Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial

Abstract

Background People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. Methods In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. Findings The mean age was 49.5 ± 8.0 (mean ± SD), LDL-C 155 ± 25 mg/dl and CD4 count 620 ± 243 cell/mm 3 . Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic = −6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic = −4.64, FDR p-value = 0.0003], and LDL-receptor [LDLR; t-statistic = −4.45, FDR p-value = 0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic = 3.50, FDR p-value = 0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic = 3.21, FDR p-value = 0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C ( r = 0.43, P < 0.0001) and change in Lp-PLA2 ( r = 0.29, P < 0.0001). Interpretation Using a proteomics approach, we demonstrated that statins led to a significant reduction in the levels of TFPI, PON3, and LDLR and an increase in Gal-4 and IGFBP-2, key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism. Pitavastatin led to a greater reduction in TFPI than pravastatin. These data highlight potential novel mechanisms of statin effects among PWH. Fund This work was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and the National Institutes of Health [P30 DK040561; Nutrition Obesity Research Center at Harvard]. M.T. was support by National Institutes of Health [5KL2TR001100-05; Harvard Catalyst KL2 grant].

Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency

“…Proteomics is a promising technique to provide new diagnostic and prognostic information as well as insights into new disease mechanisms in cancer, inflammatory disease, and cardiovascular disease. [20][21][22][23] Prior work in CVID has used conventional immunoassays for the measurement of restricted numbers of biomarkers in plasma. The proteomic approach can be useful in the identification of pathways involved in CVID with and without immune dysregulation; it can also provide information about the underlying molecular pathogenesis and provide markers for disease progression.…”

VIH, dislipidemias y perspectivas de su evolución

“…Las personas con VIH muestran un aumento de la enfermedad cardiovascular (ECV), debido en parte al aumento de la activación inmune, la inflamación y la disfunción endotelial (16).…”

“…The Framingham CVD calculator (15). Subestima el riesgo en pacientes HIV positivos European Systematic Coronary Risk Evaluation score (SCORE) (16). Poca concordancia con el DAD.…”

HIV-associated cardiovascular pathology

“…Использование статинов у ВИЧ-инфицированных пациентов оправданно и приводит к значительному снижению ингибитора пути тканевого фактора, белка параоксоназы-3 и рецептора к ЛПНП. При этом повышается уровень галектина-4 и связывающего инсулиноподобный фактор рост белка-2 -ключевых белков, вовлеченных в коагуляцию, окислительный стресс и метаболизм глюкозы [16].…”

“…При анализе электрокардиографических и эхокардиографических особенностей у ВИЧ-инфицированных выявлено, что распространенность патологи-эффективности терапии статинами у ВИЧ-инфицированных, статистически значимо снижаются на фоне приема 20 мг аторвастатина в течение года [18]. Более агрессивное липидкорригирующее действие питавастатина вызывает значительно более выраженное снижение и уровня ингибитора пути тканевого фактора по сравнению с правастатином, что раскрывает прямые и дополнительные механизмы действия статинов у ВИЧ-инфицированных [16].…”