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BackgroundInsomnia is common among people with HIV (PWH) and may be associated with increased risk of myocardial infarction (MI). This study examines the association between insomnia and MI by MI type among PWH.SettingLongitudinal cohort study of PWH at 5 Centers for AIDS Research Network of Integrated Clinical Systems sites.MethodsClinical data and patient-reported measures and outcomes from PWH in care between 2005 and 2018 were used in this study. Insomnia, measured at baseline, was defined as having difficulty falling or staying asleep with bothersome symptoms. The Centers for AIDS Research Network of Integrated Clinical Systems centrally adjudicates MIs using expert reviewers, with distinction between type 1 MI (T1MI) and type 2 MI (T2MI). Associations between insomnia and first incident MI by MI type were measured using separate Cox proportional hazard models adjusted for age, sex, race/ethnicity, traditional cardiovascular disease risk factors (hypertension, dyslipidemia, poor kidney function, diabetes, and smoking), HIV markers (antiretroviral therapy, viral suppression, and CD4 cell count), and stimulant use (cocaine/crack and methamphetamine).ResultsAmong 12,448 PWH, 48% reported insomnia. Over a median of 4.4 years of follow-up, 158 T1MIs and 109 T2MIs were identified; approximately half of T2MIs were attributed to sepsis or stimulant use. After adjustment for potential confounders, we found no association between insomnia and T1MI (hazard ratio = 1.05, 95% confidence interval: 0.76 to 1.45) and a 65% increased risk of T2MI among PWH reporting insomnia compared with PWH without insomnia (hazard ratio = 1.65, 95% confidence interval: 1.11 to 2.45).ConclusionsPWH reporting insomnia are at an increased risk of T2MI, but not T1MI, compared with PWH without insomnia, highlighting the importance of distinguishing MI types among PWH.

Background: HIV induces several metabolic derangements that contribute to cardiovascular disease, but it is unclear if HIV increases diabetes or hypertension risk. Refining longitudinal relationships between HIV-specific factors and cardiovascular disease risk factors across different care settings may help inform cardiovascular disease prevention among people with HIV (PWH). Methods: We tested the hypothesis that long-term higher cumulative viral load (viremia-copy-year) is associated with higher risk of diabetes and hypertension by analyzing electronic records of PWH from 2 distinct health systems in Chicago (Northwestern Medicine and Howard Brown Health Care) receiving care in 2004 to 2019. We used joint longitudinal-survival models to assess multivariable-adjusted associations. Subgroup analyses per site were also conducted. Results: We observed 230 (3.0%) incident diabetes cases in 7628 PWH without baseline diabetes and 496 (6.7%) hypertension cases in 7450 PWH without baseline hypertension. Pooled analysis showed a direct association of viremia-copy-year with incident hypertension (hazards ratio, 1.20 [95% CI, 1.14–1.26]) but not with diabetes (hazards ratio, 1.03 [95% CI, 0.96–1.10]). However, site-specific differences existed whereby the Northwestern-only analysis demonstrated a significant association of viremia-copy-year with hypertension (hazards ratio, 1.29 [95% CI, 1.08–1.32]). Additionally, higher social deprivation index (both sites) and diagnosis of mental health disorder (Howard Brown Health only) was associated with higher diabetes and hypertension risk. Conclusions: Cumulative viral load may be associated with incident hypertension among PWH. Associations of HIV control with cardiovascular disease risk factors among PWH may differ by health care system context.

The balance between inflammation and its resolution plays an important and increasingly appreciated role in heart failure (HF) pathogenesis. In humans, different chronic inflammatory conditions and immune-inflammatory responses to infection can lead to diverse HF manifestations. Reviewing the phenotypic and mechanistic diversity of these HF presentations offers useful clinical and scientific insights.HF risk is increased in patients with chronic inflammatory and autoimmune disorders and relates to disease severity. Inflammatory condition-specific HF manifestations exist and underlying pathophysiologic causes may differ across conditions. Although inflammatory disease-specific presentations of HF differ, chronic excess in inflammation and auto-inflammation relative to resolution of this inflammation is a common underlying contributor to HF. Further studies are needed to phenotypically refine inflammatory condition-specific HF pathophysiologies and prognoses, as well as potential targets for intervention.

Lower CD4The aim of this study was to explore the association between peripherally circulating CD4Data from 1,860 participants (1,270 PWH) without prevalent CVD from the VACS (Veterans Aging Cohort Study), a prospective, observational cohort of veterans with and without HIV infection, were analyzed. T cell subsets were quantified in baseline samples using flow cytometry. Incident CVD events were identified using International Classification of Diseases-9th Revision and International Classification of Diseases-10th Revision diagnosis and procedure codes. Participants were followed from baseline date (2005-2006) to the first of CVD incidence, death, or September 30, 2016. Cox proportional hazards regression was used to model associations between these T cell subsets and the risk for incident CVD while adjusting for demographics and other CVD risk factors.The median participant age at baseline was 51.6 years. Most were male (94%) and of Black race (69.1%). There were 344 incident CVD events (219 in PWH) during follow-up (median 9.8 years). In PWH, higher proportions (per SD increment) of T helper type 17 cells (adjusted HR: 1.19; 95% CI: 1.08-1.31), T effector memory cells re-expressing CD45RA (adjusted HR: 1.19; 95% CI: 1.07-1.34), and CD28Among PWH, T helper type 17 cells, senescent cells, and CD4

BACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes – key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke. METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models. RESULTS: We observed associations of intermediate monocytes, early-activated CD4(+) T cells, and both CD4(+) and CD8(+) T cells producing interleukin-4 after cytokine stimulation (T(h2) and T(c2), respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women. CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.

Background Type 1 myocardial infarctions (T1MIs) result from atherosclerotic plaque instability, rupture, and/or erosion. Type 2 MIs (T2MIs) are secondary to causes such as sepsis and cocaine-induced vasospasm resulting in an oxygen demand-supply mismatch and are associated with higher mortality than T1MIs. T2MIs account for a higher proportion of MIs among people living with HIV (PLWH) compared with the general population. We compared MI rates by type among aging PLWH. We hypothesized that increases in MI rates with older age would differ by MI types, and T2MIs would be more common than T1MIs in younger individuals. Methods Potential MIs from 6 sites were centrally adjudicated using physician notes, electrocardiograms, procedure results, and laboratory results. Reviewers categorized MIs by type and identified causes of T2MIs. We calculated T1MI and T2MI incidence rates. Incidence rate ratios were calculated for T2MI vs. T1MI rates per decade of age. Results We included 462 T1MIs (52%) and 413 T2MIs (48%). T1MI rates increased with older age, although T1MIs occurred in all age decades including young adults. T2MI rates were significantly higher than T1MI rates for PLWH younger than 40 years. T1MI rates were similar or higher than T2MI rates among those older than 40 years (significantly higher for those aged 50-59 and 60-69 years). Conclusions Rates of T2MIs were higher than T1MIs until age 40 years among PLWH, differing from the general population, but rates of both were high among older PLWH. Given prognostic differences between MI types, these results highlight the importance of differentiating MI types among PLWH.

HIV is an independent risk factor for heart failure (HF). Cardiac imaging studies in people with HIV (PWH) have identified myocardial pathologies, namely fibrosis and steatosis, that likely contribute to the higher risk of HF. In this review, we survey existing epidemiological, clinical, and mechanistic literature to identify potential pathways that may contribute to the burden of myocardial fibrosis and steatosis among PWH. Multiple cohort studies over the past 20 years have demonstrated a roughly 2-fold higher risk of incident HF in PWH, as well as a disproportionate burden of myocardial fibrosis and steatosis in PWH without HF. Both myocardial fibrosis and steatosis are known contributors to HF in adults without HIV. Pathways involving the NLRP3 inflammasome, TGF-β1, and adipocyte dysfunction are known to play a crucial role in the development of myocardial fibrosis and steatosis. Upregulation of these pathways in HIV due to direct effects of viral proteins, persistent immune dysregulation, gut epithelial breakdown and dysbiosis, and toxicities from antiretroviral therapy may contribute to myocardial dysfunction in HIV. Understanding these pathways may lead to more precise diagnostic and therapeutic targets to curb HF in PWH. During the past three decades, observational and mechanistic studies have provided important insights into risk factors and pathways that may contribute to the increased HF risk in PWH. Future work is needed to characterize these pathways more precisely in mechanistic studies of PWH, with the goal of ultimately deriving valuable targets for prevention, early diagnosis, and treatment of HF in PWH.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in patients with type 2 diabetes mellitus (T2DM). We sought to describe trends in prescribing for SGLT2is and GLP1-RAs in diverse care settings, including (1) the outpatient clinics of a midwestern integrated health system and (2) small- and medium-sized community-based primary care practices and health centers in 3 midwestern states. We included adults with T2DM and ≥1 outpatient clinic visit. The outcomes of interest were annual active prescription rates for SGLT2is and GLP1-RAs (separately). In the integrated health system, 22,672 patients met the case definition of T2DM. From 2013 to 2019, the overall prescription rate for SGLT2is increased from 1% to 15% (absolute difference [AD] 14%, 95% confidence interval [CI] 13% to 15%, p0.01). The GLP1-RA prescription rate was stable at 10% (AD 0%, 95% CI -1% to 1%, p = 0.9). In community-based primary care practices, 43,340 patients met the case definition of T2DM. From 2013 to 2017, the SGLT2i prescription rate increased from 3% to 7% (AD 4%, 95% CI 3% to 6%, p0.01), whereas the GLP1-RA prescription rate was stable at 2% to 3% (AD 1%, 95% CI -1 to 1%, p = 0.40). In a fully adjusted regression model, non-Hispanic Black patients had lower odds of SGLT2i or GLP1-RA prescription (odds ratio 0.56, 95% CI 0.34 to 0.89, p = 0.016). In conclusion, the increase in prescription rates was greater for SGLT2is than for GLP1-RAs in patients with T2DM in a large integrated medical center and community primary care practices. Overall, prescription rates for eligible patients were low, and racial disparities were observed.

There is currently little available evidence about the causal relationship between HIV infection and Coronavirus disease 2019 (COVID-19), and these relationships may differ across populations and socioeconomic contexts. In this study, two-sample Mendelian randomisation analyses were conducted using summary-level data from genome-wide association studies of the European ancestry population. We initially examined the causality from HIV-1 infection to the spectrum of COVID-19 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalisation, and very severe respiratory disease]. Then we additionally tested the causality from socioeconomic-position (SEP) indicators (educational attainment and household income) to HIV-1 infection, and from educational attainment and household income to the spectrum of COVID-19. We also tested the causality from HIV-1 infection to body height as a negative control. Null causality from HIV-1 infection to the spectrum of COVID-19 was found. The risk of HIV-1 infection significantly decreased as educational attainment and household income increased. Higher educational attainment was causally associated with lower odds of the spectrum of COVID-19. Higher household income was causally associated with lower odds of COVID-19 hospitalisation and very severe respiratory disease. Negative control shared a similar result with the estimates between HIV-1 infection and the spectrum of COVID-19. We concluded that HIV-1 infection was not causally associated with SARS-CoV-2 infection, COVID-19 hospitalisation, and very severe respiratory disease. Reduction in socioeconomic inequality could potentially ameliorate COVID-19-related and HIV-related health inequities.

Background: Several observational studies have found that antecedent statin use (i.e., use prior to getting admitted) was associated with lower mortality risk in hospitalized COVID-19 patients, but this is not a consistent finding. Differences maybe due to covariate imbalance, model misspecification, or selection bias. Objective: Estimate the association of antecedent statin use with adverse outcomes (in-hospital death, intubation, ICU admission) in patients admitted for COVID-19 in an academic health system in Chicago. Methods: We analyzed electronic health records from an academic health system in Chicago (Mar ‘20-Mar ‘21) comparing rates of adverse events (composite and per outcome) between antecedent users and non-users. Eligible individuals were ≥40 years old in Illinois, admitted for ≥24 hours, and tested positive for COVID-19 in the 30 days before to 7 days after admission. Antecedent use is defined as existence of statins prescription ≥30 days before admission. We used augmented inverse probability weighting (AIPW) with targeted maximum likelihood estimation to improve covariate balance and estimate the risk difference. Compared to standard methods, this approach allowed use of machine learning models and is doubly robust to misspecification. Results: Of 6267 admitted, 1337 (20%) were antecedent users. Users tend to be older, male, White, smoke, and have a comorbidity. Unadjusted analysis showed significantly higher rates of negative outcomes in non-users except in-hospital death. Analysis using AIPW improved covariate balance and showed that users had significantly lower rates of the composite outcome (RD: -3.9%, 95%CI: -6.0, -1.9) and ICU admissions (RD: -4.0, 95%CI: -7.0, -1.0). No differences in intubation and mortality rates were detected. Conclusion: Antecedent statin use is associated with lower risk of ICU admissions but not with intubation or in-hospital mortality. We were not able to confirm the mortality benefit detected by prior studies nor any differences in rates of intubations.

Background A substantial proportion of people living with HIV (PLHIV) present for care with advanced HIV disease (AHD), which may result in difficulty reaching the “90–90–90” target to end AIDS in 2030. We assessed the risk of AHD for different transmission routes to summarize the evidence for priority prevention strategies for key populations. Methods Observational studies published before September 10th, 2019 in the PubMed, EMBASE, Web of Science and Chinese electronic databases were analysed. The outcomes of interest were the number of PLHIV and AHD patients and their associated transmission routes. We assessed the risk of AHD among the different transmission routes using the multi-armed network meta-analysis based on the Bayesian method. The associations between AHD and regional policies for sex work and compulsory drug treatment were estimated using ecological linear regression. Findings One hundred and one articles were included, covering 1,297,872 PLHIV with 478,830 patients who developed AHD. The network analysis revealed that among PLHIV, heterosexual contact was associated with the highest risk of AHD, followed by injection drug use (odds ratio [OR]=0•56, 95% credible interval [CrI] 0•47–0•68), and men who have sex with men (OR=0•54, 95% CrI 0•46–0•63). Regions that criminalized sex work and compulsory drug treatment had higher risks for AHD than those that did not. Interpretation Our findings suggest HC is at a higher risk of AHD compared to IDU and MSM. This justifies the need to expand prevention campaigns and maintain efforts to increase HIV testing in the heterosexual population.

Individuals with HIV have elevated risks for cardiovascular diseases (CVDs) ranging from myocardial infarction to heart failure. Our understanding of this heightened HIV-associated cardiovascular risk has evolved over the past 2 decades. In the early era of antiretroviral therapy (ART), concern existed that ART was the primary driver of cardiovascular risk. However, it has become increasingly apparent that HIV-related viremia, immune dysregulation, and inflammation are primary drivers of HIV-associated cardiovascular risk, along with traditional cardiovascular risk factors such as tobacco smoking. Indeed, early and effective ART blunts risk for CVDs among individuals with HIV. Despite these improvements in HIV-associated cardiovascular risk, questions remain regarding how to optimally predict, prevent, and treat CVDs among individuals with HIV. Efforts are underway to define more precisely which diagnostic and therapeutic strategies will be most effective in curbing HIV-associated CVDs.

Objective: To characterize clinical phenotypes of incident heart failure (HF) among patients with various chronic inflammatory diseases (CIDs). Background: Several CIDs are associated with increased HF risk, but differences in HF phenotypes across CIDs are incompletely understood. No prior studies to our knowledge have adjudicated HF phenotypes with physician chart review across a spectrum of CIDs. Methods: We screened for patients with CIDs (and controls without CIDs) who had possible HF in a large urban medical system, then performed physician adjudication of HF endpoints. Possible HF was based on the intentionally sensitive criterion of a single inpatient or outpatient administrative code for HF; we then determined if HF was definite/probable vs. not present using standardized, validated criteria. Charts of patients with adjudicated HF were queried to define specific HF phenotypes. We then compared clinical, demographic, and HF phenotypic characteristics for HF patients with specific CIDs vs. non-CID controls using Fisher’s exact test. Results: Out of 415 patients with at least one code for HF, 192 had definite/probable HF. We observed significant differences in HF phenotypes across CIDs (Table 1). Isolated right-sided HF was more than twice as common in patients with scleroderma (27.8%) than in any other CID. Left ventricular systolic dysfunction was most common in patients with HIV and lupus (SLE); mean LVEF was 45.0% ± 18.6% for HIV and 41.3% ± 17.1% for SLE, while it was 57.7% ± 10.7% for scleroderma. Those with HIV and multiple CIDs were most likely to have coronary artery disease. Conclusions: Different CIDs are associated with different phenotypic presentations of physician-adjudicated HF, which may reflect different underlying inflammatory pathophysiologies. Future studies in larger, multi-center cohorts are needed to confirm these findings, as are mechanistic studies focused on understanding specific immunoregulatory contributors to HF.

Introduction: The COVID-19 pandemic caused disruptions in the health services delivery, especially among vulnerable populations. We assessed if the pandemic widened disparities in care for cardiometabolic conditions in a LGBTQ+-focused federally qualified health system in Chicago. Hypothesis: Disparities in monitoring cardiometabolic conditions present in 2019 worsened in 2020. Methods: We analyzed electronic health records from Howard Brown Health. We assessed HbA1c re-testing and control (≤9%) in 2019 and 2020 among people with diabetes (DM) and ≥1 HbA1c test in the prior year (2018 for 2019, 2019 for 2020) (n2019=818, n2020=1033). A similar assessment was done for hypertension (HTN) with systolic blood pressure (SBP) (n2019=2813, n2020=3660). Comparisons per demographic group per year were done using logistic regression adjusting for socio-demographic variables. Results: Re-testing rates declined from 2019 to 2020 for both HbA1c and SBP overall and across all groups. Adjusted analysis showed gay people with DM had higher rates of HbA1c re-testing than people of other sexual orientations in 2019 and experienced a significantly lower re-testing rate decline in 2020. Adjusted analysis for SBP showed that white (vs Hispanic) and straight (vs gay) people with HTN had lower SBP re-testing rates in 2019 and 2020. Rates of controlled SBP ( Conclusion: The pandemic had mixed impacts on cardiometabolic service disparities in a large LGBTQ+-focused health system. Disparities by sexual orientation for HbA1c widened during the pandemic. Similar worsening was not found for systolic blood pressure, nor for other demographic groups.

Background: Immune regulation and inflammation play a role in the pathogenesis and progression of acute and chronic heart failure (HF). Although the clinical course of acute, severe inflammatory cardiomyopathy is well described, the effects of chronic systemic inflammation on cardiovascular function over time are less clear. To investigate this question, we compared trajectories over time in left ventricular ejection fraction for patients with HF with different chronic inflammatory diseases (CIDs): HIV, systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, inflammatory bowel disease, and/or psoriasis. Methods: Using a database of patients receiving care in a large metropolitan health care system since January 1, 2000, we analyzed serial, clinically indicated echocardiograms from patients with HF with CIDs and frequency-matched patients with HF without CIDs. We included patients with ≥3 serial echocardiograms (N=974; median 6.1 years between first and most recent echo). We assessed left ventricular ejection fraction trajectories over time using latent trajectory models, then investigated differences in left ventricular ejection fraction trajectories for specific CID subtypes compared with controls. Results: Overall, the majority of patients studied (N=687; 70.5%) had left ventricular ejection fraction trajectories consistent with HF with preserved or midrange EF, whereas 255 (26.2%) had HF with reduced EF and 32 (3.3%) had HF with recovered EF. Compared with non-CID controls with HF, patients with rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus were significantly more likely than controls to have HF with preserved or midrange EF whereas patients with HIV were significantly more likely to have HF with reduced EF. Conclusions: Among patients with HF with CIDs, distinct left ventricular ejection fraction trajectory patterns associate with different specific individual CIDs. This highlights the heterogeneity of HF subtypes and changes over time across different CIDs.

IMPORTANCE: HIV-associated cardiovascular disease is increasing in prevalence, but its mechanisms remain poorly understood. OBJECTIVE: To systematically review data from advanced cardiovascular imaging studies evaluating computed tomographic coronary angiography, positron emission tomography (PET), and cardiac magnetic resonance (MR), in people living with HIV compared with uninfected individuals. DATA SOURCES: Three databases and Google Scholar were searched for studies assessing cardiovascular pathology using computed tomographic coronary angiography, cardiac MR, PET, and HIV from inception to February 11, 2022. STUDY SELECTION: Two reviewers selected original studies without any restrictions on design, date, or language, investigating HIV and cardiovascular pathology. DATA EXTRACTION AND SYNTHESIS: One investigator extracted data checked by a second investigator. Prevalence ratios (PRs) and differences in inflammation among people living with HIV and uninfected individuals were qualitatively synthesized in terms of cardiovascular pathology. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tool for observational studies. MAIN OUTCOMES AND MEASURES: Primary outcomes were computed tomographic coronary angiography–defined moderate to severe (≥50%) coronary stenosis, cardiac MR–defined myocardial fibrosis identified by late gadolinium enhancement, and PET-defined vascular and myocardial target to background ratio. Prevalence of moderate to severe coronary disease, as well as myocardial fibrosis, and PRs compared with uninfected individuals were reported alongside difference in vascular target to background ratio. RESULTS: Forty-five studies including 5218 people living with HIV (mean age, 48.5 years) and 2414 uninfected individuals (mean age, 49.1 years) were identified. Sixteen studies (n = 5107 participants) evaluated computed tomographic coronary angiography; 16 (n = 1698), cardiac MRs; 10 (n = 681), vascular PET scans; and 3 (n = 146), both computed tomographic coronary angiography and vascular PET scans. No studies originated from low-income countries. Regarding risk of bias, 22% were classified as low; 47% moderate; and 31% high. Prevalence of moderate to severe coronary disease among those with vs without HIV ranged from 0% to 52% and 0% to 27%, respectively, with PRs ranging from 0.33 (95% CI, 0.01-15.90) to 5.19 (95% CI, 1.26-21.42). Prevalence of myocardial fibrosis among those with vs without HIV ranged from 5% to 84% and 0% to 68%, respectively, with PRs ranging from 1.01 (95% CI, 0.85-1.21) to 17.35 (95% CI, 1.10-274.28). Differences in vascular target to background ratio among those with vs without HIV ranged from 0.06 (95% CI, 0.01-0.11) to 0.37 (95% CI, 0.02-0.72). CONCLUSIONS AND RELEVANCE: In this systematic review of studies of advanced cardiovascular imaging, the estimates of the associations between HIV and cardiovascular pathologies demonstrated large amounts of heterogeneity. The findings provide a summary of the available data but may not be representative of all individuals living with HIV, including those from low-income countries with higher HIV endemicity.

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.

Introduction: Novel therapies have changed the clinical course of several chronic viral and inflammatory conditions over the past two decades. As the morbidity burden of these conditions has changed, competing risks for end-organ diseases including cardiovascular diseases (CVDs) may have likewise evolved. We therefore aimed to investigate changes in the relative burden of CVD mortality over the past two decades across several chronic infectious and inflammatory conditions. Hypothesis: Changes in proportionate CVD-related mortality over the past two decades differ across distinct infectious and inflammatory conditions. Methods: We analyzed 1999-2018 Multiple Causes of Death data from the Centers of Disease Control and Prevention. For several chronic infectious and inflammatory conditions, we analyzed patterns in age-adjusted cardiovascular proportionate mortality, defined as the fraction of deaths in a calendar year with CVD as the underlying cause. We compared age-adjusted proportionate CVD mortality, stratified by sex, for systemic lupus erythematosus (SLE), hepatitis C virus (HCV), human immunodeficiency virus (HIV), inflammatory bowel disease (IBD), psoriasis (PSO), rheumatoid arthritis (RA), and systemic sclerosis (SSc). Results: Proportionate CVD mortality in the general population decreased from 40.9% of 2319606 deaths (1999) to 30.6% of 2778169 deaths (2018), whereas it increased for chronic viral conditions (HCV: 7.0% to 10.2%; HIV: 1.9% to 6.7%) and changed little in SLE (15.3% to 14.4%). Patterns of decreasing proportionate CVD mortality over time were similar for IBD and RA as in the general population. Conclusions: Patterns in proportionate CVD mortality over the past 20 years vary considerably for different chronic infectious and inflammatory conditions. The underlying contributions of infectious and inflammatory burden, off-target effects of therapies, and dynamic changes in competing mortality risk merit further study.

Understanding why persons with human immunodeficiency virus (HIV) have accelerated atherosclerosis and its sequelae, including coronary artery disease (CAD) and myocardial infarction, is necessary to provide appropriate care to a large and aging population with HIV. In this review, we delineate the diverse pathophysiologies underlying HIV-associated CAD and discuss how these are implicated in the clinical manifestations of CAD among persons with HIV. Several factors contribute to HIV-associated CAD, with chronic inflammation and immune activation likely representing the primary drivers. Increased monocyte activation, inflammation, and hyperlipidemia present in chronic HIV infection also mirror the pathophysiology of plaque rupture. Furthermore, mechanisms central to plaque erosion, such as activation of toll-like receptor 2 and formation of neutrophil extracellular traps, are also abundant in HIV. In addition to inflammation and immune activation in general, persons with HIV have a higher prevalence than uninfected persons of traditional cardiovascular risk factors, including dyslipidemia, hypertension, insulin resistance, and tobacco use. Antiretroviral therapies, although clearly necessary for HIV treatment and survival, have had varied effects on CAD, but newer generation regimens have reduced cardiovascular toxicities. From a clinical standpoint, this mix of risk factors is implicated in earlier CAD among persons with HIV than uninfected persons; whether the distribution and underlying plaque content of CAD for persons with HIV differs considerably from uninfected persons has not been definitively studied. Furthermore, the role of cardiovascular risk estimators in HIV remains unclear, as does the role of traditional and emerging therapies; no trials of CAD therapies powered to detect clinical events have been completed among persons with HIV.