Anxiety and Depression Associated With Increased Cardiovascular Disease Risk Through Accelerated Development of Risk Factors.

Background: Prior studies have incompletely assessed whether the development of cardiometabolic risk factors (CVDRF) (hypertension, hyperlipidemia, and diabetes mellitus) mediates the association between anxiety and depression (anxiety/depression) and cardiovascular disease (CVD). Objectives: The authors aimed to evaluate the following: 1) the association between anxiety/depression and incident CVDRFs and whether this association mediates the increased CVD risk; and 2) whether neuro-immune mechanisms and age and sex effects may be involved. Methods: Using a retrospective cohort design, Mass General Brigham Biobank subjects were followed for 10 years. Presence and timing of anxiety/depression, CVDRFs, and CVD were determined using ICD codes. Stress-related neural activity, chronic inflammation, and autonomic function were measured by the assessment of amygdalar-to-cortical activity ratio, high-sensitivity CRP, and heart rate variability. Multivariable regression and mediation analyses were employed. Results: Among 71,214 subjects (median age 49.6 years; 55.3% female), 27,048 (38.0%) developed CVDRFs during follow-up. Pre-existing anxiety/depression associated with increased risk of incident CVDRF (OR: 1.71 [95% CI: 1.59-1.83], P < 0.001) and with a shorter time to their development (ß = -0.486 [95% CI: -0.62 to -0.35], P < 0.001). The development of CVDRFs mediated the association between anxiety/depression and CVD events (log-odds: 0.044 [95% CI: 0.034-0.055], P < 0.05). Neuro-immune pathways contributed to the development of CVDRFs (P < 0.05 each) and significant age and sex effects were noted: younger women experienced the greatest acceleration in the development of CVDRFs after anxiety/depression. Conclusions: Anxiety/depression accelerate the development of CVDRFs. This association appears to be most notable among younger women and may be mediated by stress-related neuro-immune pathways. Evaluations of tailored preventive measures for individuals with anxiety/depression are needed to reduce CVD risk.

Brief Report: Low-Dose Methotrexate Does Not Affect Measures of HIV-1 Persistence in Individuals With Chronically Treated HIV-1 Infection.

BACKGROUND: People with HIV-1 often have chronic inflammation leading to severe non-AIDS morbidity and mortality. The AIDS Clinical Trials Group Study A5314 sought to lower inflammation with low-dose methotrexate (LDMTX). The primary study outcomes were reported previously but here we present the impact of LDMTX on multiple measures of HIV-1 persistence. METHODS: A5314 was a phase 2 randomized, double-blind, multicenter trial in 176 adult people with HIV-1 on virally suppressive antiretroviral therapy. LDMTX (5-15 mg/wk) was administered for 24 weeks with an additional 12 weeks of participant follow-up. The current analyses of HIV-1 persistence were restricted to 60 participants (30 LDMTX and 30 placebo) randomly selected from the total population. Plasma HIV-1 RNA, total HIV-1 DNA, and cell-associated HIV-1 RNA (CA HIV-1 RNA) were measured by sensitive quantitative PCR assays. RESULTS: LDMTX treatment had no significant effect on sensitive measures of plasma HIV-1 RNA, HIV-1 DNA, CA HIV-1 RNA, or CA HIV-1 RNA/DNA ratio at any time point or from baseline to week 24. As observed in the main study, absolute peripheral CD4+ and CD8+ T-cell numbers decreased from baseline to week 24 among the 30 participants receiving LDMTX compared with placebo (median decrease of -31.5 CD4+ T cells/µL, -83.5 CD8+ T cells/µL). CONCLUSIONS: LDMTX had no significant effect on any measure of HIV-1 persistence in plasma or peripheral blood mononuclear cells. Further studies are needed to determine whether other immunosuppressive and/or immunoreductive interventions are safe and capable of affecting HIV-1 persistence.

Posttraumatic stress disorder increases thrombosis risk: Evidence from a biobank data set.

Depression and anxiety are linked to deep venous thrombosis (DVT) and posttraumatic disorder (PTSD) increases risk of venous thromboembolism in women. However, the mechanisms underlying this relationship remain unknown. We hypothesized that PTSD would associate with increased DVT risk, that neuroimmune mechanisms would mediate the PTSD-DVT link, and that these associations would be stronger in women. This cohort study included N = 106 427 participants from a large biobank. PTSD and DVT were defined using ICD-10 codes. A subset (N = 1520) underwent imaging, from which we assessed stress-associated neural activity (SNA). High-sensitivity C-reactive protein (hs-CRP) levels and heart rate variability (HRV) were used as indicators of systemic inflammation and autonomic activity, respectively. Linear, logistic, and Cox regressions and mediation analyses were used to test our hypotheses. Of 106 427 participants, 4192 (3.9%) developed DVT. PTSD associated with increased DVT risk (HR [95% CI]: 1.66 [1.34, 2.07], p < .001), and this finding remained significant after adjustment for age, sex, and traditional DVT risk factors. When analyzed separately by sex, PTSD was significantly associated with DVT risk in women but not men. Further, heightened SNA and lower HRV mediated the effect of PTSD on DVT risk. Results suggest that individuals with PTSD are at increased risk for DVT, and that risk is higher in women. This relationship was partially driven by alterations in stress-associated neural activity and autonomic function, suggesting potential targets for preventive therapies. Future studies are needed to investigate whether intervening on PTSD-DVT mechanisms has downstream beneficial effects on DVT, especially among women.

Initial combination therapy with macitentan and tadalafil in patients with pulmonary arterial hypertension, with and without cardiac comorbidities.

AIMS: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities. METHODS AND RESULTS: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups. CONCLUSIONS: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups.

Anxiety and depression are associated with heightened risk of incident deep vein thrombosis: Mediation through stress-related neural mechanisms.

Controversy exists as to whether anxiety and depression increase deep vein thrombosis (DVT) risk, and the mechanisms mediating potential links remain unknown. We aimed to evaluate the association between anxiety and depression and DVT risk and determine whether upregulated stress-related neural activity (SNA), which promotes chronic inflammation, contributes to this link. Our retrospective study included adults (N = 118 871) enrolled in Mass General Brigham Biobank. A subset (N = 1520) underwent clinical 18F-FDG-PET/CT imaging. SNA was measured as the ratio of amygdalar to cortical activity (AmygAC). High-sensitivity C-reactive protein (hs-CRP) and heart rate variability (HRV) were also obtained. Median age was 58 [interquartile range (IQR) 42-70] years with 57% female participants. DVT occurred in 1781 participants (1.5%) over median follow-up of 3.6 years [IQR 2.1-5.2]. Both anxiety and depression independently predicted incident DVT risk after robust adjustment (HR [95% CI]: 1.53 [1.38-1.71], p < .001; and 1.48 [1.33-1.65], p < .001, respectively). Additionally, both anxiety and depression associated with increased AmygAC (standardized beta [95% CI]: 0.16 [0.04-0.27], p = .007, and 0.17 [0.05-0.29], p = .006, respectively). Furthermore, AmygAC associated with incident DVT (HR [95% CI]: 1.30 [1.07-1.59], p = .009). Mediation analysis demonstrated that the link between anxiety/depression and DVT was mediated by: (1) higher AmygAC, (2) higher hs-CRP, and (3) lower HRV ( < .05 for each). Anxiety and depression confer an attributable risk of DVT similar to other traditional DVT risk factors. Mechanisms appear to involve increased SNA, autonomic system activity, and inflammation. Future studies are needed to determine whether treatment of anxiety and depression can reduce DVT risk.

Impact of RA treatment strategies on lipids and vascular inflammation in rheumatoid arthritis: a secondary analysis of the TARGET randomized active comparator trial.

BACKGROUND: Treatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk. METHODS: In this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR. RESULTS: We studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms. CONCLUSIONS: Both treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02374021.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

Heart-brain axis: Pushing the boundaries of cardiovascular molecular imaging.

Despite decades of research, the heart-brain axis continues to challenge investigators seeking to unravel its complex pathobiology. Strong epidemiologic evidence supports a link by which insult or injury to one of the organs increases the risk of pathology in the other. The putative pathways have important differences between sexes and include alterations in autonomic function, metabolism, inflammation, and neurohormonal mechanisms that participate in crosstalk between the heart and brain and contribute to vascular changes, the development of shared risk factors, and oxidative stress. Recently, given its unique ability to characterize biological processes in multiple tissues simultaneously, molecular imaging has yielded important insights into the interplay of these organ systems under conditions of stress and disease. Yet, additional research is needed to probe further into the mechanisms underlying the heart-brain axis and to evaluate the impact of targeted interventions.

Effect of Stress-Related Neural Pathways on the Cardiovascular Benefit of Physical Activity.

BACKGROUND: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood. OBJECTIVES: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression. METHODS: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygAC). CVD events were ascertained from electronic health records. RESULTS: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygAC (standardized ß: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygAC reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023). CONCLUSIONS: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression.

Association of the multi-biomarker disease activity score with arterial 18-fluorodeoxyglucose uptake in rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) and atherosclerosis share many common inflammatory pathways. We studied whether a multi-biomarker panel for RA disease activity (MBDA) would associate with changes in arterial inflammation in an interventional trial. METHODS: In the TARGET Trial, RA patients with active disease despite methotrexate were randomly assigned to the addition of either a TNF inhibitor or sulfasalazine+hydroxychloroquine (triple therapy). Baseline and 24-week follow-up 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography scans were assessed for change in arterial inflammation measured as the maximal arterial target-to-blood background ratio of FDG uptake in the most diseased segment of the carotid arteries or aorta (MDS-TBRmax). The MBDA test, measured at baseline and weeks 6, 18, and 24, was assessed for its association with the change in MDS-TBRmax. RESULTS: Interpretable scans were available at baseline and week 24 for n = 112 patients. The MBDA score at week 24 was significantly correlated with the change in MDR-TBRmax (Spearman's rho = 0.239; p= 0.011) and remained significantly associated after adjustment for relevant confounders. Those with low MBDA at week 24 had a statistically significant adjusted reduction in arterial inflammation of 0.35 units vs no significant reduction in those who did not achieve low MBDA. Neither DAS28-CRP nor CRP predicted change in arterial inflammation. The MBDA component with the strongest association with change in arterial inflammation was serum amyloid A (SAA). CONCLUSIONS: Among treated RA patients, achieved MBDA predicts of changes in arterial inflammation. Achieving low MBDA at 24 weeks was associated with clinically meaningful reductions in arterial inflammation, regardless of treatment.

Comparison of cardiac magnetic resonance imaging, functional and haemodynamic variables in pulmonary arterial hypertension: insights from REPAIR.

Background: Measures that can detect large treatment effects are important for monitoring therapeutic effectiveness. The 2022 European Society of Cardiology/European Respiratory Society guidelines highlight the importance of imaging in monitoring disease status and treatment response in pulmonary arterial hypertension (PAH). Are the standardised treatment effect sizes (STES) of cardiac magnetic resonance imaging (cMRI) comparable with functional and haemodynamic variables? Methods: REPAIR (ClinicalTrials.gov: NCT02310672) was a prospective, multicentre, single-arm, open-label, 52-week phase 4 study evaluating the effect of macitentan 10 mg, with or without a phosphodiesterase 5 inhibitor (PDE5i), on right ventricular (RV) remodelling, cardiac function and cardiopulmonary haemodynamics. Both cMRI and functional assessments were performed at screening and at weeks 26 and 52; haemodynamic measurements were conducted at screening and week 26. In this post hoc analysis, STES were estimated using the parametric Cohen's d and non-parametric Cliff's delta tests. Results: At week 26, large STES (Cohen's d) were observed for 10 of the 20 cMRI variables assessed, including the prognostic measures of RV and left ventricular stroke volume and RV ejection fraction and the haemodynamic trial end-point, pulmonary vascular resistance; medium STES were observed for 6-min walk distance (6MWD). The STES were consistent in treatment-naïve patients and those escalating therapy and maintained at week 52. Similar results were obtained using the non-parametric Cliff's delta method. Conclusions: The treatment effect of macitentan, alone or in combination with a PDE5i, was comparable for several cMRI and haemodynamic variables with prognostic value in PAH, and greater than that of 6MWD in patients with PAH, highlighting the emerging relevance of cMRI in PAH.

Biomarkers of Cardiovascular Risk in Patients With Rheumatoid Arthritis: Results From the TARGET Trial.

Cardiovascular disease remains an important comorbidity in patients with rheumatoid arthritis (RA), but traditional models do not accurately predict cardiovascular risk in patients with RA. The addition of biomarkers could improve prediction. METHODS AND RESULTS: The TARGET (Treatments Against RA and Effect on FDG PET/CT) trial assessed whether different treatment strategies in RA differentially impact cardiovascular risk as measured by the change in arterial inflammation on arterial target to background ratio on fluorodeoxyglucose positron emission tomography/computed tomography scans conducted 24 weeks apart. A group of 24 candidate biomarkers supported by prior literature was assessed at baseline and 24 weeks later. Longitudinal analyses examined the association between baseline biomarker values, measured in plasma EDTA, and the change in arterial inflammation target to background ratio. Model fit was assessed for the candidate biomarkers only, clinical variables only, and models combining both. One hundred nine patients with median (interquartile range) age 58 years (53-65 years), RA duration 1.4 years (0.5-6.6 years), and 82% women had biomarkers assessed at baseline and follow-up. Because the main trial analyses demonstrated significant target to background ratio decreases with both treatment strategies but no difference across treatment groups, we analyzed all patients together. Baseline values of serum amyloid A, C-reactive protein, soluble tumor necrosis factor receptor 1, adiponectin, YKL-40, and osteoprotegerin were associated with significant change in target to background ratio. When selected candidate biomarkers were added to the clinical variables, the adjusted R2 improved from 0.20 to 0.33 (likelihood ratio P=0.0005). CONCLUSIONS: A candidate biomarker approach identified several promising biomarkers that associate with baseline and treatment-associated changes in arterial inflammation in patients with RA. These will now be tested in an external validation cohort.

PTSD increases risk for major adverse cardiovascular events through neural and cardio-inflammatory pathways.

While posttraumatic stress disorder (PTSD) is known to associate with an elevated risk for major adverse cardiovascular events (MACE), few studies have examined mechanisms underlying this link. Recent studies have demonstrated that neuro-immune mechanisms, (manifested by heightened stress-associated neural activity (SNA), autonomic nervous system activity, and inflammation), link common stress syndromes to MACE. However, it is unknown if neuro-immune mechanisms similarly link PTSD to MACE. The current study aimed to test the hypothesis that upregulated neuro-immune mechanisms increase MACE risk among individuals with PTSD. This study included N = 118,827 participants from a large hospital-based biobank. Demographic, diagnostic, and medical history data collected from the biobank. SNA (n = 1,520), heart rate variability (HRV; [n = 11,463]), and high sensitivity C-reactive protein (hs-CRP; [n = 15,164]) were obtained for a subset of participants. PTSD predicted MACE after adjusting for traditional MACE risk factors (hazard ratio (HR) [95 % confidence interval (CI)] = 1.317 [1.098, 1.580], ß = 0.276, p = 0.003). The PTSD-to-MACE association was mediated by SNA (CI = 0.005, 0.133, p < 0.05), HRV (CI = 0.024, 0.056, p < 0.05), and hs-CRP (CI = 0.010, 0.040, p < 0.05). This study provides evidence that neuro-immune pathways may play important roles in the mechanisms linking PTSD to MACE. Future studies are needed to determine if these markers are relevant targets for PTSD treatment and if improvements in SNA, HRV, and hs-CRP associate with reduced MACE risk in this patient population.

Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results.

INTRODUCTION: The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. METHODS: REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland-Altman analyses. RESULTS: The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland-Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of - 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. CONCLUSIONS: A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. TRIAL REGISTRATION NUMBER: REPAIR NCT02310672.

Mineralocorticoid Receptor Antagonism by Eplerenone and Arterial Inflammation in HIV: The MIRABELLA HIV Study.

Importance: The risk for atherosclerotic disease is increased 1.5- to 2.0-fold among persons with HIV (PWH). Increased activation of the renin-angiotensin-aldosterone system may contribute to increased arterial inflammation in this population. Objective: To determine the effects of eplerenone on arterial inflammation among well-treated PWH without known cardiovascular disease (CVD). Design, Setting, and Participants: Well-treated PWH who participated in the double-blinded, placebo-controlled, Mineralocorticoid Receptor Antagonism for Cardiovascular Health in HIV (MIRACLE HIV) study between February 2017 and March 2022 assessing the effects of eplerenone on myocardial perfusion were invited to participate in the Mineralocorticoid Receptor Antagonism By Eplerenone to Lower Arterial Inflammation in HIV (MIRABELLA) substudy if there was no current statin use. Participants were enrolled in the MIRABELLA study and underwent additional 18F-fludeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) imaging of the aorta and carotid arteries to assess arterial inflammation over 12 months of treatment with eplerenone vs placebo. Interventions: Eplerenone, 50 mg, twice a day vs identical placebo. Main Outcomes and Measures: The primary outcome was change in target to background ratio (TBR), a measure of arterial wall inflammation, in the index vessel after 12 months of treatment. The index vessel was defined as the vessel (aorta, left carotid artery, or right carotid artery) with the highest TBR at baseline in each participant. Results: A total of 26 participants (mean [SD] age, 54 [7] years; 18 male [69%]) were enrolled in the study. Treatment groups (eplerenone, 13 vs placebo, 13) were of similar age, sex, and body mass index. Eplerenone was associated with a reduction in TBR of the primary end point, the index vessel (eplerenone vs placebo: model treatment effect, -0.31; 95% CI, -0.50 to -0.11; P = .006; percentage change, -12.4% [IQR, -21.9% to -2.6%] vs 5.1% [IQR, -1.6% to 11.0%]; P = .003). We further observed a significant reduction of the TBR of the most diseased segment (MDS) of the index vessel (eplerenone vs placebo: -19.1% [IQR, -27.0% to -11.9%] vs 6.8% [IQR, -9.1% to 12.1%]; P = .007). A similar result was seen assessing the index vessel of the carotids (eplerenone vs placebo: -10.0% [IQR, -21.8% to 3.6%] vs 9.7% [IQR, -9.8% to 15.9%]; P = .046). Reduction in the TBR of MDS of the index vessel on 18F-FDG PET/CT correlated with improvement in the stress myocardial blood flow on cardiac magnetic resonance imaging (Spearman ρ = -0.67; P = .01). Conclusion and Relevance: In this small randomized clinical trial, eplerenone was associated with reduction in arterial inflammation among well-treated PWH without known CVD. In addition, reductions in arterial inflammation as measured by 18F-FDG PET/CT were related to improvements in stress myocardial perfusion. Further larger studies should explore whether eplerenone is a potential treatment strategy for inflammatory-mediated CVD in PWH. Trial Registration: ClinicalTrials.gov Identifier: NCT02740179.

The Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE): protocol for a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Inflammation is a key mediator in the development and progression of the atherosclerotic disease process as well as its resultant complications, like myocardial infarction (MI), stroke and cardiovascular (CV) death, and is emerging as a novel treatment target. Trials involving anti-inflammatory medications have demonstrated outcome benefit in patients with known CV disease. In this regard, colchicine appears to hold great promise. However, there are potential drawbacks to colchicine use, as some studies have identified an increased risk of infection, and a non-significant trend for increased all-cause mortality. Thus, a more thorough understanding of the underlying mechanism of action of colchicine is needed to enable a better patient selection for this novel CV therapy. OBJECTIVE: The primary objective of the Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE) trial is to assess the effect of colchicine on vascular inflammation in the carotid arteries and ascending aorta measured with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with type 2 diabetes mellitus (T2DM) or pre-diabetes who have experienced a recent vascular event (acute coronary syndrome (ACS)/MI, transient ischaemic attack (TIA) or stroke). Secondary objectives include determining colchicine's effect on inflammatory biomarkers (high-sensitivity C reactive protein (hs-CRP) and interleukin-6 (IL-6)). Additionally, we will assess if baseline inflammation imaging or biomarkers are associated with a treatment response to colchicine determined by imaging. Exploratory objectives will look at: (1) the difference in the inflammatory response to colchicine in patients with coronary events compared with patients with cerebral events; (2) the difference in the inflammatory response to colchicine in different vascular beds; (3) the relationship of FDG-PET imaging markers with serum biomarkers and (4) assessment of quality-of-life changes. METHODS AND DESIGN: CADENCE is a multicentre, prospective, randomised, double-blinded, placebo-controlled study to determine the effect of colchicine on arterial inflammation as assessed with imaging and circulatory biomarkers, specifically carotid arteries and aortic FDG uptake as well as hs-CRP and IL-6 among others. Patients with T2DM or pre-diabetes who have recently experienced a CV event (within 30-120 days after an ACS (ie, ST-elevation MI (STEMI) or non-STEMI)) or TIA/stroke with documented large vessel atherosclerotic disease will be randomised to treatment with either colchicine 0.6 mg oral daily or placebo. Participants will undergo baseline clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan of the ascending aorta and left and right carotid arteries. Patients will undergo treatment for 6 months and have repeat clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan at the conclusion of the study. The primary outcome will be the change in the maximum target to background ratio (TBRmax) in the ascending aorta (or carotid arteries) from baseline to follow-up on FDG PET/CT imaging. DISCUSSION: Colchicine is an exciting potential new therapy for CV risk reduction. However, its use is associated with side effects and greater understanding of its underlying mechanism of action is needed. Importantly, the current study will determine whether its anti-inflammatory action is an indirect systemic effect, or a more local plaque action that decreases inflammation. The results will also help identify patients who will benefit most from such therapy. TRIAL REGISTRATION NUMBER: NCT04181996.