Inflammation is triggered by imbalances to systemic and cellular metabolism. This occurs in the setting of cardiometabolic heart failure, for which low-grade inflammation is a commonly reported feature. In experimental models, immune cells are causal determinants in the pathophysiology of metabolic syndromes. Herein we discuss evidence for the contribution of metabolic stress to immune cell activation during cardiometabolic heart failure with preserved ejection fraction. We also discuss related therapeutic approaches along the way.

Background:Pre-clinical studies demonstrated lipids and lipoproteins influence T-cell phenotype. Several large cohort studies have also observed that plasma lipids and lipoproteins are associated with white blood cell and lymphocyte counts. However, there are little data on the relationships of lipids or lipoproteins with lymphocyte subsets in large, community-based, multi-ethnic cohorts. Objectives:The purpose of this study was to evaluate associations of plasma lipid and lipoprotein fractions with circulating lymphocyte subsets in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methods:MESA recruited 6,814 adults (aged 45-84 years) free of clinical cardiovascular disease at the baseline exam between 2000-2002. This study included 1,735 participants (49% male, 36% White) with lipoprotein and immune cell phenotyping data at baseline. Multivariable linear regression models evaluated associations between lipoprotein concentration (analyzed per 1-standard deviation (SD) increment) and lymphocyte subsets. Results:Following correction for multiple hypothesis testing (p < 0.0006), higher high-density lipoprotein (HDL)-cholesterol was associated with higher proportions of memory B-cells, while HDL-lipoprotein concentration was associated with lower pan B-cells. In analyses not corrected for multiple hypothesis testing (p < 0.05), higher concentrations of total-cholesterol, low-density lipoprotein (LDL) cholesterol and LDL-lipoproteins, triglycerides and triglyceride-rich lipoproteins were associated with higher proportions of several T-cell subsets associated with inflammation and senescence. Conversely, a higher concentration of HDL-lipoproteins were associated with lower proportions of senescence-associated T-cells. Conclusions:These results indicate plasma lipids and lipoproteins may play a role in influencing circulating immune cells. If confirmed in longitudinal studies, these findings may have implications for the development of therapeutics targeting inflammation in patients with elevated lipids.

BACKGROUND:Acute inflammatory responses during and after percutaneous coronary intervention (PCI) are associated with subsequent cardiovascular event risk, but limited data exist on acute immune cell responses regulating PCI-related inflammation. As an exploratory pilot study, our objective was to determine whether PCI acutely alters neutrophil-specific components of activation, maturity and chemotaxis in the coronary and peripheral circulation. METHODS:This prospective cohort study was conducted from October 2024 to January 2025 within an urban tertiary-care academic medical centre. Twenty-nine consecutive patients ≥18 years of age undergoing clinically indicated PCI were included. Paired blood samples were collected immediately pre-PCI and post-PCI from the peripheral arterial sheath (peripheral circulation) and coronary guide catheter (coronary circulation). RESULTS:The primary endpoints were pre-PCI to post-PCI changes in immature neutrophils (CD10-CD16- subset as a total percentage of neutrophils) and neutrophil-specific expression of markers relevant for activation and degranulation (CD62L and CD63 expression). In the immediate pre-PCI to post-PCI period, there was an acute increase in CD10-CD16- neutrophil subset in the coronary blood (1.5±0.3% vs 3.4±0.8%, p=0.012) and a decrease in CD62L neutrophil expression in both the coronary (median fluorescence intensities (MFI)=1340.4±102.3 vs 1084.0±92.8, p=0.002) and peripheral circulation (CD62L MFI=1182.4±82.7 vs 1078.1±77.9, p=0.035). No differences were observed with neutrophil degranulation, chemotaxis or migration. CONCLUSIONS:In patients undergoing PCI, we observed an acute increase in circulating neutrophil cell-specific activation and immaturity markers following PCI but no significant effects of PCI on neutrophil degranulation. Further research is needed to understand whether these effects contribute to long-term post-PCI outcomes and, if so, if neutrophil release and activation warrant targeting during PCI.

BACKGROUND:Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear. METHODS:Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms. RESULTS:Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule Vcam1. This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression. CONCLUSIONS:These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.

Antiretroviral therapy (ART) has prolonged the life expectancy of persons living with HIV, the majority of whom are now older than 50 years. Aging people with HIV are at increased risk for cardiovascular events driven by HIV-related inflammation and hypercoagulation. Apixaban is a factor Xa inhibitor that reduces cardiovascular risks and treats stroke, deep vein thrombosis, and pulmonary embolism. We assessed apixaban's impact on key parameters of HIV/SIV pathogenesis in SIV-infected, aged rhesus macaques (RMs) receiving ART. Inflammation, coagulation, T cell subsets, B cells, and macrophages and their immune activation status were monitored throughout the study. We found no significant differences between the apixaban-treated and control groups forvirus replication or CD4+ T cell recovery in blood and tissues after ART. Apixaban did not significantly affect D-dimer, immune activation, or inflammation of SIV-infected, ART-treated RMs. Apixaban-treated RMs experienced multiple bleeding episodes, tissue hemorrhages, and myocardial infarctions, as demonstrated by pathological examination of necropsy-collected tissues. Given apixaban's lack of effect on immune activation, CD4+ T cell restoration, and inflammation, along with increased risk of hemorrhage, factor Xa inhibition may not be an efficient or safe option to target and prevent cardiovascular events in aging people with HIV.

INTRODUCTION:Vascular calcification is common in chronic kidney disease (CKD) and is associated with adverse cardiac outcomes. We investigated the relationship of T50, a measure of mineral stress that is associated with vascular calcification, with left ventricular (LV) echocardiographic abnormalities among patients with CKD in the Chronic Renal Insufficiency Cohort (CRIC). METHODS:Linear regression models were used to examine the cross-sectional associations of T50 with LV mass index, and multinomial logistic regression models were used to analyze the cross-sectional associations of T50 with echocardiographic evidence of LV concentric remodeling, LV concentric hypertrophy, and LV eccentric hypertrophy. Multivariable models are adjusted for age, sex, race/ethnicity, clinical site, systolic blood pressure, body mass index, diabetes, smoking, history of cardiovascular disease, estimated glomerular filtration rate, and 24-h urinary protein. RESULTS:Among 2,280 participants, mean age was 59 years and 47.0% were female; 28.5% showed evidence of LV concentric remodeling, 15.0% showed evidence of LV eccentric hypertrophy, and 36.3% showed evidence of LV concentric hypertrophy. In unadjusted model, each 1 standard deviation (1-SD) lower of T50 was associated with greater odds for eccentric hypertrophy and concentric hypertrophy. After sequential adjustment for demographics, clinical factors, and kidney function measures, these associations were lost for eccentric hypertrophy (OR per 1-SD lower: 1.09; 95% CI: 0.92-1.29) and concentric hypertrophy (OR per 1-SD lower: 1.05; 95% CI: 0.91-1.21). In the unadjusted model, each 1-SD lower of T50 was associated with increased LV mass index; this association was lost in the multivariable-adjusted model (β = 0.33; 95% CI: -0.63 to 1.28). Similar findings were observed when T50 was examined in quartiles. CONCLUSION:Among the CRIC cohort, T50 was not associated with LV concentric remodeling, LV eccentric hypertrophy, or LV concentric hypertrophy after multivariable adjustment that included measures of kidney function.

BACKGROUND:People with HIV (PWH) are at elevated cardiovascular risk, but existing calculators have suboptimal calibration for this population. The American Heart Association developed new prediction equations (PREVENT) to replace the pooled cohort equations (PCE). PREVENT has not been validated among PWH. METHODS:Within the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, we included individuals aged 40-75 without myocardial infarction or stroke at baseline from 2001 to 2021. We calculated predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk at baseline using the PCE and the PREVENT 10-year ASCVD base equation. Myocardial infarction and stroke were systematically adjudicated. To assess discrimination, we calculated Harrell's C -index and to assess calibration we used the Greenwood-Nam-D'Agostino goodness-of-fit tests. RESULTS:We included 13 135 individuals from five sites across the United States. Mean age at enrollment was 44 ± 9 years and 18% were female. Mean predicted 10-year ASCVD risk was 5.8% by PCE and 2.9% by PREVENT. Over 5.7 ± 3.5 years of follow-up, 628 individuals had myocardial infarction or stroke. Discrimination was improved with PREVENT compared to PCE, with Harrell's C -indexes of 0.722 (95% CI 0.701, 0.741) and 0.708 (95% CI 0.687, 0.729), respectively ( P  = 0.008). Both equations underpredicted risk: the observed-to-expected ratio was 2.69 for PREVENT ( P  < 0.001) and 1.35 for PCE ( P  < 0.001). Calibration slopes were 1.998 for PREVENT and 0.932 for PCE, respectively. CONCLUSIONS:Among this cohort of PWH, the PREVENT 10-year ASCVD equations were poorly calibrated and underestimated composite risk for myocardial infarction and stroke, with observed risks more than double predicted risks.

Acute neutrophil responses following myocardial infarction (MI) play a central role in remodeling, contributing to both repair and potential maladaptive responses. Although prior studies have investigated circulating immune cell indices at a single time point during hospitalization for MI, limited data exist on acute intra-individual changes in circulating immune profiles during evolving MI. We analyzed clinical measurements, such as the count and proportion of immune cell components in a serial complete blood count, with differential tests conducted for patients hospitalized with ST-elevation MI (STEMI) in various hospitals in the Northwestern Medicine system from 1 January 2002 to 1 August 2024. Patients with STEMI diagnosis, troponin peaks ≥ 5 ng/mL, and cell count and proportion data prior to the troponin peak and within 24 h after the troponin peak were included. Primary analyses investigated the associations between the troponin peak and peri-STEMI changes in immune cell subsets. Multivariable-adjusted Cox models were used to investigate associations between these peri-STEMI immune cell changes and mortality at 1 year and 3 years. Among the 694 STEMI patients meeting the inclusion criteria, a higher troponin peak was associated with a modest peri-MI increase in neutrophil proportion. Higher adjusted peri-STEMI increases in neutrophil count and proportion were strongly associated with mortality at one and three years [hazard ratio (HR) = 1.31 (95% confidence interval (CI) 1.15-1.49) and HR = 1.27 (95% CI 1.14-1.45) per 1000 cells/μL absolute neutrophil increase, respectively]. Individuals with higher STEMI-related neutrophil increases had higher mortality at one year and three years, independent of the extent of troponin elevation.

Cardiovascular disease remains a leading cause of death in the United States, with an alarming rise in the proportion of young adults experiencing cardiovascular events. Many adolescents enter adulthood with significant cardiovascular disease risk factors. This scientific statement addresses the critical need for cardiovascular health promotion during emerging adulthood, a transitional stage between the ages of 18 and 25 or 29 years of age. We discuss the significance of social determinants of health and the interplay between individual‐level risk factors and developmental changes, including shifts in substance use, social connections, and emotional well‐being. We conclude by outlining strategies for optimizing cardiovascular health promotion and disease prevention, underscoring the importance of primordial prevention, early intervention, and tailored approaches to address the unique needs of emerging adults. Addressing these multifaceted factors is crucial for mitigating the burden of cardiovascular disease risk factors among emerging adults and promoting long‐term cardiovascular well‐being.

Coronary artery disease (CAD) is linked to atherosclerosis plaque formation. In pro-inflammatory conditions, human Natural Killer (NK) cell frequencies in blood or plaque decrease; however, NK cells are underexplored in CAD pathogenesis, inflammatory mechanisms, and CAD comorbidities, such as human cytomegalovirus (HCMV) infection and diabetes. Analysis of PBMC CITE-seq data from sixty-one CAD patients revealed higher blood NK cell SPON2 expression in CAD patients with higher stenosis severity. Conversely, NK cell SPON2 expression was lower in pro-inflammatory atherosclerosis plaque tissue with an enriched adaptive NK cell gene signature. In CAD patients with higher stenosis severity, peripheral blood NK cell SPON2 expression was lower in patients with high HCMV-induced adaptive NK cell frequencies and corresponded to lower PBMC TGFβ transcript expression with dependency on diabetes status. These results suggest that high NK cell SPON2 expression is linked to atherosclerosis pro-homeostatic status and may have diagnostic and prognostic implications in cardiovascular disease.

BACKGROUND:Limited data exist on associations of immune cell subsets with longitudinal changes in subclinical coronary artery disease. METHODS:In the MESA (Multi-Ethnic Study of Atherosclerosis) study, we used a case-cohort approach to explore associations of 28 immune cell subsets measured at baseline (2000-2002) with longitudinal changes in coronary artery calcium (CAC). We examined incident CAC from examination 2 (2002-2004) through examination 5 (2010-2012) in participants with 0 CAC at baseline using multivariable-adjusted Cox regression. In participants with CAC >0 at baseline, we analyzed changes in CAC through examination 5 using multivariable-adjusted linear mixed models. Because no studies have investigated immune cells and longitudinal CAC changes, analyses were considered exploratory, with P<0.05 as the threshold for possible significance. RESULTS:Of 975 participants with immune cells subsets and CAC measurements at baseline, 378 had CAC 0 at baseline (mean age, 58.4; 37.0% men) and 597 had CAC >0 at baseline (mean age, 65.7; 57.6% men). Natural killer cells were associated with higher incident CAC (hazard ratio [HR], 1.26 per SD higher natural killer cell proportion; P=0.03), whereas T helper type cells were associated with lower incident CAC (HR, 0.81; P=0.04). B cells were associated with CAC progression (β=53.1 Agatston units per SD higher B-cell proportion, P=0.04), whereas CD14+CD16+ monocytes (β=-71.6; P=0.03) and T regulatory cells (β=-61.9; P=0.03) were associated with lower CAC progression. CONCLUSIONS:Natural killer cells may be associated with incident CAC and T regulatory cells may be associated with attenuated CAC progression, among other findings. These warrant replication and experimental investigation.

With the advent of antiretroviral therapy (ART) that effectively suppresses HIV replication, and reduced AIDS progression, the clinical spectrum of HIV infection has dramatically changed. Currently, the people living with HIV (PLWH) who receive ART have a nearly normal prognostic of survival, yet they still experience higher morbidity and mortality than age-matched uninfected subjects. The higher risk of death in PLWH is linked to persistence of residual systemic inflammation and T-cell activation. These factors contribute to accelerated aging and higher incidence of HIV-associated non-AIDS conditions, thereby presenting new diagnostic and therapeutic challenges. This new shifting paradigm of HIV infection associates a higher incidence of cardiovascular disease (CVD), such as stroke, acute myocardial infarction and sudden cardiac death, in stark contrast to the reduced incidence of opportunistic infections. The incidence of acute myocardial infarction and coronary disease is several folds higher in PLWH than in the general population. Study of United States (US) death certificates listing HIV infection shows that the deaths from CVD doubled between 1996 and 2006. CVD will become an even more prominent comorbidity considering that more than 50% of PLWH in the US are over 50 years old, an age that more frequently associates CVD, and cardiovascular complications are more frequent in urban African-Americans and Hispanics, which are disproportionately affected by HIV. Therefore, reducing the overall risk of these complications will become the primary challenge in the management of chronic HIV infection. Not surprisingly, the REPRIEVE trial showed a substantial benefit of statins to PLWH, and the current guidelines include statin administration to PLWH. Nonhuman primate (NHP) models for the cardiovascular comorbidities associated with HIV are currently available and their use for testing new therapeutic approaches aimed at countering the effects of hypercoagulability and CVD is discussed. Their use can be of tremendous help to understand the etiology, pathophysiology, and the determinants of CVD in PLWH, which are currently poorly understood. Use of the NHP models could help in dissecting the relative contribution of the virus, behavioral factors, and ART to cardiovascular risk, having the potential to help us establish new strategic approaches aimed at controlling HIV-related CVD.

Cardiovascular adverse events (CVAEs) are recognized complications of chimeric antigen receptor (CAR) T-cell therapies. However, data are lacking regarding subtypes of adverse events that develop in patients with different malignancies, and little is known about the timeframe in which different cardiotoxicities are most likely to occur post-CAR T-cell therapies. In this study, 211 patients, including 138 lymphoma patients and 66 myeloma patients who received CAR T-cell therapies were retrospectively identified. Of these, 42 patients (19.9%) developed CVAEs post-treatment. Myeloma patients predominantly experienced heart failure while lymphoma patients predominantly experienced arrhythmia. Severe CVAEs were observed even at >12 months post-treatment. Lower baseline global longitudinal strain was significantly associated with development of post-CAR T-cell therapy CVAEs in both lymphoma and myeloma patients. These findings highlight the spectra of post-CAR T-cell cardiotoxicities in lymphoma and myeloma patients and the importance of echocardiography for pretreatment risk stratification and long-term surveillance.

BACKGROUND:Limited systematic data exist on heart failure phenotypes in contemporary HIV care, and no prior multicenter studies have investigated physician-adjudicated phenotypes and causes of heart failure in people with HIV (PWH). METHODS:We adjudicated heart failure events and sub-phenotypes occurring between January 1, 2010, and December 31, 2021, at two large urban clinical centers within the CFAR Network of Integrated Clinical Systems (CNICS) cohort. Using Cox proportional hazard regression, hazard ratios were calculated to examine associations of HIV-specific and cardiometabolic risk factors with incident heart failure among PWH. Exploratory analyses investigated presence of physician-adjudicated ischemic and nonischemic causes of HF. RESULTS:Of 402 individuals with events screened as possible heart failure, 289 were adjudicated as heart failure. Of these 289, 77 were prevalent at baseline and 212 were incident. Higher viral load and lower CD4 +  T cell count were associated with incident heart failure. In addition, older age, smoking, hypertension, diabetes mellitus, history of myocardial infarction (MI), and renal insufficiency were associated with higher heart failure risk. Nonischemic heart failure causes were more common than ischemic, and heart failure with reduced ejection fraction (HFrEF) was more common than preserved ejection fraction (HFpEF). Despite distinct demographic and risk factor compositions between the two sites, heart failure phenotypes were similar. CONCLUSION:HIV viremia, low CD4 +  T cell count, traditional CVD risk factors, and renal insufficiency were associated with higher risk for heart failure. The predominant heart failure subtype was nonischemic heart failure. While further studies are needed, our findings suggest heart failure prevention and management in PWH will require addressing complex interactions between HIV-related and traditional CVD risk factors.

Background:People with HIV (PWH) have benefited greatly from antiretroviral therapy, but face additional challenges from age-related comorbid conditions, particularly cardiovascular disease including venous thromboembolism (VTE). Little is known about the effect of HIV viremia and immunodeficiency on VTE risk in this population.Methods:We assessed incident, centrally adjudicated VTE among 21 507 PWH in care between January 2009 and December 2019 within the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. We examined the association of three measures of HIV viral load (baseline, current, cumulative) and current CD4+ cell count with VTE. Cumulative viral load (copy-days of viremia) was estimated with a time-weighted sum using the trapezoidal rule. We modeled the association between viral load and VTE using Cox proportional hazards models (marginal structural Cox models for cumulative), adjusted for demographic and clinical characteristics. We compared the 75th percentile of the viral load distribution with the 25th percentile using the hazard function from the model for all PWH with a VTE and those with a pulmonary embolism.Results:During a median of 4.8 years of follow-up, 424 PWH developed VTE. In adjusted analyses, higher cumulative viral load (75th percentile vs. 25th percentile), the strongest viral load predictor, was associated with a 1.45-fold higher risk of VTE [95% confidence interval (95% CI): 1.22-1.72]. Low CD4+ cell count less than 100 cells/mu l was associated with higher VTE risk (hazard ratio: 4.03, 95% CI: 2.76-5.89) as compared to at least 500 cells/mu l. Findings were similar for PWH who had a pulmonary embolism (n = 189).Conclusion:Reducing HIV viral load and maintaining CD4+ cell count may help mitigate VTE risk in PWH.

Heart failure (HF) is a leading cause of cardiovascular morbidity and mortality, with inflammation recognized as a key cause and byproduct. Despite observational studies linking elevated indices of inflammation with HF severity, as well as experimental models highlighting the centrality of inflammation to the pathogenesis of various types of HF, clinical trials of anti-inflammatory therapies in HF have produced inconsistent results. This variability may relate to the substrate included – differences in HF stage and/or clinical phenotype – as well as the mechanisms and target of therapeutics, whether aimed at preventing new-onset HF or treating established disease. This review evaluates clinical trials directly targeting inflammation in HF, with a focus on disease stage and symptomatology. Ultimately, by highlighting the importance of HF staging and the timing of therapeutics in prior inflammation-targeted interventions, we aim to inform more precise targets from a disease substrate perspective when designing trials of inflammation-modulating therapies in HF.

The regulation of follicular (F) and germinal center (GC) immune reactivity in human lymph nodes (LNs), particularly during the acute stages of viral infection, remains poorly understood. We have analyzed lung-draining lymph nodes (LD-LNs) from COVID-19 autopsies using multiplex imaging and spatial transcriptomics to examine the immune landscape with respect to follicular immune reactivity. We identified 3 groups of donors based on the Bcl6 prevalence of their reactive follicles (RFs): RF-Bcl6no/lo, RF-Bcl6int, and RF-Bcl6hi. A distinct B/Tfh immune landscape, associated with increased prevalence of proliferating B cell and Tfh cell subsets, was found in RF-Bcl6hi LD-LNs. The comparison between LD-LNs and subdiaphragmatic (SD) LNs from the same donor revealed a divergent Bcl6 expression between the 2 anatomical sites. LD-LN Bcl6 expression was also associated with a distinct spatial transcriptomic profile. TH1-associated genes/pathways (e.g., CXCR3, STAT5, TNF signaling) were significantly upregulated in RF-Bcl6no/lo tissues, while the RF-Bcl6hi tissues exhibited significant upregulation of GC-promoting genes/pathways (e.g., CXCL13, B-cell receptor signaling). Our findings reveal a heterogeneous F/GC landscape in COVID-19 LD-LNs, highlighting specific molecular targets and pathways that could regulate human F/GC immune dynamics during acute viral infections.