Increased proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in people with HIV may be related to abnormal coronary endothelial function, according to a study recently published in the Journal of the American Heart Association.
The life expectancy of people with HIV (PLWHIV) has dramatically improved as a result of the increased use of highly active antiretroviral therapy. As the HIV+ population ages, atherosclerotic cardiovascular disease has emerged as a leading cause of morbidity and mortality. Although traditional atherosclerotic cardiovascular disease risk factors and accelerated atherosclerosis are prevalent among people with HIV, these individuals have a higher burden of atherosclerotic cardiovascular disease and cardiovascular event rates, even after adjustment for traditional cardiovascular risk factors, which suggests significant contributions from nontraditional factors.
Abnormal coronary endothelial function is an important contributor to the development and progression of atherosclerotic cardiovascular disease, and therefore a potential target for medical interventions. Recent MRI advances now make it possible to noninvasively quantify coronary endothelial function. However, mechanisms linking HIV infection to impaired coronary endothelial function are not established. Beyond its role in cholesterol homeostasis, PCSK9 is associated with the future risk for atherosclerotic cardiovascular disease, similar to HIV. Prior studies have also shown that PCSK9 serum levels are elevated in HIV+ individuals, independent of low-density lipoprotein cholesterol (LDL-C). Because PCSK9 stimulates vascular inflammation, it may be responsible for coronary endothelial dysfunction. Therefore, this study examined the hypotheses that PCSK9 serum levels are increased and that abnormal coronary endothelial function is related to PCSK9 serum levels in people with HIV.
A total of 48 participants with HIV who were receiving antiretroviral therapy with suppressed viral replication without coronary artery disease were included. In addition, 15 age- and low-density lipoprotein cholesterol-matched healthy participants who did not have HIV underwent magnetic resonance imaging to measure coronary endothelial function, which was quantified as percentage change in coronary artery cross-sectional area during an endothelial-dependent stressor. Blood was obtained for serum PCSK9 and systemic vascular biomarkers.
Results demonstrate that serum PCSK9 levels are significantly higher in treated participants who were HIV positive compared with participants who did not have HIV. Mean serum PCSK9 was 65% higher in the participants with HIV (302 ± 146 ng/mL) than in the healthy control participants (183 ± 52 ng/mL; P <.0001). Further, coronary endothelial function was significantly reduced in those with HIV vs those without HIV (2.9% ± 9.6% vs 11.1% ± 3.7%; P <.0001). This was inversely related to PCSK9 (R = −0.51; P <.0001). Analysis of blood systemic vascular biomarkers showed significantly increased markers of endothelial activation and injury, P-selectin and thrombomodulin, in participants with HIV. Also, P-selectin was directly correlated with serum PCSK9 (R = 0.31; P =.0144).
Overall, the study authors concluded that, “The identified relationship between [PCSK9] and coronary endothelial function in people living with HIV is of potential clinical importance, because it suggests that the effects of interventions designed to lower [PCSK9] levels on coronary endothelial function should be evaluated in future studies.
“If successful, it would provide an additional intervention to limit atherosclerosis and, potentially, lower the burden of heart disease in people living with HIV.”
Leucker TM, Weiss RG, Schär M, et al. Coronary endothelial dysfunction is associated with elevated serum PCSK9 levels in people with HIV independent of low-density lipoprotein cholesterol [published online September 25, 2018]. J Am Heart Assoc. doi: 10.1161/JAHA.118.009996