Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. METHODS: Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. RESULTS: Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. CONCLUSIONS: Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.

Myocardial Involvement After Hospitalization for COVID-19 Complicated by Troponin Elevation: A Prospective, Multicenter, Observational Study.

BACKGROUND: Acute myocardial injury in hospitalized patients with coronavirus disease 2019 (COVID-19) has a poor prognosis. Its associations and pathogenesis are unclear. Our aim was to assess the presence, nature, and extent of myocardial damage in hospitalized patients with troponin elevation. METHODS: Across 25 hospitals in the United Kingdom, 342 patients with COVID-19 and an elevated troponin level (COVID+/troponin+) were enrolled between June 2020 and March 2021 and had a magnetic resonance imaging scan within 28 days of discharge. Two prospective control groups were recruited, comprising 64 patients with COVID-19 and normal troponin levels (COVID+/troponin-) and 113 patients without COVID-19 or elevated troponin level matched by age and cardiovascular comorbidities (COVID-/comorbidity+). Regression modeling was performed to identify predictors of major adverse cardiovascular events at 12 months. RESULTS: Of the 519 included patients, 356 (69%) were men, with a median (interquartile range) age of 61.0 years (53.8, 68.8). The frequency of any heart abnormality, defined as left or right ventricular impairment, scar, or pericardial disease, was 2-fold greater in cases (61% [207/342]) compared with controls (36% [COVID+/troponin-] versus 31% [COVID-/comorbidity+]; P<0.001 for both). More cases than controls had ventricular impairment (17.2% versus 3.1% and 7.1%) or scar (42% versus 7% and 23%; P<0.001 for both). The myocardial injury pattern was different, with cases more likely than controls to have infarction (13% versus 2% and 7%; P<0.01) or microinfarction (9% versus 0% and 1%; P<0.001), but there was no difference in nonischemic scar (13% versus 5% and 14%; P=0.10). Using the Lake Louise magnetic resonance imaging criteria, the prevalence of probable recent myocarditis was 6.7% (23/342) in cases compared with 1.7% (2/113) in controls without COVID-19 (P=0.045). During follow-up, 4 patients died and 34 experienced a subsequent major adverse cardiovascular event (10.2%), which was similar to controls (6.1%; P=0.70). Myocardial scar, but not previous COVID-19 infection or troponin, was an independent predictor of major adverse cardiovascular events (odds ratio, 2.25 [95% CI, 1.12-4.57]; P=0.02). CONCLUSIONS: Compared with contemporary controls, patients with COVID-19 and elevated cardiac troponin level have more ventricular impairment and myocardial scar in early convalescence. However, the proportion with myocarditis was low and scar pathogenesis was diverse, including a newly described pattern of microinfarction. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: 58667920.

Rationale and design of the Early valve replacement in severe ASYmptomatic Aortic Stenosis Trial.

BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.

Sex differences in coronary atherosclerotic plaque activity using 18F-sodium fluoride positron emission tomography.

INTRODUCTION: There are sex differences in the extent, severity, and outcomes of coronary artery disease. We aimed to assess the influence of sex on coronary atherosclerotic plaque activity measured using coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), and to determine whether 18F-NaF PET has prognostic value in both women and men. METHODS: In a post-hoc analysis of observational cohort studies of patients with coronary atherosclerosis who had undergone 18F-NaF PET CT angiography, we compared the coronary microcalcification activity (CMA) in women and men. RESULTS: Baseline 18F-NaF PET CT angiography was available in 999 participants (151 (15%) women) with 4282 patient-years of follow-up. Compared to men, women had lower coronary calcium scores (116 [interquartile range, 27-434] versus 205 [51-571] Agatston units; p = 0.002) and CMA values (0.0 [0.0-1.12] versus 0.53 [0.0-2.54], p = 0.01). Following matching for plaque burden by coronary calcium scores and clinical comorbidities, there was no sex-related difference in CMA values (0.0 [0.0-1.12] versus 0.0 [0.0-1.23], p = 0.21) and similar proportions of women and men had no 18F-NaF uptake (53.0% (n = 80) and 48.3% (n = 73); p = 0.42), or CMA values > 1.56 (21.8% (n = 33) and 21.8% (n = 33); p = 1.00). Over a median follow-up of 4.5 [4.0-6.0] years, myocardial infarction occurred in 6.6% of women (n = 10) and 7.8% of men (n = 66). Coronary microcalcification activity greater than 0 was associated with a similarly increased risk of myocardial infarction in both women (HR: 3.83; 95% CI:1.10-18.49; p = 0.04) and men (HR: 5.29; 95% CI:2.28-12.28; p < 0.001). CONCLUSION: Although men present with more coronary atherosclerotic plaque than women, increased plaque activity is a strong predictor of future myocardial infarction regardless of sex.

Thoracic aortic microcalcification activity in combined positron emission tomography and magnetic resonance imaging.

INTRODUCTION: Non-invasive detection of pathological changes in thoracic aortic disease remains an unmet clinical need particularly for patients with congenital heart disease. Positron emission tomography combined with magnetic resonance imaging (PET-MRI) could provide a valuable low-radiation method of aortic surveillance in high-risk groups. Quantification of aortic microcalcification activity using sodium [18F]fluoride holds promise in the assessment of thoracic aortopathies. We sought to evaluate aortic sodium [18F]fluoride uptake in PET-MRI using three methods of attenuation correction compared to positron emission tomography computed tomography (PET-CT) in patients with bicuspid aortic valve, METHODS: Thirty asymptomatic patients under surveillance for bicuspid aortic valve disease underwent sodium [18F]fluoride PET-CT and PET-MRI of the ascending thoracic aorta during a single visit. PET-MRI data were reconstructed using three iterations of attenuation correction (Dixon, radial gradient recalled echo with two [RadialVIBE-2] or four [RadialVIBE-4] tissue segmentation). Images were qualitatively and quantitatively analysed for aortic sodium [18F]fluoride uptake on PET-CT and PET-MRI. RESULTS: Aortic sodium [18F]fluoride uptake on PET-MRI was visually comparable with PET-CT using each reconstruction and total aortic standardised uptake values on PET-CT strongly correlated with each PET-MRI attenuation correction method (Dixon R = 0.70; RadialVIBE-2 R = 0.63; RadialVIBE-4 R = 0.64; p < 0.001 for all). Breathing related artefact between soft tissue and lung were detected using Dixon and RadialVIBE-4 but not RadialVIBE-2 reconstructions, with the presence of this artefact adjacent to the atria leading to variations in blood pool activity estimates. Consequently, quantitative agreements between radiotracer activity on PET-CT and PET-MRI were most consistent with RadialVIBE-2. CONCLUSION: Ascending aortic microcalcification analysis in PET-MRI is feasible with comparable findings to PET-CT. RadialVIBE-2 tissue attenuation correction correlates best with the reference standard of PET-CT and is less susceptible to artefact. There remain challenges in segmenting tissue types in PET-MRI reconstructions, and improved attenuation correction methods are required.

A systematic review for the evidence of recommendations and guidelines in hybrid nuclear cardiovascular imaging.

OBJECTIVES: This study aimed to evaluate the level of evidence of expert recommendations and guidelines for clinical indications and procedurals in hybrid nuclear cardiovascular imaging. METHODS: From inception to August 2023, a PubMed literature analysis of the latest version of guidelines for clinical hybrid cardiovascular imaging techniques including SPECT(/CT), PET(/CT), and PET(/MRI) was performed in two categories: (1) for clinical indications for all-in primary diagnosis; subgroup in prognosis and therapy evaluation; and for (2) imaging procedurals. We surveyed to what degree these followed a standard methodology to collect the data and provide levels of evidence, and for which topic systematic review evidence was executed. RESULTS: A total of 76 guidelines, published between 2013 and 2023, were included. The evidence of guidelines was based on systematic reviews in 7.9% of cases, non-systematic reviews in 47.4% of cases, a mix of systematic and non-systematic reviews in 19.7%, and 25% of guidelines did not report any evidence. Search strategy was reported in 36.8% of cases. Strengths of recommendation were clearly reported in 25% of guidelines. The notion of external review was explicitly reported in 23.7% of cases. Finally, the support of a methodologist was reported in 11.8% of the included guidelines. CONCLUSION: The use of evidence procedures for developing for evidence-based cardiovascular hybrid imaging recommendations and guidelines is currently suboptimal, highlighting the need for more standardized methodological procedures.

Noninvasive In Vivo Thrombus Imaging in Patients With Ischemic Stroke or Transient Ischemic Attack-Brief Report.

BACKGROUND: 18F-GP1 is a novel positron-emitting radiotracer that is highly specific for activated platelets and thrombus. In a proof-of-concept study, we aimed to determine its potential clinical application in establishing the role and origin of thrombus in ischemic stroke. METHODS: Eleven patients with recent ischemic stroke (n=9) or transient ischemic attack (n=2) underwent 18F-GP1 positron emission tomography and computed tomography angiography at a median of 11 (range, 2-21) days from symptom onset. 18F-GP1 uptake (maximum target-to-background ratio) was assessed in the carotid arteries and brain. RESULTS: 18F-GP1 uptake was identified in 10 of 11 patients: 4 in the carotid arteries only, 3 in the brain only, and 3 in both the brain and carotid arteries. In those with carotid uptake, 4 participants had >50% stenosis and 3 had nonstenotic disease. One case had bilateral stenotic disease (>70%), but only the culprit carotid artery demonstrated 18F-GP1 uptake. The average uptake was higher in the culprit (median maximum target-to-background ratio, 1.55 [interquartile range, 1.26-1.82]) compared with the contralateral nonculprit carotid artery (maximum target-to-background ratio, 1.22 [1.19-1.6]). In those with brain 18F-GP1 uptake (maximum target-to-background ratio, 6.45 [4.89-7.65]), areas of acute infarction on computed tomography correlated with brain 18F-GP1 uptake in 6 cases. Ex vivo autoradiography of postmortem infarcted brain tissue showed focal uptake corresponding to intraluminal thrombus within the culprit vessel and downstream microvasculature. There was also evidence of diffuse uptake within some of the infarcted brain tissue reflecting parenchymal petechial hemorrhage. CONCLUSIONS: 18F-GP1 positron emission tomography and computed tomography angiography is a novel noninvasive method of identifying in vivo cerebrovascular thrombosis, which holds major promise in understanding the role and origin of thrombosis in stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03943966.

Latent Coronary Plaque Morphology From Computed Tomography Angiography, Molecular Disease Activity on Positron Emission Tomography, and Clinical Outcomes.

BACKGROUND: Assessments of coronary disease activity with 18F-sodium fluoride positron emission tomography and radiomics-based precision coronary plaque phenotyping derived from coronary computed tomography angiography may enhance risk stratification in patients with coronary artery disease. We sought to investigate whether the prognostic information provided by these 2 approaches is complementary in the prediction of myocardial infarction. METHODS: Patients with known coronary artery disease underwent coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography on a hybrid positron emission tomography/computed tomography scanner. Coronary 18F-NaF uptake was determined by the coronary microcalcification activity. We performed quantitative plaque analysis of coronary computed tomography angiography datasets and extracted 1103 radiomic features for each plaque. Using weighted correlation network analysis, we derived latent morphological features of coronary lesions which were aggregated to patient-level radiomics nomograms to predict myocardial infarction. RESULTS: Among 260 patients with established coronary artery disease (age, 65±9 years; 83% men), 179 (69%) participants showed increased coronary 18F-NaF activity (coronary microcalcification activity>0). Over 53 (40-59) months of follow-up, 18 patients had a myocardial infarction. Using weighted correlation network analysis, we derived 15 distinct eigen radiomic features representing latent morphological coronary plaque patterns in an unsupervised fashion. Following adjustments for calcified, noncalcified, and low-density noncalcified plaque volumes and 18F-NaF coronary microcalcification activity, 4 radiomic features remained independent predictors of myocardial infarction (hazard ratio, 1.46 [95% CI, 1.03-2.08]; P=0.03; hazard ratio, 1.62 [95% CI, 1.04-2.54]; P=0.02; hazard ratio, 1.49 [95% CI, 1.07-2.06]; P=0.01; and hazard ratio, 1.50 (95% CI, 1.05-2.13); P=0.02). CONCLUSIONS: In patients with established coronary artery disease, latent coronary plaque morphological features, quantitative plaque volumes, and disease activity on 18F-sodium fluoride positron emission tomography are additive predictors of myocardial infarction.

Atorvastatin lowers 68Ga-DOTATATE uptake in coronary arteries, bone marrow and spleen in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Inflammation is a core component of residual cardiovascular risk in type 2 diabetes. With new anti-inflammatory therapeutics entering the field, accurate markers to evaluate their effectiveness in reducing cardiovascular disease are paramount. Gallium-68-labelled DOTATATE (68Ga-DOTATATE) has recently been proposed as a more specific marker of arterial wall inflammation than 18F-fluorodeoxyglucose (18F-FDG). This study set out to investigate whether 68Ga-DOTATATE uptake is amenable to therapeutic intervention in individuals with type 2 diabetes. METHODS: Individuals aged >50 years with type 2 diabetes underwent 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) at baseline and after 3 months treatment with atorvastatin 40 mg once daily. Primary outcome was the difference in coronary 68Ga-DOTATATE uptake, expressed as target-to-background ratio (TBR). The secondary outcome was difference in bone marrow and splenic uptake, expressed as the standardised uptake value (SUV). RESULTS: Twenty-two individuals with type 2 diabetes (mean age 63.2±6.4 years, 82% male, LDL-cholesterol 3.42±0.81 mmol/l, HbA1c 55±12 mmol/mol [7.2%±3.2%]) completed both 68Ga-DOTATATE PET/CT scans. The maximum TBR was -31% (95% CI -50, -12) lower in the coronary arteries, and bone marrow and splenic 68Ga-DOTATATE uptake was also significantly lower post statin treatment, with a mean percentage reduction of -15% (95% CI -27, -4) and -17% (95% CI -32, -2), respectively. CONCLUSIONS/INTERPRETATION: 68Ga-DOTATATE uptake across the cardio-haematopoietic axis was lower after statin therapy in individuals with type 2 diabetes. Therefore, 68Ga-DOTATATE is promising as a metric for vascular and haematopoietic inflammation in intervention studies using anti-inflammatory therapeutics in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05730634.

Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome.

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<0.001), increased left ventricular mass (86±11 versus 57±14 g/m2; P<0.001), and, in affected myocardial segments, elevated native T1 (1358±49 versus 1211±28 ms; P<0.001) and T2 (60±7 versus 38±3 ms; P<0.0001) values at their index presentation. During manganese-enhanced imaging, kinetic modeling demonstrated a substantial reduction in myocardial manganese uptake (5.1±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min], respectively; P<0.0001), consistent with markedly abnormal myocardial calcium handling. After recovery, left ejection fraction, left ventricular mass, and T2 values were comparable with those of matched control volunteers. Despite this, native and postmanganese T1 and myocardial manganese uptake remained abnormal compared with matched control volunteers (6.6±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min]; P<0.0001). 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.

Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study.

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.

Evaluating Radiation Exposure in Patients with Stable Chest Pain in the SCOT-HEART Trial.

Background In the Scottish Computed Tomography of the Heart (SCOT-HEART) trial in individuals with stable chest pain, a treatment strategy based on coronary CT angiography (CTA) led to improved outcomes. Purpose To assess 5-year cumulative radiation doses of participants undergoing investigation for suspected angina due to coronary artery disease with or without coronary CTA. Materials and Methods This secondary analysis of the SCOT-HEART trial included data from six of 12 recruiting sites and two of three imaging sites. Participants were recruited between November 18, 2010, and September 24, 2014, with follow-up through January 31, 2018. Study participants had been randomized (at a one-to-one ratio) to standard care with CT (n = 1466) or standard care alone (n = 1428). Imaging was performed on a 64-detector (n = 223) or 320-detector row scanner (n = 1466). Radiation dose from CT (dose-length product), SPECT (injected activity), and invasive coronary angiography (ICA; kerma-area product) was assessed for 5 years after enrollment. Effective dose was calculated using conversion factors appropriate for the imaging modality and body region imaged (using 0.026 mSv/mGy · cm for cardiac CT). Results Cumulative radiation dose was assessed in 2894 participants. Median effective dose was 3.0 mSv (IQR, 2.6-3.3 mSv) for coronary calcium scoring, 4.1 mSv (IQR, 2.6-6.1 mSv) for coronary CTA, 7.4 mSv (IQR, 6.2-8.5 mSv) for SPECT, and 4.1 mSv (IQR, 2.5-6.8 mSv) for ICA. After 5 years, total per-participant cumulative dose was higher in the CT group (median, 8.1 mSv; IQR, 5.5-12.4 mSv) compared with standard-care group (median, 0 mSv; IQR, 0-4.5 mSv; P < .001). In participants who underwent any imaging, cumulative radiation exposure was higher in the CT group (n = 1345; median, 8.6 mSv; IQR, 6.1-13.3 mSv) compared with standard-care group (n = 549; median, 6.4 mSv; IQR, 3.4-9.2 mSv; P < .001). Conclusion In the SCOT-HEART trial, the 5-year cumulative radiation dose from cardiac imaging was higher in the coronary CT angiography group compared with the standard-care group, largely because of the radiation exposure from CT. Clinical trial registration no. NCT01149590 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Dodd and Bosserdt in this issue.

PET-MRI of Coronary Artery Disease.

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.

Manganese-Enhanced Magnetic Resonance Imaging of the Heart.

Manganese-based contrast media were the first in vivo paramagnetic agents to be used in magnetic resonance imaging (MRI). The uniqueness of manganese lies in its biological function as a calcium channel analog, thus behaving as an intracellular contrast agent. Manganese ions are taken up by voltage-gated calcium channels in viable tissues, such as the liver, pancreas, kidneys, and heart, in response to active calcium-dependent cellular processes. Manganese-enhanced magnetic resonance imaging (MEMRI) has therefore been used as a surrogate marker for cellular calcium handling and interest in its potential clinical applications has recently re-emerged, especially in relation to assessing cellular viability and myocardial function. Calcium homeostasis is central to myocardial contraction and dysfunction of myocardial calcium handling is present in various cardiac pathologies. Recent studies have demonstrated that MEMRI can detect the presence of abnormal myocardial calcium handling in patients with myocardial infarction, providing clear demarcation between the infarcted and viable myocardium. Furthermore, it can provide more subtle assessments of abnormal myocardial calcium handling in patients with cardiomyopathies and being excluded from areas of nonviable cardiomyocytes and severe fibrosis. As such, MEMRI offers exciting potential to improve cardiac diagnoses and provide a noninvasive measure of myocardial function and contractility. This could be an invaluable tool for the assessment of both ischemic and nonischemic cardiomyopathies as well as providing a measure of functional myocardial recovery, an accurate prediction of disease progression and a method of monitoring treatment response. EVIDENCE LEVEL: 5: TECHNICAL EFFICACY: STAGE 5.

Non-invasive imaging of functional pancreatic islet beta-cell mass in people with type 1 diabetes mellitus.

AIMS: To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. METHODS: In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. RESULTS: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in 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 people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes 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 manganese uptake and age, body-mass index, or glycated haemoglobin. There was strong intra-observer (mean difference: 0.31 (limits of agreement -1.42 to 2.05) mL/100 g of tissue/min; intra-class correlation, ICC = 0.99), inter-observer (-1.23 (-5.74 to 3.27) 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-enhanced magnetic resonance imaging provides a potential reproducible non-invasive measure of functional beta-cell mass in people with type 1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoring disease progression and assessing novel immunomodulatory interventions.

Automated nonlinear registration of coronary PET to CT angiography using pseudo-CT generated from PET with generative adversarial networks.

BACKGROUND: Coronary 18F-sodium-fluoride (18F-NaF) positron emission tomography (PET) showed promise in imaging coronary artery disease activity. Currently image processing remains subjective due to the need for manual registration of PET and computed tomography (CT) angiography data. We aimed to develop a novel fully automated method to register coronary 18F-NaF PET to CT angiography using pseudo-CT generated by generative adversarial networks (GAN). METHODS: A total of 169 patients, 139 in the training and 30 in the testing sets were considered for generation of pseudo-CT from non-attenuation corrected (NAC) PET using GAN. Non-rigid registration was used to register pseudo-CT to CT angiography and the resulting transformation was used to align PET with CT angiography. We compared translations, maximal standard uptake value (SUVmax) and target to background ratio (TBRmax) at the location of plaques, obtained after observer and automated alignment. RESULTS: Automatic end-to-end registration was performed for 30 patients with 88 coronary vessels and took 27.5 seconds per patient. Difference in displacement motion vectors between GAN-based and observer-based registration in the x-, y-, and z-directions was 0.8 ± 3.0, 0.7 ± 3.0, and 1.7 ± 3.9 mm, respectively. TBRmax had a coefficient of repeatability (CR) of 0.31, mean bias of 0.03 and narrow limits of agreement (LOA) (95% LOA: - 0.29 to 0.33). SUVmax had CR of 0.26, mean bias of 0 and narrow LOA (95% LOA: - 0.26 to 0.26). CONCLUSION: Pseudo-CT generated by GAN are perfectly registered to PET can be used to facilitate quick and fully automated registration of PET and CT angiography.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

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

BACKGROUND: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR). METHODS: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol. RESULTS: In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P<0.001) and SAVR (r=0.7, P<0.001). On multivariable analysis, 18F-NaF uptake was the only predictor of peak velocity progression (P<0.001). CONCLUSIONS: In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276.

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

BACKGROUND: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. METHODS: In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score. RESULTS: A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. CONCLUSIONS: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

18F-NaF PET/MRI for Detection of Carotid Atheroma in Acute Neurovascular Syndrome.

Background MRI 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. Purpose To evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome. Materials and Methods In 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. Results A 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. Conclusion Fluorine 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 © RSNA, 2022 Online supplemental material is available for this article.