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Collagen bundle orientation (CBO) in myocardial infarct scars plays a major role in scar mechanics and complications after infarction. We aim to compare four histopathological methods for CBO measurement in myocardial scarring. Myocardial infarction was induced in 21 pigs by balloon coronary occlusion. Scar samples were obtained at 4 weeks, stained with Masson's trichrome, Picrosirius red, and Hematoxylin-Eosin (H&E), and photographed using light, polarized light microscopy, and confocal microscopy, respectively. Masson's trichrome images were also optimized to remove non-collagenous structures. Two observers measured CBO by means of a semi-automated, Fourier analysis protocol. Interrater reliability and comparability between techniques were studied by the intraclass correlation coefficient (ICC) and Bland-Altman (B&A) plots and limits of agreement. Fourier analysis showed an almost perfect interrater reliability for each technique (ICC >= 0.95, p < 0.001 in all cases). CBO showed more randomly oriented values in Masson's trichrome and worse comparability with other techniques (ICC vs. Picrosirius red: 0.79 [0.47-0.91], p = 0.001; vs. H&E-confocal: 0.70 [0.26-0.88], p = 0.005). However, optimized Masson's trichrome showed almost perfect agreement with Picrosirius red (ICC 0.84 [0.6-0.94], p < 0.001) and H&E-confocal (ICC 0.81 [0.54-0.92], p < 0.001), as well as these latter techniques between each other (ICC 0.84 [0.60-0.93], p < 0.001). In summary, a semi-automated, Fourier-based method can provide highly reproducible CBO measurements in four different histopathological techniques. Masson's trichrome tends to provide more randomly oriented CBO index values, probably due to non-specific visualization of non-collagenous structures. However, optimization of Masson's trichrome microphotographs to remove non-collagenous components provides an almost perfect comparability between this technique, Picrosirius red and H&E-confocal.

INTRODUCTION AND OBJECTIVES: The management of elderly patients with chronic coronary syndrome (CCS) is challenging. We explored the prognostic value and usefulness for decision-making of ischemic burden determined by vasodilator stress cardiac magnetic resonance (CMR) imaging in elderly patients with known or suspected CCS. METHODS: The study group comprised 2496 patients older than 70 years who underwent vasodilator stress CMR for known or suspected CCS. The ischemic burden (number of segments with stress-induced perfusion deficit) was calculated following the 17-segment model. Subsequently, we retrospectively analyzed its association with all-cause mortality and the effect of CMR-guided revascularization. RESULTS: During a median follow-up of 4.58 years, there were 430 deaths (17.2%). A higher ischemic burden was an independent predictor of mortality (HR, 1.04; 95%CI, 1.01-1.07 for each additional ischemic segment; P=.006). This association was also found in patients older than 80 years and in women (P

AIMS: The role of revascularization in chronic coronary syndrome (CCS) and the value of ischaemia vs. anatomy to guide decision-making are in constant debate. We explored the potential of a combined assessment of ischaemic burden by vasodilator stress cardiovascular magnetic resonance (CMR) and presence of multivessel disease by angiography to predict the effect of revascularization on all-cause mortality in CCS. METHODS AND RESULTS: The study group comprised 1066 CCS patients submitted to vasodilator stress CMR pre-cardiac catheterization (mean age 66 ± 11 years, 69% male). Stress CMR-derived ischaemic burden (extensive if >5 ischaemic segments) and presence of multivessel disease in angiography (two- or three-vessel or left main stem disease) were computed. The influence of revascularization on all-cause mortality was explored and adjusted hazard ratios (HRs) with the corresponding 95% confidence intervals were obtained. During a median 7.51-year follow-up, 557 (52%) CMR-related revascularizations and 308 (29%) deaths were documented. Revascularization exerted a neutral effect on all-cause mortality in the whole study group [HR 0.94 (0.74-1.19), P = 0.6], in patients without multivessel disease [n = 598, 56%, HR 1.12 (0.77-1.62), P = 0.6], and in those with multivessel disease without extensive ischaemic burden [n = 181, 17%, HR 1.66 (0.91-3.04), P = 0.1]. However, compared to non-revascularized patients, revascularization significantly reduced all-cause mortality in patients with simultaneous multivessel disease and extensive ischaemic burden (n = 287, 27%): 3.77 vs. 7.37 deaths per 100 person-years, HR 0.60 (0.40-0.90), P = 0.01. CONCLUSIONS: In patients with CCS submitted to catheterization, evidence of simultaneous extensive CMR-related ischaemic burden and multivessel disease identifies the subset in whom revascularization can reduce all-cause mortality.

BACKGROUND: Stress cardiac MRI permits comprehensive evaluation of patients with known or suspected chronic coronary syndromes (CCS). The impact of sex on the use of invasive cardiac angiography (ICA) after vasodilator stress cardiac MRI is unclear.; PURPOSE: To evaluate the impact of sex on ICA use after vasodilator stress cardiac MRI.; STUDY TYPE: Retrospective.; POPULATION: A total of 6229 consecutive patients (age [mean±standard deviation] 65.2±11.5years, 38.1% women).; FIELD STRENGTH/SEQUENCE: A 5-T; a steady-state free-precession cine sequence; stress first-pass perfusion imaging; late enhancement imaging.; ASSESSMENT: Patients underwent vasodilator stress cardiac MRI for known or suspected CCS. The ischemic burden (at stress first-pass perfusion imaging) was computed (17-segment model).; STATISTICAL TESTS: Multivariate logistic regression was used to evaluate the potential differential association between ischemic burden and use of cardiac MRI-related ICA across sex.; RESULTS: A total of 1109 (17.8%) patients were referred to ICA, among which there were significantly more men (762, 19.7%) than women (347, 14.6%). Overall, after multivariate adjustment, female sex was not associated with lower use of ICA (odds ratio [OR]=0.99; confidence interval [CI] 95%: 0.84-1.18, P=0.934). However, significant sex differences were detected across ischemic burden. Whereas women with nonischemic vasodilator stress cardiac MRI (0 ischemic segments) were less commonly submitted to ICA (OR=0.49; CI 95%: 0.35-0.69) in patients with ischemia (>1 ischemic segment), adjusted use of ICA was more frequent in women than men (OR=1.27; CI 95%: 1.1-1.5).; DATA CONCLUSIONS: In patients with known or suspected CCS submitted to undergo vasodilator stress cardiac MRI, cardiac MRI-related ICA may be overused in men without ischemia. Furthermore, ICA referral in patients with negative ischemia resulted in greater odds of revascularization in men.; EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5. © 2022 International Society for Magnetic Resonance in Medicine.

INTRODUCTION: ACTH-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus in remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. OBJECTIVES: To identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. MATHERIALS AND METHODS: A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004-2018 and with at least two years follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary-factors and proliferation-markers were evaluated in tumor samples after first surgery. RESULTS: Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin and post-surgery cortisol levels were associated with tumor- remission and relapsed-disease. The molecular markers analyzed were distinctly expressed in ACTHomas, some components (i.e., SSTR1, CRHR1 and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor-size/post-surgery serum cortisol) and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a ROC curve with an AUC of 1 (p

BACKGROUND: Coronary arteries supply oxygen and nutrients to the heart. We evaluated the dynamics of microscopic damage throughout the ischemia-reperfusion process in the wall of coronary arteries following myocardial infarction (MI). METHODS: In a swine model of reperfused MI, animals were divided into one control and four MI groups: 90-minutes ischemia without reperfusion, or followed by one minute, one week or one month reperfusion. Left anterior descending (LAD; infarct-related artery) and control right coronary arteries (RCA) were isolated. Taking the balloon inflation region as a reference, we isolated the proximal and distal LAD areas, performing histological staining and immunohistochemistry. RESULTS: Although mild changes in tunica intima were observed during ischemia, an almost complete absence of endothelium, and abnormal breaks in the internal elastic layer were found post-revascularization. In tunica media, increased thickness was observed soon after reperfusion, whereas larger thickness, disorganized muscle cell distribution and edema were found one week after reperfusion. This damage was more pronounced in distal rather than proximal LAD, whereas no changes were detected in RCA. In the tunica adventitia, vasa vasorum density decayed during ischemia in both LAD regions, but was restored after one month. Leukocyte adhesion to the artery was observed post-revascularization, developing into a massive presence in the three layers one week post-reperfusion. CONCLUSIONS: Ischemia-reperfusion can itself induce damage in the wall of the epicardial coronary artery, becoming more pronounced in the region distal to balloon inflation. Exploring these abnormalities will provide insight into the pathophysiology of coronary circulation and MI.

AIMS: Lymphopenia after ST-segment elevation myocardial infarction (STEMI) correlates with deleterious cardiac consequences and worse prognosis. An in-depth examination of genes implicated in lymphocyte proliferation, activation and regulation and their association with short- and long-term cardiac structure and function is therefore of great interest. METHODS: Peripheral blood mononuclear cells were isolated from 10 control subjects and 64 patients with a first STEMI treated with primary percutaneous coronary intervention and submitted to cardiac magnetic resonance after 1week and 6months. mRNA expression of genes implicated in lymphocyte activation (CD25 and CD69) and regulation [programmed death (PD)-1 and cytotoxic T-lymphocyte antigen (CTLA)-4] were determined by qRT-PCR. RESULTS: In comparison to controls, STEMI patients showed heightened mRNA expression of CD25 and lower PD-1 and CTLA-4 96h after coronary reperfusion. Patients with extensive infarctions (>30% of left ventricular mass) at 1week displayed a notable reduction in CD25, CD69, PD-1, and CTLA-4 expression (p

INTRODUCTION AND OBJECTIVES: Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in epithelium adhesion, is an understudied area in the MVO setting. We aimed to determine whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI. METHODS: We prospectively included 106 patients with a first STEMI treated with percutaneous coronary intervention, quantifying serum levels of EpCAM 24hours postreperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction was evaluated. RESULTS: The mean age of the sample was 59±13 years and 76% were male. Patients were dichotomized according to median EpCAM (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (P=.021) and larger infarct size (P=.019). At presentation, EpCAM values were significantly associated with the presence of MVO in univariate (OR, 0.58; 95%CI, 0.38-0.88; P=.011) and multivariate logistic regression models (OR, 0.55; 95%CI, 0.35-0.87; P=.010). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: reduced left ventricular ejection fraction (P=.009) and higher left ventricular end-systolic volume (P=.043). CONCLUSIONS: EpCAM is associated with the occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI.

OBJECTIVES: This study explored the association of ischemic burden, as measured by vasodilator stress cardiovascular magnetic resonance (CMR), with all-cause mortality and the effect of revascularization on all-cause mortality in patients with stable ischemic heart disease (SIHD). Background: In patients with SIHD, the association of ischemic burden, derived from vasodilator stress CMR, with all-cause mortality and its role for decision-making is unclear. METHODS: The registry consisted of 6,389 consecutive patients (mean age: 65 +/- 12 years; 38% women) who underwent vasodilator stress CMR for known or suspected SIHD. The ischemic burden (at stress first-pass perfusion imaging) was computed (17-segment model). The effect of CMR-related revascularization (within the following 3 months) on all-cause mortality was retrospectively explored using the electronic regional health system registry. RESULTS: During a 5.75-year median follow-up, 717 (11%) deaths were documented. In multivariable analyses, more extensive ischemic burden (per 1-segment increase) was independently related to all-cause mortality (hazard ratio: 1.04; 95% confidence interval: 1.02 to 1.07; p < 0.001). In 1,032 1:1 matched patients using a limited number of variables (516 revascularized, 516 non-revascularized), revascularization within the following 3 months was associated with less all-cause mortality only in patients with extensive CMR-related ischemia (>5 segments, n = 432; 10% vs. 24%; p = 0.01). CONCLUSIONS: In a large retrospective registry of unselected patients with known or suspected SIHD who underwent vasodilator stress CMR, extensive ischemic burden was related to a higher risk of long-term, all-cause mortality. Revascularization was associated with a protective effect only in the restricted subset of patients with extensive CMR-related ischemia. Further research will be needed to confirm this hypothesis-generating finding. (C) 2020 by the American College of Cardiology Foundation.

BACKGROUND: Following myocardial infarction (MI), we aimed to characterize morphometric and genetic changes in extracellular matrix (ECM) components from ischemia onset until late phases after coronary reperfusion in necrotic and salvaged myocardium.; RESULTS: Swine were divided into one control (n=5) and three MI groups: 90-min of ischemia without reperfusion, or followed by 1-week or 1-month reperfusion (n=5 per group). In samples from the necrotic and salvaged areas, ECM components were morphometrically quantified and mRNA levels of factors involved in ECM remodeling were evaluated. After 90-min of ischemia, fibronectin, laminin, and elastic fibers content as well as upregulated mRNA expression of tissue inhibitors of metalloproteinases (TIMP)1, TIMP2, TIMP3 and connective tissue growth factor increased in the necrotic and salvaged myocardium. In both reperfused MI groups, collagen-I, collagen-III, elastic fibers, glycosaminoglycans, laminin, and fibronectin levels heightened in the necrotic but not the salvaged myocardium. Moreover, mRNA expression of TIMP1, TIMP2 and TIMP3, as well as metalloproteinase-2 and metalloproteinase-9 heightened in the necrotic but not in the salvaged myocardium.; CONCLUSIONS: Matrix remodeling starts after ischemia onset in both necrotic and salvaged myocardium. Even if ECM composition from the salvaged myocardium was altered after severe ischemia, ECM makes a full recovery to normal composition after reperfusion. Therefore, rapid coronary reperfusion is essential not only to save cardiomyocytes but also to preserve matrix, thus avoiding impaired left ventricular remodeling.

Background Cardiac magnetic resonance (CMR) permits robust risk stratification of discharged ST-segment-elevation myocardial infarction patients, but its indiscriminate use in all cases is not feasible. We evaluated the utility of left ventricular ejection fraction (LVEF) by echocardiography for a selective use of CMR after ST-segment-elevation myocardial infarction. Methods Echocardiography and CMR were performed in 1119 patients discharged for ST-segment-elevation myocardial infarction included in a multicenter registry. The prognostic power of CMR beyond echocardiography-LVEF was assessed using adjusted C statistic, net reclassification improvement index, and integrated discrimination improvement index. Results During a 4.8-year median follow-up, 136 (12%) first major adverse cardiac events (MACE) occurred (47 cardiovascular deaths and 89 readmissions for acute heart failure). In the entire group, CMR-LVEF (but not echocardiography-LVEF) independently predicted MACE occurrence. The MACE rate significantly increased only in patients with CMR-LVEF

This study aimed to assess the time course of circulating neutrophil and lymphocyte counts and their ratio (NLR) in ST-segment elevation myocardial infarction (STEMI) and coronavirus disease (COVID)-19 and explore their associations with clinical events and structural damage. Circulating neutrophil, lymphocyte and NLR were sequentially measured in 659 patients admitted for STEMI and in 103 COVID-19 patients. The dynamics detected in STEMI (within a few hours) were replicated in COVID-19 (within a few days). In both entities patients with events and with severe structural damage displayed higher neutrophil and lower lymphocyte counts. In both scenarios, higher maximum neutrophil and lower minimum lymphocyte counts were associated with more events and more severe organ damage. NLR was higher in STEMI and COVID-19 patients with the worst clinical and structural outcomes. A canonical deregulation of the immune response occurs in STEMI and COVID-19 patients. Boosted circulating innate (neutrophilia) and depressed circulating adaptive immunity (lymphopenia) is associated with more events and severe organ damage. A greater understanding of these critical illnesses is pivotal to explore novel alternative therapies.

Vasodilator stress cardiac magnetic resonance (stressCMR) has shown robust diagnostic and prognostic value in patients with known or suspected chronic coronary syndrome (CCS). However, it is unknown whether integration of stressCMR with clinical variables in a simple clinical-imaging score can straightforwardly predict all-cause mortality in this population. We included 6187 patients in a large registry that underwent stressCMR for known or suspected CCS. Several clinical and stressCMR variables were collected, such as left ventricular ejection fraction (LVEF) and ischemic burden (number of segments with stress-induced perfusion defects (PD)). During a median follow-up of 5.56 years, we registered 682 (11%) all-cause deaths. The only independent predictors of all-cause mortality in multivariable analysis were age, male sex, diabetes mellitus (DM), LVEF and ischemic burden. Based on the weight of the chi-square increase at each step of the multivariable analysis, we created a simple clinical-stressCMR (C-CMR-10) score that included these variables (age = 65 years = 3 points, LVEF = 50% = 3 points, DM = 2 points, male sex = 1 point, and ischemic burden > 5 segments = 1 point). This 0 to 10 points C-CMR-10 score showed good performance to predict all-cause annualized mortality rate ranging from 0.29%/year (score = 0) to >4.6%/year (score = 7). The goodness of the model and of the C-CMR-10 score was separately confirmed in 2 internal cohorts (n > 3000 each). We conclude that a novel and simple clinical-stressCMR score, which includes clinical and stressCMR variables, can provide robust prediction of the risk of long-term all-cause mortality in a population of patients with known or suspected CCS.