Immune Dysregulation in Ischemic Heart Disease among Individuals with HIV

Introduction

Advancements in antiretroviral therapy (ART) have dramatically lowered HIV-related mortality and narrowed life expectancy gaps for people with HIV (PWH). However, PWH now experience high non-HIV-related morbidity from chronic conditions, particularly cardiovascular disease (CVD).^1–3 PWH have up to a two-fold risk of CVD compared to the general population,^2,4 including a higher risk of acute coronary syndrome (ACS),^2,5 subclinical atherosclerosis,⁶ and recurrent coronary events.⁷ This increased risk is due to a complex interaction of multiple factors. PWH carry a higher burden of traditional CVD risk factors, including dyslipidemia, hypertension, diabetes, obesity, smoking, renal impairment, and substance use.^8–10 Yet, CVD risk remains elevated after adjustment for these factors.⁹ Some ART drugs, particularly first-generation protease inhibitors, have also been associated with lipid abnormalities, insulin resistance, atherosclerosis, and hypertension.^11,12 In addition, HIV infection itself precipitates a chronic state of immune activation and inflammation that persists even after sustained viral suppression.^13,14 This is further exacerbated by coinfection from other viruses,^15,16 mucosal injury that facilitates microbial translocation across the intestinal epithelium into the bloodstream,^17,18 and undetected low-level HIV replication.^19,20

It is thus challenging and unrealistic to ascribe a singular mechanism to increased CVD risk among PWH. This is especially the case in the context of heart failure (HF), given its heterogeneous triggers that range from ischemic (PWH experience greater myocardial vulnerability to ischemia and infarction^21,22) to non-ischemic infectious and inflammatory causes. In this review, we summarize foundational and recent literature on ischemic heart disease (IHD) development among PWH, along with implications for HF onset and progression.

I. Epidemiology of IHD in HIV: Clinical Evidence

Arterial Disease

PWH can present with different features of IHD from the general population. Studies have found that PWH tend to have more ectatic coronary artery segments, vulnerable non-calcified plaque, and plaque in more proximal coronary arteries.^23–25 PWH are also more likely to develop type 2 myocardial infarctions (MI) that result from supply-demand mismatch and more likely to do so at an earlier age and with poorer outcomes.^26,27 In fact, ACS events can occur by as much as 10 years earlier among PWH, indicating an accelerated progression of atherosclerosis.²³

Given that asymptomatic PWH present are more likely to develop symptomatic IHD,²⁸ one of the main challenges has involved identifying subclinical disease and preventing progression. The current gold standard for diagnosing coronary artery disease (CAD) is invasive coronary angiography, a catheter-based procedure that allows for both visualization and intervention but is costly and invasive. Multiple imaging modalities are being studied to determine the most accurate non-invasive approach to assessing atherosclerotic CVD (ASCVD) risk among both individuals with and without HIV (Table 1).^29,30 This includes using ultrasound to measure carotid artery intima-media thickness, non-contrast computed tomography (CT) to determine a coronary artery calcification (CAC) score, magnetic resonance imaging (MRI) to capture high-resolution images of the vessel wall, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) to assess abnormal metabolic and inflammatory activity. CAC scores are commonly used among the general population but often underestimate IHD risk among PWH, who tend to have more non-calcified plaque.^24,31 Coronary CT angiography (CCTA) enables detection of both calcified and non-calcified plaque but is typically used in the presence of symptoms or disease, rather than for broader screening applications.^29,32

Table 1.

Types of Imaging for Clinical Phenotyping

Imaging Modality	Pros	Cons
Coronary Angiography	Serves as current gold standard	Is invasive
Ultrasound	Can measure carotid artery intima-media thickness	Has unclear clinical utility
Non-Contrast Computed Tomography (CT)	Can measure coronary artery calcification (Agatston) score	Has unclear clinical utility, cannot assess non-calcified plaque
Magnetic Resonance Imaging (MRI)	Can capture high-resolution vessel wall images, can assess coronary endothelial function	Has unclear clinical utility, expensive
18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG-PET)	Can assess abnormal metabolic/inflammatory activity	Has unclear clinical utility, expensive
Coronary CT Angiography (CCTA)	Can assess calcified and non-calcified plaque, can assess coronary endothelial function, can assess adipose tissue, non-invasive	Has unclear clinical utility

Coronary plaque is only one component of IHD. Many imaging modalities also allow assessment of coronary endothelial function (CEF) and measures of vascular inflammation and remodeling.³³ This is important because HIV viral proteins can lead to increased vascular permeability, maladaptive cellular proliferation and apoptosis, oxidative stress, and pro-inflammatory cytokine secretion.³⁴ Some of these changes may occur primarily at a microvascular level within prearterioles and arterioles.³³ Studies have found that PWH have impaired CEF and increased arterial remodeling, as determined on MRI or CT by a lower percent change in coronary blood flow and lower percent change in coronary cross-sectional area between that at rest and that during isometric handgrip exercise stress.^10,35 Impaired CEF is further associated with age³⁶ and higher levels of pro-inflammatory markers (CRP, TNF-α, IFN-γ, ICAM-1, ICAM-3).³⁷ This suggests that HIV-driven inflammation is closely tied with age-driven inflammation and both processes contribute to vascular dysfunction.

Adipose tissue may also serve as a depot of adipokines, reactive oxidative species, and other inflammatory infiltrate that can affect and be affected by adjacent vasculature.³⁸ PWH tend to have more visceral, central, epicardial, and peri-coronary adipose tissue, as well as more myocardial steatosis. These patterns of adipose tissue distribution have been associated with increased volumes of calcified and non-calcified coronary plaque^25,38,39 and levels of pro-inflammatory markers (IL-2, TNF-α, CD14, CD163, TNFR, CCL5, CX3CL1, CXCL10).^39,40 These associations do not always parallel those found among individuals without HIV, possibly due to an HIV-specific phenotype.

Implications for Heart Failure

As many as 7.2% of PWH have symptomatic heart failure (stage C or D).⁴¹ This does not account for subclinical or early heart failure (stage B), a condition that is becoming increasingly important to identify. In the past, HF and cardiomyopathy among PWH were primarily considered a result of myocarditis, direct HIV-induced injury, opportunistic infection, and autoimmunity.⁴² However, alongside advancements in ART and changes in HF pathophysiology paradigms, HF among PWH is now more commonly considered a result of metabolic dysregulation, progressive atherosclerosis, and ischemic insults, all of which are influenced by chronic immune activation and dysregulation.⁴² This coincides with a shift in more PWH presenting with a largely diastolic dysfunction phenotype associated with HF with preserved ejection fraction (HFpEF), rather than a largely systolic dysfunction phenotype associated with HF with reduced ejection fraction (HFrEF).⁴²

PWH are twice as likely to develop HF compared to the general population,^43,44 with higher rates of hospitalization and mortality among women.⁴⁵ Some of this risk is driven by ischemic causes. Not only do PWH experience higher rates of MI and ACS, but PWH also experience more extensive myocardial scarring, fibrosis, steatosis, and adverse remodeling from ischemic events.^21,46,47 Histopathology studies have also found increased interstitial mononuclear infiltrate, interstitial edema, and cardiomyocyte apoptosis.⁴⁷ This is despite similar rates of intervention and similar outcomes following percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery.^48,49 However, even after adjusting for MI, PWH continue to have up to a 1.5-fold elevated risk of HF, suggesting that HF risk is also driven by non-ischemic causes. This risk also remains elevated after adjusting for hypertension and substance use.² The etiology of ischemic and non-ischemic HF development and progression is not very well understood, even among individuals without HIV. It is multifactorial, but chronic inflammation and immune dysregulation likely play a critical role.

II. Pathophysiology of IHD in HIV: Role of Inflammation

Fundamentally, inflammation reflects an interaction between inflammation-propagating triggers (which vary from classical antigens to lipid “neo-antigens”) and immune cell responses to these triggers.⁵⁰ Landmark trials such as CANTOS,⁵¹ COLCOT,⁵² and LoDoCo2⁵³ have provided proof of concept for inflammation modulation in CVD prevention and therapy among the general population. While the specific therapies in these trials come with HIV-specific concerns regarding infection and drug-drug interactions, they are important studies for HIV, given the profound systemic and tissue-specific inflammation in PWH. Considerable data have emerged in recent years characterizing blood-based biomarkers of inflammation and IHD in PWH. While these vary in scope and focus, they offer insight on potential contributors to IHD in PWH that can be leveraged to inform mechanistic studies and guide diagnostic and therapeutic development (Table 2).

Table 2.

Immunophenotype Concept Highlights

Concept	Description
Molecular Mimicry	Similar structures between self-antigens and foreign antigens can lead to autoimmunity. A textbook example is the cross-reactivity of group A streptococci and cardiac myosin, which have similar epitopes, resulting in rheumatic heart disease.
Endothelial Dysfunction	Impaired dilation of small blood vessels affects blood flow and end-organ perfusion. A common driver is vessel wall inflammation.
Immunosenescence	Decline in immune system function with age involves maladaptive remodeling of lymphoid organs and decreased plasticity in response to immune insults. This results in increased incidence of cancer, infection, cardiovascular disease, and other diseases.
Gut-Heart Axis	An interplay exists among gut microbiota, gut metabolites, microbial translation, inflammation, diet, and cardiovascular health. The gut similarly plays a role in non-cardiovascular diseases.

Cellular and Molecular Phenotypes

Some immune processes in HIV are similar to those in IHD among the general population. Many pro-inflammatory cell subsets (such as certain regulatory T cell and monocyte populations⁵⁴) and many pro-inflammatory cytokines (such as IL-1, IL-6, IL-18, IL-32, TNFR, VEGF, CD14, CD163 (a marker of macrophage activation), oxLDL, and MCP-1 (a marker of monocyte migration)^17,55,56) have been associated with IHD development among PWH. Composite biomarkers such as GlycA,⁵⁷ which reflects glycosylation levels of major acute-phase reactants, have similar findings. Some markers such as VCAM-1 (a marker of endothelial dysfunction)⁵⁸ and CCL20 (a marker indication HIV disease progression)⁵⁴ may help distinguish immunologic signatures between healthy individuals with IHD and PWH with IHD.

Some immune processes are more specific to HIV infection. For instance, gp120, an HIV envelope glycoprotein that mediates viral entry, can spontaneously dissociate from the surface of virions and infected T cells and continue to interact with uninfected T cells, even after complete viral suppression. Not only can gp120 be detected in patients with undetectable viremia, but it has also been associated with increased levels of pro-inflammatory markers (IL-6, TNF-α, sCD163).¹⁹ gp120 and other HIV-encoded proteins such as Tat and Nef are also associated with endothelial dysfunction, leukocyte infiltration, and plaque progression.³⁴

Because HIV infection precipitates damage to intestinal epithelial cells, facilitating translocation of microbes into the circulation, certain microbial proteins may also play a role in modulating inflammation. I-FABP (intestinal fatty acid binding protein), bacterial lipopolysaccharide (LPS), and fungal cell wall component (1,3)-β-d-glucan (BDG) have been associated with increased volume of plaque, risk of MI and repeat MI, and levels of pro-inflammatory markers (IL-1β, IL-18, IL-32, TNF-α) among PWH.^17,18,59 Studies on gut dysbiosis have also found that PWH with CAD have lower α-diversity in the gut microbiome compared to PWH with no CAD.⁶⁰

Molecular mimicry may also play a role. T cell receptors in coronary plaque, especially vulnerable plaque, have been found to share matching clonotypes with viral epitopes, suggesting that T cells activated by certain viral epitopes can trigger pro-inflammatory plaque formation.⁶¹ These viral epitopes also share amino acid and nucleotide sequences with proteins expressed on cardiomyocytes, endothelial cells, and vascular smooth muscle cells, suggesting that viral infection may stimulate T cells to act against the broader cardiovascular system.⁶¹ This is not well studied in HIV but may indicate an additional autoimmune-mediated process driving IHD development. If so, such processes would be further exacerbated by co-infections from viruses such as CMV, HCV, and HBV.

HIV has also been considered a model of accelerated immunologic aging, referred to as immunosenescence.⁶² One prediction model found that PWH age 5.6 years faster than their healthy counterparts.⁶³ Studies have found that PWH with IHD have shorter leukocyte telomere lengths,⁶⁴ along with increased expression of markers of senescence and proliferation arrest (p16^INK4, p21^CIP1/WAF1)⁶⁵ and markers of T cell exhaustion (PD-1, TIGIT).⁶⁶ These effects are also seen when comparing elderly PWH to young PWH.⁶⁵

Transcriptomic and Epigenetic Phenotypes

Genomic studies may offer a better understanding of upstream mechanisms and individual risk. Polygenic risk scores (PRSs) allow us to evaluate the cumulative effect of multiple genetic variants that may predispose an individual to a certain disease. Studies have found that PRSs can better assess subclinical CAD among PWH,⁶⁷ as well as better understand expression patterns, such as pathways linking genes involved in energy metabolism with development of type 2 MIs.⁶⁸ miRNAs can also play an important regulatory role in inflammation and metabolism. Studies have found that among PWH, increased expression of miR-125a-5p and miR-139–5p are associated with increased risk of MI.⁶⁹ One study also found that B cells in elderly PWH express higher levels of miR-155 and miR-16, markers of immunosenescence.⁶⁵ Some of these miRNAs have been found to be associated with macrophage activation and lipid metabolism, but many are not well studied.

There has been recent interest in clonal hematopoiesis of indeterminate potential (CHIP), a term that encompasses somatic mutations, often loss-of-function, that accumulate with age in hematopoietic stem cells. These are often associated with hematologic malignancies.⁷⁰ Some studies have not found any significant associations,⁷¹ but some have found that PWH have a higher prevalence of CHIP genes (such as ASXL1, TET2, and DNMT3A, genes involved in epigenetic regulation) than individuals without HIV.⁷² The relevance of such findings for clinical implementation remains under investigation.

Emerging artificial intelligence tools may soon identify novel phenotypes. Some are incorporating other data, such as retinal scans.⁷³ Some are using multi-omic approaches to detect differences in plaque morphology between those with and without HIV,⁷⁴ as well as discover radiologic features indicative of specific gene expression patterns, such as TNFA-related tissue inflammation, COL1A1-related tissue fibrosis, and CD31-related vascularity.⁷⁵ However, the mechanism of many cellular, molecular, and transcriptomic markers are not well understood. More importantly, there remains a large translational gap between studies that are largely mechanistic or observational and studies that offer practical clinical applications. It is thus important to place this in context of the current state of clinical approaches to IHD in PWH, as well as emerging trials that may inform future approaches.

III. Clinical Approach to IHD in HIV: Current State and Future Directions

Risk Stratification and IHD Prevention

Current traditional risk scores are less reliable among PWH. The Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE) model, and Pooled Cohort Equation (PCE) often underestimate ASCVD risk and coronary plaque progression among PWH compared to the general population.^76,77 The Data-Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) CVD prediction model, which accounts for CD4+ T cell count, cumulative exposure to protease-inhibitors and nucleoside reverse transcriptase-inhibitors, and current use of abacavir, can improve risk assessment but is still not perfect.⁷⁸ These risk scores further underestimate risk in women, Black individuals, non-U.S. populations, and other underrepresented populations.⁷⁹ Some have also found that lipid levels may not reflect IHD risk as accurately for PWH.⁸⁰

Many PWH thus fall through the cracks and are not started on primary and secondary prevention therapies as early as they should be.⁸¹ In the past, providers have been hesitant to prescribe lipid-lowering medications to PWH due to a lack of specific guidelines, uncertainty around which statin to prescribe, and unfamiliarity of specific drug-drug-interactions with ART medications.^82,83 However, emerging data and guidelines may soon change these trends. The 2023 REPRIEVE trial found that among 7,769 PWH with low-to-moderate cardiovascular risk who were assigned to either 4mg of pitavastatin daily or placebo, pitavastatin was associated with a 35% lower risk of major adverse cardiovascular events over a median follow-up period of 5.1 years.⁸⁴ Other smaller studies have also found that statins can lower all-cause mortality, stabilize plaque progression, and attenuate levels of inflammation.^55,85,86

At the beginning of 2024, the U.S. Department of Health and Human Services (HHS) Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV released new recommendations in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), and HIV Medicine Association (HIVMA).⁸⁷ For PWH 40–75 years old with high (≥20%) 10-year ASCVD risk or with diabetes and for PWH 20–75 years old with LDL ≥190mg/dL, the recommendations are the same as those for the general population. For PWH 40–75 years old with low-to intermediate (<20%) 10-year ASCVD risk, the Panel recommends initiating at least moderate-intensity statin therapy, such as pitavastatin 4mg daily, atorvastatin 20mg daily, or rosuvastatin 10mg daily. For PWH with <5% 10-year ASCVD risk and for PWH younger than 40 years old, the benefit of statin therapy is not as well established and the decision to initiate lipid-lowering therapy requires shared decision-making involving risk analysis, patient preferences, and continued emphasis on lifestyle modifications. These guidelines advocate for a more proactive approach to prevention. Nonetheless, without a robust risk prediction tool, it will continue to be challenging to weigh the costs and benefits of lipid-lowering therapy and additional diagnostics for PWH with indeterminate risk.

Clinical trials are underway to investigate other therapeutics, especially those that may reveal important targets of inflammation and immune dysregulation (Table 3). Some therapeutics, such as low-dose methotrexate and low-dose colchicine, have not led to significant improvements in arterial and circulating markers of inflammation, potentially because they target the immune response too broadly.^88,89 Some therapeutics commonly used for other cardiovascular indications, such as aspirin, eplerenone, and PCSK9-inhibitors, may have synergistic effects on myocardial function, endothelial function, and inflammatory markers.^90–93 Similar effects may soon be seen with SGLT2-inhibitors and GLP-1 analogues. Some therapeutics, such as small molecular inhibitors, suggest the need for more precise targets. In a small pilot study, canakinumab, the IL-1β inhibitor tested in the CANTOS trial, resulted in significantly decreased levels of pro-inflammatory cell subsets (monocytes producing IL-1β and IL-6), pro-inflammatory cytokines (CRP, IL-6, CD163), and arterial inflammation.⁹⁴

Table 3.

Notable Clinical Trials Targeting Inflammation for Atherosclerotic Cardiovascular Disease Reduction in HIV and the General Population

Trial Name	Methods	Key Findings
CANTOS (2017) 51	A total of 10,061 individuals with previous myocardial infarction and elevated hsCRP levels were randomized either to canakinumab (50mg, 150mg, or 300mg administered subcutaneously every 3 months) or placebo.	At the 150mg dose, canakinumab, an IL-1β inhibitor, was associated with a 15% lower composite risk of nonfatal infarction, nonfatal stroke, and cardiovascular death, as well as a 17% lower risk of hospitalization for unstable angina requiring urgent vascularization. Canakinumab was also associated with a higher incidence of fatal infection. Individuals were followed for a median of 3.7 years.
* Hsue et al. (2018) 94	A pilot study of 10 individuals with treated HIV and with cardiovascular disease or at least one cardiovascular disease risk factor received one subcutaneous dose of 150mg canakinumab.	Canakinumab was associated with decreased levels of hsCRP, IL-6, and sCD163, as well as decreased percentages of monocytes producing IL-1β and IL-6. Individuals were followed for 12 weeks.
CIRT (2018) 95	A total of 4,786 individuals with previous myocardial infarction or multivessel coronary disease and with diabetes or metabolic syndrome were randomized to low-dose methotrexate (15–20mg weekly) or placebo.	Low-dose methotrexate was not associated with a reduction in composite risk of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. Individuals had been followed for a median of 2.3 years when the trial was stopped.
* Hsue et al. (2018) 88	A total of 176 individuals ≥40 years old with treated HIV and with increased risk of cardiovascular disease were randomized to low-dose methotrexate (5–15mg weekly) or placebo.	Low-dose methotrexate was associated with decreased CD8+ T cells, with no significant effect on endothelial function or inflammatory markers. Individuals were followed for 36 weeks.
COLCOT (2019) 52	A total of 4,745 individuals with a myocardial infarction within the past 30 days were randomized to either 0.5mg colchicine daily or placebo.	Low-dose colchicine was associated with a 23% lower composite risk of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, and urgent hospitalization for angina leading to revascularization. Colchicine was also associated with higher incidence of pneumonia and infection. Individuals were followed for a median of 22.6 months.
LoDoCo2 (2020) 53	A total of 5,522 individuals with chronic coronary disease were randomized to either 0.5mg colchicine daily or placebo.	Low-dose colchicine was associated with a 31% lower composite risk of cardiovascular death, non-procedure-related myocardial infarction, ischemic stroke, and ischemia-driven coronary revascularization, as well as a 28% lower composite risk of cardiovascular death, non-procedure-related myocardial infarction, and ischemic stroke. Individuals were followed for a median of 28.6 months.
* Hays et al. (2021) 89	A total of 81 individuals with HIV were randomized to 0.6mg colchicine daily or placebo.	Low-dose colchicine had no significant effect on endothelial function or inflammatory markers. Individuals were followed for 24 weeks.
* Leucker et al. (2020) 93	A total of 19 individuals with HIV and 11 individuals without HIV but with dyslipidemia received 420mg of evolocumab.	Evolocumab, a PSCK9 inhibitor, was associated with improved coronary endothelial function as assessed with MRI. Individuals were followed for 6 weeks.
* REPRIEVE (2023) 84	A total of 7,769 individuals with HIV with low-to-moderate cardiovascular risk were randomized to either 4mg pitavastatin daily or placebo.	Pitavastatin was associated with a 35% lower risk of major adverse cardiovascular events over a median follow-up period of 5.1 years.
* MIRACLE HIV (2023) 92	A total of 40 individuals with HIV without known cardiovascular disease were randomized to 50mg eplerenone twice daily or placebo for 12 months.	Eplerenone, a mineralocorticoid receptor antagonist, was associated with improved myocardial perfusion and function as assessed with cardiac MRI.
* MIRABELLA HIV (2023) 91	A substudy of 26 individuals with no statin use from the MIRACLE HIV trial were randomized to 50mg eplerenone twice daily or placebo for 12 months.	Eplerenone was associated with a reduction in arterial wall inflammation as assessed with 18F-FDG PET/CT.
* Mystakelis et al. (2023) 90	A total of 44 individuals with HIV (either treated or elite controllers) were randomized to 81mg aspirin or 40mg atorvastatin for 9 months.	Aspirin and atorvastatin were associated with significant reductions in levels of sCD14. Aspirin was also associated with a reduction in levels of tissue factor. Atorvastatin was also associated with a reduction in levels of IL-8.

^*This trial involved individuals with HIV.

Interventions for IHD

PCI and CABG are generally safe interventions for PWH with significant IHD.^48,49 However, despite definitive intervention, PWH experience greater vulnerability to ischemic myocardial scarring,²¹ with many long-term sequelae, including ventricular dysfunction and HF. More importantly, preventing progression to clinical IHD and HF requires different interventions and strategies. At the time, there are insufficient data to develop an HIV-specific approach. Further research is needed to understand the biological mechanisms, improve risk stratification and diagnostic tools, and evaluate current and novel therapies for PWH. In the meantime, it is important that clinicians maintain a high index of suspicion for IHD and HF in PWH with CVD risk.

Future Directions

Improving cardiovascular outcomes among PWH will require a combination of efforts. It will involve focused ASCVD risk assessment, with potential incorporation of HIV-specific immunologic phenotypes and intensified lifestyle and pharmacological approaches to risk reduction. It will involve improving integration of HIV care and primary care, with an emphasis on multidisciplinary team engagement and care coordination.² It will also involve continued steps to increase access to HIV care, including policy efforts that address housing access, economic security, mental health resources, substance use treatment programs, and other social disparities that further compound the challenges of accessing HIV care.² Afterall, improvements in cardiovascular outcomes will not happen if PWH do not first receive complete and timely ART treatment. Only through a multi-pronged effort can we decrease the gap in comorbidity-free years between individuals with and without HIV.

Summary

PWH present with unique clinical and immune phenotypes of IHD. This is observed on imaging with specific characteristics of plaque formation and endothelial function, as well as on biologic assays with specific expression patterns of cell subsets, cytokines, and nucleotides. Future studies on immune signaling pathways and their role in inflammation will deepen our understanding of mechanisms and phenotypes underlying IHD in PWH. This will have implications for diagnostics and therapeutics not only among individuals with IHD but also among individuals with other chronic inflammatory conditions.

Figure 1:

Immune Dysregulation in IHD among PWH.

Key Points:

• Individuals with HIV experience a nearly two-fold increased risk of cardiovascular disease, including ischemic heart disease and heart failure.

• The underlying pathophysiology appears to be driven by a combination of factors including chronic immune activation and dysregulation.

• Ischemic heart disease has a heterogenous presentation, but individuals with HIV have unique clinical and immune phenotypes that may distinguish mechanisms, diagnostics, and management strategies from the general population.

• Future directions will involve a combination of improved phenotyping and risk prediction, intensified prevention strategies, streamlined integration of multidisciplinary care teams, and continued policy efforts to ensure equitable access to HIV care.

Synopsis:

Individuals with HIV experience an elevated risk of ischemic heart disease and related cardiovascular sequelae. This is due to a combination of factors involving traditional comorbidities, antiretroviral therapy adverse effects, low-level viremia, viral coinfection, mucosal injury, and chronic immune activation and dysregulation. Understanding the underlying mechanisms, especially as they relate to inflammation, has implications for prevention, diagnostics, and therapeutics. This review highlights some of the foundational and recent literature on clinical phenotypes, diagnostic tools, and promising pharmacotherapies, along with future directions for translational research and clinical implementation.

Clinics Care Points:

• HIV is a significant risk factor for cardiovascular disease, and clinicians should maintain a high index of suspicion for ischemic heart disease and heart failure in patients with HIV.

• CANTOS, COLCOT, and LoDoCo2 are landmark trials that provide proof of concept for inflammation modulation in cardiovascular disease prevention, diagnostics, and therapeutics.

• Further studies are needed to translate observational and mechanistic data into clinical use.

• Future directions will involve a combination of improved phenotyping and risk stratification, intensified prevention strategies, streamlined integration of multidisciplinary care teams, and continued policy efforts to ensure equitable access to HIV care.