to-background ratio, 1.38 [IQR, 1.12–1.82] vs 1.26 [IQR, 0.99–1.66], respectively; P = .04). Higher 18F-NaF uptake was positively associated with necrosis, intraplaque hemorrhage, ulceration, and calcification and inversely associated with fibrosis (P = .04 to P < .001). In multivariable analysis, carotid stenosis at or over 70% (odds ratio, 5.72 [95% CI: 2.2, 18]) and MRI-derived adverse plaque characteristics (odds ratio, 2.16 [95% CI: 1.2, 3.9]) were both associated with the culprit versus nonculprit carotid vessel.ConclusionFluorine 18–labeled sodium fluoride PET/MRI characteristics were associated with the culprit carotid vessel in study participants with acute neurovascular syndrome.Clinical trial registration no. NCT03215550 and NCT03215563

Objectives: The purpose of this study was to investigate whether thoracic 18F-sodium fluoride positron emission tomography (PET) could improve the identification of patients at the highest risk of ischemic stroke. Background: Aortic atherosclerosis represents an important contributor to ischemic stroke risk. Identifying patients with high-risk aortic atheroma could improve preventative treatment strategies for future ischemic stroke. Methods: In a post hoc observational cohort study, we quantified thoracic aortic and coronary 18F-sodium fluoride activity in 461 patients with stable cardiovascular disease undergoing PET combined with computed tomography (CT). Progression of atherosclerosis was assessed by change in aortic and coronary CT calcium volume. Clinical outcomes were determined by the occurrence of ischemic stroke and myocardial infarction. We compared the prognostic utility of 18F-sodium fluoride activity for predicting stroke to clinical risk scores and CT calcium quantification using survival analysis and multivariable Cox regression. Results: After 12.7 ± 2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aortic 18F-sodium fluoride activity (n = 140; r = 0.31; P = 0.00016). In 461 patients, 23 (5%) patients experienced an ischemic stroke and 32 (7%) a myocardial infarction after 6.1 ± 2.3 years of follow-up. High thoracic aortic 18F-sodium fluoride activity was strongly associated with ischemic stroke (HR: 10.3 [3.1 to 34.8]; P = 0.00017), but not myocardial infarction (P = 0.40). Conversely, high coronary 18F-sodium fluoride activity was associated with myocardial infarction (HR: 4.8 [1.9 to 12.2]; P = 0.00095) but not ischemic stroke (P = 0.39). In a multivariable Cox regression model including imaging and clinical risk factors, thoracic aortic 18F-sodium fluoride activity was the only variable associated with ischemic stroke (HR: 8.19 (2.33 to 28.7), P = 0.0010). Conclusions: In patients with established cardiovascular disease, thoracic aortic 18F-sodium fluoride activity is associated with the progression of atherosclerosis and future ischemic stroke. Arterial 18F-sodium fluoride activity identifies localized areas of atherosclerotic disease activity that are directly linked to disease progression and downstream regional clinical atherothrombotic events. (DIAMOND - Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND], NCT02110303; Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis [SALTIRE II], NCT02132026; Novel Imaging Approaches To Identify Unstable Coronary Plaques, NCT01749254; and Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis, NCT01358513).

BACKGROUND: Bioprosthetic valve thrombosis may have implications for valve function and durability.OBJECTIVES: Using a novel glycoprotein IIb/IIIa receptor radiotracer 18F-GP1, we investigated whether positron emission tomography (PET)-computed tomography (CT) could detect thrombus formation on bioprosthetic aortic valves.METHODS: Ex vivo experiments were performed on human platelets and explanted bioprosthetic aortic valves. In a prospective cross-sectional study, patients with either bioprosthetic or normal native aortic valves underwent echocardiography, CT angiography, and 18F-GP1 PET-CT.RESULTS: Flow cytometric analysis, histology, immunohistochemistry, and autoradiography demonstrated selective binding of 18F-GP1 to activated platelet glycoprotein IIb/IIIa receptors and thrombus adherent to prosthetic valves. In total, 75 participants were recruited: 53 with bioprosthetic valves (median time from implantation 37 months [IQR: 12-80 months]) and 22 with normal native aortic valves. Three participants had obstructive valve thrombosis, and a further 3 participants had asymptomatic hypoattenuated leaflet thickening on CT angiography. All bioprosthetic valves, but none of the native aortic valves, demonstrated focal 18F-GP1 uptake on the valve leaflets: median maximum target-to-background ratio 2.81 (IQR: 2.29-3.48) vs 1.43 (IQR: 1.28-1.53) (P < 0.001). Higher 18F-GP1 uptake was independently associated with duration of valve implantation and hypoattenuated leaflet thickening. All 3 participants with obstructive valve thrombosis were anticoagulated for 3 months, leading to resolution of their symptoms, improvement in mean valve gradients, and a reduction in 18F-GP1 uptake.CONCLUSIONS: Adherence of activated platelets is a common and sustained finding on bioprosthetic aortic valves. 18F-GP1 uptake is higher in the presence of thrombus, regresses with anticoagulation, and has potential use as an adjunctive clinical tool. (18F-GP1 PET-CT to Detect Bioprosthetic Aortic Valve Thrombosis; NCT04073875).

Aims: To investigate whether manganese-enhancedmagnetic resonance imagingcan assess functional pancreatic beta-cellmass in people with type 1 diabetes mellitus.Methods: In a prospective case–controlstudy, 20 people with type 1 diabetesmellitus (10 with low (≥50 pmol/L) and 10 with very low (concentrations) and 15 healthy volunteers underwent manganese-enhancedmagnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescanreproducibility was performed in 10 participants.Results: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/minin healthy volunteers (median 32 [interquartile range 23–36]years, 6 women),falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in peoplewith type1 diabetes mellitus (52 [44–61]years, 6 women) and low or very lowplasma C-peptideconcentrations respectively. Pancreatic manganese uptakecorrelated strongly with plasma C-peptideconcentrations in people with type1diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = −0.054,p = 0.880). There were no statistically significant correlations between manganeseuptake and age, body-massindex, or glycated haemoglobin. There was strongintra-observer(mean difference: 0.31 (limits of agreement −1.42 to 2.05) mL/100 gof tissue/min; intra-classcorrelation, ICC = 0.99), inter-observer(−1.23 (−5.74 to3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan(−0.72 (−2.9 to 1.6)mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake.Conclusions: Manganese-enhancedmagnetic resonance imaging provides a potentialreproducible non-invasivemeasure of functional beta-cellmass in people with type1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoringdisease progression and assessing novel immunomodulatory interventions.

Cardiac computed tomography (CT) was initially developed as a non-invasive diagnostic tool to detect and quantify coronary stenosis. Thanks to the rapid technological development, cardiac CT has become a comprehensive imaging modality which offers anatomical and functional information to guide patient management. This is the second of two complementary documents endorsed by the European Association of Cardiovascular Imaging aiming to give updated indications on the appropriate use of cardiac CT in different clinical scenarios. In this article, emerging CT technologies and biomarkers, such as CT-derived fractional flow reserve, perfusion imaging, and pericoronary adipose tissue attenuation, are described. In addition, the role of cardiac CT in the evaluation of atherosclerotic plaque, cardiomyopathies, structural heart disease, and congenital heart disease is revised.

Cardiac computed tomography (CT) was introduced in the late 1990’s. Since then, an increasing body of evidence on its clinical applications has rapidly emerged. From an initial emphasis on its technical efficiency and diagnostic accuracy, research around cardiac CT has now evolved towards outcomes-based studies that provide information on prognosis, safety, and cost. Thanks to the strong and compelling data generated by large, randomized control trials, the scientific societies have endorsed cardiac CT as pivotal diagnostic test for the management of appropriately selected patients with acute and chronic coronary syndrome. This consensus document endorsed by the European Association of Cardiovascular Imaging is divided into two parts and aims to provide a summary of the current evidence and to give updated indications on the appropriate use of cardiac CT in different clinical scenarios. This first part focuses on the most established applications of cardiac CT from primary prevention in asymptomatic patients, to the evaluation of patients with chronic coronary syndrome, acute chest pain, and previous coronary revascularization.

Aims The European Association of Cardiovascular Imaging Scientific Initiatives Committee conducted a global survey to evaluate the impact of the 2019 coronavirus disease (COVID-19) pandemic on the mental well-being of cardiac imaging specialists. Methods and results In a prospective international survey performed between 23 July 2021 and 31 August 2021, we assessed the mental well-being of cardiac imaging specialists ∼18 months into the COVID-19 pandemic. One-hundred-and-twenty-five cardiac imaging specialists from 34 countries responded to the survey. More than half described feeling anxious during the pandemic, 34% felt melancholic, 27% felt fearful, and 23% respondents felt lonely. A quarter of respondents had increased their alcohol intake and more than half reported difficulties in sleeping. Two-thirds of respondents described worsening features of burnout during the past 18 months, 44% considered quitting their job. One in twenty respondents had experienced suicidal ideation during the pandemic. Despite these important issues, the majority of participants (57%) reported having no access to any formal mental health support at work. Conclusion The survey has highlighted important issues regarding the mental well-being of cardiac imaging specialists during the COVID-19 pandemic. This is a major issue in our sub-specialty, which requires urgent action and prioritization so that we can improve the mental health of cardiovascular imaging specialists.

Background:Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures. Objectives:We aimed to investigate somatostatin receptor 2 (SST2) as a novel inflammation-specific molecular imaging target in LVV. Methods:In a prospective, observational cohort study, in vivo arterial SST2expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using68Ga-DOTATATE and18F-FET-βAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing. Results:Sixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST2maximum tissue-to-blood ratio was 61.8% (P < 0.0001) higher in active/grumbling LVV than inactive LVV and 34.6% (P = 0.0002) higher than myocardial infarction, with good diagnostic accuracy (area under the curve: ≥0.86; P < 0.001 for both). Arterial SST2signal was not elevated in any of the control subjects. SST2PET/MRI was generally consistent with18F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST2maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST2expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers. Conclusions:SST2PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell and Takayasu Arteritis [PITA],NCT04071691; Residual Inflammation and Plaque Progression Long-Term Evaluation [RIPPLE],NCT04073810).

AimsPrediction of adverse events in mid-term follow-up after transcatheter aortic valve implantation (TAVI) is challenging. We sought to develop and validate a machine learning model for prediction of 1-year all-cause mortality in patients who underwent TAVI and were discharged following the index procedure.Methods and resultsThe model was developed on data of patients who underwent TAVI at a high-volume centre between January 2013 and March 2019. Machine learning by extreme gradient boosting was trained and tested with repeated 10-fold hold-out testing using 34 pre- and 25 peri-procedural clinical variables. External validation was performed on unseen data from two other independent high-volume TAVI centres. Six hundred four patients (43% men, 81 ± 5 years old, EuroSCORE II 4.8 [3.0–6.3]%) in the derivation and 823 patients (46% men, 82 ± 5 years old, EuroSCORE II 4.7 [2.9–6.0]%) in the validation cohort underwent TAVI and were discharged home following the index procedure. Over the 12 months of follow-up, 68 (11%) and 95 (12%) subjects died in the derivation and validation cohorts, respectively. In external validation, the machine learning model had an area under the receiver-operator curve of 0.82 (0.78–0.87) for prediction of 1-year all-cause mortality following hospital discharge after TAVI, which was superior to pre- and peri-procedural clinical variables including age 0.52 (0.46–0.59) and the EuroSCORE II 0.57 (0.51–0.64), P ConclusionMachine learning based on readily available clinical data allows accurate prediction of 1-year all-cause mortality following a successful TAVI.

Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease.

Background Discordant echocardiographic measurements are observed in up to one third of patients with aortic stenosis (AS), in whom computed tomography (CT) derived aortic valve calcium scoring is now recommended. Nonetheless, CT calcium scoring only evaluates calcific valve thickening and is unable to assess non-calcific fibrotic thickening, which could be a relevant contributor of AS. Aim of the present study was to generate a quick and robust contrast-CT method based on a gaussian mixture model (GMM) for the assessment of fibro-calcific aortic valve thickening in AS patients, and to investigate its reproducibility and associations with echocardiographic parameters of AS severity and disease progression. Methods A post-hoc analysis of 136 patients with calcific AS (24 with severe, 81 moderate and 31 mild AS) enrolled in the SALTIRE2 trial (Study Investigating the Effects of Drugs used to Treat Osteoporosis on the Progression of Aortic Stenosis) (NCT-02132026) was performed. Aortic valve fibrocalcific volume was calculated using a GMM applied on contrast-CT at baseline and at 1-year follow up. The software estimated the Hounsfield Units (HU) distribution of 3 compartments (blood pool, non-calcific and calcific tissue) within the aortic valve volume of interest, automatically generating thresholds for non-calcific and calcific volumes, respectively computed as the lower 99.7 and the upper 99.7 percentile of the blood pool HU distribution (Figure). Thus, Fibrocalcific volume was measured as the sum of non-calcific and calcific volumes, indexed for CT annulus area and compared to echo parameters of AS severity. Scan-rescan reproducibility and analysis of AS progression were also assessed. Results Image analysis took 5.8 ± 1.0 minutes per scan and showed excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -9% to 7%). Indexed-fibrocalcific volume correlated well with echocardiographic aortic peak velocity (rho=0.70, p Conclusions This contrast CT-based approach based on a GMM is able to provide robust and relatively rapid assessment of fibrocalcific thickening in patients with AS. Fibrocalcific volume measured using this method, correlates well with other markers of AS severity, predicts disease progression and holds promise in tracking disease progression and response to novel therapies.

BackgroundThe diagnosis and management of myocardial infarction is increasingly complex andestablishing the presence of intracoronary thrombosis has major implications for both theclassification and treatment of myocardial infarction.ObjectivesTo investigate whether positron emission tomography (PET) and computed tomography (CT)could non-invasively detect in vivo thrombus formation in human coronary arteries using anovel glycoprotein IIb/IIIa receptor antagonist-based radiotracer, 18F-GP1.MethodsIn a single centre observational case-control study, patients with or without acute myocardialinfarction underwent coronary 18F-GP1 PET-CT angiography. Coronary artery 18F-GP1 uptakewas assessed visually and quantified using maximum target-to-background ratios.Results18F-GP1 PET-CT angiography was performed in 49 patients with, and 50 patients without,acute myocardial infarction (61±9 years, 75% male). Coronary 18F-GP1 uptake was apparentin 39 (80%) of the 49 culprit lesions in patients with acute myocardial infarction. False negativescans appeared to relate to time delays to scan conduct and low thrombus burden in smallcalibre distal arteries. On multivariable regression analysis, culprit vessel status was the onlyindependent variable associated with higher 18F-GP1 uptake. Extra-coronary cardiac 18F-GP1findings included a high frequency of infarct-related intramyocardial uptake (35%) as well asleft ventricular (8%) or left atrial (2%) thrombus.ConclusionsCoronary 18F-GP1 PET-CT angiography is the first non-invasive selective technique to identifyin vivo coronary thrombosis in patients with acute myocardial infarction. This novel approachcan further define the role and location of thrombosis within the heart and has the potential toinform the diagnosis, management, and treatment of patients with acute myocardial infarction.

Simultaneous positron emission tomography and magnetic resonance imaging (PET-MRI) combines the anatomical detail and tissue characterization of MRI with the functional information from PET. Within the coronary arteries, this hybrid technique can be used to identify biological activity combined with anatomically high-risk plaque features to better understand the processes underlying coronary atherosclerosis. Furthermore, the downstream effects of coronary artery disease on the myocardium can be characterized by providing information on myocardial perfusion, viability, and function. This review will describe the current capabilities of PET-MRI in coronary artery disease and discuss the limitations and future directions of this emerging technique. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.

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 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.

Objectives The authors explored the development and validation of machine-learning models for augmenting the echocardiographic grading of aortic stenosis (AS) severity. Background In AS, symptoms and adverse events develop secondarily to valvular obstruction and left ventricular decompensation. The current echocardiographic grading of AS severity focuses on the valve and is limited by diagnostic uncertainty. Methods Using echocardiography (ECHO) measurements (ECHO cohort, n = 1,052), we performed patient similarity analysis to derive high-severity and low-severity phenogroups of AS. We subsequently developed a supervised machine-learning classifier and validated its performance with independent markers of disease severity obtained using computed tomography (CT) (CT cohort, n = 752) and cardiovascular magnetic resonance (CMR) imaging (CMR cohort, n = 160). The classifier’s prognostic value was further validated using clinical outcomes (aortic valve replacement [AVR] and death) observed in the ECHO and CMR cohorts. Results In 1,964 patients from the 3 multi-institutional cohorts, 1,346 (68%) subjects had either nonsevere or discordant AS severity. Machine learning identified 1,117 (57%) patients as having high-severity and 847 (43%) as having low-severity AS. High-severity patients in CT and CMR cohorts had higher valve calcium scores and left ventricular mass and fibrosis, respectively than the low-severity group. In the ECHO cohort, progression to AVR and progression to death in patients who did not receive AVR was faster in the high-severity group. Compared with the conventional classification of disease severity, machine-learning–based severity classification improved discrimination (integrated discrimination improvement: 0.07; 95% confidence interval: 0.02 to 0.12) and reclassification (net reclassification improvement: 0.17; 95% confidence interval: 0.11 to 0.23) for the outcome of AVR at 5 years. For both ECHO and CMR cohorts, we observed prognostic value of the machine-learning classifications for subgroups with asymptomatic, nonsevere or discordant AS. Conclusions Machine learning can integrate ECHO measurements to augment the classification of disease severity in most patients with AS, with major potential to optimize the timing of AVR.

Coronary computed tomography angiography (CTA) has shown great technological improvements over the last 2 decades. High accuracy of CTA in detecting significant coronary stenosis has promoted CTA as a substitute for conventional invasive coronary angiography in patients with suspected coronary artery disease. In patients with coronary stenosis, CTA-derived physiological assessment is surrogate for intracoronary pressure and velocity wires, and renders possible decision-making about revascularization solely based on computed tomography. Computed tomography coronary anatomy with functionality assessment could potentially become a first line in diagnosis. Noninvasive imaging assessment of plaque burden and morphology is becoming a valuable substitute for intravascular imaging. Recently, wall shear stress and perivascular inflammation have been introduced. These assessments could support risk management for both primary and secondary cardiovascular prevention. Anatomy, functionality, and plaque composition by CTA tend to replace invasive assessment. Complete CTA assessment could provide a 1-stop-shop for diagnosis, risk management, and decision-making on treatment.

ObjectiveIn patients with abdominal aortic aneurysms, sodium [18F]fluoride positron emission tomography identifies aortic microcalcification and disease activity. Increased uptake is associated with aneurysm expansion and adverse clinical events. The effect of endovascular aneurysm repair (EVAR) on aortic disease activity and sodium [18F]fluoride uptake is unknown. This study aimed to compare aortic sodium [18F]fluoride uptake before and after treatment with EVAR.MethodsIn a preliminary proof-of-concept cohort study, preoperative and post-operative sodium [18F]fluoride positron emission tomography-computed tomography angiography was performed in patients with an infrarenal abdominal aortic aneurysm undergoing EVAR according to current guideline-directed size treatment thresholds. Regional aortic sodium [18F]fluoride uptake was assessed using aortic microcalcification activity (AMA): a summary measure of mean aortic sodium [18F]fluoride uptake.ResultsTen participants were recruited (76±6 years) with a mean aortic diameter of 57±2 mm at time of EVAR. Mean time from EVAR to repeat scan was 62±21 months. Prior to EVAR, there was higher abdominal aortic AMA when compared with the thoracic aorta (AMA 1.88 vs 1.2; p18F]fluoride uptake was markedly reduced in the suprarenal (ΔAMA 0.62, p=0.03), neck (ΔAMA 0.72, p=0.02) and body of the aneurysm (ΔAMA 0.69, p=0.02) while it remained unchanged in the thoracic aorta (ΔAMA 0.11, p=0.41).ConclusionsEVAR is associated with a reduction in AMA within the stented aortic segment. This suggests that EVAR can modify aortic disease activity and aortic sodium [18F]fluoride uptake is a promising non-invasive surrogate measure of aneurysm disease activity.

ObjectiveWe sought to evaluate the potential impact of racial difference (Asians vs Caucasians) on the clinical usefulness of pressure recovery (PR) adjustment for preventing discordant aortic stenosis (AS) grading in patients with severe AS.MethodsData from 1450 patients (mean age, 70.2±10.6 years; 290 (20%) Caucasians; aortic valve area (AVA), 0.77±0.26 cm2) were retrospectively analysed. PR-adjusted AVA was calculated using a validated equation. Discordant grading of severe AS was defined as AVA of 2and mean gradient of ResultsBefore PR adjustment, 1186 patients showed AVA values of 2; after PR adjustment, 170 (14.3%) were reclassified as having moderate AS. PR adjustment decreased the frequency of discordant grading from 31.4% to 14.1% in Caucasians and from 13.8% to 7.9% in Asians. Patients with reclassification to moderate AS after PR adjustment had a significantly lower risk of a composite of aortic valve replacement or all-cause death than did those with severe AS after PR adjustment (HR 0.38; 95% CI 0.31–0.46; pConclusionsClinically relevant PR occurred, regardless of race in patients with moderate to severe AS. Routine PR adjustment may be useful for reconciling discordant AS grading.

Non-invasive positron emission tomography (PET) of vascular inflammation and atherosclerotic plaque by identifying increased uptake of 18F-fluordeoxyglucose (18F-FDG) is a powerful tool for monitoring disease activity, progression, and its response to therapy. 18F-FDG PET/computed tomography (PET/CT) of the aorta and carotid arteries has become widely used to assess changes in inflammation in clinical trials. However, the recent advent of hybrid PET/magnetic resonance (PET/MR) scanners has advantages for vascular imaging due to the reduction in radiation exposure and improved soft tissue contrast of MR compared to CT. Important for research and clinical use is an understanding of the scan-rescan repeatability of the PET measurement. While this has been studied for PET/CT, no data is currently available for vascular PET/MR imaging. In this study, we determined the scan-rescan measurement repeatability of 18F-FDG PET/MR in the aorta and carotid arteries was less than 5%, comparable to similar findings for 18F-FDG PET/CT.

INTRODUCTION: Vitamin K antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.MATERIAL AND METHODS: Female Apoe-/- mice (age 12 weeks) were fed Western-type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18 F]-NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed.RESULTS: Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran.CONCLUSION: Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

Background Aortic microcalcification activity is a recently described method of measuring aortic sodium [18F]fluoride uptake in the thoracic aorta on positron emission tomography. In this study, we aimed to compare and to modify this method for use within the infrarenal aorta of patients with abdominal aortic aneurysms. Methods Twenty-five patients with abdominal aortic aneurysms underwent an sodium [18F]fluoride positron emission tomography and computed tomography scan. Maximum and mean tissue-to-background ratios (TBR) and abdominal aortic microcalcification activity were determined following application of a thresholding and variable radius method to correct for vertebral sodium [18F]fluoride signal spill-over and the nonlinear changes in aortic diameter, respectively. Agreement between the methods, and repeatability of these approaches were assessed. Results The aortic microcalcification activity method was much quicker to perform than the TBR method (14 versus 40 min, p Conclusions Aortic microcalcification activity is a quick and simple method which demonstrates good intra-observer and inter-observer repeatabilities and provides measures of sodium [18F]fluoride uptake that are comparable to established methods.

OBJECTIVES: The aim of this study was to describe the potential of 18F-sodium fluoride ( 18F-NaF) positron emission tomography (PET) to identify graft vasculopathy and to investigate the influence of coronary artery bypass graft (CABG) surgery on native coronary artery disease activity and progression. BACKGROUND: As well as developing graft vasculopathy, CABGs have been proposed to accelerate native coronary atherosclerosis.METHODS: Patients with established coronary artery disease underwent baseline 18F-NaF PET, coronary artery calcium scoring, coronary computed tomographic angiography, and 1-year repeat coronary artery calcium scoring. Whole-vessel coronary microcalcification activity (CMA) on 18F-NaF PET and change in calcium scores were quantified in patients with and without CABG surgery. RESULTS: Among 293 participants (mean age 65 ± 9 years, 84% men), 48 (16%) underwent CABG surgery 2.7 years [IQR: 1.4-10.4 years] previously. Although all arterial and the majority (120 of 128 [94%]) of vein grafts showed no 18F-NaF uptake, 8 saphenous vein grafts in 7 subjects had detectable CMA. Bypassed native coronary arteries had 3 times higher CMA values (2.1 [IQR: 0.4-7.5] vs 0.6 [IQR: 0-2.7]; P < 0.001) and greater progression of 1-year calcium scores (118 Agatston unit [IQR: 48-194 Agatston unit] vs 69 [IQR: 21-142 Agatston unit]; P = 0.01) compared with patients who had not undergone CABG, an effect confined largely to native coronary plaques proximal to the graft anastomosis. In sensitivity analysis, bypassed native coronary arteries had higher CMA (2.0 [IQR: 0.4-7.5] vs 0.8 [IQR: 0.3-3.2]; P < 0.001) and faster disease progression (24% [IQR: 16%-43%] vs 8% [IQR: 0%-24%]; P = 0.002) than matched patients (n = 48) with comparable burdens of coronary artery disease and cardiovascular comorbidities in the absence of bypass grafting. CONCLUSIONS: Native coronary arteries that have been bypassed demonstrate increased disease activity and more rapid disease progression than nonbypassed arteries, an observation that appears independent of baseline atherosclerotic plaque burden. Microcalcification activity is not a dominant feature of graft vasculopathy.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) was first described over 80 years ago. The term has been widely and inconsistently used in clinical practice, influencing various aspects of disease classification, investigation and management. MINOCA encompasses a heterogenous group of conditions that include both atherosclerotic and non-atherosclerotic disease resulting in myocardial damage that is not due to obstructive coronary artery disease. In many ways, it is a term that describes a moment in the diagnostic pathway of the patient and is arguably not a diagnosis. Central to the definition is also the distinction between myocardial infarction and injury. The universal definition of myocardial infarction distinguishes acute myocardial infarction, including those with MINOCA, from other causes of myocardial injury by the presence of clinical evidence of ischaemia. However, these ischaemic features are often non-specific causing diagnostic confusion, and can create difficulties for patient management and follow-up. The purpose of this review is to summarise our current understanding of MINOCA and highlight important issues relating to the diagnosis, investigation and management of patients with MINOCA.

BACKGROUND: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. METHODS: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year in ISCHEMIA trial screen failures with INOCA) was an international cohort study conducted from 2014–2019 involving angina assessments (Seattle Angina Questionnaire [SAQ]) and stress echocardiograms 1-year apart. This was an ancillary study that included patients with history of angina who were not randomized in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease (CAD) status and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between changes in SAQ Angina Frequency score and change in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and compared CIAO participants with ISCHEMIA participants with obstructive CAD who had stress echocardiography before enrollment, as CIAO participants did. RESULTS: INOCA participants in CIAO were more often female (66% of 208 vs. 26% of 865 ISCHEMIA participants with obstructive CAD, p

Calcific aortic valve disease is the most common valvular disease and confers significant morbidity and mortality. There are currently no medical therapies that successfully halt or reverse the disease progression, making surgical replacement the only treatment currently available. The majority of patients will receive a bioprosthetic valve, which themselves are prone to degeneration and may also need replaced, adding to the already substantial healthcare burden of aortic stenosis. Echocardiography and computed tomography can identify late-stage manifestations of the disease process affecting native and bioprosthetic aortic valves but cannot detect or quantify early molecular changes. 18F-fluoride positron emission tomography, on the other hand, can non-invasively and sensitively assess disease activity in the valves. The current review outlines the pivotal role this novel molecular imaging technique has played in improving our understanding of native and bioprosthetic aortic valve disease, as well as providing insights into its feasibility as an important future research and clinical tool. Electronic supplementary material The online version of this article (10.1007/s12350-020-02411-x) contains supplementary material, which is available to authorized users.

Learning objectives Aortic stenosis is the archetypal heart valve disease with which many doctors, cardiologists or otherwise, retain the most familiarity. The global healthcare burden of aortic stenosis continues to rise, yet it remains one of the last major cardiovascular diseases for which we have no preventative or disease-modifying medical therapy. Aortic valve replacement is the only ‘curative’ intervention and carries attendant risks, both peri-procedural and remote. Thus, the decision to offer intervention must be carefully considered and taken with the final objective that governs most treatments in mind: to improve symptoms or prognosis. There is also substantial debate surrounding the optimal timing of intervention. Intervene too early and patients may be unnecessarily exposed to the risks of valve replacement. Intervene too late and some patients may sustain irreversible cardiac damage that is associated with an increased risk of heart failure and death. Valve replacement in symptomatic patients with severe aortic stenosis is usually uncontroversial, given their poor prognosis and the strong probability of improving their quality of life. Decisions regarding the management of patients with asymptomatic, isolated, severe aortic stenosis, however, are more complex. In this group, the predominant purpose of intervention would be to improve prognosis. In the absence of robust data, standard care in most cases has remained close observation, usually until symptoms develop.1–3 Implicit in this strategy is the concept that patients with asymptomatic severe aortic stenosis have a very good prognosis, and that there is consequently no net benefit to aortic valve replacement. However, this paradigm has latterly become the subject of scrutiny for several reasons. Symptom assessment is frequently challenging in elderly, …

Funder: National Institute for Health Research (NIHR), OBJECTIVES: The management of severe aortic stenosis mandates consideration of aortic valve intervention for symptomatic patients. However, for asymptomatic patients with severe aortic stenosis, recent randomised trials supported earlier intervention. We conducted a systematic review and meta-analysis to evaluate all the available data comparing the two management strategies. METHODS: PubMed, Cochrane and Web of Science databases were systematically searched from inception until 10 January 2022. The search key terms were 'asymptomatic', 'severe aortic stenosis' and 'intervention'. RESULTS: Meta-analysis of two published randomised trials, AVATAR and RECOVERY, included 302 patients and showed that early intervention resulted in 55% reduction in all-cause mortality (HR=0.45, 95% CI 0.24 to 0.86; I2 0%) and 79% reduction in risk of hospitalisation for heart failure (HR=0.21, 95% CI 0.05 to 0.96; I2 15%). There was no difference in risk of cardiovascular death between the two groups (HR=0.36, 95% CI 0.03 to 3.78; I2 78%). Additionally, meta-analysis of eight observational studies showed improved mortality in patients treated with early intervention (HR=0.38, 95% CI 0.26 to 0.56; I2 77%). CONCLUSION: This meta-analysis provides evidence that, in patients with severe asymptomatic aortic stenosis, early intervention reduces all-cause mortality and improves outcomes compared with conservative management. While this is very encouraging, further randomised controlled studies are needed to draw firm conclusions and identify the optimal timing of intervention. PROSPERO REGISTRATION NUMBER: CRD42022301037.

Background: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. Methods: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. Results: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55–74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62–760 ng/L) at presentation and 1165 ng/L (interquartile range, 277–3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. Conclusions: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03338504.

Background: Aortic microcalcification activity is a recently described method of measuring aortic 18F-sodium fluoride uptake in the thoracic aorta on positron emission tomography . In this study, we aimed to compare and to modify this method for use within the infrarenal aorta of patients with abdominal aortic aneurysms.Methods: Twenty-five patients with abdominal aortic aneurysms underwent an 18F-sodium fluoride positron emission tomography and computed tomography scan. Maximum and mean tissue to background ratios (TBR) and abdominal aortic microcalcification activity were determined following application of a thresholding and variable radius method to correct for vertebral 18F-sodium fluoride signal spill-over and the non-linear changes in aortic diameter respectively. Agreement between the methods, and repeatability of these approaches were assessed.Results: The aortic microcalcification activity method was three-fold quicker to perform than the TBR method (14 versus 40 min, pConclusions: Aortic microcalcification activity is a quick and simple method which demonstrates good intra-observer and inter-observer repeatabilities and provides measures of 18F-sodium fluoride uptake that are comparable to established methods.

Aortic microcalcification activity is a recently described method of measuring aortic sodium [Twenty-five patients with abdominal aortic aneurysms underwent an sodium [The aortic microcalcification activity method was much quicker to perform than the TBR method (14 versus 40 min, p 0.001). There was moderate-to-good agreement between TBR and aortic microcalcification activity measurements for maximum (interclass correlation co-efficient, 0.67) and mean (interclass correlation co-efficient, 0.88) values. These correlations sequentially improved with the application of thresholding (intraclass correlation coefficient 0.93, 95% confidence interval 0.89-0.95) and variable diameter (intraclass correlation coefficient 0.97, 95% confidence interval 0.94-0.99) techniques. The optimised method had good intra-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.36 and limits of agreement - 0.43 to 0.43) and inter-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.47 and limits of agreement - 0.53 to 0.53) repeatability.Aortic microcalcification activity is a quick and simple method which demonstrates good intra-observer and inter-observer repeatabilities and provides measures of sodium [

Bioprosthetic valve dysfunction (BVD) and bioprosthetic valve failure (BVF) may be caused by structural or nonstructural valve dysfunction. Both surgical and transcatheter bioprosthetic valves have limited durability because of structural valve deterioration. The main objective of this summary of experts participating in a virtual workshop was to propose standardized definitions for nonstructural and structural BVD and BVF following aortic or mitral biological valve replacement with the goal of facilitating research reporting and implementation of these terms in clinical practice. Definitions of structural BVF, based on valve reintervention or death, underestimate the true incidence of BVF. However, definitions solely based on the presence of high transprosthetic gradient at a given echocardiogram during follow-up overestimate the incidence of structural BVD and BVF. Definitions of aortic or mitral structural BVD must therefore include the confirmation by imaging of permanent structural changes to the leaflets alongside evidence of deterioration in valve hemodynamic function at echocardiography follow-up.