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Young PLWH at Low-Risk for CVD: 50% have Plaque 23% Vulnerable Plaque, CAC in 35%
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Assessment of Coronary Artery Disease With Computed Tomography Angiography and Inflammatory and Immune Activation Biomarkers Among Adults With HIV Eligible for Primary Cardiovascular Prevention
among persons with HIV
This study found a substantial prevalence of CAD even in young PWH with low traditional ASCVD risk. Key markers of innate immune activation and arterial inflammation were associated with CAD in this group with well-controlled HIV disease, independent of traditional risk factors. Further study of this cohort will help to determine the effects of statin therapy to modulate these pathways and reduce plaque in this population.
CVD is a major source of morbidity and mortality among PWH receiving ART, but little is known regarding the extent of CAD and key associated factors in those with low to moderate traditional cardiovascular risk. This study, performed in a large primary prevention cohort of relatively young patients, expands our understanding of CAD in HIV, demonstrating a substantial prevalence of coronary atherosclerosis, including vulnerable plaque. Markers of innate immune activation and arterial inflammation are associated with CAD in this group with well-controlled HIV disease.
Studies to date have shown excess CAD occurring at a younger age among PWH.25 Two key studies using CTA suggested an increased prevalence of plaque in this population. However, such studies have often been limited to men13and/or have been relatively small.11,14 To our knowledge, prior studies have not assessed plaque using CTA in a prospectively recruited asymptomatic primary prevention cohort with low to moderate ASCVD risk, assessed in the current era of modern ART, using the gold standard ACC/AHA pooled cohort equation (PCE) for risk calibration. This question is of critical importance to the large group of relatively young PWH at risk for but without known CVD. In this regard, these baseline data from the mechanistic substudy of REPRIEVE provide useful information on the degree and type of CAD among this primary prevention group. Plaque was seen in nearly 50% and CAC in 35% of our population, despite a mean age of 51 years and a median ASCVD risk of 4.5%. Plaque characteristics in this group suggest a low prevalence of significant stenosis, but vulnerable plaque characteristics were seen in nearly one-quarter. It will be critical in future studies to determine how this unique plaque phenotype relates to major adverse cardiovascular events over time.
Comparator data from other primary prevention populations with low to moderate risk are available for CAC score, but very limited data are available for more detailed plaque characteristics. Data from the Framingham Heart Study and Cardia Study Cohorts showed a prevalence of CAC scores greater than 0 of 30% and 28%, respectively, in patients aged 50 years, either free of cardiac disease or with a low Framingham Risk score.26,27 However, the CAC score is only a single measure of coronary atherosclerosis, and our study also assessed noncalcified plaque and vulnerable plaque. In this regard, our study showed vulnerable plaque in 23% of participants compared with 15% in the much older PROMISE population of symptomatic patients with higher ASCVD risk, assessed in an identical fashion with contrast-enhanced CT by the same imaging core.19 In contrast, a CAC score greater than 0 was observed in 65% of the PROMISE population but 35% of our study population, consistent with more advanced traditional risk patterns of the PROMISE population.28
In this study, we assessed specific biomarkers hypothesized to play a role in premature CAD among PWH. In adjusted analyses, controlling for ASCVD risk, the inflammatory and immune markers LpPLA2 and IL-6 were associated with plaque presence independent of traditional risk factors. IL-6 was also associated with CAC and vulnerable plaque.
Conclusions and Relevance In this study of a large primary prevention cohort of individuals with well-controlled HIV and low to moderate ASCVD risk, CAD, including noncalcified, nonobstructive, and vulnerable plaque, was highly prevalent. Participants with plaque demonstrated higher levels of immune activation and arterial inflammation, independent of traditional ASCVD risk and HIV parameters.
Presence of plaque (Figure) as well as the degree of stenosis, extent of CAC, vulnerable plaque features, and composition and distribution, as summarized in the Leaman score, were higher with increasing ASCVD risk categories (Table 2; eFigure 2 in Supplement 1).. Importantly, coronary plaques were found in 52 of 175 participants (30%) with a very low ASCVD risk (<2.5%) and 22 of 175 participants (13%) had vulnerable plaque features. In comparison, among the group with ASCVD risk less than 7.5%, 272 of 605 (45%) demonstrated plaque, and 118 of these 605 (20%) had vulnerable plaque.
Participants with plaque were older, more likely to be male and White, to have a family history of premature CVD, to have a history of hypertension, to have increased fasting glucose and LDL-C levels, and tended to smoke. No significant differences were seen in current or nadir CD4 levels or ART duration.
Those with coronary plaque had higher levels of IL-6, LpPLA2, oxLDL, and MCP-1 than those without coronary plaque (eg, median [IQR] IL-6 level, 1.71 [1.05-3.04] pg/mL vs 1.45 [0.96-2.60] pg/mL; P = .008) (Table 3). Higher levels of IL-6, LpPLA2, oxLDL, and MCP-1 were also seen to varying degrees among those with vulnerable plaque, CAC, and Leaman scores greater than 5 (eTable 4 in Supplement 1).
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The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that findings from a sub-study of REPRIEVE (A5332/A5332s, an international clinical trial studying heart disease prevention in people living with HIV) have been published in the Journal of the American Medical Association Network Open (JAMA Network Open). The study found that approximately half of study participants, who were considered by traditional measures to be at low-to-moderate risk of future heart disease, had atherosclerotic plaque in their coronary arteries.
While it is well-known that people living with HIV are at increased risk of cardiovascular events, including heart attacks and strokes, little is understood about the prevalence and extent of atherosclerosis in heart blood vessels and associated biological factors. The Mechanistic sub-study of REPRIEVE was designed to specifically identify factors that contribute to cardiovascular disease among people living with HIV.
"This sub-study of REPRIEVE is seeking to better understand why people living with HIV develop heart disease, even when their HIV is well controlled and they don't have many traditional risk factors," said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. "REPRIEVE is the largest study of cardiovascular disease among people living with HIV and this is an important early report that sets the stage for future important findings."
Today's publication describes baseline data on 755 participants between the ages of 40 and 75 years old, who were enrolled at 31 sites across the United States. The sub-study used coronary CT angiography to assess the amount of plaque in participants' coronary arteries and then correlated those findings with blood samples that measured inflammation and immune activation.
Nearly half the participants (49 percent) had plaque in their coronary arteries, though the plaques were mostly seen in just a few areas of the coronary arteries. The presence of plaque was associated with a higher burden of risk factors, but also with higher levels of inflammation independent of traditional risk scores. In almost all individuals (97 percent), the plaque was mild and did not cause a narrowing of more than 50 percent of the coronary artery. While significant narrowing was rare, about one-quarter of participants (23 percent) had plaque with features that could potentially cause problems in the future (also known as vulnerable plaque).
In the general population, epidemiologic studies have shown that future cardiovascular disease increases with higher ASCVD PCE (atherosclerotic cardiovascular disease pooled cohort equation) risk scores, an index of traditional risk. REPRIEVE recruited participants with low to moderate ASCVD risk and a low average 10-year risk score of 4.5 percent. The clinical significance of mild or even significant plaque in asymptomatic people with low cardiovascular risk is unknown, as is the effectiveness of statin therapy to prevent cardiovascular disease in this population. REPRIEVE will address these important questions by following these participants to determine if the plaque reported in the Mechanistic sub-study of REPRIEVE is clinically significant (whether it is related to future cardiovascular events), whether statin therapy can reduce plaque and markers of inflammation, and if statin therapy can reduce the incidence of heart attacks and strokes.
"Heart disease is a major cause of illness and death among people living with HIV, including those with well-controlled HIV disease receiving antiretroviral treatment," said Steven Grinspoon, M.D., Massachusetts General Hospital. "Until now, our understanding of coronary artery disease among people living with HIV has been very limited. These findings significantly expand our knowledge and provide important insights that will lay the foundation to ultimately help us better support the health and well-being of people living with HIV."
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