Subclinical Atherosclerosis Burden by 3D Ultrasound in Mid-Life: The PESA Study

BACKGROUND: Detection of subclinical atherosclerosis improves risk prediction beyond cardiovascular risk factors (CVRFs) and risk scores, but quantification of plaque burden may improve it further. Novel 3-dimensional vascular ultrasound (3DVUS) provides accurate volumetric quantification of plaque burden. OBJECTIVES: The authors evaluated associations between 3DVUS-based plaque burden and CVRFs and explored potential added value over simple plaque detection. METHODS: The authors included 3,860 (92.2%) PESA (Progression of Early Subclinical Atherosclerosis) study participants (age 45.8 ± 4.3 years; 63% men). Bilateral carotid and femoral territories were explored by 3DVUS to determine the number of plaques and territories affected, and to quantify global plaque burden defined as the sum of all plaque volumes. Linear regression and proportional odds models were used to evaluate associations of plaque burden with CVRFs and estimated 10-year cardiovascular risk. RESULTS: Plaque burden was higher in men (63.4 mm3 [interquartile range (IQR): 23.8 to 144.8 mm3] vs. 25.7 mm3 [IQR: 11.5 to 61.6 mm3] in women; p < 0.001), in the femoral territory (64 mm3 [IQR: 27.6 to 140.5 mm3] vs. 23.1 mm3 [IQR: 9.9 to 48.7 mm3] in the carotid territory; p < 0.001), and with increasing age (p < 0.001). Age, sex, smoking, and dyslipidemia were more strongly associated with femoral than with carotid disease burden, whereas hypertension and diabetes showed no territorial differences. Plaque burden was directly associated with estimated cardiovascular risk independently of the number of plaques or territories affected (p < 0.01). CONCLUSIONS: 3DVUS quantifies higher plaque burden in men, in the femoral territory, and with increasing age during midlife. Plaque burden correlates strongly with CVRFs, especially at the femoral level, and reflects estimated cardiovascular risk more closely than plaque detection alone. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318).The PESA study is cofunded equally by the Fundacion Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The study also receives funding from the Institute of Health Carlos III (PI15/02019) and the European Regional Development Fund (ERDF). The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Dr. Sanchez-Gonzalez is an employee of Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Stephen J. Nicholls, MD, served as Guest Editor for this paperS

Does Socioeconomic Status Influence the Risk of Subclinical Atherosclerosis?: A Mediation Model

BACKGROUND: Socioeconomic status (SES)-education, income level, and occupation-is associated with cardiovascular risk. OBJECTIVES: This study aimed to investigate the association between SES and subclinical atherosclerosis and the potential mechanisms involved. METHODS: SES, lifestyle habits (smoking, dietary patterns, physical activity, and hours of sleep), traditional risk factors, and subclinical atherosclerosis extent were prospectively assessed in 4,025 individuals aged 40 to 54 years without known cardiovascular disease enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) study. After factors associated with atherosclerosis were identified, a multiple mediation model was created to quantify the effect of SES on subclinical atherosclerosis as explained by lifestyle behaviors. RESULTS: Although education level was significantly associated with the presence of atherosclerosis, no differences were found according to income level in this population. Participants with lower education presented with a higher risk of generalized atherosclerosis than those with higher education (odds ratio: 1.46; 95% confidence interval: 1.15 to 1.85; p = 0.002). Lifestyle behaviors associated with both education level and atherosclerosis extent were: smoking status, number of cigarettes/day, and dietary pattern, which explained 70.5% of the effect of SES on atherosclerosis. Of these, tobacco habit (smoking status 35% and number of cigarettes/day 32%) accounted for most of the explained differences between groups, whereas dietary pattern did not remain a significant mediator in the multiple mediation model. CONCLUSIONS: Despite the relative economic homogeneity of the cohort, lower education level is associated with increased subclinical atherosclerosis, mainly mediated by the higher and more frequent tobacco consumption. Smoking cessation programs are still needed, particularly in populations with lower education level.The PESA study is cofunded equally by the Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; and Banco Santander, Madrid, Spain. The study also receives funding from the Institute of Health Carlos III (PI15/02019) and the European Regional Development Fund. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No707642; and from the American Heart Association under grantnumber14SFRN20490315. Dr. Bueno has received research funding from the Instituto de Salud Carlos III (PIE16/00021), AstraZeneca, Bristol-Myers Squibb, Janssen, and Novartis; has received consulting fees from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, and Novartis; and has received speaking fees or support for attending scientific meetings from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, Ferrer, Novartis, Servier, and MEDSCAPE-the heart.org.S

Vascular Inflammation in Subclinical Atherosclerosis Detected by Hybrid PET/MRI

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited. OBJECTIVES: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). METHODS: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake). RESULTS: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001). CONCLUSIONS: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).The PESA study is cofunded equally by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Banco Santander. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019) and the European Regional Development Fund (ERDF) “A way to make Europe.” The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Dr. Sanchez-González is an employee of Philips Healthcare. Dr. Bueno has received research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 & PI17/01799), AstraZeneca, Bristol-Myers Squibb, Janssen, and Novartis; has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, and Novartis; and has received speaking fees or support for attending scientific meetings from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, Novartis, and MEDSCAPE-the heart.org.S

Bone marrow activation in response to metabolic syndrome and early atherosclerosis.

Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8-53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3-L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis-characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts-and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].The PESA study is funded by the CNIC and Santander Bank. The present study was partially funded by an intramural grant CNIC-Severo Ochoa to D.S. and B.I. B.I. is supported by the European Commission (H2020-HEALTH 945118 and ERC-CoG 819775). The CNIC is supported by the ISCIII, the Ministry of Science and Innovation, and the Pro CNIC Foundation. CNIC is a Severo Ochoa Center of Excellence (CEX2020-001041-S).S

Predicting Subclinical Atherosclerosis in Low-Risk Individuals Ideal Cardiovascular Health Score and Fuster-BEWAT Score

BACKGROUND The ideal cardiovascular health score (ICHS) is recommended for use in primary prevention. Simpler tools not requiring laboratory tests, such as the Fuster-BEWAT (blood pressure [B], exercise [E], weight [W], alimentation [A], and tobacco [T]) score (FBS), are also available. OBJECTIVES The purpose of this study was to compare the effectiveness of ICHS and FBS in predicting the presence and extent of subclinical atherosclerosis. METHODS A total of 3,983 participants 40 to 54 years of age were enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) cohort. Subclinical atherosclerosis was measured in right and left carotids, abdominal aorta, right and left iliofemoral arteries, and coronary arteries. Subjects were classified as having poor, intermediate, or ideal cardiovascular health based on the number of favorable ICHS or FBS. RESULTS With poor ICHS and FBS as references, individuals with ideal ICHS and FBS showed lower adjusted odds of having atherosclerotic plaques (ICHS odds ratio [OR]: 0.41; 95\% confidence interval [CI]: 0.31 to 0.55 vs. FBS OR: 0.49; 95\% CI: 0.36 to 0.66), coronary artery calcium (CACS) >= 1 (CACS OR: 0.41; 95\% CI: 0.28 to 0.60 vs. CACS OR: 0.53; 95\% CI: 0.38 to 0.74), higher number of affected territories (OR: 0.32; 95\% CI: 0.26 to 0.41 vs. OR: 0.39; 95\% CI: 0.31 to 0.50), and higher CACS level (OR: 0.40; 95\% CI: 0.28 to 0.58 vs. OR: 0.52; 95\% CI: 0.38 to 0.72). Similar levels of significantly discriminating accuracy were found for ICHS and FBS with respect to the presence of plaques (C-statistic: 0.694; 95\% CI: 0.678 to 0.711 vs. 0.692; 95\% CI: 0.676 to 0.709, respectively) and for CACS >= 1 (C-statistic: 0.782; 95\% CI: 0.765 to 0.800 vs. 0.780; 95\% CI: 0.762 to 0.798, respectively). CONCLUSIONS Both scores predict the presence and extent of subclinical atherosclerosis with similar accuracy, highlighting the value of the FBS as a simpler and more affordable score for evaluating the risk of subclinical disease. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.The PESA study was co-funded by Fundacion Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and Banco Santander. Funding was also provided by Institute of Health Carlos III (PI15/02019) and European Regional Development Fund. CNIC is supported by the Ministry of Economy, Industry and Competitiveness and Pro CNIC Foundation; and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work is part of a project that received funding from the European Union Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant 707642 and American Heart Association grant 14SFRN20490315. Dr. Bueno has received research funding from Instituto de Salud Carlos III (PIE16/00021), AstraZeneca, Bristol-Myers Squibb, Janssen, and Novartis; is a consultant for Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, and Novartis; and has received speakers fees and travel and attendance support from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer, Ferrer, Novartis, Servier, and Medscape. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Matthew Budoff, MD, served as Guest Editor for this paper.S

Determinants of Progression and Regression of Subclinical Atherosclerosis Over 6 Years.

BACKGROUND Atherosclerosis is a systemic disease that frequently begins early in life. However, knowledge about the temporal disease dynamics (ie, progression or regression) of human subclinical atherosclerosis and their determinants is scarce. OBJECTIVES This study sought to investigate early subclinical atherosclerosis disease dynamics within a cohort of middle-aged, asymptomatic individuals by using multiterritorial 3-dimensional vascular ultrasound (3DVUS) imaging. METHODS A total of 3,471 participants from the PESA (Progression of Early Subclinical Atherosclerosis) cohort study (baseline age 40-55 years; 36% female) underwent 3 serial 3DVUS imaging assessments of peripheral arteries at 3-year intervals. Subclinical atherosclerosis was quantified as global plaque volume (mm3) (bilateral carotid and femoral plaque burden). Multivariable logistic regression models for progression and regression were developed using stepwise forward variable selection. RESULTS Baseline to 6-year subclinical atherosclerosis progression occurred in 32.7% of the cohort (17.5% presenting with incident disease and 15.2% progressing from prevalent disease at enrollment). Regression was observed in 8.0% of those patients with baseline disease. The effects of higher low-density lipoprotein cholesterol (LDL-C) and elevated systolic blood pressure (SBP) on 6-year subclinical atherosclerosis progression risk were more pronounced among participants in the youngest age stratum (Pinteraction = 0.04 and 0.02, respectively). CONCLUSIONS Over 6 years, subclinical atherosclerosis progressed in one-third of middle-age asymptomatic subjects. Atherosclerosis regression is possible in early stages of the disease. The impact of LDL-C and SBP on subclinical atherosclerosis progression was more pronounced in younger participants, a finding suggesting that the prevention of atherosclerosis and its progression could be enhanced by tighter risk factor control at younger ages, with a likely long-term impact on reducing the risk of clinical events. (Progression of Early Subclinical Atherosclerosis [PESA; also PESA-CNIC-Santander]; NCT01410318).S

Accurate quantification of atherosclerotic plaque volume by 3D vascular ultrasound using the volumetric linear array method.

Direct quantification of atherosclerotic plaque volume by three-dimensional vascular ultrasound (3DVUS) is more reproducible than 2DUS-based three-dimensional (2D/3D) techniques that generate pseudo-3D volumes from summed 2D plaque areas; however, its accuracy has not been reported. We aimed to determine 3DVUS accuracy for plaque volume measurement with special emphasis on small plaques (a hallmark of early atherosclerosis). The in vitro study consisted of nine phantoms of different volumes (small and medium-large) embedded at variable distances from the surface (superficial vs. >5 cm-depth) and comparison of 3DVUS data generated using a novel volumetric-linear array method with the real phantom volumes. The in vivo study was undertaken in a rabbit model of atherosclerosis in which 3DVUS and 2D/3D volume measurements were correlated against gold-standard histological measurements. In the in vitro setting, there was a strong correlation between 3DVUS measures and real phantom volume both for small (3.0-64.5 mm(3) size) and medium-large (91.1-965.5 mm(3) size) phantoms embedded superficially, with intraclass correlation coefficients (ICC) of 0.99 and 0.98, respectively; conversely, when phantoms were placed at >5 cm, the correlation was only moderate (ICC = 0.67). In the in vivo setting there was strong correlation between 3DVUS-measured plaque volumes and the histological gold-standard (ICC = 0.99 [4.02-92.5 mm(3) size]). Conversely, the correlation between 2D/3D values and the histological gold standard (sum of plaque areas) was weaker (ICC = 0.87 [49-520 mm(2) size]), with large dispersion of the differences between measurements in Bland-Altman plots (mean error, 79.2 mm(2)). 3DVUS using the volumetric-linear array method accurately measures plaque volumes, including those of small plaques. Measurements are more accurate for superficial arterial territories than for deep territories.S

Differential effect of vascularity between long- and short-term survivors with IDH1/2 wild-type glioblastoma

[EN] Introduction: IDH1/2 wt glioblastoma (GB) represents the most lethal tumour of the central nervous system. Tumour vascularity is associated with overall survival (OS), and the clinical relevance of vascular markers, such as rCBV, has already been validated. Nevertheless, molecular and clinical factors may have different influences on the beneficial effect of a favourable vascular signature. Purpose: To evaluate the association between the rCBV and OS of IDH1/2 wt GB patients for long-term survivors (LTSs) and short-term survivors (STSs). Given that initial high rCBV may affect the patient's OS in follow-up stages, we will assess whether a moderate vascularity is beneficial for OS in both groups of patients. Materials and methods: Ninety-nine IDH1/2 wt GB patients were divided into LTSs (OS >= 400 days) and STSs (OS < 400 days). Mann-Whitney and Fisher, uni- and multiparametric Cox, Aalen's additive regression and Kaplan-Meier tests were carried out. Tumour vascularity was represented by the mean rCBV of the high angiogenic tumour (HAT) habitat computed through the haemodynamic tissue signature methodology (available on the ONCOhabitats platform). Results: For LTSs, we found a significant association between a moderate value of rCBV(mean) and higher OS (uni- and multiparametric Cox and Aalen's regression) (p = 0.0140, HR = 1.19; p = 0.0085, HR = 1.22) and significant stratification capability (p = 0.0343). For the STS group, no association between rCBV(mean) and survival was observed. Moreover, no significant differences (p > 0.05) in gender, age, resection status, chemoradiation, or MGMT methylation were observed between LTSs and STSs. Conclusion: We have found different prognostic and stratification effects of the vascular marker for the LTS and STS groups. We propose the use of rCBV(mean) at HAT as a vascular marker clinically relevant for LTSs with IDH1/2 wt GB and maybe as a potential target for randomized clinical trials focused on this group of patients.DPI2016-80054-R (Programa Estatal de Promocion del Talento y su Empleabilidad en I +D+i).; European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 844646; H2020-SC1-BHC-2018-2020 (No. 825750); MTS4up project (National Plan for Scientific and Technical Research and Innovation 2013-2016, No. DPI2016-80054-R); European Union's Horizon 2020 research and innovation programme under Marie Sklodowska-Curie, Grant/Award Number: 844646; Research Council of Norway, Grant/Award Number: 261984; South-Eastern Norway Regional Health Authority, Grant/Award Number: 2017073; European Research Council (ERC) under the European Union's Horizon 2020, Grant/Award Number: 758657Álvarez-Torres, MDM.; Fuster García, E.; Reynes, G.; Juan-Albarracín, J.; Chelebian-Kocharyan, EA.; Oleaga, L.; Pineda, J.... (2021). Differential effect of vascularity between long- and short-term survivors with IDH1/2 wild-type glioblastoma. NMR in Biomedicine. 34(4):1-11. https://doi.org/10.1002/nbm.446211134

Three-dimensional cardiac fibre disorganization as a novel parameter for ventricular arrhythmia stratification after myocardial infarction

Aims: Myocardial infarction (MI) alters cardiac fibre organization with unknown consequences on ventricular arrhythmia. We used diffusion tensor imaging (DTI) of three-dimensional (3D) cardiac fibres and scar reconstructions to identify the main parameters associated with ventricular arrhythmia inducibility and ventricular tachycardia (VT) features after MI. Methods and results: Twelve pigs with established MI and three controls underwent invasive electrophysiological characterization of ventricular arrhythmia inducibility and VT features. Animal-specific 3D scar and myocardial fibre distribution were obtained from ex vivo high-resolution contrast-enhanced T1 mapping and DTI sequences. Diffusion tensor imaging-derived parameters significantly different between healthy and scarring myocardium, scar volumes, and left ventricular ejection fraction (LVEF) were included for arrhythmia risk stratification and correlation analyses with VT features. Ventricular fibrillation (VF) was the only inducible arrhythmia in 4 out of 12 infarcted pigs and all controls. Ventricular tachycardia was also inducible in the remaining eight pigs during programmed ventricular stimulation. A DTI-based 3D fibre disorganization index (FDI) showed higher disorganization within dense scar regions of VF-only inducible pigs compared with VT inducible animals (FDI: 0.36; 0.36-0.37 vs. 0.32; 0.26-0.33, respectively, P = 0.0485). Ventricular fibrillation induction required lower programmed stimulation aggressiveness in VF-only inducible pigs than VT inducible and control animals. Neither LVEF nor scar volumes differentiated between VF and VT inducible animals. Re-entrant VT circuits were localized within areas of highly disorganized fibres. Moreover, the FDI within heterogeneous scar regions was associated with the median VT cycle length per animal (R2 = 0.5320). Conclusion: The amount of scar-related cardiac fibre disorganization in DTI sequences is a promising approach for ventricular arrhythmia stratification after MI.The CNIC (Madrid, Spain) is supported by the Ministry of Science, Innovation and Universities and the Pro CNIC Foundation. The CNIC and the BSC (Barcelona, Spain) are Severo Ochoa Centers of Excellence (SEV-2015-0505 and SEV-2011-0067, respectively). This study was supported by grants from Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (RD12/0042/0036, CB16/11/00458), Spanish Ministry of Science, Innovation and Universities (SAF2016-80324-R, PI16/02110, and DTS17/00136), and by the European Commission [ERA-CVD Joint Call (JTC2016/APCIN-ISCIII-2016), grant#AC16/00021]. The study was also partially supported by the Fundacion Interhospitalaria para la Investigacion Cardiovascular (FIC, Madrid, Spain), the Spanish Society of Cardiology (Dr. Pedro Zarco award) and the Heart Rhythm section of the Spanish Society of Cardiology (DFR). J.J. is supported by R01 Grant HL122352 from the National Heart Lung and Blood Institute, USA National Institutes of Health. J.A.S. is funded by the CompBioMed project, H2020-EU.1.4.1.3 European Union's Horizon 2020 research and innovation programme, grant#675451. D.G.L. has received financial support through the 'la Caixa' Fellowship Grant for Doctoral Studies, 'la Caixa' Banking Foundation, Barcelona, Spain.S

Metoprolol blunts the time-dependent progression of infarct size.

Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.This study received funding from the Ministry of Science and Innovation (“RETOS 2019” Grant no. PID2019-107332RB-I00), from the Instituto de Salud Carlos III (ISCIII; PI16/02110) and the European Regional Development Fund (ERDF) “A way of making Europe” (# AC16/00021), and from the Spanish Society of Cardiology through a 2017 Translational Research grant. BI has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-Consolidator Grant agreement no. 819775). M.L received support from a 2015 Severo Ochoa CNIC intramural grant. X.R. received support from the SEC-CNIC CARDIOJOVEN fellowship program. R.F-J is a recipient of funding from the Carlos III Institute of Health-Fondo de Investigacion Sanitaria (PI19/01704) and has received funding from the European Union Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No 707642. EO is recipient of funds from Programa de Atracción de Talento (2017-T1/BMD-5185) of Comunidad de Madrid. The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación (MICINN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S