Evolving mechanisms and presentations of cardiovascular disease in people with HIV: implications for management.

People with HIV (PWH) are at elevated risk for cardiovascular diseases (CVDs), including myocardial infarction, heart failure, and sudden cardiac death, among other CVD manifestations. Chronic immune dysregulation resulting in persistent inflammation is common among PWH, particularly those with sustained viremia and impaired CD4+ T cell recovery. This inflammatory milieu is a major contributor to CVDs among PWH, in concert with common comorbidities (such as dyslipidemia and smoking) and, to a lesser extent, off-target effects of antiretroviral therapy. In this review, we discuss the clinical and mechanistic evidence surrounding heightened CVD risks among PWH, implications for specific CVD manifestations, and practical guidance for management in the setting of evolving data.

CCR2+ monocytes promote white matter injury and cognitive dysfunction after myocardial infarction.

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells after experimental myocardial infarction revealed increased expression of monocyte chemoattractant proteins. In parallel, myocardial infarction increased crosstalk between brain-resident myeloid cells and oligodendrocytes, leading to neuroinflammation, white matter injury, and cognitive dysfunction. Inhibition of monocyte recruitment preserved white matter integrity and cognitive function, linking monocytes to neurodegeneration after myocardial infarction. Together, these preclinical and clinical results demonstrate that monocyte infiltration into the brain after myocardial infarction initiate neuropathological events that lead to vascular dementia.

Myocardial strain is associated with adverse cardiac events in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

BACKGROUND: Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T-cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy-related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T-cell therapy. OBJECTIVES: To determine the association of baseline GLS with adverse cardiovascular events in adults receiving CAR-T cell therapy. METHODS: Patients who had an echocardiogram within 6 months prior to receiving CAR T-cell therapy were retrospectively identified. Clinical data and cardiac events were collected via chart review. Echocardiograms were analyzed offline for GLS, left ventricular ejection fraction, and Doppler parameters. Multivariable logistic regression was used to determine the association between adverse cardiovascular events and echocardiographic parameters. RESULTS: Among 75 CAR T-cell therapy patients (mean age 63.9, 34.7% female), nine patients (12%) experienced cardiac events (CEs) including cardiovascular death, new/worsening heart failure, and new/worsening arrhythmia within 1 year of treatment. In univariable models, higher baseline GLS (OR 0.78 [0.63, 0.96], p = .021) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.40 [1.08, 1.81], p = .012) was associated with a higher risk of CE. After adjusting for age and LDH, higher baseline GLS (OR 0.65 [0.48-0.88], p = <.01) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.56 [1.06, 2.29], p = .024) was associated with a higher risk of CE. CONCLUSION: Lower GLS and higher mitral E/e' on a baseline echocardiogram were associated with higher risk for CEs in patients receiving CAR T-cell therapy.

Precision Phenotyping of Heart Failure in People with HIV: Early Insights and Challenges.

PURPOSE OF REVIEW: People with HIV have an elevated risk of developing heart failure even with optimally controlled disease. In this review, we outline the various mechanisms through which HIV infection may directly and indirectly contribute to heart failure pathology and highlight the emerging relationship between HIV, chronic inflammation, and cardiometabolic disease. RECENT FINDINGS: HIV infection leads to chronic inflammation, immune dysregulation, and metabolic imbalances even in those with well controlled disease. These dysregulations occur through several diverse mechanisms which may lead to manifestations of different phenotypes of heart failure in people with HIV. While it has long been known that people with HIV are at risk of developing heart failure, recent studies have suggested numerous complex mechanisms involving chronic inflammation, immune dysregulation, and metabolic derangement through which this may be mediated. Further comprehensive studies are needed to elucidate the precise relationship between these mechanisms and the development of different subtypes of heart failure in people with HIV.

Associations between alcohol and cigarette use and type 1 and 2 myocardial infarction among people with HIV.

OBJECTIVES: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand-supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. DESIGN AND METHODS: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. RESULTS: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. CONCLUSIONS: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender.

Parasite DNA and Markers of Decreased Immune Activation Associate Prospectively with Cardiac Functional Decline over 10 Years among Trypanosoma cruzi Seropositive Individuals in Brazil.

Parasitemia and inflammatory markers are cross-sectionally associated with chronic Chagas cardiomyopathy (CCC) among patients with Trypanosoma cruzi. However, the prospective association of the parasite load and host immune response-related characteristics with CCC (that is, progressors) among T. cruzi seropositive individuals has only been partially defined. In a cohort of T. cruzi seropositive patients in Montes Claros and São Paulo, Brazil who were followed over 10 years, we identified the association of a baseline T. cruzi parasite load and systemic markers of inflammation with a decline in cardiac function and/or the presence of cardiac congestion 10 years later. The progressors (n = 21) were individuals with a significant decline in the left ventricular ejection fraction and/or elevated markers of cardiac congestion after 10 years. The controls (n = 31) had normal markers of cardiac function and congestion at the baseline and at the follow-up. They were matched with the progressors on age, sex, and genetic ancestry. The progressors had higher mean parasite loads at the baseline than the controls (18.3 vs. 0.605 DNA parasite equivalents/20 mL, p < 0.05). Of the 384 inflammation-related proteins analyzed, 47 differed significantly at a false discovery rate- (FDR-) corrected p < 0.05 between the groups. There were 44 of these 47 proteins that were significantly higher in the controls compared to in the progressors, including the immune activation markers CCL21, CXCL12, and HCLS1 and several of the tumor necrosis factor superfamily of proteins. Among the individuals who were seropositive for T. cruzi at the baseline and who were followed over 10 years, those with incident CCC at the 10-year marker had a comparatively higher baseline of T. cruzi parasitemia and lower baseline markers of immune activation and chemotaxis. These findings generate the hypothesis that the early impairment of pathogen-killing immune responses predisposes individuals to CCC, which merits further study.

Tobacco smoking and binge alcohol use are associated with incident venous thromboembolism in an HIV cohort.

BACKGROUND: People with HIV (PWH) are at increased risk of cardiovascular comorbidities and substance use is a potential predisposing factor. We evaluated associations of tobacco smoking and alcohol use with venous thromboembolism (VTE) in PWH. METHODS: We assessed incident, centrally adjudicated VTE among 12 957 PWH within the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort between January 2009 and December 2018. Using separate Cox proportional hazards models, we evaluated associations of time-updated alcohol and cigarette use with VTE, adjusting for demographic and clinical characteristics. Smoking was evaluated as pack-years and never, former, or current use with current cigarettes per day. Alcohol use was parameterized using categorical and continuous alcohol use score, frequency of use, and binge frequency. RESULTS: During a median of 3.6 years of follow-up, 213 PWH developed a VTE. One-third of PWH reported binge drinking and 40% reported currently smoking. In adjusted analyses, risk of VTE was increased among both current (HR: 1.44, 95% CI: 1.02-2.03) and former (HR: 1.44, 95% CI: 0.99-2.07) smokers compared to PWH who never smoked. Additionally, total pack-years among ever-smokers (HR: 1.10 per 5 pack-years; 95% CI: 1.03-1.18) was associated with incident VTE in a dose-dependent manner. Frequency of binge drinking was associated with incident VTE (HR: 1.30 per 7 days/month, 95% CI: 1.11-1.52); however, alcohol use frequency was not. Severity of alcohol use was not significantly associated with VTE. CONCLUSIONS: Current smoking and pack-year smoking history were dose-dependently associated with incident VTE among PWH in CNICS. Binge drinking was also associated with VTE. Interventions for smoking and binge drinking may decrease VTE risk among PWH.

Nonclassical Monocytes (CD14dimCD16+) Are Associated With Carotid Intima-Media Thickness Progression for Men but Not Women: The Multi-Ethnic Study of Atherosclerosis-Brief Report.

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Heart Failure in Chronic Infectious and Inflammatory Conditions: Mechanistic Insights from Clinical Heterogeneity.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Immune Dysregulation in Myocardial Fibrosis, Steatosis, and Heart Failure: Current Insights from HIV and the General Population.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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-ß1, 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.

Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart Association.

As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end points, and small interventional studies examining surrogate CVD end points. The purpose of this document is to provide a thorough review of the existing evidence on HIV-associated CVD, in particular atherosclerotic CVD (including myocardial infarction and stroke) and heart failure, as well as pragmatic recommendations on how to approach CVD prevention and treatment in HIV in the absence of large-scale randomized controlled trial data. This statement is intended for clinicians caring for people with HIV, individuals living with HIV, and clinical and translational researchers interested in HIV-associated CVD.

Mortality following myocardial infarction among HIV-infected persons: the Center for AIDS Research Network Of Integrated Clinical Systems (CNICS).

BACKGROUND: Persons with human immunodeficiency virus (HIV) have higher risks for myocardial infarction (MI) than the general population. This is driven in part by higher type 2 MI (T2MI, due to coronary supply-demand mismatch) rates among persons with HIV (PWH). In the general population, T2MI has higher mortality than type 1 MI (T1MI, spontaneous and generally due to plaque rupture and thrombosis). PWH have a greater burden of comorbidities and may therefore have an even greater excess risk for complication and death in the setting of T2MI. However, mortality patterns after T1MI and T2MI in HIV are unknown. METHODS: We analyzed mortality after MI among PWH enrolled in the multicenter, US-based Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort (N = 28,186). Incident MIs occurring between January 1, 1996, and December 31, 2014, were centrally adjudicated and classified as T1MI or T2MI. We first compared mortality following T1MI vs. T2MI among PWH. Cox survival analyses and Bayesian model averaging were then used to evaluate pre-MI covariates associated with mortality following T1MI and T2MI. RESULTS: Among the 596 out of 28,186 PWH who experienced MI (2.1%; 293 T1MI and 303 T2MI), mortality rates were significantly greater after T2MI (22.2/100 person-years; 1-, 3-, and 5-year mortality 39%, 52%, and 62%) than T1MI (8.2/100 person-years; 1-, 3-, and 5-year mortality 15%, 22%, and 30%). Significant mortality predictors after T1MI were higher HIV viral load, renal dysfunction, and older age. Significant predictors of mortality after T2MI were low body-mass index (BMI) and detectable HIV viral load. CONCLUSIONS: Mortality is high following MI for PWH and substantially greater after T2MI than T1MI. Predictors of death after MI differed by type of MI, reinforcing the different clinical scenarios associated with each MI type and the importance of considering MI types separately.

Differences in statin utilization and lipid lowering by race, ethnicity, and HIV status in a real-world cohort of persons with human immunodeficiency virus and uninfected persons.

BACKGROUND: Risks for cardiovascular diseases, including myocardial infarction and stroke, are elevated in people with HIV infection (PWH). However, no trials of statin utilization with clinical cardiovascular disease (CVD) end points have been completed in PWH, and there are sparse real-world data regarding statin use and lipid-lowering effectiveness. We therefore used a unique cohort of PWH and uninfected controls to evaluate (1) differences in statin types used for PWH versus uninfected persons; (2) lipid lowering achieved by statin use for PWH versus uninfected persons; and (3) racial and ethnic disparities in appropriate statin use among PWH and uninfected persons. METHODS: We analyzed a cohort of 5,039 PWH and 10,011 uninfected demographically matched controls who received care at a large urban medical center between January 1, 2000, and May 17, 2017. Medication administration records, prescription data, and validated natural language processing algorithms were used to determine statin utilization. Statins were categorized by generic active ingredient name and intensity (high, moderate, or low). Lipid values collected in routine clinical care were available for analysis. The first set of analyses was restricted to PWH and uninfected matched controls taking statins and compared (1) differences in statin type and (2) difference in cholesterol levels after versus before statin initiation by HIV status. For the second set of analyses, we first used prevalent CVD risk factors to determine participants with statin indications and then determined how many of these participants were taking statins. We then compared statin utilization among persons with indications for statins by race/ethnic group for PWH and uninfected matched controls using multivariable-adjusted logistic regression. RESULTS: Among people prescribed statins, PWH were more likely than controls to have ever taken pravastatin (34.8% vs 12.3%, P < .001) or atorvastatin (72.2% vs 65.6%, P = .002) and less likely to have ever taken simvastatin (14.2% vs 39.5%, P < .001). Among PWH with indications for statin utilization, 55.7% of whites, 39.4% of blacks, and 45.8% of Hispanics were prescribed statins (P < .001). These differences in statin prescription by race/ethnicity remained significant after adjustment for demographics (including insurance status), cardiovascular risk factors, antiretroviral therapy use, HIV viremia, and CD4 count. These racial/ethnic disparities in statin utilization were less pronounced among uninfected persons. CONCLUSIONS: Among PWH with statin indication(s), blacks and Hispanics were less likely than whites to have been prescribed a statin. These racial/ethnic disparities were less pronounced among uninfected persons. There were significant differences in type of statin used for PWH compared to uninfected matched controls. Future efforts addressing disparities in CVD prevention among PWH are warranted.

Differences by HIV serostatus in coronary artery disease severity and likelihood of percutaneous coronary intervention following stress testing.

BACKGROUND: HIV-infected persons develop coronary artery disease (CAD) more commonly and earlier than uninfected persons; however, the role of non-invasive testing to stratify CAD risk in HIV is not well defined. METHODS AND RESULTS: Patients were selected from a single-center electronic cohort of HIV-infected patients and uninfected controls matched 1:2 on age, sex, race, and type of cardiovascular testing performed. Patients with abnormal echocardiographic or nuclear stress testing who subsequently underwent coronary angiography were included. Logistic regressions were used to assess differences by HIV serostatus in two co-primary endpoints: (1) severe CAD (≥70% stenosis of at least one coronary artery) and (2) performance of percutaneous coronary intervention (PCI). HIV-infected patients (N = 189) were significantly more likely to undergo PCI following abnormal stress test when compared with uninfected persons (N = 319) after adjustment for demographics, CAD risk factors, previous coronary intervention, and stress test type (OR 1.85, 95% CI 1.12-3.04, P = 0.003). No associations between HIV serostatus and CAD were statistically significant, although there was a non-significant trend toward greater CAD for HIV-infected patients. CONCLUSIONS: HIV-infected patients with abnormal cardiovascular stress testing who underwent subsequent coronary angiography did not have a significantly greater CAD burden than uninfected controls, but were significantly more likely to receive PCI.

Monoclonal Antibodies for Lipid Management.

In recent years, biochemical and genetic studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a major mediator of low-density lipoprotein cholesterol (LDL-c) levels and thereby a potential novel target for reducing risk of coronary heart disease (CHD). These observations led to the development of PCSK9 inhibitors, which lower LDL-c levels more than any other non-invasive lipid-lowering therapy presently available. The PCSK9 inhibitors furthest along in clinical trials are subcutaneously injected monoclonal antibodies. These PCSK9 inhibitors have demonstrated LDL-c-lowering efficacy with acceptable safety in phase III clinical trials and may offer a useful therapy in addition to maximally tolerated HMG-CoA reductase inhibitors (statins) in certain patient groups. Longer-term data are required to ensure sustained efficacy and safety of this new class of medications. This review provides an overview of the biology, genetics, development, and clinical trials of monoclonal antibodies designed to inhibit PCSK9.

Cardiovascular Complications of HIV in Endemic Countries.

Effective combination antiretroviral therapy (ART) has enabled human immunodeficiency virus (HIV) infection to evolve from a generally fatal condition to a manageable chronic disease. This transition began two decades ago in high-income countries and has more recently begun in lower income, HIV endemic countries (HIV-ECs). With this transition, there has been a concurrent shift in clinical and public health burden from AIDS-related complications and opportunistic infections to those associated with well-controlled HIV disease, including cardiovascular disease (CVD). In the current treatment era, traditional CVD risk factors and HIV-related factors both contribute to an elevated risk of myocardial infarction, stroke, heart failure, and arrhythmias. In HIV-ECs, the high prevalence of persons living with HIV and growing prevalence of CVD risk factors will contribute to a growing epidemic of HIV-associated CVD. In this review, we discuss the epidemiology and pathophysiology of cardiovascular complications of HIV and the resultant implications for public health efforts in HIV-ECs.