Franczyk Beata, Młynarska Ewelina, Rysz-Górzyńska Magdalena, Gluba-Sagr Anna, Rysz Jacek, Sheth Sohum, Surma Stanislaw, Banach Maciej, Toth Peter P
Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 113 Żeromskiego Street, Lodz 90-549, Poland.
Department of Ophthalmology and Visual Rehabilitation, Medical University of Lodz, Lodz 90-549, Poland.
Am J Prev Cardiol. 2025 Jul 21;23:101068. doi: 10.1016/j.ajpc.2025.101068. eCollection 2025 Sep.
Historically high-density lipoproteins (HDL) have been viewed as antiatherogenic and beneficial. This conclusion was based on early prospective longitudinal cohorts and the broad functionality of these lipoproteins which include reverse cholesterol transport as well as activities that antagonize oxidation, inflammation, thrombosis, and endothelial dysfunction. It is also a key participant in immunity, engages in glucose homeostasis, and is a critical vehicle for microRNA translocation between tissues. The HDLs are polymolecular assemblies of enormous complexity. These lipoprotein particles are highly responsive in terms of cargo specificity to the interior milieu. In response to a broad range of supportive evidence, therapies have been developed that increase either serum levels of HDL particles or the mass of cholesterol in circulating HDL. Therapies that raised serum HDL-C using such agents as nicotinic acid, fibrates, or cholesterol ester transfer protein inhibitors were unsuccessful at impacting residual cardiovascular risk over and above baseline statin therapy. Although an early trial with apo-AI fueled initial enthusiasm, a subsequent trial with a recombinant form of this agent was unable to reproduce its capacity to induce plaque regression as measured by IVUS. Infusible HDL mimetics have also been largely unsuccessful in reducing non-calcified plaque volume, myocardial infarct size, or cardiovascular events. More trials of longer duration and in greater numbers of patients need to be performed. Recent epidemiological studies indicate that the relationship between HDL-C and risk for cardiovascular morbidity and mortality is more complex than previously thought. Depending upon the cohort and the intensity of adjustment for risk factor covariates, the relationship is no longer viewed as inverse linear; rather, it is more U-shaped (with some exceptions) with high and low levels of HDL-C both being associated with heightened risk for events. The issue clearly requires much greater investigation. Given the enormous complexity of the HDL proteome and lipidome and the range of functions it has the capacity to participate in, the potential to harness beneficial effects from HDL remain a viable possibility. However, the HDL code is yet to be fully deciphered. A polymolecular assembly as complex as mature HDL is not a simple task to study. Risk algorithms need to reassess the validity of attributing cardioprotection from high HDL-C as this may lead to underestimation of true risk.
历史上，高密度脂蛋白（HDL）一直被视为具有抗动脉粥样硬化作用且有益。这一结论基于早期的前瞻性纵向队列研究以及这些脂蛋白的广泛功能，包括逆向胆固醇转运以及对抗氧化、炎症、血栓形成和内皮功能障碍的活性。它也是免疫的关键参与者，参与葡萄糖稳态调节，并且是组织间微小RNA转运的关键载体。HDL是极其复杂的多分子聚集体。这些脂蛋白颗粒在货物特异性方面对内部环境高度敏感。基于大量支持性证据，已开发出提高血清HDL颗粒水平或循环HDL中胆固醇含量的疗法。使用烟酸、贝特类药物或胆固醇酯转运蛋白抑制剂等药物提高血清HDL-C的疗法，在影响基线他汀类药物治疗之外的残余心血管风险方面未取得成功。尽管早期一项关于载脂蛋白A-I的试验引发了最初的热情，但随后一项使用该药物重组形式的试验无法重现其通过血管内超声测量诱导斑块消退的能力。可输注的HDL模拟物在减少非钙化斑块体积、心肌梗死面积或心血管事件方面也大多未取得成功。需要进行更多持续时间更长、患者数量更多的试验。最近的流行病学研究表明，HDL-C与心血管发病率和死亡率风险之间的关系比以前认为的更为复杂。根据队列以及对风险因素协变量的调整强度，这种关系不再被视为呈反向线性；相反，它更呈U形（有一些例外情况），HDL-C水平过高和过低都与事件风险增加相关。显然，这个问题需要更深入的研究。鉴于HDL蛋白质组和脂质组极其复杂，以及它能够参与的功能范围，利用HDL的有益作用仍有可能。然而，HDL的编码尚未完全破译。研究像成熟HDL这样复杂的多分子聚集体并非易事。风险算法需要重新评估将心脏保护归因于高HDL-C的有效性，因为这可能导致对真实风险的低估。
