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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.

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

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.

Supplemental Digital Content is available in the text., Background: The future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score, or coronary artery stenosis severity. We assessed whether noncalcified low-attenuation plaque burden on coronary CT angiography (CCTA) might be a better predictor of the future risk of myocardial infarction. Methods: In a post hoc analysis of a multicenter randomized controlled trial of CCTA in patients with stable chest pain, we investigated the association between the future risk of fatal or nonfatal myocardial infarction and low-attenuation plaque burden (% plaque to vessel volume), cardiovascular risk score, coronary artery calcium score or obstructive coronary artery stenoses. Results: In 1769 patients (56% male; 58±10 years) followed up for a median 4.7 (interquartile interval, 4.0–5.7) years, low-attenuation plaque burden correlated weakly with cardiovascular risk score (r=0.34; P

Introduction: The integrin receptor αvβ3 is upregulated by vascular endothelial cells, macrophages and myofibroblasts during cardiac interstitial remodeling. We evaluated the role for the novel αvβ3 radiotracer 18F-fluciclatide in the non-invasive assessment of repair post-myocardial infarction. Methods: We performed combined PET/CT and CT-coronary angiography (CTCA) imaging of the heart following intravenous administration of 18F-fluciclatide (230mBq) in 21 patients 12±4 days after acute ST-elevation myocardial infarction, 7 stable patients with occlusion of a major coronary vessel for >6months, and 9 healthy volunteers. ECG-gated PET data was acquired over 30 minutes, 40 minutes after ligand injection. Subjects also underwent Cardiac MRI (CMR) with assessment of late gadolinium enhancement and T1 mapping. PET data was fused with the CTCA and re-orientated into the left ventricular short-axis plane. The infarct site was identified through co-registration with CMR and delineated using regions of interest and a 16-segment approach. PET values, corrected for blood activity, were expressed as a mean tissue-to-background ratio. Myocardial extracellular volume (ECV) in a 16-segment model was quantified on CMR using T1 mapping pre-and post-gadolinium administration. Results: 18F-fluciclatide uptake correlated with cardiac ECV (r=0.37(0.29-0.45),p Conclusions: 18F-Fluciclatide uptake localises to sites of acute myocardial infarction and correlates with extracellular volume on CMR. This holds great potential in the non-invasive quantification of active myocardial remodeling.

Supplemental Digital Content is available in the text., Background— Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. Methods and Results— Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle–induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. Conclusions— These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.

Introduction: Excessive inflammation after myocardial infarction (MI) can be detrimental to the recovery of cardiac function. Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) can detect myocardial cellular inflammation after MI. We aimed to determine the time course and duration of USPIO-enhancement following acute MI. Methods: Twenty-one patients with acute MI were studied in the 3-month period following acute MI. Repeated T2*-weighted 3T MRI was performed throughout and 24 h after USPIO (ferumoxytol, 4 mg/kg) administration at 4±3, 12±2, 21±4 and 90±9 days. Myocardial regions of interest (ROIs) were drawn and categorised into infarct and non-infarct regions by the presence or absence of late gadolinium enhancement (LGE). R2* values within ROIs were determined to assess the time course and duration of uptake and clearance of USPIO. Results: Following single-dose USPIO administration 2-7 days after acute MI, USPIO uptake is demonstrable at 24 h (p Conclusions: For the first time, we have shown USPIO-enhanced MRI can detect and quantify infarct-related cellular inflammation in the first 2 weeks following acute MI.