van Eekeren Louise E, Vadaq Nadira, Blaauw Marc J T, Groenendijk Albert L, Vos Wilhelm A J W, Nelwan Erni J, Verbon Annelies, Stalenhoef Janneke E, Berrevoets Marvin A H, van Lunzen Jan, Netea Mihai G, Weijers Gert, Riksen Niels P, Rutten Joost H W, de Mast Quirijn, Tjwa Eric T T L, Joosten Leo A B, van der Ven André J A M
Department of Internal Medicine, Radboudumc, Nijmegen, 6500 HB, the Netherlands.
Radboud Center for Infectious Diseases, Radboudumc, Nijmegen, 6500 HB, the Netherlands.
BMC Med. 2025 Feb 11;23(1):78. doi: 10.1186/s12916-025-03914-5.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a key risk factor for cardiovascular disease (CVD), potentially driven by shared metabolic mechanisms. Metabolic perturbations associated with MASLD and CVD remain underexplored in people with HIV (PWH).
We used data from the longitudinal multicenter 2000HIV study comprising 1895 virally suppressed PWH, out of which 970 had available liver and carotid artery measurements. Transient elastography with controlled attenuation parameter (CAP) was performed for the assessment of liver steatosis (CAP > 263 dB/m) and fibrosis (LSM ≥ 7.0). Historic and future incident CVD within 2-year follow-up, defined as myocardial infarction, stroke, peripheral arterial disease, and angina pectoris, were extracted from the medical files, while atherosclerotic plaque(s) in the carotid arteries were assessed using ultrasonography. Metabolic perturbations were analyzed using mass spectrometry-based untargeted metabolomics (n = 500 metabolites) and nuclear magnetic resonance spectroscopy for targeted lipids and other metabolites (n = 246 metabolites).
PWH with liver steatosis were more likely to have arterial plaques (47% vs. 36%; P value = 0.003) and CVD history (11% vs. 6.8%; P value = 0.021) than PWH without liver steatosis. These associations were only significant in lean PWH, in contrast to those with BMI ≥ 25 kg/m. Metabolic pathways associated with liver steatosis and fibrosis primarily involved lipid and amino acid metabolism, and they were validated by targeted lipoproteomic measurements. Interestingly, metabolomic pathways and lipoproteomic signatures associated with MASLD were mostly distinct from those associated with CVD parameters. However, several metabolic pathways were shared, especially in lean PWH. These include arachidonic acid metabolism and formation of prostaglandin, purine metabolism, cholecalciferol metabolism, and glycine, serine, alanine, and threonine metabolism.
Metabolic disturbances linked to liver steatosis and CVD diverge across BMI categories in PWH. Lean PWH, unlike their overweight/obese counterparts, show common metabolic perturbations between MASLD and CVD, particularly involving arachidonic acid metabolism. This suggests that lean PWH with liver steatosis may face a heightened risk of CVD due to shared metabolic pathways, potentially opening avenues for targeted interventions, such as aspirin therapy, to mitigate this risk.
代谢功能障碍相关脂肪性肝病（MASLD）是心血管疾病（CVD）的关键危险因素，可能由共同的代谢机制驱动。在感染HIV的人群（PWH）中，与MASLD和CVD相关的代谢紊乱仍未得到充分研究。
我们使用了来自纵向多中心2000HIV研究的数据，该研究包括1895名病毒抑制的PWH，其中970人有可用的肝脏和颈动脉测量数据。采用受控衰减参数（CAP）的瞬时弹性成像技术评估肝脏脂肪变性（CAP＞263dB/m）和纤维化（LSM≥7.0）。从医疗档案中提取2年随访期内的既往和未来发生的CVD，定义为心肌梗死、中风、外周动脉疾病和心绞痛，同时使用超声检查评估颈动脉中的动脉粥样硬化斑块。使用基于质谱的非靶向代谢组学（n = 500种代谢物）和核磁共振波谱法分析靶向脂质和其他代谢物（n = 246种代谢物）来分析代谢紊乱情况。
与无肝脏脂肪变性的PWH相比，有肝脏脂肪变性的PWH更有可能有动脉斑块（47%对36%；P值 = 0.003）和CVD病史（11%对6.8%；P值 = 0.021）。这些关联仅在体重正常的PWH中显著，与BMI≥25kg/m²的PWH相反。与肝脏脂肪变性和纤维化相关的代谢途径主要涉及脂质和氨基酸代谢，并通过靶向脂蛋白组学测量得到验证。有趣的是，与MASLD相关的代谢组学途径和脂蛋白组学特征大多与与CVD参数相关的不同。然而，有几种代谢途径是共享的，尤其是在体重正常的PWH中。这些包括花生四烯酸代谢和前列腺素的形成、嘌呤代谢、胆钙化醇代谢以及甘氨酸、丝氨酸、丙氨酸和苏氨酸代谢。
与肝脏脂肪变性和CVD相关的代谢紊乱在不同BMI类别的PWH中有所不同。与超重/肥胖的PWH不同，体重正常的PWH在MASLD和CVD之间表现出共同的代谢紊乱，特别是涉及花生四烯酸代谢。这表明有肝脏脂肪变性的体重正常的PWH可能由于共享的代谢途径而面临更高的CVD风险，这可能为有针对性的干预措施（如阿司匹林治疗）开辟途径，以降低这种风险。
