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Aims: The role of change in left atrial (LA) parameters prior to the onset of heart failure (HF) remains unclear. We used cardiac magnetic resonance (CMR) imaging to investigate the relationship between longitudinal change in LA function and incident HF in a multi-ethnic population with subclinical cardiovascular disease (CVD)., Methods and Results: In this prospective multi-ethnic cohort study, 2470 participants (60 ± 9 years, 47% males), free at baseline of clinical CVD, had LA volume and function assessed via multimodality tissue tracking on CMR imaging at baseline (2000-02) and a second study 9.4 ± 0.6 years later. Free of HF, 73 participants developed incident HF [HF with preserved ejection fraction (HFpEF), n = 39; reduced ejection fraction (HFrEF), n = 34] 7.1 ± 2.1 years after the second study. An annual decrease of 1 SD unit in peak LA strain (ΔLASmax) was most strongly associated with the risk of HFpEF [subdistribution hazard ratios (HR) = 2.56, 95% confidence interval (CI) (1.34-4.90), P = 0.004] and improved model reclassification and discrimination in predicting HFpEF [C-statistic = 0.84, 95% CI (0.79-0.90); net reclassification index (NRI) = 0.34, P = 0.01; and integrated discrimination index (IDI) = 0.02, P = 0.02], whilst an annual decrease of 1 mL/m2 of pre-atrial indexed LA volumes (ΔLAVipreA) was most strongly associated with the risk of HFrEF [subdistribution HR = 1.88, 95% CI (1.44-2.45), P < 0.001] and improved model reclassification and discrimination in predicting HFrEF [C-statistic = 0.81, 95% CI (0.72-0.90); NRI = 0.31, P = 0.03; and IDI = 0.01, P = 0.50] after adjusting for event-specific risk factors and baseline LA measures., Conclusion: ΔLASmax and ΔLAVipreA were associated with and incrementally predictive of HFpEF and HFrEF, after adjusting for risk factors and baseline LA measures in this population of subclinical CVD., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group ( p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.

Background and Aims: Cardiomyocyte hypertrophy and interstitial fibrosis are key components of myocardial remodeling in Heart Failure (HF) with preserved (HFpEF) or reduced ejection fraction (HFrEF). MicroRNAs (miRNAs) are non-coding, evolutionarily conserved RNA molecules that may offer novel insights into myocardial remodeling. This study aimed to characterize miRNA expression in HFpEF (LVEF  ≥  45%) and HFrEF (LVEF < 45%) and its association with myocardial remodeling., Methods: Prospectively enrolled symptomatic HF patients (HFpEF:n = 36; HFrEF:n = 31) and controls (n = 23) underwent cardiac magnetic resonance imaging with T1-mapping and circulating miRNA expression (OpenArray system)., Results: 13 of 188 miRNAs were differentially expressed between HF groups (11 downregulated in HFpEF). Myocardial extracellular volume (ECV) was increased in both HF groups (HFpEF 30 ± 5%; HFrEF 30 ± 3%; controls 26 ± 2%, p < 0.001). miR-128a-3p, linked to cardiac hypertrophy, fibrosis, and dysfunction, correlated positively with ECV in HFpEF (r = 0.60, p = 0.01) and negatively in HFrEF (r =  - 0.51, p = 0.04). miR-423-5p overexpression, previously associated HF mortality, was inversely associated with LVEF (r =  - 0.29, p = 0.04) and intracellular water lifetime ( τ ic ) (r =  - 0.45, p < 0.05) in both HF groups, and with NT-proBNP in HFpEF (r =  - 0.63, p < 0.01)., Conclusions: miRNA expression profiles differed between HF phenotypes. The differential expression and association of miR-128a-3p with ECV may reflect the distinct vascular, interstitial, and cellular etiologies of HF phenotypes., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Otavio R Coelho-Filho reports financial support was provided by State of Sao Paulo Research Foundation. Otavio R Coelho-Filho reports was provided by. Otavio R Coelho-Filho reports a relationship with 10.13039/100004325AstraZeneca Pharmaceuticals LP that includes: funding grants and speaking and lecture fees. Otavio R Coelho-Filho reports a relationship with 10.13039/100002429Amgen Inc that includes: funding grants. Otavio R Coelho-Filho reports a relationship with 10.13039/100004319Pfizer Inc that includes: funding grants and speaking and lecture fees. Otavio R Coelho-Filho reports a relationship with 10.13039/100004336Novartis AG that includes: speaking and lecture fees. Otavio R Coelho-Filho reports a relationship with 10.13039/100004326Bayer AG that includes: speaking and lecture fees. Otavio R Coelho-Filho reports a relationship with 10.13039/100001003Boehringer Ingelheim Ltd that includes: speaking and lecture fees. Otavio R Coelho-Filho reports a relationship with 10.13039/100007723Takeda Pharmaceutical Company Limited that includes: funding grants and speaking and lecture fees. Tomas G Neilan reports a relationship with H3 Biomedicine Inc that includes: funding grants. Tomas G Neilan reports a relationship with 10.13039/100002429Amgen Inc that includes: funding grants. Tomas G Neilan reports a relationship with 10.13039/100006483AbbVie Inc that includes: funding grants. Tomas G Neilan reports a relationship with 10.13039/100004325AstraZeneca that includes: funding grants. T.G.N. has received support from 10.13039/100004325AstraZeneca, Bristol Myer Squibb, 10.13039/100006483AbbVie, 10.13039/100002429Amgen, and H3 Biomedicine. O.R.C.F. has received research grants and/or speaking honoraria from 10.13039/100002429Amgen, 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer, 10.13039/100001003Boehringer Ingelheim, 10.13039/100004336Novartis, 10.13039/100007723Takeda, and 10.13039/100004319Pfizer. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Background and Aims: Carotid intima-media thickness (cIMT) is inconsistent in predicting cardiovascular risk. This may stem from the variability of the media thickness (cM) outweighing the intimal thickness (cIT) as the sign of atherosclerosis. Thus, we evaluated in type 2 diabetes (T2D) individuals, the association between carotid measures and coronary artery calcification (CAC)., Methods and Results: Association between the presence of CAC and cIT, cM, and cIMT were examined on 224 individuals. Logistic binary regression was used to assess CAC predictors. The Akaike information criterion (AIC) and log-likelihood test (LLT) were used to assess differences among univariate models. The cIT (0.335 mm vs 0.363 mm; p = 0.001) and cIMT (0.715 vs 0.730; p = 0.019), but not cM (0.386 mm vs 0,393 mm; p = 0.089) were higher among individuals with CAC. In unadjusted analysis, cIT (273;-134; p = 0.001) showed greater relationship with CAC, when compared to cIMT (279;-137; p = 0.022) and cM (281;-139; p = 0.112) based on the AIC and LLT, respectively. In multivariate logistic regression, CAC was related to carotid plaque (OR): 1.91, 95% confidence interval (CI):1.08, 3.38; p = 0.027), and high-cIT (OR: 2.70, 95%CI:1.51, 4.84; p = 0.001), but not to high-cIMT (OR:1.70, 95%CI:0.96, 3.00; p = 0.067) nor high-cM (OR:1.33, 95%CI:0.76, 2.34; p = 0.322)., Conclusion: In T2D individuals, cIT is a better predictor of CAC than cIMT; cM is not associated with CAC., Competing Interests: Declaration of competing interest The authors declare no known competing financial or personal interests that could influence this work., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Sodium glucose cotransporter 2 inhibitors (SGLT2) have been increasingly pursued as a promising target for addressing residual cardiovascular risk. Prior trials demonstrated that SGLT2i not only promotes glucose-lowering, but also improves endothelial dysfunction, adiposity, fluid overload, and insulin sensitivity thus contributing to hemodynamic changes implicated in its cardiorenal benefits. The mechanisms in the effect of SGLT2i on blood pressure and their potential role in preventing cardiovascular events are hereby revised., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Barreto, Campos-Staffico, Nadruz, Quinaglia and Sposito.)

Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use., Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction., Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022., Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months., Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months., Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups., Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use., Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.

Objective: Women with HIV (WWH) have heightened heart failure risk. Plasma OPN (osteopontin) is a powerful predictor of heart failure outcomes in the general population. Limited data exist on relationships between plasma OPN and surrogates of HIV-associated heart failure risk., Design: Prospective, cross-sectional., Methods: We analyzed relationships between plasma OPN and cardiac structure/function (assessed using cardiovascular magnetic resonance imaging) and immune activation (biomarkers and flow cytometry) among 20 WWH and 14 women without HIV (WWOH)., Results: Plasma OPN did not differ between groups. Among WWH, plasma OPN related directly to the markers of cardiac fibrosis, growth differentiation factor-15 (ρ = 0.51, P = 0.02) and soluble interleukin 1 receptor-like 1 (ρ = 0.45, P = 0.0459). Among WWH (but not among WWOH or the whole group), plasma OPN related directly to both myocardial fibrosis (ρ = 0.49, P = 0.03) and myocardial steatosis (ρ = 0.46, P = 0.0487). Among the whole group and WWH (and not among WWOH), plasma OPN related directly to the surface expression of C-X3-C motif chemokine receptor 1 (CX3CR1) on nonclassical (CD14-CD16+) monocytes (whole group: ρ = 0.36, P = 0.04; WWH: ρ = 0.46, P = 0.04). Further, among WWH and WWOH (and not among the whole group), plasma OPN related directly to the surface expression of CC motif chemokine receptor 2 (CCR2) on inflammatory (CD14+CD16+) monocytes (WWH: ρ = 0.54, P = 0.01; WWOH: ρ = 0.60, P = 0.03), and in WWH, this held even after controlling for HIV-specific parameters., Conclusion: Among WWH, plasma OPN, a powerful predictor of heart failure outcomes, related to myocardial fibrosis and steatosis and the expression of CCR2 and CX3CR1 on select monocyte subpopulations. OPN may play a role in heart failure pathogenesis among WWH., Clinicaltrialsgov Registration: NCT02874703., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Women with HIV (WWH) face heightened risks of heart failure; however, insights on immune/inflammatory pathways potentially contributing to left ventricular (LV) systolic dysfunction among WWH remain limited., Setting: Massachusetts General Hospital, Boston, Massachusetts., Methods: Global longitudinal strain (GLS) is a sensitive measure of LV systolic function, with lower cardiac strain predicting incident heart failure and adverse heart failure outcomes. We analyzed relationships between GLS (cardiovascular magnetic resonance imaging) and monocyte activation (flow cytometry) among 20 WWH and 14 women without HIV., Results: WWH had lower GLS compared to women without HIV (WWH vs. women without HIV: 19.4±3.0 vs. 23.1±1.9%, P<0.0001). Among the whole group, HIV status was an independent predictor of lower GLS. Among WWH (but not among women without HIV), lower GLS related to a higher density of expression of HLA-DR on the surface of CD14+CD16+ monocytes (ρ = -0.45, P = 0.0475). Further, among WWH, inflammatory monocyte activation predicted lower GLS, even after controlling for CD4+ T-cell count and HIV viral load., Conclusions: Additional studies among WWH are needed to examine the role of inflammatory monocyte activation in the pathogenesis of lower GLS and to determine whether targeting this immune pathway may mitigate risks of heart failure and/or adverse heart failure outcomes., Trial Registration: Clinical trials.gov registration: NCT02874703., Competing Interests: MT, MA, ZDD, TQ, MW, CGD, DAA, LTF, GASA, MDN, MJH, and CTL have no disclosures. TLS receives research funding to her institution from Pfizer, Inc., unrelated to the present project. THB has equity in Excision BioTherapeutics and is a member of their Scientific Advisory Board, unrelated to the present project. TGN has been a consultant to and received fees from Bristol Myers Squibb, AbbVie, Intrinsic Imaging, Roche, Genentech, Sanofi, CRO Oncology, C4 Therapeutic, and H3-Biomedicine, unrelated to the present project. TGN has received research funding from AstraZeneca and Bristol Myers Squibb, unrelated to the present project. MVZ is Principal Investigator of an Industry-Sponsored Research Grant from Gilead Sciences, Inc. to her institution, unrelated to the present project., (Copyright: © 2022 Toribio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS., Objectives: This study aimed to detail the role of GCS and GRS in ICI myocarditis., Methods: In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death., Results: Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n = 42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P < 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P < 0.001). Over a median follow-up of 30 days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95% CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95% CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95% CI: 0.70-0.91]) and GRS (AUC: 0.76 [95% CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95% CI: 0.58-0.82]), LVEF (AUC: 0.69 [95% CI: 0.56-0.81]), and age (AUC: 0.54 [95% CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002)., Conclusions: GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health (P30CA008748 to DG and CLC; R01HL137562, R01HL130539; and T32HL007208-39 to DAZ). Dr Mahmood has received consultancy fees from Health and Wellness Partners, OMR Globus, Alpha Detail, and Opinion Research Team. Dr Zhang is consultant for MERCK. Dr Sullivan has served as a consultant for Merck and Novartis. Dr Heinzerling has received consultancy, advisory board, and speaker fees from Merck Sharp & Dohme, BMS, Roche, Novartis, Amgen, Sun Pharma, Pierre Fabre, and CureVac. Dr Gavira has received research support from Amgen. Dr Zubiri has served as a consultant to Merck and is supported by a SEOM (Sociedad Española de Oncología Médica) grant. Dr Yang has received research funding from CSL Behring. Dr Nohria has received research support from Amgen and has been a consultant for Takeda Oncology, Boehringer Ingelheim, and AstraZeneca; and he has received support from the Catherine Geoff Fitch fund and Gelb Master Clinician Fund. Dr Fradley has received consulting fees from AstraZeneca and Abbott and has received a research grant from Medtronic. Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg and from Christina and Paul Kazilionis, the Michael and Kathryn Park Endowed Chair in Cardiology, and a Hassenfeld Scholar Award; has received advisory fees from AbbVie, Amgen, C4 Therapeutics, H3-Biomedicine, Genentech, Roche, BMS, and Intrinsic Imaging; has received grant funding from AstraZeneca; and he is also supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL130539, R01HL137562, K24HL150238). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. All rights reserved.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known., Objectives: To assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i., Methods: Individuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane., Results: A total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [-1.7 (5.9) vs. -1.1 (5.3); p < 0.001)., Conclusions: In individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function., (© 2022. The Author(s).)

This study aims to evaluate the efficacy of the Pooled Cohort Equation (PCE), U.S. Preventative Services Task Force (USPSTF), and Framingham Risk Score (FRS) models in predicting ASCVD events among patients receiving radiation therapy (RT) for head and neck cancer (HNCA). From a large cohort of HNCA patients treated with RT, ASCVD events were adjudicated. Observed vs. predicted ASCVD events were compared. We compared rates by statin eligibility status. Regression models and survival analysis were used to identify the relationship between predicted risk and post-RT outcomes. Among the 723 identified patients, 274 (38%) were statin-eligible based on USPSTF criteria, 359 (49%) based on PCE, and 234 (32%) based on FRS. During follow-up, 17% developed an ASCVD, with an event rate of 27 per 1000 person-years, 68% higher than predicted (RR 1.68 (95% CI: 1.02, 2.12), p < 0.001). In multivariable regression, there was no difference in event rates by statin eligibility status (p > 0.05). Post-RT, the observed event rate was higher than the predicted ASCVD risk across all grades of predicted risk (p < 0.05) and the observed risk of an ASCVD event was high even among patients predicted to have a low risk of ASCVD. In conclusion, current ASCVD risk calculators significantly underestimate the risk for ASCVD among patients receiving RT for HNCA.

Background Left atrial (LA) and left ventricular (LV) structural and functional parameters have independent prognostic values as predictors of atrial fibrillation (AF). Purpose To investigate the prognostic value of a left atrioventricular coupling index (LACI) and average annualized change in LACI (hereafter, ΔLACI) measured by cardiac MRI to predict incident AF in a population-based sample from the Multi-Ethnic Study of Atherosclerosis (MESA). Materials and Methods In a secondary analysis of the prospective MESA, 1911 study participants without clinically recognized AF and cardiovascular disease at baseline had LACI assessed with cardiac MRI at baseline (examination 1, 2000-2002) and 10 years later (examination 5, 2010-2012). LACI was defined as the ratio of LA to LV end-diastolic volumes. Univariable and multivariable Cox proportional hazard models were used to evaluate the associations of LACI and average ΔLACI with incident AF. Results Among the 1911 participants (mean age, 59 years ± 9 [standard deviation]; 907 men), 87 incident AF events occurred over 3.9 years ± 0.9 after the second imaging (examination 5). After adjustment for traditional risk factors, greater LACI and ΔLACI were independently associated with AF (hazard ratio, 1.69 [95% CI: 1.46, 1.96] and 1.71 [95% CI: 1.50, 1.94], respectively; both P < .001). Adjusted models for LACI and ΔLACI showed improvement in model discrimination compared with currently used AF risk score (Cohort for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation, or CHARGE-AF, score) model (area under receiver operating characteristic curve [AUC], 0.78 vs 0.74; and AUC, 0.80 vs 0.74, respectively; both P < .001); and to the final model including individual LA or LV parameters for predicting AF incidence (AUC, 0.78 vs 0.76; and AUC, 0.80 vs 0.78, respectively; both P < .001). Conclusion Atrioventricular coupling (left atrioventricular coupling index [LACI]) and coupling change (annual change in LACI) were strong predictors for atrial fibrillation (AF) in a multiethnic population. Both had incremental prognostic value for predicting AF over traditional risk factors, and superior discrimination compared with the Cohort for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation, or CHARGE-AF, score and to individual left atrial or left ventricular parameters. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Leiner in this issue.

Background: Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm., Methods: We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety., Results: Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26)., Conclusion: Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy., Competing Interests: TGN is supported, in part, through a kind gift from Curtis Greer and Pamela Kohlberg. TGN also reports acting as a consultant for Parexel, H3 Biomedicine, Bristol Myers-Squibb, Abbvie and Intrinsic Imaging, unrelated to the current research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Optimal control of traditional risk factors only partially attenuates the exceeding cardiovascular mortality of individuals with diabetes. Employment of machine learning (ML) techniques aimed at the identification of novel features of risk prediction is a compelling target to tackle residual cardiovascular risk. The objective of this study is to identify clinical phenotypes of T2D which are more prone to developing cardiovascular disease., Methods: The Brazilian Diabetes Study is a single-center, ongoing, prospective registry of T2D individuals. Eligible patients are 30 years old or older, with a confirmed T2D diagnosis. After an initial visit for the signature of the informed consent form and medical history registration, all volunteers undergo biochemical analysis, echocardiography, carotid ultrasound, ophthalmologist visit, dual x-ray absorptiometry, coronary artery calcium score, polyneuropathy assessment, advanced glycation end-products reader, and ambulatory blood pressure monitoring. A 5-year follow-up will be conducted by yearly phone interviews for endpoints disclosure. The primary endpoint is the difference between ML-based clinical phenotypes in the incidence of a composite of death, myocardial infarction, revascularization, and stroke. Since June/2016, 1030 patients (mean age: 57 years, diabetes duration of 9.7 years, 58% male) were enrolled in our study. The mean follow-up time was 3.7 years in October/2021., Conclusion: The BDS will be the first large population-based cohort dedicated to the identification of clinical phenotypes of T2D at higher risk of cardiovascular events. Data derived from this study will provide valuable information on risk estimation and prevention of cardiovascular and other diabetes-related events., Clinicaltrials.gov Identifier: NCT04949152.

Stricter control of risk factors has been pursued as a compelling strategy to mitigate cardiovascular events (CVE) in type 2 diabetes (T2D) individuals. However, the achievement rate of the recommended goals has remained low in clinical practice. This study investigated the 2019 ESC guideline recommendation attainment among T2D individuals enrolled in a national cohort held in Brazil. Data from 1030 individuals (mean age: 58 years old; 54% male; mean T2D duration: 9.7 years) were analyzed. The control rates were 30.6% for SBP, 18.8% for LDL-C, and 41% for A1c, and only 3.2% of the study participants met all three targets. Statins and high-intensity lipid-lowering therapy prescription rates were 45% and 8.2%, respectively. Longer T2D duration and those at higher CV risk were less likely to be controlled. Longer diabetes duration and higher CV risk were inversely related to the chance of achieving the recommended targets. Treatment escalation using conventional therapies would be sufficient to gain optimal control in most of the study sample. In conclusion, a minimal proportion of T2D individuals comply with guidelines-oriented CV prevention targets. Given the significant burden of the disease, and the substantial effect size predicted for these therapies, bridging this gap between guidelines and clinical practice should be considered an urgent call to public health managers.

Background: Preclinical studies indicate that the concurrent use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) may improve outcomes in broad groups of patients with cancer. There are limited data on the association between the use of RAAS inhibitors and outcomes among patients treated with immune checkpoint inhibitors (ICIs)., Methods: We performed a retrospective study of all patients treated with an ICI in a single academic network. Of 10,903 patients, 5910 were on any anti-hypertensive medication. Of those on anti-hypertensive therapy, 3426 were prescribed a RAAS inhibitor during ICI treatment, and 2484 were prescribed other anti-hypertensive medications. The primary outcome was overall survival in the entire cohort and in sub-groups by cancer types., Results: Thoracic cancer (34%) and melanoma (16%) were the most common types of cancer. Those prescribed a RAAS inhibitor were older, more frequently male, and had more cardiovascular risk factors. In a Cox proportional hazard model, the concurrent use of RAAS inhibitors was associated with better overall survival (hazard ratio (HR):0.92, [95% Confidence Interval (CI):0.85-0.99], P = .032). Patients with gastrointestinal (HR:0.82, [95% CI: 0.67-1.01], P = .057) and genitourinary cancer (HR:0.81, [95% CI:0.64-1.01], P = .067) had a non-statistically significant better overall survival., Conclusions: In this large retrospective study, patients with hypertension who were concomitantly taking a RAAS inhibitor during ICI therapy had better overall survival. This benefit was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in patients with cancer who receive ICI therapy., Competing Interests: Conflict of interest statement Dr. Neilan has been a consultant to and received fees from Parexel Imaging, Intrinsic Imaging, H3-Biomedicine, Amgen, Sanofi, Genentech, Roche and AbbVie, outside of the current work. Dr. Neilan also reports consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to immune checkpoint inhibitors and research support from AstraZeneca for work related to immune checkpoint inhibitors. Dr. Sullivan has been a consultant to Asana, AstraZeneca, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Pfizer, Replimune; and received research funding from Amgen and Merck, all outside of the current work. Dr. Jain has received an Honorarium from Amgen; Consultant fees from Chugai, Elpis, Pfizer, SPARC, SynDevRx; Owns equity in Accurius, Enlight, SynDevRx; Served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a research Grant from Boehringer Ingelheim. No funding or reagent from these organizations was used in this study. Dr. Reynolds has received research funding from Project Datasphere and consultant to Teladoc all outside of the current work. Dr. Michielin received fees for advisory roles from BMS, MSD, GSK, Novartis, Roche, Pierre-Fabre and Amgen and research funding from BMS, MSD and Amgen. Other authors have no conflicts of interest or financial disclosure., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Anecdotal reports have suggested increased soft tissue calcification in individuals with long-term exposures to high blood glucose. The association of costal cartilage calcification (CCC), a reliably quantifiable marker obtainable from non-contrast cardiac computed tomography (CT) with cumulative fasting blood glucose (FBG) exposure, is unknown. In this study, we aimed to determine the association between quantified CCC and cumulative glucose exposure using non-contrast coronary artery calcium (CAC) scoring computed tomography (CT) images in the Multi-Ethnic Study of Atherosclerosis (MESA)., Methods: The volume of bilateral CCC was quantified in high-density pixels (threshold of Hounsfield Unit>180) using the CAC scoring CT images acquired in the 5 th MESA exam. Prior long-term cumulative exposure to FBG was calculated by area under the FBG-time curve over ten years before the time of the CT exam., Results: A total of 2,305 participants (mean age: 69, female/male: 1.3) were included in this study. The median CCC volume was lower in females than males (1158 mm 3 [IQR: 1751] vs. 3054 mm 3 [3851], p<0.001). In cross-sectional analysis, quantified CCC was associated with FBG (9% increase per SD) and HbA1c (7% increase per SD) at the CT exam only in female participants after adjustment for age, race, BMI, and glomerular filtration rate. Only in female participants, quantified CCC was also associated with prior cumulative FBG (3% increase per decile change). In the subgroup of females with zero CAC scores, the adjusted CCC was still associated with FBG (13% increase per SD) at the time of CT exam and with prior cumulative FBG exposure (4% increase per decile change) before the CT exam., Conclusions: The CCC, a reliably quantified marker in non-contrast cardiac CT, is associated with 10-year cumulative FBG exposure only in female participants, even those with zero CAC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AS declared a shared affiliation with one of the authors, CW, to the handling editor at time of review., (Copyright © 2021 Shabani, Pishgar, Akhtarkhavari, Quinaglia, Budoff, Bluemke, Barr, Post, Wu, Arbab-Zadeh, Sidhaye, Lima and Demehri.)

Aim: In patients with type 2 diabetes mellitus (T2DM) a progressive thinning in the central retinal thickness (CRT) is mainly related to neuroretinal degeneration and occurs before the decline in visual acuity or capillary density. We investigated the change in CRT by optical coherence tomography (OCT) in T2DM patients after 12 weeks of treatment with dapagliflozin or glibenclamide., Methods: Ninety-seven patients (57 ± 7 years) with T2DM and clinical or subclinical atherosclerosis were randomized 1:1 to dapagliflozin (10 mg/day) or glibenclamide (5 mg/day) on top of metformin XR 1.5 g/day. OCT was obtained in all patients enrolled in the study, both at the time of randomization and at the end of the study., Results: Baseline and post-treatment values of fasting glucose and glycated hemoglobin were equivalent in the two arms. There was no difference in change in diabetic retinopathy status after therapy. The center subfield thickness changed by +2(6)μm in the dapagliflozin group and by -1(7) μm in the glibenclamide group (P = 0.001)., Conclusion: A short-term treatment with dapagliflozin may increase CRT as compared with equivalent glycemic control with glibenclamide., Competing Interests: Declaration of Competing Interests None of the authors had competing interests in this trial., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

We compared the effect of dapagliflozin versus glibenclamide on the ratio of lean-to total mass in patients with type 2 diabetes mellitus, carotid subclinical atherosclerosis, HbA1c 7.0-9.0% and 40-70 years-old. Ninety-eight patients (61% male; mean age 57 ± 7 years) were randomized into dapagliflozin 10 mg/day or glibenclamide 5 mg/day on top of metformin. Body composition was measured by Dual Energy X-Ray at randomization and after 12 weeks of treatment. Glycemic control was equivalent in both groups. Dapagliflozin decreased total body mass (-2741 g [95% CI: -3360 to 1945]; p < 0.001) and lean mass (-347 g [95% CI: -761 to -106]; p < 0.001), while glibenclamide increased total body mass (1060 g [95% CI: 140 to 1836]; p < 0.001) and lean mass (929 g [95% CI: 575 to 1283]; p < 0.001) for the differences between arms. The lean-to-total mass ratio increased by 1.2% in the dapagliflozin group and 0,018% in the glibenclamide group (p < 0.001). Dapagliflozin reduced the risk of a negative balance in the lean-to total mass ratio [OR: 0.16 (95% CI: 0.05 to 0.45); p < 0.001] even after adjustment for baseline lean-to total mass ratio, waist circumference, HOMAIR, HbA1c, mean of the two hands handgrip strength and gait speed [OR: 0.13 (95% CI: 0.03-0.57); p < 0.007]. In conclusion, under equivalent glycemic control, dapagliflozin reduced total body mass but increased the ratio of lean-to-total mass when compared with glibenclamide.

Background: There are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis on or after treatment with immune checkpoint inhibitors (ICIs)., Methods: This was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI. A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, we compared patients who developed an event on an ICI with patients treated with an ICI who did not develop a pericardial event. Cox proportional-hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias., Results: There were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (IQR: 64-411), yielding an incidence rate of 1.57 events per 100 person-years. There was a more than fourfold increase in risk of pericarditis or a pericardial effusion among patients on an ICI compared with controls not treated with ICI after adjusting for potential confounders (HR 4.37, 95% CI 2.09 to 9.14, p<0.001). Patients who developed pericardial disease while on an ICI had a trend for increased all-cause mortality compared with patients who did not develop a pericardial event (HR 1.53, 95% CI 0.99 to 2.36, p=0.05). When comparing those who developed pericardial disease after ICI treatment with those who did not, a higher dose of corticosteroid pre-ICI (>0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00 to 6.57, p=0.049)., Conclusions: ICI use was associated with an increased risk of development of pericardial disease among patients with cancer and a pericardial event on an ICI was associated with a trend towards increase in mortality., Competing Interests: Competing interests: TGN has been a consultant to and received fees from Intrinsic Imaging, H3-Biomedicine, Amgen, Roche, and AbbVie, outside of the current work. TGN also reports consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to immune checkpoint inhibitors and grant funding from AstraZeneca. RS has been a consultant to Asana, Bristol Myers Squibb, Merck, Replimune; and received research funding from Amgen and Merck, all outside of the current work. KLR has received research funding from Project Datasphere. AN receives research support from Amgen and is a consultant for Takeda Oncology, AstraZeneca and Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: The new coronavirus disease (COVID-19) is a systemic disease. Mounting evidence depict signs and symptoms involving multiple organs, most of which supported by pathological data. A plausible link to these manifestations is vascular and endothelial dysfunction/damage. However, much of the current knowledge relies on opinion and incipient evidence. We aim to objectively appraise current evidence on the association between COVID-19 and vascular disease, specifically endotheliitis and vasculitis., Methods: Two researchers independently entered the search terms COVID-19 OR SARS-CoV-2 AND vasculitis, endotheliitis OR endothelium in the following online platforms: MedRxiv and LitCovid (PubMed). The search period was set from November 1, 2019 to August 28, 2020. Manuscripts with unavailable full texts, not in English, mainly on pre-clinical data, presenting only study designs or not directly related to the topics of this review were excluded. Retrospective and prospective studies, especially longitudinal ones, were given priority to the purpose of this review. Since there was paucity of prospective controlled evidence, case reports/series were also considered., Results: A total of 318 manuscripts were initially found. Sixty-seven (21%) were excluded: 59 (18.5%) met exclusion criteria and 8 (2.5%) were duplicates. One hundred and forty-two manuscripts (44,6%) did not provide original data and were also excluded: 35 (11%) were comments, 108 (33.9%) reviews; 1 (0.3%) position paper. One hundred and seven (33.6%) studies were considered for the present scoping review: 81 (25,5%) case reports/series; 18 (5.7%) prospective; 8 (2.5%) retrospective. Viral inclusions in endothelial cells, mononuclear cell infiltrates in the intima of small vessels and markers of endothelial cell apoptosis were demonstrated. Specificities of COVID-19 may lead to diverse vascular manifestations in different levels of the vascular bed., Conclusions: Evidence indicates that COVID-19 targets vasculature and endothelium. However, high quality data is still lacking and studies with prospective designs and appropriately matched controls are needed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Heart Failure (HF) is the most common cause of death in Friedreich's ataxia (FRDA), an inherited mitochondrial disease. Myocardial fibrosis and myocardial hypertrophy are well-documented autopsy features among FRDA patients with HF., Objectives: To leverage the unique tissue characterization features of cardiac magnetic resonance (CMR) for characterizing myocardial remodeling in patients with genetically confirmed FRDA without HF and preserved left ventricular ejection fraction (LVEF > 55%)., Methods: Twenty-seven FRDA's patients (age 27.6 ± 9.7 years, 15 women) and 10 healthy controls (32.6±7.3 years, 5 women) underwent a CMR for assessment of LV function, myocardial T1, late gadolinium enhancement (LGE), extracellular volume fraction (ECV), and intracellular water-lifetime (τic), a marker of cardiomyocyte size., Results: As compared to controls, FRDA patients had a preserved LVEF (LVEF: 70.5±7.4% vs. 63.9±9.0%, P<0.058), larger LV mass index (LVMASSi: 61±21.7 vs. 45±4.2g/m2, P<0.02), and decreased LV end-diastolic volume index (LVEDVi 53.1±12.0 vs. 75.7±16.1ml/m2, P<0.001), compared with controls. Additionally, ECV and cardiomyocyte size (τic,) were larger in FRDA patients (ECV: 0.36 ±0.05 vs. 0.25±0.02, P<0.001; τic: 0.15±0.08 vs. 0.06±0.03 s, P = 0.02). ECV and τic were positively associated with LV mass-to-volume ratio (ECV: r = 0.57, P = 0.003; τic: r = 0.39; P = 0.05). LVMASSi and cardiomyocyte mass-index [(1-ECV)·LVMASSi] declined with age at the CMR exam, independent of the age at initial diagnosis., Conclusions: LV hypertrophy and concentric LV remodeling in FRDA are associated at the tissue level with an expansion of the ECV and an increase in cardiomyocyte size. The adverse tissue remodeling assessed by ECV and τic is associated with more severe cardiomyopathy classification, suggesting a role for these markers in tracking disease progression., Competing Interests: The authors have read the journal’s policy and have the following competing interests: TGN has consultancy agreements with Parexel, Intrinsic Imaging, BMS, and Aprea Therapeutics unrelated to this research. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Background: The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy., Methods: In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R)., Results: Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by - 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and - 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments., Conclusions: Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.

Hypertension has been listed in several case series and retrospective cohorts as a potential risk factor for the incidence and severity of the new coronavirus (SARS-CoV-2)-associated disease (COVID-19). The debate is noteworthy because almost one billion people around the globe are estimated to have hypertensive diseases, according to the Global Burden of Disease study. Considering the SARS-CoV-2's high infectivity rates, a possible interaction between COVID-19 and hypertension is worrisome. Additionally, antihypertensive drugs, especially the renin-angiotensin-aldosterone system (RAAS) inhibitors, could also influence the natural course of COVID-19 infection. Not only can these associations hold from an epidemiologic standpoint, a mechanistic scenario possibly exists. Hypertension and antihypertensive drugs can increase the expression of transmembrane angiotensin-converting enzyme (ACE)-2 receptors, the entry target of the viruses, thus facilitating infectivity. On the other hand, an increase in ACE-2 could be protective considering the anti-inflammatory, antithrombotic effects of the ACE-2-angiotensin 1-7/Mas pathway. So far, little is known about the whole picture. Observational studies appear to indicate at least a twofold increased risk of mortality for hypertensive patients with COVID-19; however, the previous and continued use of RAAS inhibitors may be protective in this subgroup of patients. The scarcity of randomized clinical trials precludes evidence-based decision-making. At least one randomized study in a non-specified sub-analysis demonstrated no relationship between an angiotensin-converting enzyme inhibitor and incidence or severity of the disease. It is reflected mainly by observational studies and, therefore, by international cardiology societies' guidelines, which state that antihypertensive drugs, particularly RAAS inhibitors, should not be discontinued unless necessary on a case-by-case basis.

Background: Patients with type 2 diabetes mellitus (T2DM) remain at increased cardiovascular residual risk and endothelial dysfunction, even after optimizing metabolic control and treatment by sodium-glucose-2 transporter inhibitors (SGLT2-is). The present study was based on the hypothesis that proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9i) therapy may mitigate endothelial dysfunction in T2DM patients who are on regular treatment by SGLT2-i., Methods: The EXCEED-BHS3 is a prospective, single-center, investigator-blinded, open-label, randomized clinical trial. Participants ( n  = 110) will be randomized (1:1) to either empagliflozin 25 mg/day alone or empagliflozin 25 mg/day plus evolocumab 140 mg every 2 weeks in addition to optimal medical care. The primary endpoint was defined as the change in the 1-min flow-mediated dilation (FMD) after 16 weeks of treatment. The secondary endpoint is the FMD change after ischemia/reperfusion injury protocol (reserve FMD) after 16 weeks of treatment. Exploratory outcomes comprise the change in FMD and reserve FMD after 8 weeks of treatment and the change after 16 weeks of treatment in the following parameters: plasma levels of nitric oxide, vascular cell adhesion molecule-1 and isoprostane, high-density lipoprotein (HDL) and low-density lipoprotein subfractions profile, HDL function, blood pressure, body mass index, waist circumference and adipokines., Conclusion: This will be the first study to evaluate the add-on effect of PCSK9i on endothelial function of T2DM patients under regular use of empagliflozin., Trial Registration: ClinicalTrials.gov identifier: NCT03932721., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)