Invasive vs. conservative management of older patients with non-ST-elevation acute coronary syndrome: individual patient data meta-analysis.

BACKGROUND AND AIMS: Older patients with non-ST-elevation acute coronary syndrome (NSTEACS) are less likely to receive guideline-recommended care including coronary angiography and revascularization. Evidence-based recommendations regarding interventional management strategies in this patient cohort are scarce. This meta-analysis aimed to assess the impact of routine invasive vs. conservative management of NSTEACS by using individual patient data (IPD) from all available randomized controlled trials (RCTs) including older patients. METHODS: MEDLINE, Web of Science and Scopus were searched between 1 January 2010 and 11 September 2023. RCTs investigating routine invasive and conservative strategies in persons >70 years old with NSTEACS were included. Observational studies or trials involving populations outside the target range were excluded. The primary endpoint was a composite of all-cause mortality and myocardial infarction (MI) at 1 year. One-stage IPD meta-analyses were adopted by use of random-effects and fixed-effect Cox models. This meta-analysis is registered with PROSPERO (CRD42023379819). RESULTS: Six eligible studies were identified including 1479 participants. The primary endpoint occurred in 181 of 736 (24.5%) participants in the invasive management group compared with 215 of 743 (28.9%) participants in the conservative management group with a hazard ratio (HR) from random-effects model of 0.87 (95% CI 0.63-1.22; P = .43). The hazard for MI at 1 year was significantly lower in the invasive group compared with the conservative group (HR from random-effects model 0.62, 95% CI 0.44-0.87; P = .006). Similar results were seen for urgent revascularization (HR from random-effects model 0.41, 95% CI 0.18-0.95; P = .037). There was no significant difference in mortality. CONCLUSIONS: No evidence was found that routine invasive treatment for NSTEACS in older patients reduces the risk of a composite of all-cause mortality and MI within 1 year compared with conservative management. However, there is convincing evidence that invasive treatment significantly lowers the risk of repeat MI or urgent revascularisation. Further evidence is needed from ongoing larger clinical trials.

Role of Human Epicardial Adipose Tissue-Derived miR-92a-3p in Myocardial Redox State.

BACKGROUND: Visceral obesity is directly linked to increased cardiovascular risk, including heart failure. OBJECTIVES: This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes. METHODS: This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years. RESULTS: EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase-derived superoxide (O2.-) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events. CONCLUSIONS: EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.

Deep-Learning for Epicardial Adipose Tissue Assessment With Computed Tomography: Implications for Cardiovascular Risk Prediction.

BACKGROUND: Epicardial adipose tissue (EAT) volume is a marker of visceral obesity that can be measured in coronary computed tomography angiograms (CCTA). The clinical value of integrating this measurement in routine CCTA interpretation has not been documented. OBJECTIVES: This study sought to develop a deep-learning network for automated quantification of EAT volume from CCTA, test it in patients who are technically challenging, and validate its prognostic value in routine clinical care. METHODS: The deep-learning network was trained and validated to autosegment EAT volume in 3,720 CCTA scans from the ORFAN (Oxford Risk Factors and Noninvasive Imaging Study) cohort. The model was tested in patients with challenging anatomy and scan artifacts and applied to a longitudinal cohort of 253 patients post-cardiac surgery and 1,558 patients from the SCOT-HEART (Scottish Computed Tomography of the Heart) Trial, to investigate its prognostic value. RESULTS: External validation of the deep-learning network yielded a concordance correlation coefficient of 0.970 for machine vs human. EAT volume was associated with coronary artery disease (odds ratio [OR] per SD increase in EAT volume: 1.13 [95% CI: 1.04-1.30]; P = 0.01), and atrial fibrillation (OR: 1.25 [95% CI: 1.08-1.40]; P = 0.03), after correction for risk factors (including body mass index). EAT volume predicted all-cause mortality (HR per SD: 1.28 [95% CI: 1.10-1.37]; P = 0.02), myocardial infarction (HR: 1.26 [95% CI:1.09-1.38]; P = 0.001), and stroke (HR: 1.20 [95% CI: 1.09-1.38]; P = 0.02) independently of risk factors in SCOT-HEART (5-year follow-up). It also predicted in-hospital (HR: 2.67 [95% CI: 1.26-3.73]; P ≤ 0.01) and long-term post-cardiac surgery atrial fibrillation (7-year follow-up; HR: 2.14 [95% CI: 1.19-2.97]; P ≤ 0.01). CONCLUSIONS: Automated assessment of EAT volume is possible in CCTA, including in patients who are technically challenging; it forms a powerful marker of metabolically unhealthy visceral obesity, which could be used for cardiovascular risk stratification.

Surgical treatment of endometrioid endometrial carcinoma - laparotomy versus laparoscopy

Objective: Recent publications have raised doubts about the oncological safety of a laparoscopic approach in the treatment of endometrial cancer. The aim of this study was to investigate the beneficial aspects of laparoscopy versus laparotomy in patients with endometrial cancer, and present oncological outcomes. Material and Methods: A retrospective study of patients who underwent surgery for the treatment of endometrioid endometrial cancer was performed. Surgical outcomes and complications in patients who were treated by laparoscopy or open surgery were compared. The patients were followed for 5-years. Patients' characteristics, tumor stage, complications rate and oncologic outcome were analyzed. Results: A total of 151 patients were included. The laparoscopy (n=80) and laparotomy (n=71) groups were homogeneous in regards of demographic data and tumor stage. Median average blood loss (1.31 vs. 1.92 g/dL), the mean duration of hospitalization (5.73 vs. 12.25 days), intraoperative (0 vs. 6%), and severe postoperative complications (5.1 vs. 14.3%) were significantly lower in the laparoscopy group. The numbers of pelvic or para-aortic lymph nodes removed during systematic lymphadenectomy were similar in both groups. Women who underwent laparoscopy and those who underwent laparotomy had similar five-year recurrence-free survival rates (88.7% vs. 91.5%, p=0.864), as well as similar overall five-year survival rates (91.2% vs. 97.2%, p=0.094). Conclusion: The oncological outcome of laparoscopy was similar to that of laparotomy in the treatment of patients with endometrial cancer. However, surgical outcomes and morbidity rates were significantly better in patients treated by laparoscopy. Clinical trials are essential to evaluate the oncological efficacy of laparoscopy in patients with endometrial cancer.

Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19.

BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [<6·99] C19-RS; hazard ratio [HR] 3·31 [95% CI 1·49-7·33], p=0·0033; and 2·58 [1·10-6·05], p=0·028), adjusted for clinical factors, biochemical biomarkers of inflammation and myocardial injury, and technical parameters. The adjusted HR for in-hospital mortality was 8·24 (95% CI 2·16-31·36, p=0·0019) in patients who received no dexamethasone treatment, but 2·27 (0·69-7·55, p=0·18) in those who received dexamethasone after the scan, suggesting that vascular inflammation might have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0·61, p=0·00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. INTERPRETATION: Radiotranscriptomic analysis of CT angiography scans introduces a potentially powerful new platform for the development of non-invasive imaging biomarkers. Application of this platform in routine CT pulmonary angiography scans done in patients with COVID-19 produced the radiotranscriptomic signature C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation and responsible for adverse clinical outcomes, which predicts in-hospital mortality and might allow targeted therapy. FUNDING: Engineering and Physical Sciences Research Council, British Heart Foundation, Oxford BHF Centre of Research Excellence, Innovate UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, Onassis Foundation.

Effect of tumor morcellation in patients with early uterine sarcoma: a multicenter study in Germany

Objective: The use of power morcellation at laparoscopy may worsen survival rates for patients with malignancy. The aim of the present study was to report the outcome of patients with early-stage uterine sarcoma after morcellation or total en-bloc resection, and evaluate potential signs of sarcoma preoperatively. Material and Methods: This multicenter retrospective study consisted of patients, who underwent surgery for FIGO-stage-1 uterine sarcoma. Twenty-four patients were divided into a non-morcellation group and a morcellation group. Clinical records and the outcomes of patients, including one-, three- and five-year survival rates were reviewed. Preoperative characteristics of patients with sarcoma were compared to those of a control group with uterine myoma (1:4 ratio), matched by age and type of operation. Results: Obesity was an independent risk factor for uterine myoma. Tumor growth, solitary growth, largest-diameter lesion >8.0 cm, and anechoic areas suggesting necrosis and increased vascularization were significantly more common in the sarcoma group. A large tumor diameter was significantly associated with mortality. Patients in the non-morcellation group had a slightly lower disease-free survival, but poorer overall survival (OS) rates compared to patients in the morcellation group, but neither difference was statistically significant. Patients in the non-morcellation group, who had undergone a re-exploration experienced late recurrence, but no upstaging was evident after the operation. Conclusion: Preoperative ultrasound characteristics could be useful to distinguish sarcoma from leiomyoma of uterus. Morcellation of a sarcoma may increase abdominal and pelvic recurrence rates, but may not be associated with OS in patients with FIGO-stage-1 disease.

Impact of lymphadenectomy on short- and long-term complications in patients with endometrial cancer.

INTRODUCTION: Early endometrial cancer is primarily treated surgically via hysterectomy, adenectomy and, depending on tumor stage and subtype, lymphadenectomy. Systematic lymph node dissection is known to cause surgical complications. The aim of the present study was to investigate morbidity and mortality rates associated with lymphadenectomy in patients with endometrial cancer who underwent surgery in a routine clinical setting. METHODS: We collected data from 232 patients who were operated for endometrial carcinoma between 2006 and 2018 at the University of Lubeck, Germany. Surgical complications were viewed in relation to surgical risk factors. Additionally, a questionnaire concerning long-term lymphatic complications and survival was completed. Survival was compared between patients who underwent lymphadenectomy (group I) and those who did not (group II). RESULTS: Patients in group I needed revision surgery significantly more often due to postoperative complications (such as lymphoceles) compared to those in group II (p = 0.01). The results indicate more serious complications in patients who underwent a systematic lymphadenectomy and in those with lymph node metastases. 15% of patients who underwent a systematic lymphadenectomy had lymph node metastases. Recurrences occurred in 12.5% of cases and were significantly more frequent in patients who had undergone a lymphadenectomy, even if the lymph nodes were negative (p = 0.02). A comparison of survival data during the follow-up period revealed no significant difference. The study highlighted the need for a better preoperative risk stratification and the avoidance of lymphadenectomy for surgical staging alone.

Cardiac Magnetic Resonance to Detect the Underlying Substrate in Patients with Frequent Idiopathic Ventricular Arrhythmias.

BACKGROUND: A routine diagnostic work-up does not identify structural abnormalities in a substantial proportion of patients with idiopathic ventricular arrhythmias (VAs). We investigated the added value of cardiac magnetic resonance (CMR) imaging in this group of patients. METHODS: A single-centre prospective study was undertaken of 72 patients (mean age 46 ± 16 years; 53% females) with frequent premature ventricular contractions (PVCs ≥ 500/24 h) and/or non-sustained ventricular tachycardia (NSVT), an otherwise normal electrocardiogram, normal echocardiography and no coronary artery disease. RESULTS: CMR provided an additional diagnostic yield in 54.2% of patients. The most prevalent diagnosis was previous myocarditis (23.6%) followed by possible PVC-related cardiomyopathy (20.8%), non-ischaemic cardiomyopathy (8.3%) and ischaemic heart disease (1.4%). The predictors of abnormal CMR findings were male gender, age and PVCs/NSVT non-outflow tract-related or with multiple morphologies. Patients with VAs had an impaired peak left ventricular (LV) global radial strain (GRS) compared with the controls (28.88% (IQR: 25.87% to 33.97%) vs. 36.65% (IQR: 33.19% to 40.2%), p < 0.001) and a global circumferential strain (GCS) (-17.66% (IQR: -19.62% to -16.23%) vs. -20.66% (IQR: -21.72% to -19.6%), p < 0.001). CONCLUSION: CMR reveals abnormalities in a significant proportion of patients with frequent idiopathic VAs. Male gender, age and non-outflow tract PVC origin can be clinical indicators for CMR referral.

Perivascular fat imaging by computed tomography (CT): a virtual guide.

Imaging in medicine has been revolutionised by technological, computational and research advances over the past decades. Computed tomography (CT), in particular, has seen rapid evolution especially in the field of cardiovascular non-invasive imaging. It is being recognised as the first-line tool for the assessment of stable and unstable disease with diagnostic, prognostic and re-stratification potential. Vascular inflammation is a key component of the atherosclerotic process and has been shown to induce molecular, transcriptional and structural changes to perivascular adipose tissue (PVAT). Being a diverse structure itself, PVAT surrounds the human vessels and is characterised by a highly rich secretome, including, amongst others, adipokines, cytokines, gaseous messengers and miRNAs It is implicated in a bidirectional interplay with the adjacent vascular wall, affecting and being affected by aspects of its biology, mainly inflammation. In this review, we discuss the current status of cardiac CT in imaging vascular inflammation through PVAT phenotyping. LINKED ARTICLES: This article is part of a themed issue on Molecular imaging - visual themed issue. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.21/issuetoc.

Effects of canagliflozin on human myocardial redox signalling: clinical implications.

AIMS: Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. METHODS AND RESULTS: Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.-) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.- production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. CONCLUSIONS: We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.

Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease.

BACKGROUND: Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. OBJECTIVES: The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes. METHODS: A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints. RESULTS: Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. CONCLUSIONS: These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183).

Is ABO blood group a risk or prognostic factor for patients with endometrioid endometrial cancer? A retrospective analysis in Germany.

BACKGROUND: A relationship is known to exist between gastric and pancreatic cancers and ABO antigens, caused by various immune modulations related to the ABO blood group of the patient. A similar relationship with regard to gynaecological cancers remains controversial. MATERIALS AND METHODS: Patients who underwent surgery for endometrioid endometrial cancer in International Federation of Gynaecology and Obstetrics (FIGO) stage I, II, III or IV from 2006 to 2018 were identified. The research explored the existence of a relationship between the patients' blood group or Rhesus factor and the incidence of endometrial cancer, grade (G1, G2, G3), FIGO stage, nodal status, recurrence, menopausal status, parity, and body mass index. Statistical methods such as the chi-square test, analysis of variance and the Scheffé post-hoc test were used. RESULTS: Two hundred and two patients with endometrioid endometrial cancer were included: 96 had blood group A, 19 blood group B, 75 blood group 0, and 12 had blood group AB. This distribution corresponds to the general blood group distribution in Germany. The vast majority of the dependent variables, such as grade, FIGO stage, nodal status or recurrence were not significantly associated with ABO blood group or Rhesus factor status. The relative frequencies of G1 and G3 endometrial cancers with respect to blood group were similar. Menopausal status, parity, and body mass index were not related to more advanced FIGO stages at initial diagnosis or to ABO blood group. DISCUSSION: Blood group screening would probably not be helpful in the diagnosis of endometrioid endometrial carcinomas in early stages compared to the current gold standard. Furthermore, a specific blood group does not increase either the risk of recurrence or the risk of a dedifferentiated type of endometrial carcinoma.

Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases.

Obesity is associated with changes in the secretome of adipose tissue (AT), which affects the vasculature through endocrine and paracrine mechanisms. Wingless-related integration site 5A (WNT5A) and secreted frizzled-related protein 5 (SFRP5), adipokines that regulate noncanonical Wnt signaling, are dysregulated in obesity. We hypothesized that WNT5A released from AT exerts endocrine and paracrine effects on the arterial wall through noncanonical RAC1-mediated Wnt signaling. In a cohort of 1004 humans with atherosclerosis, obesity was associated with increased WNT5A bioavailability in the circulation and the AT, higher expression of WNT5A receptors Frizzled 2 and Frizzled 5 in the human arterial wall, and increased vascular oxidative stress due to activation of NADPH oxidases. Plasma concentration of WNT5A was elevated in patients with coronary artery disease compared to matched controls and was independently associated with calcified coronary plaque progression. We further demonstrated that WNT5A induces arterial oxidative stress and redox-sensitive migration of vascular smooth muscle cells via Frizzled 2-mediated activation of a previously uncharacterized pathway involving the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) and the GTPase RAC1. Our study identifies WNT5A and its downstream vascular signaling as a link between obesity and vascular disease pathogenesis, with translational implications in humans.

A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography.

BACKGROUND: Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction. METHODS AND RESULTS: We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62-0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P < 0.001). In Study 3, FRP was significantly higher in 44 patients presenting with acute myocardial infarction compared with 44 matched controls, but unlike FAI, remained unchanged 6 months after the index event, confirming that FRP detects persistent PVAT changes not captured by FAI. CONCLUSION: The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art.

State-of-the-art review article. Atherosclerosis affecting fat: What can we learn by imaging perivascular adipose tissue?

Perivascular adipose tissue (PVAT) surrounding the human coronary arteries, secretes a wide range of adipocytokines affecting the biology of the adjacent vascular wall in a paracrine way. However, we have recently found that PVAT also behaves as a sensor of signals coming from the vascular wall, to which it reacts by changing its morphology and secretory profile. Indeed, vascular inflammation, a key feature of vascular disease pathogenesis, leads to the release of inflammatory signals that disseminate into local fat, inducing local lipolysis and inhibiting adipogenesis. This ability of PVAT to sense inflammatory signals from the vascular wall, can be used as a "thermometer" of the vascular wall, allowing for non-invasive detection of coronary inflammation. Vascular inflammation induces a shift of PVAT's composition from lipid to aqueous phase, resulting into increased computed tomography (CT) attenuation around the inflamed artery, forming a gradient with increasing attenuation closer to the inflamed coronary artery wall. These spatial changes in PVAT's attenuation are easily detected around culprit lesions during acute coronary syndromes. A new biomarker designed to captured these spatial changes in PVAT's attenuation around the human coronary arteries, the Fat Attenuation Index (FAI), has additional predictive value in stable patients for cardiac mortality and non-fatal heart attacks, above the prediction provided by the current state of the art that includes risk factors, calcium score and presence of high risk plaque features. The use of perivascular FAI in clinical practice may change the way we interpret cardiovascular CT angiography, as it is applicable to any coronary CT angiogram, and it offers dynamic information about the inflammatory burden of the coronary arteries, providing potential guidance for preventive measures and invasive treatments.