1. 年轻非肥胖人群血脂偏高的成因分析
1.1 遗传与代谢异常基础
年轻非肥胖人群血脂偏高并非罕见现象，其成因复杂，往往涉及遗传 predispositions 和早期代谢异常。其中，家族性高胆固醇血症（Familial Hypercholesterolemia, FH）是一种重要的遗传性疾病，其特征是低密度脂蛋白胆固醇（LDL-C）水平显著升高，可导致儿童期甚至胎儿期就出现动脉粥样硬化 123。FH 主要由参与LDL受体介导途径的基因突变引起，多数表现为常染色体显性遗传。纯合子型FH（HoFH）患者的血浆LDL-C水平至少是杂合子型FH（HeFH）的两倍，是正常水平的四倍以上，且预后更差 1。由于LDL受体功能严重受损，HoFH患者对增强受体活性的药物（如他汀类）反应不佳或效果甚微 1。
除了单基因遗传缺陷，脂代谢相关基因多态性也对血脂水平有显著影响。全基因组关联研究（GWAS）已识别出超过150个与血脂异常水平相关的基因座，这些基因座解释了总变异的约40% 456。例如，参考文献7提及的基因型，包括APOA5 S19W、APOA5 -1131T > C、APOE、GCKR、TRIB1和TBL2/MLXIPL等，都与严重高甘油三酯血症显著相关。LPL活性在甘油三酯代谢中扮演关键角色，基因增强LPL与心肌梗死、缺血性心脏病和冠心病风险降低相关 8。此外，遗传风险评分（PRS）分析显示，高多基因负荷的LDL-C或甘油三酯升高变异与冠状动脉疾病（CAD）风险增加相关。例如，芬兰FINRISK队列研究显示，LDL-C PRS最高5%人群的LDL-C中位数为3.78 mmol/L，而最低人群为2.87 mmol/L；甘油三酯PRS最高5%人群的甘油三酯中位数为1.55 mmol/L，最低人群为0.97 mmol/L 9。这些多基因变异的累积效应虽然单个影响较小，但总体上可显著影响血脂水平，进而增加心血管疾病风险 79。
代谢综合征的早期表现，特别是胰岛素抵抗，与脂代谢紊乱密切相关。胰岛素抵抗是代谢功能障碍相关脂肪肝病（MAFLD）发展的关键致病因素 1011。当胰岛素抵抗发生时，肝脏对胰岛素的敏感性降低，导致糖异生抑制不足，但肝脏脂肪生成（de novo lipogenesis, DNL）却持续不受抑制地增加 11。这种肝脏选择性胰岛素抵抗导致游离脂肪酸（FFA）向肝脏的输送增加，促进肝脏内甘油三酯合成和累积，进而引发高甘油三酯血症。此外，胰岛素抵抗还会导致脂肪组织功能障碍，释放过多的游离脂肪酸，加剧肝脏和肌肉组织的胰岛素抵抗，形成恶性循环 1213。在一些研究中，代谢综合征的早期迹象，如中心性肥胖、中度高血压、高甘油三酯、高胰岛素血症、葡萄糖耐受不良和胰岛素抵抗，在仅两到六个月内就可能在年轻个体中出现 14。一项针对超重/肥胖学龄儿童的研究也揭示，腹部肥胖（14.3%-16.7%）和高胆固醇血症（9.5%）的早期表现，提示了代谢综合征在年轻群体中的潜在风险 15。甚至，睑缘炎也被发现与代谢综合征显著相关，并可作为其早期迹象，尤其与高血脂和冠状动脉疾病的早期发展相关 16。
1.2 生活方式相关诱因
除了遗传和代谢异常，不健康的生活方式是年轻非肥胖人群血脂偏高的重要诱因。
饮食结构失衡在其中扮演核心角色。高糖和精制碳水化合物的过量摄入是导致甘油三酯（TG）升高的主要因素之一。这些膳食成分在体内迅速转化为葡萄糖，刺激胰岛素分泌，并最终通过肝脏从头脂肪生成（de novo lipogenesis）途径转化为脂肪酸和甘油三酯，进而导致高甘油三酯血症 17。例如，富含果糖和葡萄糖的膳食尤其会增加肝内甘油三酯（IHTG）的积累，这与非酒精性脂肪肝病（NAFLD）的发生发展密切相关 17。此外，反式脂肪酸的摄入不仅会升高低密度脂蛋白胆固醇（LDL-C），还会降低高密度脂蛋白胆固醇（HDL-C），增加心血管疾病风险。相比之下，膳食纤维（尤其是可溶性纤维）摄入不足则会影响血脂水平。膳食纤维能促进肠道蠕动，增加粪便中胆固醇和胆汁酸的排泄，并改变肠道微生物群落，从而降低总胆固醇和LDL-C水平 1819。例如，一项针对轻度高胆固醇血症受试者的研究发现，燕麦（富含可溶性纤维）的摄入显著降低了总胆固醇和非HDL-C，并调节了肠道菌群，其降胆固醇作用与肠道菌群的调节密切相关 20。而不饱和脂肪酸，特别是来自地中海饮食模式中的单不饱和脂肪酸和多不饱和脂肪酸，被证明对改善血脂谱具有益处，包括降低LDL-C和甘油三酯 2122。高脂肪、低碳水化合物的生酮饮食，虽然在某些情况下有助于体重管理，但可能导致部分患者胆固醇水平显著升高，甚至加剧高胆固醇血症，这在有潜在高脂血症的个体中尤为明显 2324。
体力活动不足，尤其是久坐习惯和缺乏规律的有氧运动或抗阻训练，是导致脂代谢酶活性降低和血脂异常的独立风险因素。久坐行为会导致代谢灵活性受损，特别是骨骼肌细胞线粒体对丙酮酸代谢能力的抑制，这可能通过影响线粒体膜磷脂酰乙醇胺（PE）的丰度来实现，进而阻碍碳水化合物和脂肪之间的燃料转换能力 25。长期缺乏运动会降低脂蛋白脂肪酶（LPL）的活性，LPL是分解富含甘油三酯的脂蛋白的关键酶，其活性下降直接导致甘油三酯清除率降低。高强度间歇训练（HIIT）已被证明能有效促进脂肪减少，其中一个重要机制是乳酸水平升高诱导脂肪酸合酶（FASN）乳酰化，从而抑制脂肪合成 26。这提示，规律的体力活动，特别是高强度运动，对改善脂代谢具有积极作用。
睡眠剥夺与昼夜节律紊乱也对血脂水平产生负面影响。睡眠不足和不规律的作息会干扰机体的内分泌系统，导致皮质醇等应激激素分泌异常。皮质醇具有促进脂肪分解的作用，但在生理性昼夜节律下，早晨皮质醇浓度的升高对调节皮下脂肪组织的脂肪分解至关重要 27。然而，睡眠障碍（如阻塞性睡眠呼吸暂停，OSA）可能会抑制生长激素的夜间分泌，生长激素同样具有脂解作用。研究显示，OSA患者夜间生长激素浓度显著降低，从而导致脂肪分解受损，而经鼻持续气道正压通气（CPAP）治疗后，生长激素水平迅速恢复，脂肪分解也随之改善 28。慢性睡眠不足和昼夜节律紊乱还会影响食欲调节激素（如瘦素和胃饥饿素）的平衡，可能增加对高能量食物的渴望，进而间接影响血脂水平。
1.3 环境与心理因素
除了遗传、代谢和生活方式因素，环境与心理因素也日益被认为是影响年轻非肥胖人群血脂水平的重要推手。
慢性压力对脂蛋白代谢的干扰机制复杂且多方面。长期或反复的心理压力会导致交感神经系统持续兴奋，并激活下丘脑-垂体-肾上腺（HPA）轴，从而释放更多的儿茶酚胺和糖皮质激素（如皮质醇）29。这些应激激素会影响脂肪细胞的脂肪分解和脂肪生成，并可能通过炎症反应间接影响脂代谢。例如，慢性压力与促炎细胞因子（如IL-6、TNF-α）的释放增加有关，这些细胞因子可以干扰肝脏的脂蛋白合成与清除，导致甘油三酯和低密度脂蛋白胆固醇（LDL-C）水平升高30。一些研究表明，慢性压力还可能通过影响胃饥饿素（Ghrelin）等激素的分泌，进一步影响食欲和食物选择，可能导致对高脂肪、高糖食物的偏好，从而间接促进血脂异常29。此外，压力诱导的氧化应激也可能加速脂蛋白的氧化修饰，使其更具致动脉粥样硬化性30。
环境污染物，特别是持久性有机污染物（POPs），可以通过多种途径影响脂代谢。POPs多为亲脂性物质，容易在脂肪组织中积累31。这些污染物可以作为内分泌干扰物，模拟或拮抗内源性激素的作用，从而干扰正常的脂代谢过程。例如，它们可能通过干扰核受体（如过氧化物酶体增殖物激活受体PPARs、肝X受体LXRs）的活性来影响脂肪细胞的分化、脂质合成和分泌功能31。氯丹酮（Chlordecone）等有机氯农药，作为广泛存在的POPs，已被证明能改变胆固醇稳态和脂蛋白代谢，它可以通过激活孕烷X受体（PXR）和雌激素受体α（ERα）来影响胆固醇的转运和脂蛋白的组成32。长期的环境污染物暴露，即使剂量较低，也可能通过累积效应，对年轻个体的脂代谢产生持续性影响，增加血脂异常的风险。
社交模式变化，尤其是与孤独感和社会隔离相关的因素，也可能对血脂产生间接作用。研究发现，社会隔离与心血管代谢疾病风险增加有关。一项针对小鼠的研究发现，单独饲养的小鼠比群居小鼠更容易出现动脉粥样硬样病变，这与脂质代谢紊乱有关，而与体重、饮食或交感神经活动无关33。机制研究表明，慢性隔离会降低下丘脑催产素的产生，催产素通过肝脏中的催产素受体（OXTR）调节胆汁酸的产生和脂蛋白脂肪酶（LPL）的活性，从而影响脂质代谢33。这意味着，社交连接的缺乏可能通过脑-肝轴影响脂质代谢，进而影响血脂水平。此外，现代社会中对外卖的依赖和酒精摄入的增加也是值得关注的因素。高糖高脂的外卖食品往往缺乏膳食纤维和不饱和脂肪，长期食用易导致脂质过量摄入。酒精摄入，特别是过量饮酒，会干扰肝脏的脂代谢，增加甘油三酯的合成，并可能导致高甘油三酯血症。这些间接影响共同构成了年轻非肥胖人群血脂异常的环境与心理诱因。
2. 年轻非肥胖人群血脂偏高的潜在危害
2.1 心血管系统早期损害
年轻非肥胖人群血脂偏高，即便尚未达到临床诊断标准或未出现明显症状，也已对心血管系统造成早期损害，为未来心血管疾病的发生埋下隐患。
动脉粥样硬化的亚临床证据在年轻血脂异常患者中日益普遍。动脉粥样硬化是一个漫长而隐匿的进展过程，通常在临床症状出现前数十年就已经开始。颈动脉内膜中层厚度（Carotid Intima-Media Thickness, CIMT）增厚是评估亚临床动脉粥样硬化的重要非侵入性指标，反映了血管壁的早期结构改变。研究显示，即使是儿童期的心血管危险因素，包括总胆固醇和甘油三酯水平，也与成年期的亚临床心血管疾病（如CIMT增厚）存在显著关联 34。冠状动脉钙化（Coronary Artery Calcification, CAC）评分是预测心血管事件风险的另一重要指标，它能直接反映冠状动脉粥样硬化斑块的钙化程度。尽管CAC在年轻人群中检出率相对较低，但一旦出现，即提示较高的心血管风险。在一些遗传性高胆固醇血症患者中，即使接受他汀类药物治疗，若存在CAC，其心血管事件风险仍显著高于无CAC的患者 35。非低密度脂蛋白胆固醇（non-HDL-C）和载脂蛋白B（apoB）是比LDL-C更能全面反映致动脉粥样硬化脂蛋白颗粒总数的指标，它们与亚临床动脉粥样硬化和未来心血管事件风险的关联性更强 36。
LDL-C/甘油三酯升高与心肌微结构改变之间存在密切关联。长期高水平的LDL-C和甘油三酯不仅促进动脉粥样硬化斑块形成，还可能直接或间接影响心肌细胞功能和结构。高甘油三酯血症常伴随着高密度脂蛋白胆固醇（HDL-C）水平降低和LDL颗粒变小变密（sdLDL），这些异常脂蛋白更容易渗透血管壁并被氧化修饰，引发炎症反应，导致血管内皮功能障碍。这种持续的炎症和脂质沉积可能导致心肌微循环障碍，影响心肌细胞的氧供和营养，进而引起心肌微结构改变，如左心室舒张功能障碍。左心室舒张功能障碍是心力衰竭的早期表现之一，可在临床症状出现前数年甚至数十年被检测到，且在年轻血脂异常人群中已发现其发生率增加。多囊卵巢综合征（PCOS）女性，由于常伴有血脂异常（如总胆固醇升高、HDL-C降低），也被发现面临更高的心血管代谢疾病风险，包括高血压和2型糖尿病，这些疾病都可能通过加重脂代谢紊乱来损害心肌结构和功能 37。
脂蛋白(a) [Lp(a)] 升高对早发缺血性卒中的特异性风险不容忽视。Lp(a)是一种遗传决定的脂蛋白，其结构与LDL相似，但额外含有载脂蛋白(a)。Lp(a)水平升高独立于LDL-C，被认为是心血管疾病的独立危险因素，尤其与早发动脉粥样硬化性心血管疾病（ASCVD）和缺血性卒中风险显著相关 38。一项研究发现，Lp(a)水平升高与冠状动脉钙化独立相关，提示其在早期动脉粥样硬化形成中的作用 39。在年轻患者中，若出现不明原因的缺血性卒中，应高度怀疑Lp(a)升高的可能性。尽管目前针对Lp(a)的靶向治疗仍在发展中，但识别高水平Lp(a)的个体对于早期风险评估和采取更积极的干预策略至关重要。
2.2 代谢与多器官功能异常
血脂偏高，特别是高甘油三酯血症，在年轻非肥胖人群中不仅影响心血管系统，还会导致全身性的代谢紊乱和多器官功能异常。
高甘油三酯血症与胰岛素抵抗的恶性循环是其中一个关键机制。胰岛素抵抗是指身体细胞对胰岛素的反应性降低，导致血糖升高，胰腺代偿性分泌更多胰岛素以维持血糖正常。研究表明，高甘油三酯血症即使在没有肥胖的情况下，也与胰岛素抵抗相关，并可导致代偿性高胰岛素血症40。这种慢性高胰岛素血症反过来会增加富含甘油三酯的脂蛋白的生成，形成一个“胰岛素抵抗、高胰岛素血症、高甘油三酯血症”的恶性循环，加速动脉粥样硬化的进程4041。游离脂肪酸（FFA）在其中扮演了重要角色，长期升高的FFA水平会对葡萄糖稳态产生有害影响，这被称为“脂毒性”，而同时存在高血糖时则形成更具协同作用的“糖脂毒性”4243。FFA的过度暴露，特别是饱和脂肪酸如棕榈酸，会通过浸润胰岛β细胞，损害其功能并诱导细胞死亡，导致胰岛素分泌能力下降42444546。胰岛β细胞是胰岛素的唯一生产者，其功能障碍将严重影响血糖调节44。这种脂毒性还会导致胰岛β细胞内质网应激、氧化应激、线粒体功能障碍、自噬受损及炎症反应，进一步加剧β细胞功能障碍和死亡42。
非酒精性脂肪性肝病（NAFLD）的进展路径与血脂异常密切相关。NAFLD是一种常见的慢性肝脏疾病，其特点是肝脏中脂肪过度积累，并且与高血脂有着双向关系。NAFLD可以从单纯性脂肪肝（肝脏脂肪变性）发展为非酒精性脂肪性肝炎（NASH），进而可能进展为肝纤维化、肝硬化甚至肝癌4748。高甘油三酯血症和胰岛素抵抗是NAFLD发生的两个重要驱动因素47。在胰岛素抵抗状态下，脂肪组织释放更多的游离脂肪酸进入肝脏，肝脏对这些脂肪酸的摄取和从头合成甘油三酯的能力增强，但其输出甘油三酯的能力相对不足，导致肝脏脂肪溢出和堆积47。此外，高脂血症诱导的氧化应激和炎症反应在NAFLD的进展中也扮演关键角色，导致肝细胞损伤和炎症。研究表明，酮戊二酸（α-Ketoglutarate, AKG）能通过激活AMPK-PGC-1α/Nrf2通路，有效缓解高脂血症引起的肝脏脂质积累、线粒体功能障碍和氧化应激，这提示了干预NAFLD的潜在靶点47。
血脂异常对肾脏的损伤也不容忽视。代谢综合征，包括肥胖、高血糖、血脂异常和高血压，是慢性肾脏病（CKD）的重要风险因素49。高甘油三酯血症和低高密度脂蛋白胆固醇（HDL-C）与肾小球高滤过、蛋白尿、肾功能下降及肾小球足细胞损伤密切相关495051。血脂异常可能通过多种机制直接损害肾脏：首先，异常脂蛋白（特别是氧化修饰的LDL）可以沉积在肾小球和肾小管，引起局部炎症反应和氧化应激，导致肾小球硬化和肾小管间质纤维化5051。其次，高甘油三酯血症可能通过改变肾脏细胞的脂质代谢，导致肾脏局部脂毒性。例如，脂肪甘油三酯脂肪酶（ATGL）的缺陷会导致肾脏异位脂肪沉积和足细胞凋亡，进而损害肾小球滤过屏障，引起蛋白尿52。此外，血脂异常还会通过促进内皮功能障碍、激活肾素-血管紧张素-醛固酮系统（RAAS）等途径，间接加重肾脏损伤4953。糖尿病肾病（DKD）的发生和进展中，脂代谢紊乱同样扮演了重要角色，高甘油三酯和低HDL-C与白蛋白尿和肾小球滤过率下降的风险增加相关5051。
2.3 长期健康预后影响
年轻非肥胖人群血脂偏高，虽然短期内可能无明显症状，但其对长期健康预后的负面影响是深远且累积的。
累积LDL-C暴露对全因死亡率的影响是当前研究的重点。动脉粥样硬化是一个进展缓慢且始于年轻阶段的过程。累积的低密度脂蛋白胆固醇（LDL-C）暴露，即“LDL-C暴露时间-浓度积分”，被认为是心血管疾病（CVD）风险的重要预测因子。研究表明，一个人一生中累积的LDL-C暴露量与未来发生CVD事件的风险密切相关，且与LDL-C暴露的年龄曲线进程独立相关 54。年轻时积累的相同LDL-C暴露量，相较于老年时期积累的，会带来更高的风险增幅 54。例如，Coronary Artery Risk Development in Young Adults (CARDIA) 研究数据显示，对于18至30岁的无症状成年人，在调整了性别、种族和传统风险因素后，LDL-C对年龄曲线下的面积（即累积暴露）与CVD事件风险显著相关（每增加100 mg/dl×年，风险比增加1.053，p < 0.0001） 54。这强调了从生命早期开始控制LDL-C的重要性 54。更进一步的研究提示，即使是短暂性或间歇性的早期高脂血症，也会改变组织巨噬细胞，加速动脉粥样硬化进程，其影响可能与持续性高脂血症相似，甚至在某些机制上更为有害 55。一项涵盖儿童至成人的纵向研究也发现，从儿童期到成年期持续存在非高密度脂蛋白胆固醇（non-HDL-C）血脂异常的个体，其CVD事件风险显著增加，而那些儿童期血脂异常但在成年期恢复正常的个体，其风险与从未出现血脂异常的个体相似 56。这表明早期干预和持续管理对预防过早CVD事件至关重要 56。
血脂异常与早发冠心病/糖尿病的共病风险显著。年轻时期的血脂异常，即使是非肥胖个体，也常与其他代谢紊乱，如胰岛素抵抗，相互作用，共同促进疾病发展。例如，青春期发病的2型糖尿病（T2D）患者，在长达十年的随访中，高血压、LDL-C血脂异常和高甘油三酯血症的累积发生率分别高达59%、33%和37% 57。在随访结束时，54%的年轻T2D患者除了糖尿病外，还伴有至少两种心血管危险因素 57。这些共病风险的叠加，导致这些年轻患者面临更高的心血管并发症和死亡率 57。早发冠心病（Premature Coronary Artery Disease, PCAD），通常指50岁前发病的冠心病，其患者常常伴有较高的心血管危险因素负担，其中吸烟、高血压和高胆固醇血症最为常见 58。PCAD患者的预后较差，在10年随访期内，52.9%的患者至少经历一次主要不良心血管事件（MACE），20.9%的患者死亡，且患者对危险因素的控制情况不佳，例如，31.7%至37.2%的患者持续吸烟，81.7%至89.3%的患者LDL-C水平未能达到目标值 58。代谢性血脂异常（高甘油三酯和低HDL-C）在2型糖尿病患者中非常普遍，并与复合心血管结局和冠状动脉疾病事件的更高风险相关 59。
生活质量降低对社会功能的影响虽然不直接体现在死亡率或发病率上，但对于年轻人群而言，其影响同样重要。长期血脂异常和随之而来的亚临床动脉粥样硬化可能导致一系列症状前改变，例如运动耐力下降、容易疲劳等，这些都可能影响年轻人的日常生活、学习和工作表现。随着疾病进展，即使是亚临床阶段的轻微心血管功能障碍，也可能在体育活动、日常劳作中表现出耐力不足或疲劳感，从而限制其社交活动和职业发展。例如，低LDL-C/HDL-C比值被认为是全因死亡率的有力预测指标，甚至优于传统的血脂指标 60。这意味着，即使在没有明确疾病诊断的情况下，血脂水平的失衡也可能预示着身体状态的不佳，并间接影响生活质量。更重要的是，长期面临潜在健康风险的心理负担也可能导致焦虑和抑郁，进一步影响年轻个体的全面健康状况和社会功能。因此，对年轻非肥胖人群血脂偏高的早期识别和干预，不仅是为了预防严重的心血管事件，也是为了维护其长期的生活质量和健康福祉。
3. 年轻非肥胖血脂偏高人群的综合干预策略
3.1 生活方式优化与行为干预
针对年轻非肥胖人群的血脂偏高问题，生活方式的优化和行为干预是基石，旨在通过非药物手段改善血脂谱，降低心血管疾病风险。
饮食调整是核心干预措施之一。推荐地中海饮食模式，该模式以其丰富的全谷物、蔬菜、水果、豆类、坚果和橄榄油为特色，强调鱼类和家禽的适量摄入，以及红肉的限制。地中海饮食能够显著降低血压，尤其是在肥胖人群中效果更为显著 61。具体的实施建议包括：增加富含Omega-3脂肪酸的鱼类摄入（如鲑鱼、鲭鱼），每周至少两次；每日摄入少量坚果（如核桃、杏仁）和种子，它们富含不饱和脂肪酸和膳食纤维；选择初榨橄榄油作为主要烹饪用油。同时，推荐采用低升糖指数（GI）饮食，以全谷物（如糙米、全麦面包、燕麦）替代精制碳水化合物（如白米饭、白面包），以减少餐后血糖和胰岛素的剧烈波动，从而抑制肝脏脂肪合成。可溶性膳食纤维的摄入也至关重要，如燕麦、大麦、豆类、苹果、柑橘类水果和亚麻籽。可溶性纤维能够减少肠道对胆固醇的吸收，增加胆汁酸排泄，从而降低总胆固醇和LDL-C水平 62 63。一项研究发现，燕麦的摄入显著降低了轻度高胆固醇血症患者的总胆固醇和非HDL-C水平，并调节了肠道菌群，表明其降胆固醇作用与肠道菌群的调节密切相关。
运动处方应结合有氧运动和抗阻训练。高强度间歇训练（HIIT）对改善甘油三酯和高密度脂蛋白胆固醇（HDL-C）具有显著效果。HIIT通常包括短时间的高强度运动爆发，随后是短暂的恢复期，重复进行。一项针对超重/肥胖年轻女性的研究表明，HIIT结合抗阻训练（HIIT+RT）比单独HIIT更能有效改善身体成分、心肺健康和糖脂代谢，表现为肌肉量、峰值摄氧量（VOpeak）和肺活量的更大提升 64。虽然有些研究发现单独的HIIT可能不会显著改变总胆固醇、HDL-C、LDL-C或甘油三酯水平，但结合抗阻训练能更好地提升肌肉脂代谢能力，增加瘦体重，从而间接改善脂代谢状况 65。抗阻训练通过增加肌肉量和基础代谢率，有助于消耗更多的脂肪酸，改善胰岛素敏感性，进而影响血脂水平。一项综述指出，高强度有氧训练可以改善高密度脂蛋白胆固醇，而抗阻训练对低密度脂蛋白胆固醇水平可能产生积极影响，尽管联合训练的效果尚不一致 66。在一些研究中，HIIT结合L-瓜氨酸补充剂被发现能改善肥胖伴代谢功能障碍相关脂肪肝病青少年患者的非高密度脂蛋白胆固醇、极低密度脂蛋白胆固醇和甘油三酯水平 67。
睡眠与压力管理对于维持健康的脂代谢同样重要。长期睡眠不足和慢性压力会导致内分泌紊乱，如皮质醇水平升高，进而影响脂肪代谢和胰岛素敏感性。因此，建立规律的作息，确保每晚7-9小时的充足睡眠至关重要。建议通过创造舒适的睡眠环境、睡前避免电子产品和咖啡因等方式来改善睡眠质量。对于压力管理，可以尝试正念减压（Mindfulness-Based Stress Reduction, MBSR）技术，如冥想、瑜伽和深呼吸练习，这些方法有助于降低皮质醇水平，平衡自主神经系统，从而减少慢性压力对脂代谢的负面影响。此外，培养健康的兴趣爱好、保持积极的社交互动也有助于缓解心理压力。
3.2 药物与靶向治疗选择
当年轻非肥胖人群通过生活方式干预仍无法达到血脂目标时，或存在高危因素（如家族性高胆固醇血症），药物治疗则成为必要的选择。
传统药物：他汀类药物的适用人群及剂量调整
他汀类药物（Statins）是目前治疗高胆固醇血症的一线药物，通过抑制HMG-CoA还原酶减少胆固醇合成，从而降低低密度脂蛋白胆固醇（LDL-C）水平。对于儿童和青少年而言，他汀类药物在家族性高胆固醇血症（FH）的治疗中具有明确的有效性和安全性 6869707172。国际指南普遍推荐在儿童期启动他汀治疗，特别是针对FH儿童，以降低成年后心血管疾病的风险 73。
- 适用人群： 主要适用于LDL-C显著升高且通过生活方式干预无效的年轻FH患者。例如，若儿童期LDL-C持续升高，特别是伴有家族史或早发心血管疾病风险的，应考虑启动他汀治疗 73。对于高危或极高危的FH患者，可能在更低的LDL-C水平下就需要启动药物干预。在FH患者中，他汀治疗通常可在儿童期开始，一项长达20年的随访研究显示，儿童期启动他汀治疗能够减缓颈动脉内膜中层厚度（CIMT）的进展，并降低成年期心血管疾病的风险 68。
- 剂量调整： 儿童和青少年他汀治疗应从小剂量开始，并根据LDL-C的反应和耐受性逐步调整。治疗目标通常是将LDL-C降至较低水平，例如<3.4 mmol/L（130 mg/dL），甚至<2.6 mmol/L（100 mg/dL）或更低，具体目标需个体化评估 68。短期的临床试验显示，他汀类药物在儿童和青少年中耐受性良好，对生长发育无显著不良影响，肝功能和肌酶水平无明显异常 70717273。然而，长期安全性仍需持续监测 707173。
新型疗法：PCSK9抑制剂和APOC3靶向药物
对于对他汀类药物不耐受或无法达到治疗目标的患者，新型降脂药物提供了更有效的选择。
- PCSK9抑制剂： PCSK9抑制剂（如依洛尤单抗Evolocumab、阿利西尤单抗Alirocumab）通过阻断PCSK9蛋白与LDL受体的结合，增加肝脏LDL受体数量，从而显著降低血浆LDL-C水平。它们特别适用于伴有家族性高胆固醇血症、对传统降脂药物反应不佳或不耐受的患者 7475767778。PCSK9抑制剂具有强大的降脂效果，通常能使LDL-C降低50%以上，部分患者甚至能达到70%以上的降幅 7475767879。例如，在日本进行的真实世界研究显示，依洛尤单抗能显著降低纯合子FH患者LDL-C水平45.7%，杂合子FH患者55.9%，高危高胆固醇血症患者63.3% 79。一项涵盖FH和高风险患者的真实世界研究也证实，PCSK9抑制剂能使LDL-C降低约59%，非高密度脂蛋白胆固醇和载脂蛋白B也有显著降低 78。此外，这些药物通常耐受性良好，不良反应发生率较低 74757679。
- APOC3靶向药物： 载脂蛋白C3 (APOC3) 是一种抑制脂蛋白脂肪酶（LPL）活性的蛋白，通过抑制APOC3可以有效降低甘油三酯水平。新型APOC3靶向药物，如反义寡核苷酸（ASO）olezarsen和小干扰RNA（siRNA）plozasiran，为严重高甘油三酯血症（sHTG）患者提供了新的治疗选择 808182。Plozasiran在SHASTA-2临床试验中显示，能显著降低重度高甘油三酯血症患者的甘油三酯水平达57%，并使大多数患者的甘油三酯水平降至低于500 mg/dL（急性胰腺炎风险阈值），同时改善其他脂蛋白参数，且安全性良好 80。Plozasiran对混合性高脂血症患者的甘油三酯水平也显示出显著的降低作用 83。这些药物特别适用于高甘油三酯血症导致的急性胰腺炎风险较高或传统药物效果不佳的患者。
基因检测指导：家族性高胆固醇血症的早筛与早期他汀干预
基因检测在FH的诊断和管理中发挥着越来越重要的作用。FH是一种遗传性疾病，早期诊断对于预防心血管事件至关重要。
- 早筛： 对于有FH家族史的儿童，推荐进行级联筛查（cascade screening），即从FH患者开始，对其一级亲属进行血脂和基因检测 69。FH的诊断主要依赖于遗传检测和临床评分，通过基因检测识别FH突变（如LDLR、APOB、PCSK9基因变异），可以明确诊断，并在症状出现前进行干预 84。人工智能（AI）和机器学习（ML）在FH的筛查、诊断和风险分层方面展现出巨大潜力，有望提高早期诊断的准确性和效率 84。
- 早期他汀干预： 对于基因检测确诊的FH儿童，早期启动他汀治疗具有显著的长期益处。研究表明，在儿童期开始他汀治疗，能够显著降低FH患者成年后的心血管事件发生率和死亡率 68。儿童脂质异常的治疗指南已经发布，旨在为临床医生提供指导，以更好地管理这一特殊人群 85。早期、积极的干预可以有效控制LDL-C水平，延缓动脉粥样硬化的进展，从而改善患者的长期预后。
需要注意的是，所有药物治疗都应在专业医生的指导下进行，并结合患者的具体情况、风险评估和耐受性进行个体化调整和长期监测。
3.3 动态监测与长期管理
对于年轻非肥胖血脂偏高人群，动态监测与长期管理是确保干预策略有效性并预防未来心血管事件的关键。这不仅涉及常规血脂指标的监测，还包括新兴标志物、多学科协作以及利用数字健康工具的创新方法。
监测指标： 除了传统的低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）和甘油三酯（TG）之外，应增加对其他新兴脂质指标的关注，以更全面地评估心血管风险。
- 脂蛋白(a) [Lp(a)]：Lp(a)是一种遗传决定的脂蛋白，其水平升高独立于其他血脂指标，是心血管疾病（特别是早发动脉粥样硬化和缺血性卒中）的独立危险因素 86。在评估年轻血脂偏高患者的风险时，特别是有早发心血管疾病家族史的个体，应定期检测Lp(a)水平 86。目前，针对Lp(a)的靶向降脂疗法正在快速发展，例如PCSK9抑制剂中的小干扰RNA（siRNA）可以有效降低Lp(a)水平 8788。
- 非HDL-C（Non-HDL-C）：非HDL-C代表了所有致动脉粥样硬化脂蛋白颗粒中的胆固醇总量，包括LDL-C、极低密度脂蛋白胆固醇（VLDL-C）和中间密度脂蛋白胆固醇（IDL-C）。在甘油三酯水平较高或存在糖尿病、代谢综合征的患者中，非HDL-C可能比LDL-C更能准确反映心血管风险，因此应作为常规监测指标。
- 载脂蛋白B（ApoB）：ApoB是每个致动脉粥样硬化脂蛋白颗粒的结构蛋白，其浓度直接反映了循环中致动脉粥样硬化颗粒的数量。与非HDL-C类似，ApoB被认为是比LDL-C更优的心血管风险预测指标，尤其是在甘油三酯较高或HDL-C较低的情况下 88。
- 高敏C反应蛋白（hs-CRP）：虽然不是脂质指标，但hs-CRP作为炎症标志物，其升高提示血管炎症，与心血管疾病风险密切相关，可作为血脂异常患者心血管风险评估的补充指标。
多学科协作： 鉴于血脂异常的复杂性和对全身健康的影响，整合多学科资源，提供个性化的综合干预方案至关重要。
- 心内科医生：负责评估心血管风险，制定降脂目标，并指导药物治疗，特别是对于高危或已有心血管事件的患者。
- 营养科医生：提供专业的饮食指导，根据患者的血脂谱、生活习惯和偏好，制定个性化的地中海饮食、低升糖指数饮食或富含可溶性纤维的饮食计划 8990。
- 运动康复科医生或运动生理学家：协助患者进行有规律的体育锻炼，如步行、慢跑、游泳等有氧运动，以改善脂代谢和胰岛素敏感性 9192。
- 内分泌科医生：对于伴有胰岛素抵抗、糖尿病前期或糖尿病的患者，内分泌科医生可协助管理血糖，并评估内分泌因素对血脂的影响。
- 心理健康专家：处理患者可能面临的慢性压力、焦虑和抑郁，提供压力管理技术，如正念冥想和瑜伽，以减轻心理因素对脂代谢的负面影响。
这种多学科协作模式能够确保患者获得全面、协调且持续的健康管理，从而优化治疗效果和长期预后。
数字健康工具： 随着技术的发展，可穿戴设备和数字健康平台为血脂异常的动态监测和行为反馈提供了新的机遇。
- 可穿戴设备（如运动手环、智能手表）：这些设备可以实时追踪运动量（步数、距离、活动强度）、心率、睡眠模式和睡眠质量。通过对这些数据的分析，可以帮助患者更好地理解自己的生活习惯对血脂的影响，并及时调整 93。例如，规律的活动模式被证实与更好的心血管代谢健康相关 93。
- 连续血糖监测（Continuous Glucose Monitoring, CGM）：对于伴有胰岛素抵抗或糖尿病风险的患者，CGM可以提供实时的血糖波动数据，帮助患者了解不同食物和活动对血糖的影响，从而更好地调整饮食和运动，间接改善胰岛素敏感性和脂代谢。
- 移动应用程序和健康管理平台：这些平台可以整合可穿戴设备数据、饮食记录和药物依从性信息，提供个性化的健康报告、提醒和指导。有些平台还具备在线咨询功能，方便患者与医疗团队进行沟通，获得及时反馈。
利用这些数字工具可以实现对患者代谢状态的实时代谢追踪，促进患者行为的积极改变，增强自我管理能力，从而在日常生活中持续优化血脂水平。
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参考文献
1Homozygous Familial Hypercholesterolemia.PubMed
Atsushi Nohara, Hayato Tada, Masatsune Ogura, et al.
J Atheroscler Thromb. 2021 Jul 1;28(7):665-678. doi: 10.5551/jat.RV17050. Epub 2021 Apr 18.
Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis.Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases.This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.
2Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.PubMed
Albert Wiegman, Susanne Greber-Platzer, Shazia Ali, et al.
Circulation. 2024 Jan 30;149(5):343-353. doi: 10.1161/CIRCULATIONAHA.123.065529. Epub 2023 Oct 20.
BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. METHODS: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. RESULTS: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. CONCLUSIONS: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.
3Advancements in the Treatment of Homozygous Familial Hypercholesterolemia.PubMed
Archna Bajaj, Marina Cuchel
J Atheroscler Thromb. 2022 Aug 1;29(8):1125-1135. doi: 10.5551/jat.RV17065. Epub 2022 Apr 24.
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often ＞400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.
4Genetic and microbiome influence on lipid metabolism and dyslipidemia.PubMed
Maria Luisa Matey-Hernandez, Frances M K Williams, Tilly Potter, et al.
Physiol Genomics. 2018 Feb 1;50(2):117-126. doi: 10.1152/physiolgenomics.00053.2017. Epub 2017 Dec 20.
Disruption in the metabolism of lipids is broadly classified under dyslipidemia and relates to the concentration of lipids in the blood. Dyslipidemia is a predictor of cardio-metabolic disease including obesity. Traditionally, the large interindividual variation has been related to genetic factors and diet. Genome-wide association studies have identified over 150 loci related to abnormal lipid levels, explaining ~40% of the total variation. Part of the unexplained variance has been attributed to environmental factors including diet, but the extent of the dietary contribution remains unquantified. Furthermore, other factors are likely to influence lipid metabolism including the gut microbiome, which plays an important role in the digestion of different dietary components including fats and polysaccharides. Here we describe the contributing role of host genetics and the gut microbiome to dyslipidemia and discuss the potential therapeutic implications of advances in understanding the gut microbiome to the treatment of dyslipidemia.
5Insights from population-based analyses of plasma lipids across the allele frequency spectrum.PubMed
Gina M Peloso, Pradeep Natarajan
Curr Opin Genet Dev. 2018 Jun;50:1-6. doi: 10.1016/j.gde.2018.01.003. Epub 2018 Feb 13.
Plasma lipid levels are heritable quantitative risk factors and therapeutic targets for cardiovascular disease. Plasma lipids have been a model for translating genetic observations across the allele frequency spectrum to unique biological and therapeutic insights. Most large studies to date predominately comprised of individuals of European ancestry. This review focuses on contemporary evidence from 2016 to 2017 looking at the effect of genetic variants on plasma lipid levels across the allele frequency spectrum with incrementally larger sample sizes and the contribution of non-European ancestry studies to the genetic etiology of plasma lipid levels. To date, over 250 loci have been associated with plasma lipid levels and several of these loci have additional evidence of association with rare coding variants providing evidence for causal genes at the locus.
6Genetics of lipid disorders.PubMed
James Pirruccello, Sekar Kathiresan
Curr Opin Cardiol. 2010 May;25(3):238-42. doi: 10.1097/HCO.0b013e328338574d.
PURPOSE OF REVIEW: In this review, we will highlight recent advances in identifying genes and gene regions responsible for the variation in serum lipid levels. We will also consider the next directions for research based on these advances. RECENT FINDINGS: Large-scale genome-wide association studies have successfully screened common variants across the genome for association with serum lipids and have generated novel hypotheses about the causes of serum lipid variation. SUMMARY: Deep sequencing of genome-wide association signals promises to expand the catalogue of variants responsible for serum lipid variation and, with a full catalogue of variants, we may develop a panel of polymorphisms with clinical utility. In parallel, functional exploration of the genome-wide association signals should expand our knowledge of lipoprotein metabolism and generate targets for pharmacologic intervention.
7Polygenic determinants of severe hypertriglyceridemia.PubMed
Jian Wang, Matthew R Ban, Guang Yong Zou, et al.
Hum Mol Genet. 2008 Sep 15;17(18):2894-9. doi: 10.1093/hmg/ddn188. Epub 2008 Jul 1.
Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects.
8Insights Into Causal Effects of Genetically Proxied Lipids and Lipid-Modifying Drug Targets on Cardiometabolic Diseases.PubMed
Liwan Fu, Qin Liu, Hong Cheng, et al.
J Am Heart Assoc. 2025 Feb 4;14(3):e038857. doi: 10.1161/JAHA.124.038857. Epub 2025 Jan 27.
BACKGROUND: The differential impact of serum lipids and their targets for lipid modification on cardiometabolic disease risk is debated. This study used Mendelian randomization to investigate the causal relationships and underlying mechanisms. METHODS: Genetic variants related to lipid profiles and targets for lipid modification were sourced from the Global Lipids Genetics Consortium. Summary data for 10 cardiometabolic diseases were compiled from both discovery and replication data sets. Expression quantitative trait loci data from relevant tissues were employed to evaluate significant lipid-modifying drug targets. Comprehensive analyses including colocalization, mediation, and bioinformatics were conducted to validate the results and investigate potential mediators and mechanisms. RESULTS: Significant causal associations were identified between lipids, lipid-modifying drug targets, and various cardiometabolic diseases. Notably, genetic enhancement of LPL (lipoprotein lipase) was linked to reduced risks of myocardial infarction (odds ratio [OR], 0.65 [95% CI, 0.57-0.75], =2.60×10; OR, 0.59 [95% CI, 0.49-0.72], =1.52×10), ischemic heart disease (OR, 0.968 [95% CI, 0.962-0.975], =5.50×10; OR, 0.64 [95% CI, 0.55-0.73], =1.72×10), and coronary heart disease (OR, 0.980 [95% CI, 0.975-0.985], =3.63×10; OR, 0.64 [95% CI, 0.54-0.75], =6.62×10) across 2 data sets. Moreover, significant Mendelian randomization and strong colocalization associations for the expression of LPL in blood and subcutaneous adipose tissue were linked with myocardial infarction (OR, 0.918 [95% CI, 0.872-0.967], =1.24×10; PP.H4, 0.99) and coronary heart disease (OR, 0.991 [95% CI, 0.983-0.999], =0.041; PP.H4=0.92). Glucose levels and blood pressure were identified as mediators in the total effect of LPL on cardiometabolic outcomes. CONCLUSIONS: The study substantiates the causal role of lipids in specific cardiometabolic diseases, highlighting LPL as a potent drug target. The effects of LPL are suggested to be influenced by changes in glucose and blood pressure, providing insights into its mechanism of action.
9Polygenic Hyperlipidemias and Coronary Artery Disease Risk.PubMed
Pietari Ripatti, Joel T Rämö, Nina J Mars, et al.
Circ Genom Precis Med. 2020 Apr;13(2):e002725. doi: 10.1161/CIRCGEN.119.002725. Epub 2020 Mar 10.
BACKGROUND: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. METHODS: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). RESULTS: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS). CONCLUSIONS: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.
10Role of Insulin Resistance in MAFLD.PubMed
Yoshitaka Sakurai, Naoto Kubota, Toshimasa Yamauchi, et al.
Int J Mol Sci. 2021 Apr 16;22(8):4156. doi: 10.3390/ijms22084156.
Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.
11Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease.PubMed
Tao Bo, Ling Gao, Zhenyu Yao, et al.
Cell Metab. 2024 May 7;36(5):947-968. doi: 10.1016/j.cmet.2024.04.006.
Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.
12Insulin Resistance, Obesity and Lipotoxicity.PubMed
Dilek Yazıcı, Havva Sezer
Adv Exp Med Biol. 2017;960:277-304. doi: 10.1007/978-3-319-48382-5_12.
Lipotoxicity , originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. Lipotoxicity has roles in insulin resistance and pancreatic beta cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling, have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.
13Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance.PubMed
Iwona Kojta, Marta Chacińska, Agnieszka Błachnio-Zabielska
Nutrients. 2020 May 3;12(5):1305. doi: 10.3390/nu12051305.
Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. The exact mechanism by which adipose tissue induces insulin resistance is still unclear. It has been demonstrated that obesity is associated with the adipocyte dysfunction, macrophage infiltration, and low-grade inflammation, which probably contributes to the induction of insulin resistance. Adipose tissue synthesizes and secretes numerous bioactive molecules, namely adipokines and cytokines, which affect the metabolism of both lipids and glucose. Disorders in the synthesis of adipokines and cytokines that occur in obesity lead to changes in lipid and carbohydrates metabolism and, as a consequence, may lead to insulin resistance and type 2 diabetes. Obesity is also associated with the accumulation of lipids. A special group of lipids that are able to regulate the activity of intracellular enzymes are biologically active lipids: long-chain acyl-CoAs, ceramides, and diacylglycerols. According to the latest data, the accumulation of these lipids in adipocytes is probably related to the development of insulin resistance. Recent studies indicate that the accumulation of biologically active lipids in adipose tissue may regulate the synthesis/secretion of adipokines and proinflammatory cytokines. Although studies have revealed that inflammation caused by excessive fat accumulation and abnormalities in lipid metabolism can contribute to the development of obesity-related insulin resistance, further research is needed to determine the exact mechanism by which obesity-related insulin resistance is induced.
14Soluble insulin receptor and metabolic syndrome.PubMed
Marcia Hiriart-Urdanivia, Carmen Sánchez-Soto, Myrian Velasco, et al.
Gac Med Mex. 2019;155(5):500-503. doi: 10.24875/GMM.M20000339.
The metabolic syndrome describes a group of signs that increase the likelihood for developing type 2 diabetes mellitus, cardiovascular diseases and some types of cancer. The action of insulin depends on its binding to membrane receptors on its target cells. We wonder if blood insulin could travel bound to proteins and if, in the presence of hyperinsulinemia, a soluble insulin receptor might be generated. We used young adult Wistar rats (which have no predisposition to obesity or diabetes), whose drinking water was added 20 % of sugar and that were fed a standard diet ad libitum for two and six months. They were compared with control rats under the same conditions, but that had running water for consumption. At two months, the rats developed central obesity, moderate hypertension, high triglyceride levels, hyperinsulinemia, glucose intolerance and insulin resistance, i.e., metabolic syndrome. Electrophoresis of the rats' plasma proteins was performed, followed by Western Blot (WB) for insulin and for the outer portion of the insulin receptor. The bands corresponding to insulin and to the receptor external part were at the same molecular weight level, 25-fold higher than that of free insulin. We demonstrated that insulin, both in control animals and in those with hyperinsulinemia, travels bound to the receptor outer portion (ectodomain), which we called soluble insulin receptor, and that is released al higher amounts in response to plasma insulin increase; in rats with metabolic syndrome and hyperinsulinemia, plasma levels are much higher than in controls. Soluble insulin receptor increase in blood might be an early sign of metabolic syndrome.
15Metabolic Syndromes in Overweight/Obese School-Age Children.PubMed
Lia Otiashvili
Glob Pediatr Health. 2022 Sep 8;9:2333794X221122716. doi: 10.1177/2333794X221122716. eCollection 2022.
The research aimed at studying the phenomenological structure of metabolic syndromes in overweight and obese school-age children. The cohort of 210 students participated in the cross-sectional study. Among them 84 children (40%) were overweight/obese and 126 students (60%)-with normal weight. The incidence of abdominal obesity and arterial hypertension were studied and lipid profile was assessed in obese children. The results of research revealed the early manifestation of abdominal obesity (14.3%-16.7%), arterial hypertension (the elevation of systolic pressure-27.4%, the increase in diastolic pressure-10.7%) and hypercholesterolemia (9.5%) in the population of overweight/obese school age children, which allows to take prompt corrective actions on metabolic syndrome and reduce the risk of its formation.
16Blepharitis as an early sign of metabolic syndrome: a nationwide population-based study.PubMed
Chia-Yi Lee, Hung-Chi Chen, Hui-Wen Lin, et al.
Br J Ophthalmol. 2018 Sep;102(9):1283-1287. doi: 10.1136/bjophthalmol-2017-310975. Epub 2017 Nov 16.
BACKGROUND: To investigate the relationship between blepharitis and metabolic syndrome (MetS) by using the Longitudinal Health Insurance Database (LHID) of Taiwan. METHODS: This retrospective cohort study was conducted using data collected from the LHID for the period from 2009 to 2013. This study enrolled patients who received a diagnosis of blepharitis according to the International Classification of Diseases, Ninth Revision, diagnostic code. The exclusion criteria were legal blindness, eyeball removal, ocular tumours prior to the diagnosis of blepharitis, and patients diagnosed with blepharitis and initiated antibiotic treatment concurrently. An age-matched, gender-matched and disease-matched population without blepharitis served as the control group. Multivariate analysis with a multiple Cox regression model was applied to analyse the data. RESULTS: In this study, a total of 10 093 patients with blepharitis were included in the study group, and another 40 372 participants without blepharitis were included in the control group. Conditional logistic regression revealed a higher cumulative probability of hyperlipidaemia and coronary arterial disease. After adjustment, patients with blepharitis had a higher probability of developing new MetS than controls. According to subgroup analysis, hyperlipidaemia and coronary artery diseases were significantly correlated with the prior development of blepharitis. However, hypertension and diabetes mellitus and insulin resistance showed no correlation with blepharitis. CONCLUSION: Blepharitis is significantly related to MetS and can serve as an early sign of MetS. Additional studies should examine the relationship between blepharitis and MetS in terms of severity.
17Dietary carbohydrates and fats in nonalcoholic fatty liver disease.PubMed
Hannele Yki-Järvinen, Panu K Luukkonen, Leanne Hodson, et al.
Nat Rev Gastroenterol Hepatol. 2021 Nov;18(11):770-786. doi: 10.1038/s41575-021-00472-y. Epub 2021 Jul 13.
The global prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased in parallel with the epidemic of obesity. Controversy has emerged around dietary guidelines recommending low-fat-high-carbohydrate diets and the roles of dietary macronutrients in the pathogenesis of metabolic disease. In this Review, the topical questions of whether and how dietary fats and carbohydrates, including free sugars, differentially influence the accumulation of liver fat (specifically, intrahepatic triglyceride (IHTG) content) are addressed. Focusing on evidence from humans, we examine data from stable isotope studies elucidating how macronutrients regulate IHTG synthesis and disposal, alter pools of bioactive lipids and influence insulin sensitivity. In addition, we review cross-sectional studies on dietary habits of patients with NAFLD and randomized controlled trials on the effects of altering dietary macronutrients on IHTG. Perhaps surprisingly, evidence to date shows no differential effects between free sugars, with both glucose and fructose increasing IHTG in the context of excess energy. Moreover, saturated fat raises IHTG more than polyunsaturated or monounsaturated fats, with adverse effects on insulin sensitivity, which are probably mediated in part by increased ceramide synthesis. Taken together, the data support the use of diets that have a reduced content of free sugars, refined carbohydrates and saturated fat in the treatment of NAFLD.
18The Effect of Dietary Fibre on Gut Microbiota, Lipid Profile, and Inflammatory Markers in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.PubMed
Omorogieva Ojo, Osarhumwese Osaretin Ojo, Nazanin Zand, et al.
Nutrients. 2021 May 26;13(6):1805. doi: 10.3390/nu13061805.
BACKGROUND: A disequilibrium of the gut microbial community has been closely associated with systemic inflammation and metabolic syndromes including type 2 diabetes. While low fibre and high fat diets may lead to dysbiosis of the gut microbiome as a result of the loss of useful microbes, it has been reported that a high fibre diet may prevent the fermentation of protein and may promote eubiosis of gut microbiota. AIM: This review aims to evaluate the effect of dietary fibre (DF) on gut microbiota, lipid profile, and inflammatory markers in patients with type 2 diabetes. METHODS: The PRISMA framework was relied on to conduct this systematic review and meta-analysis. Searches were carried out using electronic databases and reference list of articles. RESULTS: Eleven studies were included in the systematic review, while ten studies were included in the meta-analysis. The findings revealed five distinct areas including the effects of DF on (a) gut microbiota (122 participants); (b) lipopolysaccharides (LPS, 79 participants) and lipopolysaccharides binding protein (LBP, 81 participants); (c) lipid profile; (d) inflammatory markers; and (e) body mass index (BMI, 319 participants). The relative abundance of increased by 0.73 (95% CI: 0.57, 0.89) in the DF group in contrast to the control ( < 0.05). With respect to LPS, the level was lower in the DF group than the control and the difference was significant ( < 0.05). The standardised mean difference for LPS was -0.45 (95% CI: -0.90, -0.01) although the difference between the two groups in relation to LBP was not significant ( = 0.08) and the mean difference was 0.92 (95% CI: -0.12, 1.95). While there was a decrease of -1.05 (95% CI: -2.07, -0.02) with respect to total cholesterol (356 participants) in the DF group as compared with the control ( < 0.05), both groups were not significantly different ( > 0.05) in the other lipid parameters. The difference between the groups was significant ( < 0.05) in relation to C-reactive protein, and the mean difference was 0.43 (95% CI: 0.02, 0.84). This could be due to the short duration of the included studies and differences in participants' diets including the amount of dietary fibre supplements. However, the groups were not significantly different ( > 0.05) with respect to the other inflammatory markers. The meta-analysis of the BMI showed that the DF group decreased by -0.57 (95% CI: -1.02, -0.12) as compared with the control and this was significant ( < 0.01). CONCLUSION: DF significantly ( < 0.05) increased the relative abundance of and significantly decreased ( < 0.05) LPS, total cholesterol, and BMI as compared with the control. However, DF did not seem to have an effect that was significant on LBP, triglyceride, HDL cholesterol, LDL cholesterol, IL-6, TNF-α, adiponectin, and leptin. These findings have implications for public health in relation to the use of dietary fibre in nutritional interventions and as strategies for managing type 2 diabetes.
19Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus.PubMed
M Chandalia, A Garg, D Lutjohann, et al.
N Engl J Med. 2000 May 11;342(19):1392-8. doi: 10.1056/NEJM200005113421903.
BACKGROUND: The effect of increasing the intake of dietary fiber on glycemic control in patients with type 2 diabetes mellitus is controversial. METHODS: In a randomized, crossover study, we assigned 13 patients with type 2 diabetes mellitus to follow two diets, each for six weeks: a diet containing moderate amounts of fiber (total, 24 g; 8 g of soluble fiber and 16 g of insoluble fiber), as recommended by the American Diabetes Association (ADA), and a high-fiber diet (total, 50 g; 25 g of soluble fiber and 25 g of insoluble fiber), containing foods not fortified with fiber (unfortified foods). Both diets, prepared in a research kitchen, had the same macronutrient and energy content. We compared the effects of the two diets on glycemic control and plasma lipid concentrations. RESULTS: Compliance with the diets was excellent. During the sixth week, the high-fiber diet, as compared with the the sixth week of the ADA diet, mean daily preprandial plasma glucose concentrations were 13 mg per deciliter [0.7 mmol per liter] lower (95 percent confidence interval, 1 to 24 mg per deciliter [0.1 to 1.3 mmol per liter]; P=0.04) and mean median difference, daily urinary glucose excretion 1.3 g (0.23; 95 percent confidence interval, 0.03 to 1.83 g; P= 0.008). The high-fiber diet also lowered the area under the curve for 24-hour plasma glucose and insulin concentrations, which were measured every two hours, by 10 percent (P=0.02) and 12 percent (P=0.05), respectively. The high-fiber diet reduced plasma total cholesterol concentrations by 6.7 percent (P=0.02), triglyceride concentrations by 10.2 percent (P=0.02), and very-low-density lipoprotein cholesterol concentrations by 12.5 percent (P=0.01). CONCLUSIONS: A high intake of dietary fiber, particularly of the soluble type, above the level recommended by the ADA, improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 2 diabetes.
20The Prebiotic Effects of Oats on Blood Lipids, Gut Microbiota, and Short-Chain Fatty Acids in Mildly Hypercholesterolemic Subjects Compared With Rice: A Randomized, Controlled Trial.PubMed
Dengfeng Xu, Meiyuan Feng, YiFang Chu, et al.
Front Immunol. 2021 Dec 9;12:787797. doi: 10.3389/fimmu.2021.787797. eCollection 2021.
Phytochemicals derived from oats are reported to possess a beneficial effect on modulating dyslipidemia, specifically on lowering total and LDL cholesterol. However, deeper insights into its mechanism remain unclear. In this randomized controlled study, we assigned 210 mildly hypercholesterolemic subjects from three study centers across China (Beijing, Nanjing, and Shanghai) to consume 80 g of oats or rice daily for 45 days. Plasma lipid profiles, short chain fatty acids (SCFAs), and fecal microbiota were measured. The results showed that total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C) decreased significantly with both oats and rice intake after 30 and 45 days. The reduction in TC and non-HDL-C was greater in the participants consuming oats compared with rice at day 45 ( = 0.011 and 0.049, respectively). Oat consumption significantly increased the abundance of and , and the relative abundance of , , and , and decreased unclassified In the oat group, abundance was negatively correlated with LDL-C ( = 0.01, = -0.31) and, TC and LDL-C were negatively correlated to ( = 0.02, = -0.29; = 0.03, = -0.27, respectively). , , and were positively correlated with plasma butyric acid and valeric acid concentrations and negatively correlated to isobutyric acid. HDL-C was negatively correlated with valeric acid ( = 0.02, = -0.25) and total triglyceride (TG) was positively correlated to isovaleric acid ( = 0.03, = 0.23). Taken together, oats consumption significantly reduced TC and LDL-C, and also mediated a prebiotic effect on gut microbiome. , , , and , and plasma SCFA correlated with oat-induced changes in plasma lipids, suggesting prebiotic activity of oats to modulate gut microbiome could contribute towards its cholesterol-lowering effect.
21Natural Products from Mediterranean Diet: From Anti-hyperlipidemic Agents to Dietary Epigenetic Modulators.PubMed
Deligiannidou Georgia-Eirini, Sygkouna Athina, Vanden Berghe Wim, et al.
Curr Pharm Biotechnol. 2019;20(10):825-844. doi: 10.2174/1573407215666190628150921.
BACKGROUND: Cardiovascular Diseases (CVD) are, currently, the major contributor to global mortality and will continue to dominate mortality rates in the future. Hyperlipidemia refers to the elevated levels of lipids and cholesterol in the blood, and is also identified as dyslipidemia, manifesting in the form of different disorders of lipoprotein metabolism. These abnormalities may lead to the development of atherosclerosis, which can lead to coronary artery disease and stroke. In recent years, there is a growing interest in the quest for alternative therapeutic treatments based on natural products, offering better recovery and the avoidance of side effects. Recent technological advances have further improved our understanding of the role of epigenetic mechanisms in hyperlipidemic disorders and dietary prevention strategies. OBJECTIVE: This is a comprehensive overview of the anti-hyperlipidemic effects of plant extracts, vegetables, fruits and isolated compounds thereof, with a focus on natural products from the Mediterranean region as well as the possible epigenetic changes in gene expression or cardiometabolic signaling pathways. METHODS: For the purpose of this study, we searched the PubMed, Scopus and Google Scholar databases for eligible articles and publications over the last five years. The keywords included: "hyperlipidemia", "plant extract", "herbs", "natural products", "vegetables", "cholesterol" and others. We initially included all relevant articles referring to in vitro studies, animal studies, Randomized Controlled Trials (RCTs) and previous reviews. CONCLUSION: Many natural products found in the Mediterranean diet have been studied for the treatment of hyperlipidemia. The antihyperlipidemic effect seems to be dose and/or consumption frequency related, which highlights the fact that a healthy diet can only be effective in reversing disease markers if it is consistent and within the framework of a healthy lifestyle. Finally, epigenetic biomarkers are increasingly recognized as new lifestyle management tools to monitor a healthy dietary lifestyle for the prevention of hyperlipidaemic disorders and comorbidities to promote a healthy life.
22Mediterranean Diet and Cardiovascular Risk: Beyond Traditional Risk Factors.PubMed
Javier Delgado-Lista, Pablo Perez-Martinez, Antonio Garcia-Rios, et al.
Crit Rev Food Sci Nutr. 2016;56(5):788-801. doi: 10.1080/10408398.2012.726660.
A strict adherence to the Mediterranean Diet (MedDiet) has repeatedly been linked to a low risk of cardiovascular disease in several situations. Initially, the mechanisms considered as possible causes of this were based on the effects of this dietary pattern on the so-called traditional risk factors (especially lipids and blood pressure). However, the high relative reduction in the prevalence of cardiovascular morbidity and mortality were not proportional to the limited findings about regulation of those traditional risk factors. In addition to several studies confirming the above effects, current research on the MedDiet is being focused on defining its effects on non-traditional risk factors, such as endothelial function, inflammation, oxidative stress, or on controlling the conditions which predispose people to cardiovascular events, such as obesity, metabolic syndrome or type 2 diabetes mellitus. In the current article, after briefly reviewing the known effects of the MedDiet on the traditional risk factors, we will mainly focus on reviewing the current evidence about the effects that this dietary pattern exerts on alternative factors, including postprandial lipemia or coagulation, among others, as well as providing a short review on future directions.
23Ketogenic diets, not for everyone.PubMed
Ira J Goldberg, Nouran Ibrahim, Cindy Bredefeld, et al.
J Clin Lipidol. 2021 Jan-Feb;15(1):61-67. doi: 10.1016/j.jacl.2020.10.005. Epub 2020 Oct 31.
BACKGROUND: The adoption of low-carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. OBJECTIVE: The objective of this study is to display the potentially harmful effects of the ketogenic diet on cholesterol levels in patients with or without underlying hyperlipidemia. METHODS: We describe 5 patients who developed marked increases in plasma cholesterol on ketogenic diets and assessed whether they had a well-described underlying genetic hyperlipidemia. RESULTS: Three out of 5 patients had extraordinary increases of blood cholesterol levels to over 500 mg/dL. The other 2 patients more than doubled their low-density lipoprotein cholesterol levels on a ketogenic diet. One patient had an APOE E2/E2 genotype. A higher burden of common genetic polymorphisms was found in 2 patients, with no major mutations found. No potential genetic cause was seen in a fourth patient, and the fifth patient had no genetic testing. Three patients, including the one who was most hypercholesterolemic, had a marked reduction in cholesterol after reverting to a more liberal diet. One refused to change his diet but had a satisfactory low-density lipoprotein cholesterol reduction on ezetimibe. CONCLUSION: These cases should serve as a caution that high-fat low-carbohydrate diets have the potential to exacerbate or cause hypercholesterolemia in patients with or without underlying genetic hyperlipidemia.
24Ketogenic diet in epileptic children: impact on lipoproteins and oxidative stress.PubMed
Patricia Azevedo Lima, Leticia Pereira de Brito Sampaio, Nágila Raquel Teixeira Damasceno
Nutr Neurosci. 2015;18(8):337-44. doi: 10.1179/1476830515Y.0000000036. Epub 2015 Jul 15.
OBJECTIVES: Ketogenic diet (KD) is an important therapy used in the control of drug-refractory seizures. The major goal of this review is to update the knowledge about the adverse effects of KD on lipoproteins, lipid profile, and cardiometabolic risk. METHODS: Articles on the effect of the KD on plasma lipoproteins of children and adolescents with refractory epilepsy, which were published in the past 15 years and indexed in the PubMed and MedLine databases, were included. RESULTS: Dyslipidemia was recurrent in children, and adolescents treated with KD. Evidence suggests that hypercholesterolemia promotes structural modifications in low-density lipoprotein particles. Such modifications possibly favor oxidative processes and contribute to changes in the size of lipoproteins, particularly related to small and denser LDL. However, oxidative modifications in LDL of children on KD are not described in the literature. DISCUSSION: The positive effects of KD on the health of children and adolescents with refractory epilepsy are unquestionable. Conversely, this positive role is associated with significant and negative changes in lipid metabolism. Moreover, the positive effects are possibly related to oxidative reactions and unbalance of antioxidants that can contribute to an increased cardiometabolic risk. Therefore, this review invites clinicians and researchers to investigate the lipid and oxidative metabolism in their clinical practice and trials, respectively.
25Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.PubMed
Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, et al.
J Clin Invest. 2024 Apr 23;134(11):e167371. doi: 10.1172/JCI167371.
Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation. Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here, we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC), that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in the absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux toward lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.
26High-intensity interval training induces lactylation of fatty acid synthase to inhibit lipid synthesis.PubMed
Xuefei Chen, Wenhua Huang, Jingbo Zhang, et al.
BMC Biol. 2023 Sep 19;21(1):196. doi: 10.1186/s12915-023-01698-9.
BACKGROUND: The aim of study was to observe the effect of increased lactate levels during high-intensity interval training (HIIT) on protein lactylation, identify the target protein, and investigate the regulatory effect of lactylation on the function of the protein. METHODS: C57B/L6 mice were divided into 3 groups: the control group, HIIT group, and dichloroacetate injection + HIIT group (DCA + HIIT). The HIIT and DCA + HIIT groups underwent 8 weeks of HIIT treatment, and the DCA + HIIT group was injected DCA before HIIT treatment. The expression of lipid metabolism-related genes was determined. Protein lactylation in subcutaneous adipose tissue was identified and analyzed using 4D label-free lactylation quantitative proteomics and bioinformatics analyses. The fatty acid synthase (FASN) lactylation and activity was determined. RESULTS: HIIT had a significant effect on fat loss; this effect was weakened when lactate production was inhibited. HIIT significantly upregulated the protein lactylation while lactate inhibition downregulated in iWAT. FASN had the most modification sites. Lactate treatment increased FASN lactylation levels, inhibited FASN activity, and reduced palmitate and triglyceride synthesis in 3T3-L1 cells. CONCLUSIONS: This investigation revealed that lactate produced by HIIT increased protein pan-lactylation levels in iWAT. FASN lactylation inhibited de novo lipogenesis, which may be an important mechanism in HIIT-induced fat loss.
27Effects of morning rise in cortisol concentration on regulation of lipolysis in subcutaneous adipose tissue.PubMed
J S Samra, M L Clark, S M Humphreys, et al.
Am J Physiol. 1996 Dec;271(6 Pt 1):E996-1002. doi: 10.1152/ajpendo.1996.271.6.E996.
Cortisol has a well-defined circadian rhythm. The aim of the study was to examine the effect of the morning rise in cortisol concentration on lipolysis in adipose tissue. Ten healthy subjects were studied on two occasions, and six of these were studied on three occasions. During the first two occasions, either a control or cortisol suppression study was performed by using metyrapone, and on the third occasion exogenous cortisol replacement was given in addition to metyrapone. Lipolysis in the subcutaneous adipose tissue of the anterior abdominal wall was studied by measurement of arteriovenous differences. Reduction in the early morning rise in cortisol led to significantly decreased venoarterialized differences for nonesterified fatty acids (P < 0.05) and glycerol (P < 0.01), attributable in part to decreased hormone-sensitive lipase (EC 3.1.1.3) action (P < 0.05) in adipose tissue. At the same time the arterialized plasma triacylglycerol concentration increased (P < 0.005) with a significant reduction in the adipose lipoprotein lipase (EC 3.1.1.34) rate of action (P < 0.05). In the replacement study, values were identical to those of the control study, showing that metyrapone had no nonspecific effects on lipolysis. We conclude that the morning rise in plasma cortisol concentration plays an important role in the regulation of lipolysis in adipose tissue in normal healthy adults.
28Hormonal and metabolic profiles in subjects with obstructive sleep apnea syndrome and the acute effects of nasal continuous positive airway pressure (CPAP) treatment.PubMed
B G Cooper, J E White, L A Ashworth, et al.
Sleep. 1995 Apr;18(3):172-9.
Nocturnal secretion of growth hormone is impaired in patients with obstructive sleep apnea (OSA), but the metabolic consequences have not been reported. We measured blood levels of the hormones insulin, C-peptide, growth hormone, cortisol and glucagon together with the intermediary metabolites of carbohydrate (glucose, pyruvate, lactate, alanine) and lipid metabolism [glycerol, nonesterified fatty acids (NEFA), 3-hydroxybutyrate] in six obese nondiabetic men with OSA on two nights. In the first study, the untreated subjects showed frequent apneas and consequent hypoxemia. The hormone and metabolite concentrations were compared with those obtained on the following night when the subjects were treated effectively with nasal continuous positive airway pressure (CPAP). There were no significant differences in the concentrations of insulin, C-peptide, cortisol or glucagon. We confirmed a marked reduction in growth hormone concentrations in OSA, with a significant increase on the CPAP night. The nocturnal profiles of glucose, pyruvate, lactate, alanine and glycerol showed no differences between the two nights, but concentrations of NEFA and 3-hydroxybutyrate, both products of lipolysis, were significantly greater on the treatment night. Because growth hormone has a lipolytic action, the results suggest that suppression of secretion of growth hormone in untreated OSA results in impaired lipolysis, which is rapidly reversed by nasal CPAP.
29An Integrative Review on Role and Mechanisms of Ghrelin in Stress, Anxiety and Depression.PubMed
Anjana Bali, Amteshwar Singh Jaggi
Curr Drug Targets. 2016;17(5):495-507. doi: 10.2174/1389450116666150518095650.
Ghrelin is orexigenic hormone primarily synthesized by endocrine X/A-like cells of gastric oxyntic mucosa to stimulate appetite and food intake along with regulation of growth hormone and insulin secretion; glucose and lipid metabolism; gastrointestinal motility; blood pressure, heart rate and neurogenesis. Furthermore, peripherally (after crossing the blood brain barrier) as well as centrally synthesized ghrelin (in the hypothalamus) regulates diverse functions of central nervous system including stress-associated behavioral functions. Exposure to stress alters the ghrelin levels and alteration in ghrelin levels significantly affects neuro-endocrinological parameters; metabolism-related physiology, behavior and mood. Studies have shown both anxiolytic and anxiogenic role of ghrelin suggesting its dual role in modulating anxiety-related behavior. However, it is proposed that increase in ghrelin levels during stress condition is an endogenous stress coping behavior and increased ghrelin levels may be required to prevent excessive anxiety. In preclinical and clinical studies, an elevation in ghrelin levels during depression has been correlated with their antidepressant activities. Ghrelin-induced modulation of stress and associated conditions has been linked to alteration in hypothalamic-pituitary-adrenal (HPA) axis; autonomic nervous system (mainly sympathetic nervous system and serotonergic neurotransmission. A reciprocal relationship has been reported between corticotropin-releasing hormone (CRH) and ghrelin as ghrelin increases the release of CRH, ACTH and corticosteroids; while CRH decreases the expression of ghrelin. Similarly, ghrelin increases the serotonin turnover and in turn, serotonin controls ghrelin signaling to modulate anxiety-related behavior. The present review discusses the dual role of ghrelin in stress and related behavioral disorders along with possible mechanisms.
30Recent Progress of Chronic Stress in the Development of Atherosclerosis.PubMed
Shang Gao, Xiang Wang, Ling-Bing Meng, et al.
Oxid Med Cell Longev. 2022 Mar 8;2022:4121173. doi: 10.1155/2022/4121173. eCollection 2022.
With the development of the times, cardiovascular diseases have become the biggest cause of death in the global aging society, causing a serious social burden. Atherosclerosis is a chronic inflammatory disease, which can occur in large and medium-sized blood vessels in the whole body. It takes atherosclerotic plaque as the typical pathological change and endothelial injury as the core pathophysiological mechanism. It is the pathological basis of coronary heart disease, peripheral artery disease, cerebrovascular disease, and other diseases. Recent studies have shown that chronic stress plays an important role in the occurrence and development of atherosclerosis, endothelial injury, lipid metabolism, and chronic inflammation. This process involves a large number of molecular targets. It is usually the cause of atherosclerotic cardiovascular and cerebrovascular diseases. If chronic stress factors exist for a long time, patients have genetic susceptibility, and the combination of environmental factors triggers the pathogenesis, which may eventually lead to complete blockage of the blood vessels, unstable rupture of plaques, and serious adverse cardiovascular events. This paper reviews the role of chronic stress in the occurrence and development of atherosclerosis, focusing on the pathophysiological mechanism.
31White adipose tissue: storage and effector site for environmental pollutants.PubMed
D Müllerová, J Kopecký
Physiol Res. 2007;56(4):375-382. doi: 10.33549/physiolres.931022. Epub 2006 Aug 22.
White adipose tissue (WAT) represents a reservoir of lipophilic environmental pollutants, especially of those which are resistant to biological and chemical degradation - so-called persistent organic pollutants (POPs). Large amounts of different congeners and isomers of these compounds exhibit a variety of adverse biological effects. Interactions among different classes of compounds, frequently with opposing effects, complicate hazard evaluation and risk assessment. WAT is the key organ for energy homeostasis and it also releases metabolites into the circulation and adipokines with systemic effects on insulin sensitivity and fuel partitioning in muscles and other tissues. Its beneficial role is lost in obesity when excessive accumulation of WAT contributes to severe diseases, such as diabetes. POPs may crossroad or modulate the effect of endogenous ligands of nuclear transcription factors, participating in differentiation, metabolism and the secretory function of adipocytes. These mechanisms include, most importantly: i) endocrine disrupting potency of POPs mixtures on androgen, estrogen or thyroid hormone metabolism/functions in WAT, ii) interference of dioxin-like chemicals with retinoic acid homeostasis, where impact on retinoid receptors is expected, and iii) interaction with transcriptional activity of peroxisome proliferator-activated receptors is likely. Thus, the accumulation and action of POPs in WAT represents a unitary mechanism explaining, at least in part, the effects of POPs in the whole organism. By modulating WAT differentiation, metabolism and function, the POPs could affect not only the physiological role of WAT, but they may also influence the development of obesity-associated diseases.
32Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERalpha) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice.PubMed
Junga Lee, Richard C Scheri, Yuan Zhang, et al.
Toxicol Appl Pharmacol. 2008 Dec 1;233(2):193-202. doi: 10.1016/j.taap.2008.08.011. Epub 2008 Aug 26.
Chlordecone (CD) is one of many banned organochlorine (OC) insecticides that are widespread persistent organic pollutants. OC insecticides alter lipid homeostasis in rodents at doses that are not neurotoxic or carcinogenic. Pretreatment of mice or rats with CD altered tissue distribution of a subsequent dose of [(14)C]CD or [(14)C]cholesterol (CH). Nuclear receptors regulate expression of genes important in the homeostasis of CH and other lipids. In this study, we report that CD suppresses in vitro reporter systems for human liver X receptors (LXRs) and activates those for human farnesoid X receptor (FXR), pregnane X receptor (PXR) and estrogen receptor alpha (ERalpha) in a concentration-dependent manner (0-50 muM). Consistent with human PXR activation in vitro, three days after a single dose of CD (15 mg/kg) hepatic microsomal CYP3A11 protein increases in C57BL/6 mice. CD decreases hepatic CH ester content without altering total CH concentration. Apolipoprotein A-I (apoA-I) contents of hepatic lipoprotein-rich and microsomal fractions of CD-treated mice are higher than controls. There is a significant reduction in non-high density lipoprotein CH but not apolipoprotein B-48/100 (apoB-48/100) in plasma from CD-treated mice after a 4 h fast. At 14 days after 15 mg CD/kg apoA-I and apoB-100 proteins but not CYP3A11 protein in hepatic microsomes are similar to controls. This work indicates that altered CH homeostasis is a mode of OC insecticide action of relevance after a single dose. This at least partially explains altered CH tissue distribution in CD-pretreated mice.
33Social Bonds Retain Oxytocin-Mediated Brain-Liver Axis to Retard Atherosclerosis.PubMed
Seien Ko, Atsushi Anzai, Xueyuan Liu, et al.
Circ Res. 2025 Jan 3;136(1):78-90. doi: 10.1161/CIRCRESAHA.124.324638. Epub 2024 Nov 27.
BACKGROUNDS: Social interaction with others is essential to life. Although social isolation and loneliness have been implicated as increased risks of cardiometabolic and cardiovascular diseases and all-cause mortality, the cellular and molecular mechanisms by which social connection maintains cardiometabolic and cardiovascular health remain largely unresolved. METHODS: To investigate how social connection protects against cardiometabolic and cardiovascular diseases, atherosclerosis-prone, high-fat diet-fed mouse siblings were randomly assigned to either individual or grouped housing for 12 weeks. Histological, flow cytometric, biochemical, gene, and protein analyses were performed to assess atherosclerotic lesions, systemic metabolism, inflammation, and stress response. The effects of oxytocin on hepatocytes and subsequent cardiometabolic and cardiovascular function were investigated by in vivo and in vitro approaches. RESULTS: mice housed individually developed larger vulnerable atherosclerotic lesions by disrupted lipid metabolism compared with those of mice in regular group housing, irrespective of body weight, eating behavior, feeding conditions, sympathetic nervous activity, glucocorticoid response, or systemic inflammation. Mechanistically, the chronic isolation reduced the hypothalamic production of oxytocin, which controls bile acid production and LPL (lipoprotein lipase) activity through the peripheral OXTR (oxytocin receptor) in hepatocytes, whose downstream targets include , , and . While hepatocyte-specific OXTR-null mice and mice receiving adeno-associated virus targeting OXTR on hepatocytes led to severe dyslipidemia and aggravated atherosclerosis, oral oxytocin supplementation to socially isolated mice, but not to hepatocyte-specific OXTR conditional knockout mice, improved lipid profiles and retarded atherosclerosis development. CONCLUSIONS: These results identify a novel brain-liver axis that links sociality to hepatic lipid metabolism, thus proposing a potential therapeutic strategy for loneliness-associated atherosclerosis progression.
34Childhood Cardiovascular Risk Factors and Adult Cardiovascular Events.PubMed
David R Jacobs, Jessica G Woo, Alan R Sinaiko, et al.
N Engl J Med. 2022 May 19;386(20):1877-1888. doi: 10.1056/NEJMoa2109191. Epub 2022 Apr 4.
BACKGROUND: Childhood cardiovascular risk factors predict subclinical adult cardiovascular disease, but links to clinical events are unclear. METHODS: In a prospective cohort study involving participants in the International Childhood Cardiovascular Cohort (i3C) Consortium, we evaluated whether childhood risk factors (at the ages of 3 to 19 years) were associated with cardiovascular events in adulthood after a mean follow-up of 35 years. Body-mass index, systolic blood pressure, total cholesterol level, triglyceride level, and youth smoking were analyzed with the use of i3C-derived age- and sex-specific z scores and with a combined-risk z score that was calculated as the unweighted mean of the five risk z scores. An algebraically comparable adult combined-risk z score (before any cardiovascular event) was analyzed jointly with the childhood risk factors. Study outcomes were fatal cardiovascular events and fatal or nonfatal cardiovascular events, and analyses were performed after multiple imputation with the use of proportional-hazards regression. RESULTS: In the analysis of 319 fatal cardiovascular events that occurred among 38,589 participants (49.7% male and 15.0% Black; mean [±SD] age at childhood visits, 11.8±3.1 years), the hazard ratios for a fatal cardiovascular event in adulthood ranged from 1.30 (95% confidence interval [CI], 1.14 to 1.47) per unit increase in the z score for total cholesterol level to 1.61 (95% CI, 1.21 to 2.13) for youth smoking (yes vs. no). The hazard ratio for a fatal cardiovascular event with respect to the combined-risk z score was 2.71 (95% CI, 2.23 to 3.29) per unit increase. The hazard ratios and their 95% confidence intervals in the analyses of fatal cardiovascular events were similar to those in the analyses of 779 fatal or nonfatal cardiovascular events that occurred among 20,656 participants who could be evaluated for this outcome. In the analysis of 115 fatal cardiovascular events that occurred in a subgroup of 13,401 participants (31.0±5.6 years of age at the adult measurement) who had data on adult risk factors, the adjusted hazard ratio with respect to the childhood combined-risk z score was 3.54 (95% CI, 2.57 to 4.87) per unit increase, and the mutually adjusted hazard ratio with respect to the change in the combined-risk z score from childhood to adulthood was 2.88 (95% CI, 2.06 to 4.05) per unit increase. The results were similar in the analysis of 524 fatal or nonfatal cardiovascular events. CONCLUSIONS: In this prospective cohort study, childhood risk factors and the change in the combined-risk z score between childhood and adulthood were associated with cardiovascular events in midlife. (Funded by the National Institutes of Health.).
35Subclinical coronary atherosclerosis and cardiovascular risk stratification in heterozygous familial hypercholesterolemia patients undergoing statin treatment.PubMed
Marcio H Miname, Marcio S Bittencourt, Khurram Nasir, et al.
Curr Opin Lipidol. 2019 Apr;30(2):82-87. doi: 10.1097/MOL.0000000000000573.
PURPOSE OF REVIEW: To discuss the heterogeneity of atherosclerotic cardiovascular disease (ASCVD) risk in heterozygous familial hypercholesterolemia and evidence and limitations of clinical risk scores and subclinical coronary atherosclerosis (SCA) imaging to evaluate risk. RECENT FINDINGS: Risk evaluation in contemporary familial hypercholesterolemia cohorts needs to consider the cause of the familial hypercholesterolemia phenotype, for example the presence of autosomal molecular defects that impart a greater ASCVD risk than in polygenic hypercholesterolemia, prospective follow-up and the impact of statin treatment. As atherosclerosis is multifactorial, clinical scores like the Montreal familial hypercholesterolemia score and SAFEHEART risk equation have been proposed to stratify ASCVD in statin-treated, molecularly defined familial hypercholesterolemia individuals. However, these scores need further validation. SCA distribution in familial hypercholesterolemia individuals undergoing conventional lipid-lowering treatment is heterogeneous, with 45-50% of individuals not presenting any coronary artery calcification (CAC). One study suggests that the absence of CAC associates with no ASCVD events in asymptomatic familial hypercholesterolemia individuals undergoing statin therapy despite elevated residual LDL-cholesterol levels. In contrast, the presence of CAC was independently associated with ASCVD events. SUMMARY: ASCVD risk is heterogeneous in statin-treated familial hypercholesterolemia individuals. Further studies are necessary to determine how risk stratification, especially with SCA detection, impacts on prescription of proprotein convertase subtilisin kexin type 9 inhibitors within a cost-constrained environment.
36Excess Apolipoprotein B and Cardiovascular Risk in Women and Men.PubMed
Camilla Ditlev Lindhardt Johannesen, Anne Langsted, Børge Grønne Nordestgaard, et al.
J Am Coll Cardiol. 2024 Jun 11;83(23):2262-2273. doi: 10.1016/j.jacc.2024.03.423.
BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) are highly correlated measures of atherogenic lipoproteins. OBJECTIVES: The study investigators hypothesized that excess apoB is associated with an increased risk of myocardial infarction (MI), atherosclerotic cardiovascular disease (ASCVD), and all-cause mortality. METHODS: The study included 53,484 women and 41,624 men not taking statins from the Copenhagen General Population Study. Associations of excess apoB with the risk of MI, ASCVD, and all-cause mortality were estimated by Cox proportional hazards regressions with 95% CIs. Excess apoB was defined as measured levels of apoB minus expected levels of apoB from LDL-C alone; expected levels were defined by linear regressions of LDL-C levels vs apoB levels in individuals with triglycerides ≤1 mmol/L (89 mg/dL). RESULTS: During a median follow-up of 9.6 years, 2,048 MIs, 4,282 ASCVD events, and 8,873 deaths occurred. There was a dose-dependent association between excess apoB and the risk of MI and ASCVD in both women and men, as well as an association with the risk of all-cause mortality in women. For ASCVD in women compared with those with excess apoB <11 mg/dL, the multivariable adjusted HR was 1.08 (95% CI: 0.97-1.21) for excess apoB 11 to 25 mg/dL, 1.30 (95% CI: 1.14-1.48) for 26 to 45 mg/dL, 1.34 (95% CI: 1.14-1.58) for 46 to 100 mg/dL, and 1.75 (95% CI: 1.08-2.83) for excess apoB >100 mg/dL. Corresponding HRs in men were 1.14 (95% CI: 1.02-1.26), 1.41 (95% CI: 1.26-1.57), 1.41 (95% CI: 1.25-1.60), and 1.52 (95% CI: 1.13-2.05), respectively. Results were robust across the entire LDL-C spectrum. CONCLUSIONS: Excess apoB (ie, the value of apoB above that contributed by LDL-C levels alone) is associated dose-dependently with an increased risk of MI and ASCVD in women and men. This finding demonstrates that apoB provides important predictive value beyond LDL-C across the entire LDL-C spectrum.
37Long-term cardiometabolic disease risk in women with PCOS: a systematic review and meta-analysis.PubMed
V Wekker, L van Dammen, A Koning, et al.
Hum Reprod Update. 2020 Nov 1;26(6):942-960. doi: 10.1093/humupd/dmaa029.
BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with cardiometabolic disease, but recent systematic reviews and meta-analyses of longitudinal studies that quantify these associations are lacking. OBJECTIVE AND RATIONALE: Is PCOS a risk factor for cardiometabolic disease? SEARCH METHODS: We searched from inception to September 2019 in MEDLINE and EMBASE using controlled terms (e.g. MESH) and text words for PCOS and cardiometabolic outcomes, including cardiovascular disease (CVD), stroke, myocardial infarction, hypertension (HT), type 2 diabetes (T2D), metabolic syndrome and dyslipidaemia. Cohort studies and case-control studies comparing the prevalence of T2D, HT, fatal or non-fatal CVD and/or lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) between women with and without PCOS of ≥18 years of age were eligible for this systematic review and meta-analysis. Studies were eligible regardless of the degree to which they adjusted for confounders including obesity. Articles had to be written in English, German or Dutch. Intervention studies, animal studies, conference abstracts, studies with a follow-up duration less than 3 years and studies with less than 10 PCOS cases were excluded. Study selection, quality assessment (Newcastle-Ottawa Scale) and data extraction were performed by two independent researchers. OUTCOMES: Of the 5971 identified records, 23 cohort studies were included in the current systematic review. Women with PCOS had increased risks of HT (risk ratio (RR): 1.75, 95% CI 1.42 to 2.15), T2D (RR: 3.00, 95% CI 2.56 to 3.51), a higher serum concentration of TC (mean difference (MD): 7.14 95% CI 1.58 to 12.70 mg/dl), a lower serum concentration of HDL-C (MD: -2.45 95% CI -4.51 to -0.38 mg/dl) and increased risks of non-fatal cerebrovascular disease events (RR: 1.41, 95% CI 1.02 to 1.94) compared to women without PCOS. No differences were found for LDL-C (MD: 3.32 95% CI -4.11 to 10.75 mg/dl), TG (MD 18.53 95% CI -0.58 to 37.64 mg/dl) or coronary disease events (RR: 1.78, 95% CI 0.99 to 3.23). No meta-analyses could be performed for fatal CVD events due to the paucity of mortality data. WIDER IMPLICATIONS: Women with PCOS are at increased risk of cardiometabolic disease. This review quantifies this risk, which is important for clinicians to inform patients and to take into account in the cardiovascular risk assessment of women with PCOS. Future clinical trials are needed to assess the ability of cardiometabolic screening and management in women with PCOS to reduce future CVD morbidity.
38Lipoprotein(a) Testing Patterns in a Large Health System.PubMed
Michelle Kelsey, Courtney Page, Brooke Alhanti, et al.
Am J Cardiol. 2021 Aug 15;153:43-50. doi: 10.1016/j.amjcard.2021.05.018. Epub 2021 Jun 29.
Lipoprotein (a) [Lp(a)] is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). As directed therapy for Lp(a) emerges, it is important to understand patterns of Lp(a) testing in routine clinical practice. We set out to characterize Lp(a) testing across a large academic health system. Using electronic health record (EHR) data from 2014 to 2019, we compared patients who underwent Lp(a) testing to date-matched peers who had low density lipoprotein (LDL-C) assessment alone. We analyzed ordering provider characteristics and rates of initiation of new lipid lowering therapy (LLT) within 12 months after testing. Of 1,296 adults with Lp(a) test results, 629 (48.5%) had prior history of ASCVD and 667 (51.4%) did not. Compared with those with LDL-C testing alone, individuals who underwent Lp(a) testing were more like to have a myocardial infarction or ischemic stroke at a young age and multiple prior cardiovascular events. Though the majority of Lp(a) tests were ordered in outpatient encounters, a higher proportion of Lp(a) tests compared with LDL-C tests were performed in the inpatient setting. Neurology and psychiatry were the most common specialty to order Lp(a) tests in our cohort. There was a significantly increased initiation of LLT after Lp(a) testing compared with LDL-C testing across all medication types. Consistent with guidelines, Lp(a) testing is used in those with early onset ASCVD, and among those with multiple cardiovascular events. Lp(a) testing is associated with more aggressive LLT in following year. Further research is needed to characterize Lp(a) testing across larger populations.
39Independent Association of Lipoprotein(a) and Coronary Artery Calcification With Atherosclerotic Cardiovascular Risk.PubMed
Anurag Mehta, Nestor Vasquez, Colby R Ayers, et al.
J Am Coll Cardiol. 2022 Mar 1;79(8):757-768. doi: 10.1016/j.jacc.2021.11.058.
BACKGROUND: Elevated lipoprotein(a) [Lp(a)] and coronary artery calcium (CAC) score are individually associated with increased atherosclerotic cardiovascular disease (ASCVD) risk but have not been studied in combination. OBJECTIVES: This study sought to investigate the independent and joint association of Lp(a) and CAC with ASCVD risk. METHODS: Plasma Lp(a) and CAC were measured at enrollment among asymptomatic participants of the MESA (Multi-Ethnic Study of Atherosclerosis) (n = 4,512) and DHS (Dallas Heart Study) (n = 2,078) cohorts. Elevated Lp(a) was defined as the highest race-specific quintile, and 3 CAC score categories were studied (0, 1-99, and ≥100). Associations of Lp(a) and CAC with ASCVD risk were evaluated using risk factor-adjusted Cox regression models. RESULTS: Among MESA participants (61.9 years of age, 52.5% women, 36.8% White, 29.3% Black, 22.2% Hispanic, and 11.7% Chinese), 476 incident ASCVD events were observed during 13.2 years of follow-up. Elevated Lp(a) and CAC score (1-99 and ≥100) were independently associated with ASCVD risk (HR: 1.29; 95% CI: 1.04-1.61; HR: 1.68; 95% CI: 1.30-2.16; and HR: 2.66; 95% CI: 2.07-3.43, respectively), and Lp(a)-by-CAC interaction was not noted. Compared with participants with nonelevated Lp(a) and CAC = 0, those with elevated Lp(a) and CAC ≥100 were at the highest risk (HR: 4.71; 95% CI: 3.01-7.40), and those with elevated Lp(a) and CAC = 0 were at a similar risk (HR: 1.31; 95% CI: 0.73-2.35). Similar findings were observed when guideline-recommended Lp(a) and CAC thresholds were considered, and findings were replicated in the DHS. CONCLUSIONS: Lp(a) and CAC are independently associated with ASCVD risk and may be useful concurrently for guiding primary prevention therapy decisions.
40Hyperinsulinaemia and hypertriglyceridaemia.PubMed
G Steiner
J Intern Med Suppl. 1994;736:23-6.
Hyperinsulinaemia and hypertriglyceridaemia are frequently associated. This may be as a part of the syndrome of insulin resistance or in diabetes, particularly non-insulin-dependent diabetes (NIDDM). The importance of this association lies in the facts that atherosclerosis is the most frequent complication of diabetes, that hypertriglyceridaemia is a risk factor for coronary artery disease in diabetic populations and that hyperinsulinaemia also appears to be a risk factor for atherosclerosis. Hypertriglyceridaemia, even without obesity, is associated with resistance to insulin. This can result in compensatory hyperinsulinaemia. Chronic hyperinsulinaemia has been shown to increase the production of triglyceride (TG)-rich lipoproteins. The vast majority of particles in the TG-rich lipoprotein spectrum are in the intermediate-density-lipoprotein (IDL) range. Furthermore, increased levels of TG result primarily from increased numbers of these particles, rather than from increased particle size. This is important because, at least in nondiabetic individuals, increased levels of IDL are associated with increased atherosclerosis. Thus, there may be a vicious cycle of insulin resistance, hyperinsulinaemia, hypertriglyceridaemia and atherosclerosis. We have found that by reducing plasma TG levels alone, one can increase sensitivity to insulin and break this cycle.
41Hyperinsulinemia and hypertriglyceridemia, a vicious cycle with atherogenic potential.PubMed
G Steiner, M Vranic
Int J Obes. 1982;6 Suppl 1:117-24.
This paper reviews and integrates a number of experiments which suggest the existence of a vicious cycle. In this cycle hypertriglyceridemia can lead to insulin resistance even without concomitant obesity or non-insulin dependent diabetes. This insulin resistance may be the basis for the hyperinsulinemia response to a glucose challenge. The hyperinsulinemia can stimulate VLDL-triglyceride production. This increase in production, if it is not accompanied by an equivalent increase in removal, will result in hypertriglyceridemia. The whole cycle would accelerate VLDL-triglyceride turnover and may increase the supply of potentially atherogenic VLDL-remnants.
42Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes.PubMed
Maria Lytrivi, Anne-Laure Castell, Vincent Poitout, et al.
J Mol Biol. 2020 Mar 6;432(5):1514-1534. doi: 10.1016/j.jmb.2019.09.016. Epub 2019 Oct 16.
The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic β-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in β-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic β-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in β-cells, potentially contributing to their glucose-lowering effects in T2D.
43Role of fatty acids in the pathogenesis of ß-cell failure and Type-2 diabetes.PubMed
Cecilia Jiménez-Sánchez, Lucie Oberhauser, Pierre Maechler
Atherosclerosis. 2024 Nov;398:118623. doi: 10.1016/j.atherosclerosis.2024.118623. Epub 2024 Oct 4.
Pancreatic ß-cells are glucose sensors in charge of regulated insulin delivery to the organism, achieving glucose homeostasis and overall energy storage. The latter function promotes obesity when nutrient intake chronically exceeds daily expenditure. In case of ß-cell failure, such weight gain may pave the way for the development of Type-2 diabetes. However, the causal link between excessive body fat mass and potential degradation of ß-cells remains largely unknown and debated. Over the last decades, intensive research has been conducted on the role of lipids in the pathogenesis of ß-cells, also referred to as lipotoxicity. Among various lipid species, the usual suspects are essentially the non-esterified fatty acids (NEFA), in particular the saturated ones such as palmitate. This review describes the fundamentals and the latest advances of research on the role of fatty acids in ß-cells. This includes intracellular pathways and receptor-mediated signaling, both participating in regulated glucose-stimulated insulin secretion as well as being implicated in ß-cell dysfunction. The discussion extends to the contribution of high glucose exposure, or glucotoxicity, to ß-cell defects. Combining glucotoxicity and lipotoxicity results in the synergistic and more deleterious glucolipotoxicity effect. In recent years, alternative roles for intracellular lipids have been uncovered, pointing to a protective function in case of nutrient overload. This requires dynamic storage of NEFA as neutral lipid droplets within the ß-cell, along with active glycerolipid/NEFA cycle allowing subsequent recruitment of lipid species supporting glucose-stimulated insulin secretion. Overall, the latest studies have revealed the two faces of the same coin.
44Nicotinamide Mononucleotide (NMN) Ameliorates Free Fatty Acid-Induced Pancreatic β-Cell Dysfunction via the NAD/AMPK/SIRT1/HIF-1α Pathway.PubMed
Yan Wang, Si Liu, Linyao Ying, et al.
Int J Mol Sci. 2024 Sep 30;25(19):10534. doi: 10.3390/ijms251910534.
As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.
45Pleiotropic effects of fatty acids on pancreatic beta-cells.PubMed
E P Haber, H M A Ximenes, J Procópio, et al.
J Cell Physiol. 2003 Jan;194(1):1-12. doi: 10.1002/jcp.10187.
Hyperlipidemia is frequently associated with insulin resistance states as found in type 2 diabetes and obesity. Effects of free fatty acids (FFA) on pancreatic beta-cells have long been recognized. Acute exposure of the pancreatic beta-cell to FFA results in an increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. We recently showed that palmitate augments insulin release in the presence of non-stimulatory concentrations of glucose. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release. These results imply that physiological plasma levels of FFA are important for beta-cell function. Although, it has been accepted that fatty acid oxidation is necessary for its stimulation of insulin secretion, the possible mechanisms by which fatty acids (FA) affect insulin secretion are discussed in this review. Long-chain acyl-CoA (LC-CoA) controls several aspects of the beta-cell function including activation of certain types of protein kinase C (PKC), modulation of ion channels, protein acylation, ceramide- and/or nitric oxide (NO)-mediated apoptosis, and binding to nuclear transcriptional factors. The present review also describes the possible effects of FA on insulin signaling. We showed for the first time that acute exposure of islets to palmitate upregulates the intracellular insulin-signaling pathway in pancreatic islets. Another aspect considered in this review is the source of FA for pancreatic islets. In addition to be exported to the medium, lipids can be transferred from leukocytes (macrophages) to pancreatic islets in co-culture. This process consists an additional source of FA that may plays a significant role to regulate insulin secretion.
46The fate of intracellular S1P regulates lipid droplet turnover and lipotoxicity in pancreatic beta-cells.PubMed
Yadi Tang, Mariola Majewska, Britta Leß, et al.
J Lipid Res. 2024 Aug;65(8):100587. doi: 10.1016/j.jlr.2024.100587. Epub 2024 Jun 29.
Lipotoxicity has been considered the main cause of pancreatic beta-cell failure during type 2 diabetes development. Lipid droplets (LD) are believed to regulate the beta-cell sensitivity to free fatty acids (FFA), but the underlying molecular mechanisms are largely unclear. Accumulating evidence points, however, to an important role of intracellular sphingosine-1-phosphate (S1P) metabolism in lipotoxicity-mediated disturbances of beta-cell function. In the present study, we compared the effects of an increased irreversible S1P degradation (S1P-lyase, SPL overexpression) with those associated with an enhanced S1P recycling (overexpression of S1P phosphatase 1, SGPP1) on LD formation and lipotoxicity in rat INS1E beta-cells. Interestingly, although both approaches led to a reduced S1P concentration, they had opposite effects on the susceptibility to FFA. Overexpression of SGPP1 prevented FFA-mediated caspase-3 activation by a mechanism involving an enhanced lipid storage capacity and prevention of oxidative stress. In contrast, SPL overexpression limited LD biogenesis, content, and size, while accelerating lipophagy. This was associated with FFA-induced hydrogen peroxide formation, mitochondrial fragmentation, and dysfunction, as well as ER stress. These changes coincided with the upregulation of proapoptotic ceramides but were independent of lipid peroxidation rate. Also in human EndoC-βH1 beta-cells, suppression of SPL with simultaneous overexpression of SGPP1 led to a similar and even more pronounced LD phenotype as that in INS1E-SGPP1 cells. Thus, intracellular S1P turnover significantly regulates LD content and size and influences beta-cell sensitivity to FFA.
47α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway.PubMed
Danyu Cheng, Mo Zhang, Yezi Zheng, et al.
Redox Biol. 2024 Aug;74:103230. doi: 10.1016/j.redox.2024.103230. Epub 2024 Jun 13.
α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions.
48ZDY2013 Inhibits the Development of Non-Alcoholic Fatty Liver Disease by Regulating the Intestinal Microbiota and Modulating the PI3K/Akt Pathway.PubMed
Qiang Teng, Huihui Lv, Lingling Peng, et al.
Nutrients. 2024 Mar 27;16(7):958. doi: 10.3390/nu16070958.
Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic condition whose impact on human health is increasingly significant. The imbalance of the gut microbiome, linked to insulin resistance, heightened intestinal permeability, and pro-inflammatory reactions, may be the linchpin in the development of NAFLD. In our research, the impact of ZDY2013 administration for 12 weeks on gut microbiota dysbiosis induced by a high-fat, high-fructose, high-cholesterol (FHHC) diet in male C57BL/6n mice was investigated. Research results presented that the intervention of ZDY2013 in mice fed with the FHHC diet could restore their liver function and regulate oxidative stress. Compared to mice in the model group, the intervention of ZDY2013 significantly regulated the gut microbiota, inhibited the LPS/NF-κB pathway, and led to a lower level of colonic inflammation in the mice administered with ZDY2013. It also improved insulin resistance to regulate the PI3K/Akt pathway and lipid metabolism, thereby resulting in reduced fat accumulation in the liver. The above results suggest that the intervention of ZDY2013 can hinder the progression of diet-induced NAFLD by reducing inflammation to regulate the PI3K/Akt pathway and regulating gut microbiota disturbance.
49Metabolic Syndrome-Related Kidney Injury: A Review and Update.PubMed
Lirong Lin, Wei Tan, Xianfeng Pan, et al.
Front Endocrinol (Lausanne). 2022 Jun 23;13:904001. doi: 10.3389/fendo.2022.904001. eCollection 2022.
Metabolic syndrome (MetS) includes visceral obesity, hyperglycemia, dyslipidemia, and hypertension. The prevalence of MetS is 20-25%, which is an important risk factor for chronic kidney disease (CKD). MetS causes effects on renal pathophysiology, including glomerular hyperfiltration, RAAS, microalbuminuria, profibrotic factors and podocyte injury. This review compares several criteria of MetS and analyzes their differences. MetS and the pathogenesis of CKD includes insulin resistance, obesity, dyslipidemia, inflammation, oxidative stress, and endothelial dysfunction. The intervention of MetS-related renal damage is the focus of this article and includes controlling body weight, hypertension, hyperglycemia, and hyperlipidemia, requiring all components to meet the criteria. In addition, interventions such as endoplasmic reticulum stress, oxidative stress, gut microbiota, body metabolism, appetite inhibition, podocyte apoptosis, and mesenchymal stem cells are reviewed.
50Atherogenic dyslipidemia and diabetic nephropathy.PubMed
Giuseppina Russo, Pamela Piscitelli, Annalisa Giandalia, et al.
J Nephrol. 2020 Oct;33(5):1001-1008. doi: 10.1007/s40620-020-00739-8. Epub 2020 Apr 23.
Chronic kidney disease is associated with altered lipid metabolism and lipid accumulation. Although it is though that hyperlipemia is a consequence of kidney dysfunction, several lines of evidence support that hyperlipidemia may contribute to the onset and progression of kidney disease, also in diabetes. This review describes the results of recent observational studies supporting the concept that glucose is only partly responsible for kidney damage onset, while a cluster of factors, including hypertriglyceridemia and low HDL-cholesterol, could play a relevant role in inducing onset and progression of DKD. We also report the results of randomized clinical trials investigating in type 2 diabetic patients the role of drug improvement of hypertriglyceridemia on renal outcomes. Finally, we discuss putative mechanisms linking hyperlipidemia (i.e. hypertriglyceridemia or low HDL cholesterol) with kidney disease.
51Lipid abnormality in diabetic kidney disease and potential treatment advancements.PubMed
Qian Ming Tu, Hui Min Jin, Xiu Hong Yang
Front Endocrinol (Lausanne). 2025 Mar 18;16:1503711. doi: 10.3389/fendo.2025.1503711. eCollection 2025.
Numerous studies have shown that dyslipidemia increases the risk of atherosclerotic cardiovascular disease (ASCVD) and significantly impacts the occurrence and progression of diabetic kidney disease (DKD). Early interventions for lipid metabolism disorders in DKD may improve renal function. This article reviews the clinical characteristics of dyslipidemia, mechanisms of lipid-induced renal injury, and advances in lipid-lowering therapy in DKD. We searched PubMed, Web of Science, and EMBASE to identify relevant articles, using keywords such as "diabetic kidney disease", "diabetic nephropathy", "diabetes", "dyslipidemia", "kidney", "cardiovascular disease", and "lipid therapy". High triglyceride (TG) and low high-density lipoprotein (HDL) are associated with increased risks of albuminuria and estimated glomerular filtration rate (eGFR) decline. Abnormal lipid metabolism may damage glomerular podocytes and renal tubular epithelial cells via ectopic lipid deposition, eventually impairing glomerular filtration function and increasing urinary albumin excretion. Lipid-lowering therapies can ameliorate lipid accumulation, downregulate inflammatory mediator expressions, and alleviate renal fibrosis. Fibrate and statin applications exhibit beneficial effects, reducing albuminuria and slowing eGFR decline in early DKD. However, the long-term effects of statins and fibrates on renal outcomes remain controversial. Pro-protein convertase subtilisin/kexin 9 (PCSK9)-targeted interventions have minimal side effects on the kidneys and seem effective in reducing inflammation and improving renal impairment compared with statins and fibrates. In addition, LDL apheresis (LDL-A) and double filtration plasmapheresis (DFPP) are promising clinical applications in diabetic patients with severe hypercholesterolemia or lipid-lowering drug intolerance.
52Atgl deficiency induces podocyte apoptosis and leads to glomerular filtration barrier damage.PubMed
Wen Chen, Youzhao Jiang, Jian Han, et al.
FEBS J. 2017 Apr;284(7):1070-1081. doi: 10.1111/febs.14038. Epub 2017 Mar 22.
UNLABELLED: Abnormal lipid metabolism, renal lipid accumulation and lipotoxicity are associated with the pathological features of glomerulopathy. However, the mechanisms by which lipid accumulation leads to the development or progression of this disease have not been fully elucidated. In this work, we have identified a role for the rate-limiting enzyme in lipolysis, adipose triglyceride lipase (ATGL; also called patatin-like phospholipase domain-containing protein 2), in renal lipid metabolism and kidney disease. ATGL-deficient (Atgl(-/-)) mice displayed albuminuria, accompanied by ectopic deposition of fat in the kidney. Magnetic resonance imaging demonstrated that the contrast agent gadopentetic acid was retained in kidney tissue, suggesting defects in the glomerular filtration barrier. Furthermore, transmission electron microscopy revealed lipid deposits in the podocyte, along with foot process fusion and morphological changes suggestive of apoptosis. Indeed, shRNA-mediated depletion of ATGL promoted podocyte apoptosis, accompanied by increased levels of intracellular reactive oxygen species (ROS) and F-actin fibre redistribution. These effects could be partially reversed by treatment with the antioxidant N-acetylcysteine. These data suggest that ATGL deficiency induces renal lipid accumulation, proteinuria and glomerular filtration barrier dysfunction and implicate increased intracellular ROS levels in inducing podocyte F-actin rearrangement, foot process fusion and apoptosis that underlie these pathological features. ENZYMES: Adipose triglyceride lipase, EC3.1.1.3.
53Diabetic nephropathy.PubMed
Themis Zelmanovitz, Fernando Gerchman, Amely Ps Balthazar, et al.
Diabetol Metab Syndr. 2009 Sep 21;1(1):10. doi: 10.1186/1758-5996-1-10.
Diabetic nephropathy is the leading cause of chronic renal disease and a major cause of cardiovascular mortality. Diabetic nephropathy has been categorized into stages: microalbuminuria and macroalbuminuria. The cut-off values of micro- and macroalbuminuria are arbitrary and their values have been questioned. Subjects in the upper-normal range of albuminuria seem to be at high risk of progression to micro- or macroalbuminuria and they also had a higher blood pressure than normoalbuminuric subjects in the lower normoalbuminuria range. Diabetic nephropathy screening is made by measuring albumin in spot urine. If abnormal, it should be confirmed in two out three samples collected in a three to six-months interval. Additionally, it is recommended that glomerular filtration rate be routinely estimated for appropriate screening of nephropathy, because some patients present a decreased glomerular filtration rate when urine albumin values are in the normal range. The two main risk factors for diabetic nephropathy are hyperglycemia and arterial hypertension, but the genetic susceptibility in both type 1 and type 2 diabetes is of great importance. Other risk factors are smoking, dyslipidemia, proteinuria, glomerular hyperfiltration and dietary factors. Nephropathy is pathologically characterized in individuals with type 1 diabetes by thickening of glomerular and tubular basal membranes, with progressive mesangial expansion (diffuse or nodular) leading to progressive reduction of glomerular filtration surface. Concurrent interstitial morphological alterations and hyalinization of afferent and efferent glomerular arterioles also occur. Podocytes abnormalities also appear to be involved in the glomerulosclerosis process. In patients with type 2 diabetes, renal lesions are heterogeneous and more complex than in individuals with type 1 diabetes. Treatment of diabetic nephropathy is based on a multiple risk factor approach, and the goal is retarding the development or progression of the disease and to decrease the subject's increased risk of cardiovascular disease. Achieving the best metabolic control, treating hypertension (<130/80 mmHg) and dyslipidemia (LDL cholesterol <100 mg/dl), using drugs that block the renin-angiotensin-aldosterone system, are effective strategies for preventing the development of microalbuminuria, delaying the progression to more advanced stages of nephropathy and reducing cardiovascular mortality in patients with diabetes.
54Time Course of LDL Cholesterol Exposure and Cardiovascular Disease Event Risk.PubMed
Michael J Domanski, Xin Tian, Colin O Wu, et al.
J Am Coll Cardiol. 2020 Sep 29;76(13):1507-1516. doi: 10.1016/j.jacc.2020.07.059.
BACKGROUND: Incident cardiovascular disease (CVD) increases with increasing low-density lipoprotein cholesterol (LDL-C) concentration and exposure duration. Area under the LDL-C versus age curve is a possible risk parameter. Data-based demonstration of this metric is unavailable and whether the time course of area accumulation modulates risk is unknown. OBJECTIVES: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we assessed the relationship of area under LDL-C versus age curve to incident CVD event risk and modulation of risk by time course of area accumulation-whether risk increase for the same area increment is different at different ages. METHODS: This prospective study included 4,958 asymptomatic adults age 18 to 30 years enrolled from 1985 to 1986. The outcome was a composite of nonfatal coronary heart disease, stroke, transient ischemic attack, heart failure hospitalization, cardiac revascularization, peripheral arterial disease intervention, or cardiovascular death. RESULTS: During a median 16-year follow-up after age 40 years, 275 participants had an incident CVD event. After adjustment for sex, race, and traditional risk factors, both area under LDL-C versus age curve and time course of area accumulation (slope of LDL-C curve) were significantly associated with CVD event risk (hazard ratio: 1.053; p < 0.0001 per 100 mg/dl × years; hazard ratio: 0.797 per mg/dl/year; p = 0.045, respectively). CONCLUSIONS: Incident CVD event risk depends on cumulative prior exposure to LDL-C and, independently, time course of area accumulation. The same area accumulated at a younger age, compared with older age, resulted in a greater risk increase, emphasizing the importance of optimal LDL-C control starting early in life.
55Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis.PubMed
Minoru Takaoka, Xiaohui Zhao, Hwee Ying Lim, et al.
Nature. 2024 Oct;634(8033):457-465. doi: 10.1038/s41586-024-07993-x. Epub 2024 Sep 4.
Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1 resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.
56Non-High-Density Lipoprotein Cholesterol Levels From Childhood to Adulthood and Cardiovascular Disease Events.PubMed
Feitong Wu, David R Jacobs, Stephen R Daniels, et al.
JAMA. 2024 Jun 4;331(21):1834-1844. doi: 10.1001/jama.2024.4819.
IMPORTANCE: Elevated non-high-density lipoprotein cholesterol (non-HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non-HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown. OBJECTIVE: To examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019. EXPOSURES: Child (age 3-19 years) and adult (age 20-40 years) non-HDL-C age- and sex-specific z scores and categories according to clinical guideline-recommended cutoffs for dyslipidemia. MAIN OUTCOMES AND MEASURES: Incident fatal and nonfatal CVD events adjudicated by medical records. RESULTS: Over a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non-HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non-HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non-HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non-HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non-HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non-HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]). CONCLUSIONS AND RELEVANCE: Individuals with persistent non-HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non-HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non-HDL-C levels may help prevent premature CVD.
57Cardiovascular risk factor progression in adolescents and young adults with youth-onset type 2 diabetes.PubMed
Rachana D Shah, Barbara H Braffett, et al.
J Diabetes Complications. 2022 Mar;36(3):108123. doi: 10.1016/j.jdiacomp.2021.108123. Epub 2022 Jan 3.
AIMS: Youth-onset type 2 diabetes (T2D) confers a high risk of early adverse cardiovascular morbidity. We describe the cumulative incidence and prevalence of cardiovascular risk factors over time and examine relationships with diabetes progression in young adults with youth-onset T2D from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Longitudinal data was used to evaluate the relationships between hypertension, LDL-C dyslipidemia, hypertriglyceridemia, and smoking with risk factors in 677 participants. RESULTS: Baseline mean age was 14 ± 2 years and mean follow-up 10.2 ± 4.5 years. The 14-year cumulative incidence of hypertension, LDL-C dyslipidemia, and hypertriglyceridemia was 59%, 33%, and 37% respectively. Average prevalence of reported smoking was 23%. Male sex, non-Hispanic white race/ethnicity, obesity, poor glycemic control, lower insulin sensitivity, and reduced beta-cell function were significantly associated with an unfavorable risk profile. At end of follow-up, 54% had ≥2 cardiovascular risk factors in addition to T2D. CONCLUSIONS: Cardiovascular risk factor incidence and prevalence was high over a decade of follow-up in young adults with youth-onset T2D. Glucose control and management of cardiovascular risk factors is critical in youth with T2D for prevention of cardiovascular morbidity and mortality.
58Risk Factor Burden and Long-Term Prognosis of Patients With Premature Coronary Artery Disease.PubMed
Michel Zeitouni, Robert M Clare, Karen Chiswell, et al.
J Am Heart Assoc. 2020 Dec 15;9(24):e017712. doi: 10.1161/JAHA.120.017712. Epub 2020 Dec 8.
Background Coronary artery disease (CAD) is increasing among young adults. We aimed to describe the cardiovascular risk factors and long-term prognosis of premature CAD. Methods and Results Using the Duke Databank for Cardiovascular Disease, we evaluated 3655 patients admitted between 1995 and 2013 with a first diagnosis of obstructive CAD before the age of 50 years. Major adverse cardiovascular events (MACEs), defined as the composite of death, myocardial infarction, stroke, or revascularization, were ascertained for up to 10 years. Cox proportional hazard regression models were used to assess associations with the rate of first recurrent event, and negative binomial log-linear regression was used for rate of multiple event recurrences. Past or current smoking was the most frequent cardiovascular factor (60.8%), followed by hypertension (52.8%) and family history of CAD (39.8%). Within a 10-year follow-up, 52.9% of patients had at least 1 MACE, 18.6% had at least 2 recurrent MACEs, and 7.9% had at least 3 recurrent MACEs, with death occurring in 20.9% of patients. Across follow-up, 31.7% to 37.2% of patients continued smoking, 81.7% to 89.3% had low-density lipoprotein cholesterol levels beyond the goal of 70 mg/dL, and 16% had new-onset diabetes mellitus. Female sex, diabetes mellitus, chronic kidney disease, multivessel disease, and chronic inflammatory disease were factors associated with recurrent MACEs. Conclusions Premature CAD is an aggressive disease with frequent ischemic recurrences and premature death. Individuals with premature CAD have a high proportion of modifiable cardiovascular risk factors, but failure to control them is frequently observed.
59Metabolic Dyslipidemia and Cardiovascular Outcomes in Type 2 Diabetes Mellitus: Findings From the Look AHEAD Study.PubMed
Arnaud D Kaze, Prasanna Santhanam, Solomon K Musani, et al.
J Am Heart Assoc. 2021 Apr 6;10(7):e016947. doi: 10.1161/JAHA.120.016947. Epub 2021 Mar 17.
Background Metabolic dyslipidemia (high triglyceride) and low high-density lipoprotein cholesterol (HDL-C) is highly prevalent in type 2 diabetes mellitus (T2DM). The extent to which diabetes mellitus-related abnormalities in the triglyceride-HDL-C profile associates with cardiovascular disease (CVD) risk is incompletely understood. We evaluated the associations of triglyceride and HDL-C status with CVD outcomes in individuals with T2DM. Methods and Results We analyzed data from 4199 overweight/obese adults with T2DM free of CVD with available data on triglyceride and HDL-C at baseline (2001-2004) in the Look AHEAD (Action for Health in Diabetes) study. We used Cox proportional models to estimate hazard ratios (HRs) and 95% CIs of: (1) composite CVD outcome (myocardial infarction, stroke, hospitalization for angina, and/or death from cardiovascular causes); (2) coronary artery disease events; and (3) cerebrovascular accidents (stroke). Of the 4199 participants, 62% (n=2600) were women, with a mean age of 58 years (SD, 7), and 40% (n=1659) had metabolic dyslipidemia at baseline. Over a median follow-up of 9.5 years (interquartile range, 8.7-10.3), 500 participants experienced the composite CVD outcome, 396 experienced coronary artery disease events, and 100 experienced stroke. Low HDL-C was associated with higher hazards of the composite CVD outcome (HR, 1.36; 95% CI, 1.12-1.64 [=0.002]) and coronary artery disease events (HR, 1.46; 95% CI, 1.18-1.81 [=0.001]) but not stroke (HR, 1.38; 95% CI, 0.90-2.11 [=0.140]). Compared with patients with normal triglyceride and normal HDL, participants with metabolic dyslipidemia had higher risks of the composite CVD outcome (HR, 1.30; 95% CI, 1.03-1.63 [=0.025]) and coronary artery disease events (HR, 1.48; 95% CI, 1.14-1.93 [=0.003]) but not stroke (HR, 1.23; 95% CI, 0.74-2.05 [=0.420]). Conclusions In a large sample of overweight/obese individuals with T2DM, metabolic dyslipidemia was associated with higher risks of CVD outcomes. Our findings highlight the necessity to account for metabolic dyslipidemia in CVD risk stratification among patients with T2DM. Registration URL: https://www.lookaheadtrial.org; Unique identifier: NCT00017953.
60LDL-C/HDL-C ratio and risk of all-cause mortality in patients with intracerebral hemorrhage.PubMed
Shoujiang You, Chongke Zhong, Jiaping Xu, et al.
Neurol Res. 2016 Oct;38(10):903-8. doi: 10.1080/01616412.2016.1204797. Epub 2016 Jul 14.
BACKGROUND: The low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio has been recognized as a strong risk predictor of cardiovascular diseases. However, the association between the LDL-C/HDL-C ratio and the prognosis of acute intracranial hemorrhage (ICH) is unclear. Thus, we prospectively investigated whether a low LDL-C/HDL-C ratio could predict all-cause mortality and whether LDL-C/HDL-C ratio is superior to traditional lipid profiles in predicting mortality among Chinese patients with acute ICH. METHODS: A prospective cohort study of 356 patients with acute ICH was conducted, and the mean follow-up time point was 80.4 days. Participants were divided into four categories based on LDL-C/HDL-C ratio quartiles. Three-month outcomes were evaluated by in-person or telephone interviews with patients or their family members. The end point was three-month mortality from all causes. RESULTS: Forty-seven deaths from all causes were documented. The multivariate analysis found that LDL-C/HDL-C ratio [hazard ratio (HR) = 0.49, p = 0.008] and LDL-C (HR = 0.27, p = 0.044) were significantly associated with all-cause mortality. The Kaplan-Meier curves show that patients in the lowest quartiles had the highest cumulative incidence rates (log-rank p = 0.027). After adjusting for covariates, a low LDL-C/HDL-C ratio was associated with a 3.55-fold increase in the risk of all-cause mortality (HR, 3.55 [95% confidence interval, 1.04-12.14]; P-trend = 0.011) when the highest and lowest quartiles were compared. The C-statistic of the LDL-C/HDL-C ratio was significantly larger than other traditional lipid profiles (all p < 0.05). CONCLUSIONS: A low LDL-C/HDL-C ratio was independently associated with an increased risk of all-cause mortality at three months in patients with ICH. Moreover, the LDL-C/HDL-C ratio appeared to be a best lipid predictor of all-cause mortality than traditional lipid profiles.
61Presence of Hypertension Is Reduced by Mediterranean Diet Adherence in All Individuals with a More Pronounced Effect in the Obese: The Hellenic National Nutrition and Health Survey (HNNHS).PubMed
Emmanuella Magriplis, Demosthenes Panagiotakos, Ioannis Kyrou, et al.
Nutrients. 2020 Mar 23;12(3):853. doi: 10.3390/nu12030853.
Hypertension is a major risk of cardiovascular diseases. This study's aim was to examine associations between hypertension and a priori known lifestyle risk factors, including weight status and Mediterranean diet adherence. The study included a representative sample of the adult population (N = 3775 (40.8% males)), from the Hellenic National Nutrition and Health Survey (HNNHS), which took place from September 2013 to May 2015. Demographic and anthropometric data were collected using validated questionnaires, and blood pressure (BP) measurements were performed for the two main metropolitan areas (N = 1040; 41.1%). Hypertension diagnosis was according to the International Classification of Diseases (ICD-10) guidelines. Weighted proportions, extended Mantel-Haenszel (M-H) analyses, and multiple logistic regressions (for the survey data) were performed. Mean systolic BP (SBP) and diastolic BP (DBP) were 118.6 mmHg and 72.2 mmHg respectively, with both values being higher in males compared to females in all age groups ( < 0.001). Study participants with hyperlipidemia or diabetes, and those overweight, were almost twice as likely to be hypertensives, with the odds increasing to 4 for those obese ( for all, < 0.05). Stricter Mediterranean diet adherence significantly decreased the likelihood of hypertension by 36% (OR: 0.64; 95% CI: 0.439, 0.943), and a significant interaction was found between Mediterranean diet adherence and weight status on hypertension. The presence of hypertension is clustered with comorbidities, but is significantly associated with modifiable risk factors, including Mediterranean diet and weight status, underlining the need for personalized medical nutritional treatment.
62Update on dyslipidemia.PubMed
Abhimanyu Garg, Vinaya Simha
J Clin Endocrinol Metab. 2007 May;92(5):1581-9. doi: 10.1210/jc.2007-0275.
Recently, considerable progress has been made in understanding the genetic basis of dyslipidemias and in studying the safety and efficacy of lipid-lowering drugs for coronary heart disease (CHD) prevention. Novel loci have been identified for monogenic hypercholesterolemia, such as low-density lipoprotein (LDL) receptor (LDLR)-associated protein, proprotein convertase subtilisin-like kexin type 9, and ATP-binding cassette transporters ABCG5 and ABCG8. LDLR-associated protein promotes clustering of LDLRs into clathrin-coated pits for LDL uptake; proprotein convertase subtilisin-like kexin type 9 is involved in LDLR degradation; and ABCG5 and 8 pump sterols out of the hepatic and intestinal cells into bile and intestinal lumen, respectively. A novel gene encoding apolipoprotein AV, an activator of lipoprotein lipase, has also been linked to familial hypertriglyceridemia. Linkage of familial combined hyperlipidemia to upstream stimulatory factor 1 remains controversial. Recent guidelines of the Adult Treatment Panel III emphasize intensive reduction of LDL or non-high-density lipoprotein cholesterol in patients at high risk of CHD. However, of the four recently concluded trials comparing high- vs. low-dose statin therapy, only two showed an unequivocal reduction in cardiovascular endpoints. Because intensive statin therapy can increase the risk of myopathy and hepatotoxicity, it is important to consider its risk-benefit ratio in individual patients. Restriction of dietary saturated and trans-fat and cholesterol, along with increased intake of soluble fiber, can also achieve substantial LDL cholesterol lowering. Fibrates may reduce the risk of acute pancreatitis in severely hypertriglyceridemic patients and may be beneficial for CHD prevention. However, the safety and efficacy of combined therapy of fibrates and statins needs to be established.
63Combined effect of vegetable protein (soy) and soluble fiber added to a standard cholesterol-lowering diet.PubMed
D J Jenkins, C W Kendall, C C Mehling, et al.
Metabolism. 1999 Jun;48(6):809-16. doi: 10.1016/s0026-0495(99)90184-1.
Dietary treatment of hyperlipidemia focuses on reducing saturated fat and dietary cholesterol. Other aspects of diet are not emphasized at present, despite growing evidence that a number of plant components decrease serum cholesterol. We therefore determined whether a combination of two plant components, vegetable protein and soluble fiber, further reduce serum lipids when incorporated into the currently advocated low-saturated-fat diet. Thirty-one hyperlipidemic men and women ate two 1-month low-fat (<7% of total energy from saturated fat), low-cholesterol (<80 mg cholesterol/d) metabolic diets in a randomized crossover study. The major differences between test and control diets were an increased amount of vegetable protein (93% v 23% of total protein), of which 33 g/d was soy, and a doubling of soluble fiber. Fasting blood samples were obtained at the start and end of each phase. On the last 3 days of each phase, fecal collections were obtained. Compared with the low-fat control diet, the test diet decreased total cholesterol (6.2% +/- 1.2%, P < .001), low-density lipoprotein (LDL) cholesterol (6.7% +/- 1.7%, P < .001), apolipoprotein B (8.2% +/- 1.2%, P < .001), and the ratios of LDL to high-density lipoprotein (HDL) cholesterol (6.3% +/- 2.0%, P = .004) and apolipoprotein B to A-I (5.4% +/- 1.5%, P = .001). A combination of vegetable protein and soluble fiber significantly improved the lipid-lowering effect of a low-saturated-fat diet. The results support expanding the current dietary advice to include increased vegetable protein and soluble fiber intake so that the gap in effectiveness between a good diet and drug therapy is reduced.
64Combined high-intensity interval and resistance training improves cardiorespiratory fitness more than high-intensity interval training in young women with overweight/obesity: a randomized controlled trial.PubMed
Yifei Wang, Xin Yang, Jiamei Deng, et al.
Front Endocrinol (Lausanne). 2024 Nov 11;15:1450944. doi: 10.3389/fendo.2024.1450944. eCollection 2024.
OBJECTIVE: This study aimed to compare the effects of high-intensity interval training (HIIT) combined with resistance training (RT) versus HIIT alone on body composition, cardiorespiratory fitness and glycolipid metabolism in young women with overweight/obesity. METHODS: This randomized controlled trial divided 40 subjects into an experimental group (HIIT+RT) and a control group (HIIT). Both groups underwent training three times per week for eight weeks. Body composition, cardiorespiratory fitness and glycolipid levels were assessed before and after the intervention. RESULTS: The results revealed that compared to baseline, both the experimental and control groups showed significant improvements in body weight, body mass index (BMI), Body fat, waist circumference (WC), waist-hip ratio (WHR), peak oxygen uptake (VOpeak), vital capacity (VC), oxygen pulse (VO/HR), minute ventilation, resting heart rate, blood oxygen saturation, blood pressure, fasting blood glucose, triglycerides and high-density lipoprotein cholesterol (<0.05). Additionally, a significant increase in muscle mass and a significant reduction in 2-hour postprandial glucose were observed in the experimental group (<0.05). Muscle mass (mean difference: 2.75%), VOpeak (mean difference: 1.61 mL/min/kg), VC (mean difference: 334mL), and VO/HR (mean difference: 0.51mL/beat) showed greater improvement in the HIIT+RT group compared to the HIIT group (<0.05). CONCLUSION: In conclusion, an 8-week regimen of either combined HIIT and RT or HIIT significantly improves body composition, cardiorespiratory fitness and glycolipid metabolism in women with overweight/obesity. However, the combined training appears to offer more benefits than HIIT alone. Further research is needed to evaluate the long-term effects and feasibility of combined training. TRIAL REGISTRATION: https://www.chictr.org.cn/, identifier ChiCTR2300075961.
65Increased Lean Body Mass After Bodyweight-Based High Intensity Interval Training in Overweight and Obese Men.PubMed
James F Timmons, Andrew Beatty, Conor Stout, et al.
Res Q Exerc Sport. 2023 Jun;94(2):418-426. doi: 10.1080/02701367.2021.2002247. Epub 2022 Apr 1.
The effects of 8 weeks of bodyweight exercise-based, high-intensity interval training (BWHIIT) on body composition and blood-based markers of metabolic health were investigated in overweight and obese, sedentary young men. In a parallel group, PRE-POST design, n = 30 men (age, 25.7 ± 4.3 y; body mass index, 27.7 ± 2.1 kg m; 26.1 ± 5.2% body fat) were randomized to BWHIIT (n = 20) or a control group (CON; n = 10). BWHIIT consisted of supervised, group-based training sessions (~30 minutes) performed 3 times weekly. Each session consisted of 6 high-intensity bodyweight-based exercises, with each exercise being performed for 4 minutes in the manner of 8 sets of 20 seconds of exercise, 10 seconds of rest. Prior to commencing training (PRE), and 36 h after the final training session (POST), an overnight fasted blood sample was drawn, and body composition was assessed by dual-energy X-ray absorptiometry. Eighteen participants completed the intervention (CON, n = 9; BWHIIT, n = 9). Lean body mass (LBM) was increased at POST in BWHIIT compared to CON (P = .011, η = .359), with the mean (95% confidence limits) increase in LBM from PRE to POST within BWHIIT being 1.23 (0.55, 1.92) kg. Body mass and fat mass were unchanged in both groups from PRE to POST. BWHIIT had no effect on serum concentrations of total cholesterol, HDL-C, LDL-C, triglycerides, NEFA, hsCRP, or glucose. Eight weeks of bodyweight exercise-based high intensity interval training by overweight and obese sedentary young men increased LBM by ~2%, but fat mass and blood-based markers of metabolic health were unchanged.
66Responses of blood lipids to aerobic, resistance, and combined aerobic with resistance exercise training: a systematic review of current evidence.PubMed
Konstantinos Tambalis, Demosthenes B Panagiotakos, Stavros A Kavouras, et al.
Angiology. 2009 Oct-Nov;60(5):614-32. doi: 10.1177/0003319708324927. Epub 2008 Oct 30.
This review considers the effectiveness of aerobic exercise training with different intensities (moderate and high) as well as the type of exercise (aerobic, resistance, and combined aerobic with resistance) in altering the blood lipids. We reviewed various trials via a systematic search of PubMed, published reviews, and references from original articles. We selected studies that involved aerobic and/or resistance and/or combined exercise training in healthy adults over a limit of 12 weeks and had examined the response of training to one or more of the following: triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. We selected a total of 84 studies, 58 were randomized controlled trials. Comparisons between intensities of aerobic exercise programs resulted in favorable effects only for high intensity. The most frequently observed alteration was an increase in the high-density lipoprotein cholesterol, whereas reductions in triglycerides, total cholesterol, and low-density lipoprotein cholesterol appeared less often. Moreover, the evidence of the positive effect of resistance exercise marks out a trend mainly for the low-density lipoprotein cholesterol levels, whereas for combined exercise, results extracted from a short list of published studies show improvements in values of both the high-density lipoprotein cholesterol and the low-density lipoprotein cholesterol. High-intensity aerobic training results in improvement in high-density lipoprotein cholesterol. For resistance and combined exercise, the results are inconsistent. The heterogeneity between the types of exercise did not allow reliable comparisons.
67Impact of L-Citrulline Supplementation and HIIT on Lipid Profile, Arterial Stiffness, and Fat Mass in Obese Adolescents with Metabolic-Dysfunction-Associated Fatty Liver Disease: A Randomized Clinical Trial.PubMed
Alan Arturo Rodríguez-Carrillo, Mario Ramón Espinoza-Vargas, Katya Vargas-Ortiz, et al.
Nutrients. 2025 Jan 23;17(3):402. doi: 10.3390/nu17030402.
BACKGROUND: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and obesity contribute to vascular dysfunction through oxidative stress, heightening cardiovascular risk. Oral supplementation with L-citrulline (L-cit), a precursor of L-arginine (L-arg) and nitric oxide, and high-intensity interval training (HIIT) may improve vascular function and cardiometabolic health. OBJECTIVES: This study aimed to evaluate the combined effects of L-cit supplementation and HIIT on arterial stiffness, body composition, glucose metabolism, lipid profile, and blood pressure (BP) in adolescents with MASLD and obesity. METHODS: In this double-blind, placebo-controlled, randomized clinical trial (ClinicalTrials.gov (NCT05778266), 44 adolescents (15-19 years) with MASLD and obesity were assigned to HIIT + L-cit (n = 14), HIIT + placebo (n = 14), or L-cit (n = 15) for 12 weeks. HIIT sessions (85% and 60% peak heart rate during intense and recovery periods) occurred thrice weekly. Training volume progressively increased, and participants performed 20 min of HITT per session in the last 8 weeks. RESULTS: Outcomes included pulse wave velocity (PWV), augmentation index (Aix75), VO2peak, body composition, BP, glucose and lipid profiles, and hepatic steatosis. Compared to L-cit, HIIT + L-cit improved non-high-density lipoprotein cholesterol ( = 0.04), very-low-density lipoprotein cholesterol ( = 0.01), triglycerides ( = 0.02), and VO2peak ( = 0.001). No significant between-group changes were found in PWV, AIx75, hepatic steatosis, and body composition. HIIT + placebo improved VO2peak ( = 0.002), and L-cit decreased the degree of steatosis ( = 0.038). CONCLUSIONS: HIIT + L-cit supplementation enhanced lipid profile and cardiorespiratory fitness, while HIIT + placebo improved cardiorespiratory capacity, and L-cit alone decreased hepatic steatosis. Thus, L-cit could be an adjuvant strategy to manage obesity-related MASLD in adolescents.
6820-Year Follow-up of Statins in Children with Familial Hypercholesterolemia.PubMed
Ilse K Luirink, Albert Wiegman, D Meeike Kusters, et al.
N Engl J Med. 2019 Oct 17;381(16):1547-1556. doi: 10.1056/NEJMoa1816454.
BACKGROUND: Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce. METHODS: We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima-media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. RESULTS: Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter) - a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter [2.59 mmol per liter]) were achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings (mean difference adjusted for sex, -0.0001 mm per year; 95% confidence interval, -0.0010 to 0.0008). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs. 26% and 0% vs. 7%, respectively). CONCLUSIONS: In this study, initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. (Funded by the AMC Foundation.).
69Pediatric hyperlipidemia.PubMed
Ankit Garg, S Radhakrishnan
Indian Heart J. 2024 Mar;76 Suppl 1(Suppl 1):S104-S107. doi: 10.1016/j.ihj.2023.11.269. Epub 2024 Apr 8.
The leading cause of mortality worldwide is atherosclerotic cardiovascular disease. Atherosclerotic plaques are well known to originate early in the childhood. Identifying hyperlipidemia in early childhood creates an opportunity to prevent major cardiovascular events in adults. Children with identified risk factors are at an increased risk of developing cardiovascular incidents in later life. This article emphasizes the diagnosis and management of pediatric hyperlipidemia with reference to the recent guidelines. In terms of etiology pediatric hyperlipidemia are divided into primary and secondary causes. The mainstay of management includes high-risk target screening, early risk factor identification and lifestyle modifications in vulnerable population. Drug therapy is recommended in primary hyperlipidemia and in children with no response to lifestyle changes.
70Statins for children with familial hypercholesterolemia.PubMed
Alpo Vuorio, Jaana Kuoppala, Petri T Kovanen, et al.
Cochrane Database Syst Rev. 2017 Jul 7;7(7):CD006401. doi: 10.1002/14651858.CD006401.pub4.
BACKGROUND: Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid-lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low-density lipoprotein cholesterol levels. While statins seem to be safe and well-tolerated in children, their long-term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review. OBJECTIVES: To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia. SEARCH METHODS: Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline.Date of most recent search: 20 February 2017. SELECTION CRITERIA: Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion and extracted data. MAIN RESULTS: We found 26 potentially eligible studies, of which we included nine randomized placebo-controlled studies (1177 participants). In general, the intervention and follow-up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low-density lipoprotein cholesterol concentration at all time points (moderate quality evidence). Serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations, did not differ between treated and placebo groups at any time point (low quality evidence). The risks of myopathy (low quality evidence) and clinical adverse events (moderate quality evidence) were very low and also similar in both groups. In one study simvastatin was shown to improve flow-mediated dilatation of the brachial artery (low quality evidence), and in another study treatment with pravastatin for two years induced a significant regression in carotid intima media thickness (low quality evidence). AUTHORS' CONCLUSIONS: Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia. No significant safety issues were identified. Statin treatment seems to be safe in the short term, but long-term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long-term randomized controlled trials are needed to establish the long-term safety issues of statins.
71Statins for children with familial hypercholesterolemia.PubMed
Alpo Vuorio, Jaana Kuoppala, Petri T Kovanen, et al.
Cochrane Database Syst Rev. 2019 Nov 7;2019(11):CD006401. doi: 10.1002/14651858.CD006401.pub5.
BACKGROUND: Familial hypercholesterolemia is one of the most common inherited metabolic diseases and is an autosomal dominant disorder meaning heterozygotes, or carriers, are affected. Those who are homozygous have severe disease. The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data from Denmark and next generation sequencing data suggest the frequency may be closer to 1 in 250. Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both. Coronary atherosclerosis has been detected in men with heterozygous familial hypercholesterolemia as young as 17 years old and in women with heterozygous familial hypercholesterolemia at 25 years old. Since the clinical complications of atherosclerosis occur prematurely, especially in men, lifelong treatment, started in childhood, is needed to reduce the risk of cardiovascular disease. In children with the disease, diet was the cornerstone of treatment but the addition of lipid-lowering medications has resulted in a significant improvement in treatment. Anion exchange resins, such as cholestyramine and colestipol, were found to be effective, but they are poorly tolerated. Since the 1990s studies carried out on children aged 6 to 17 years with heterozygous familial hypercholesterolemia have demonstrated significant reductions in their serum total and low-density lipoprotein cholesterol levels. While statins seem to be safe and well-tolerated in children, their long-term safety in this age group is not firmly established. This is an update of a previously published version of this Cochane Review. OBJECTIVES: To assess the effectiveness and safety of statins in children with heterozygous familial hypercholesterolemia. SEARCH METHODS: Relevant studies were identified from the Group's Inborn Errors and Metabolism Trials Register and Medline. Date of most recent search: 04 November 2019. SELECTION CRITERIA: Randomized and controlled clinical studies including participants up to 18 years old, comparing a statin to placebo or to diet alone. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion and extracted data. MAIN RESULTS: We found 26 potentially eligible studies, of which we included nine randomized placebo-controlled studies (1177 participants). In general, the intervention and follow-up time was short (median 24 weeks; range from six weeks to two years). Statins reduced the mean low-density lipoprotein cholesterol concentration at all time points (high-quality evidence). There may be little or no difference in liver function (serum aspartate and alanine aminotransferase, as well as creatinine kinase concentrations) between treated and placebo groups at any time point (low-quality evidence). There may be little or no difference in myopathy (as measured in change in creatinine levels) (low-quality evidence) or clinical adverse events (moderate-quality evidence) with statins compared to placebo. One study on simvastatin showed that this may slightly improve flow-mediated dilatation of the brachial artery (low-quality evidence), and on pravastatin for two years may have induced a regression in carotid intima media thickness (low-quality evidence). No studies reported rhabdomyolysis (degeneration of skeletal muscle tissue) or death due to rhabdomyolysis, quality of life or compliance to study medication. AUTHORS' CONCLUSIONS: Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia. Few or no safety issues were identified. Statin treatment seems to be safe in the short term, but long-term safety remains unknown. Children treated with statins should be carefully monitored and followed up by their pediatricians and their care transferred to an adult lipidologist once they reach 18 years of age. Large long-term randomized controlled trials are needed to establish the long-term safety issues of statins.
72The Effect of Statins in Children and Adolescents With Familial Hypercholesterolemia: A Systematic Review.PubMed
Sarah Dombalis, Angela Nash
J Pediatr Health Care. 2021 May-Jun;35(3):292-303. doi: 10.1016/j.pedhc.2020.11.007. Epub 2020 Dec 17.
INTRODUCTION: Familial hypercholesterolemia (FH) is a genetic disorder that causes elevated low-density lipoprotein-cholesterol (LDL-C) levels. If undiagnosed and untreated in childhood, affected individuals can suffer premature health complications. Statins reduce the risks of complications for adults, but less is known about children. This systematic review examined the effectiveness of statin therapy for lowering LDL-C levels in children with FH. METHOD: Medline Ovid, Embase, CINAHL, and Allied Health Literature Plus were searched for studies that examined the effectiveness of stains in children ages 1-18 years with heterozygous FH. RESULTS: Of the 706 articles identified, 10 were included in the review. Statin therapy significantly reduced LDL-C levels in pediatric patients with FH. Statins were safe and well-tolerated with minimal adverse effects. DISCUSSION: Pediatric providers should be familiar with diagnosis, treatment, and management of FH to successfully lower LDL-C levels and avoid potential long-term health effects. Evidence suggests statins are safe and effective in children with FH.
73Management of familial hypercholesterolaemia in childhood.PubMed
Uma Ramaswami, Steve E Humphries
Curr Opin Pediatr. 2020 Oct;32(5):633-640. doi: 10.1097/MOP.0000000000000943.
PURPOSE OF REVIEW: All guidelines for the management of heterozygous familial hypercholesterolaemia in children and young people recommend statins to lower LDL-cholesterol (LDL-C) concentrations, to reduce the individual's adult risk of developing cardiovascular disease (CVD). Here, we review recent findings regarding the efficacy and safety of the use of stains in childhood. RECENT FINDINGS: As expected from their safety profile in adults, there is no evidence from short-term trials or long-term follow-up that statin use in children is associated with any adverse effects on growth, pubertal development or muscle or liver toxicity. Long-term follow-up indicates benefits with respect to lower CVD rates. Factors that influence adherence are discussed, as is the role of the underlying genetic causes for hypercholesterolaemia and of variation at other genes in determining the LDL-C-lowering effect. SUMMARY: Based on the good safety profile, and the expert opinion guidelines, clinicians should consider prescribing statins for children with hypercholesterolaemia from the age of at least 10 years (and earlier if CVD risk is particularly high in the family). Uptitrating statin dosage and the use of additional lipid-lowering therapies should be considered so that LDL-C concentrations are lowered to recommended targets.
74Efficacy and safety of PCSK9 inhibitors in real life.PubMed
Antón González-Guerrero, Eugenia Navarrete-Rouco, David Benaiges, et al.
Clin Investig Arterioscler. 2025 Sep-Oct;37(5):500755. doi: 10.1016/j.arteri.2024.500755. Epub 2025 Jan 25.
OBJECTIVE: To confirm the effectiveness and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in daily clinical practice. METHODS: Retrospective observational study of patients from hospital registry of PCSK9 inhibitor treatment with a follow-up ≥ 6 months. The lipid-lowering effect and safety were evaluated. RESULTS: Of the 193 patients included in the study, 168 (87%) had cardiovascular disease, and 54 (28%) had familial hypercholesterolemia; 85 (44%) were intolerant to statins/ezetimibe. No differences between alirocumab and evolocumab groups regarding the rate of LDL-C reduction ≥ 50% (82.8% vs. 83.1%), achievement of the therapeutic target (60.9% vs. 65.5%), or complete remission (60.2% vs. 58.5%) were found. An erythema at the injection site in one patient treated with alirocumab and urticaria in one patient treated with evolocumab were recorded. According to the logistic regression analysis, complete remission of LDL-C in subjects treated with PCSK9 inhibitors was positively associated with increased age (OR: 1.045; 95%CI: 1.0-1.092; P=.049) and active smoking (OR: 4.562; 95%CI: 1.434-14.515; P=.010), and negatively associated with female gender (OR: 0.403; 95%CI: 0.171-0.949; P=.038), baseline LDL-C levels (OR: 0.969; 95%CI: 0.957-0.981; P<.001)and statin/ezetimibe intolerance (OR: 0.403; 95%CI: 0.176-0.925; P=.041). CONCLUSION: This real-world practice study has confirmed that PCSK9 inhibitors are effective, safe and well tolerated, with lipid-lowering effects comparable to those described in randomized controlled trials, regardless of the monoclonal antibody used.
75PCSK9 inhibitors revisited: Effectiveness and safety of PCSK9 inhibitors in a real-life Spanish cohort.PubMed
Juan Vicente-Valor, Xandra García-González, Sara Ibáñez-García, et al.
Biomed Pharmacother. 2022 Feb;146:112519. doi: 10.1016/j.biopha.2021.112519. Epub 2021 Dec 28.
INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have emerged as a therapeutic option for patients with hypercholesterolemia who do not attain low-density lipoprotein cholesterol (LDL-C) goals and/or are intolerant to other lipid-lowering drugs. Our aim was to analyze the effectiveness and safety of PCSK9i in routine clinical practice and factors related to poor outcomes. MATERIALS AND METHODS: We conducted an ambispective study in 115 patients who recieved alirocumab or evolocumab, in a tertiary level hospital. From February 2017 to April 2020, patients were recruited and followed up for a median of 20.4 months. The main outcomes were relative reduction in LDL-C, percentage of patients achieving the therapeutic goals established by 2016 ESC/EAS guidelines, incidence of major cardiovascular events (MACEs) and drug-related adverse events (ADRs). RESULTS: The median LDL-C achieved was 57.0 mg/dL (relative reduction of 59.9% from baseline, p< 0.001). After adjusting for confounders, smaller LDL-C reductions were related to female sex, absence of concomitant lipid-lowering therapy and treatment with alirocumab. Overall, 84.6% of the patients achieved the therapeutic goals. During follow-up, 7 MACEs were detected. ADRs, generally considered mild, affected 38.1% of the participants (mainly mialgias and arthralgias) and triggered discontinuations in 8.7% of cases. CONCLUSIONS: PCSK9i are effective and safe, although certain factors may influence their effectiveness. Interestingly, our results suggest that alirocumab and evolocumab may not be therapeutic equivalents, as initially suggested.
76The First Report of a Real-world Experience With a PCSK9 Inhibitor in a Large Familial Hyperlipidemia and Very-high-risk Middle Eastern Population.PubMed
Sajid Iqbal, Hani Mohamed Sabbour, Mohsin Sohail Siddiqui, et al.
Clin Ther. 2022 Oct;44(10):1297-1309. doi: 10.1016/j.clinthera.2022.08.005. Epub 2022 Sep 17.
PURPOSE: Evolocumab, a monoclonal inhibitor of proprotein convertase subtilisin/kexin 9, has been shown to reduce proatherogenic lipoproteins in patients with or without familial hypercholesterolemia (FH), diabetes mellitus, or atherosclerotic cardiovascular disease (ASCVD). We explored the safety profile and clinical effectiveness of evolocumab in an outpatient population of Emirati individuals with FH diagnosed per Dutch Lipid Clinic Network criteria, previous ASCVD, or statin intolerance. METHODS: This study was a retrospective review of patients initiating evolocumab treatment for any indication at Imperial College London Diabetes Centre between 2017 and 2020. All individuals followed up for at least 90 days or with at least one lipid panel postinitiation were included. Participants were subclassified into primary prevention (no previous ASCVD event, n = 81) and secondary prevention (any prior clinical ASCVD event, n = 102) groups. FINDINGS: Evolocumab was initiated in 183 individuals (mean [SD] age, 51.5 [12.4] years; 51% male); 108 (59%) had a clinical or genetic FH diagnosis, and 70.5% had diabetes mellitus. Statin intolerance was a treatment indication in 60 (32.8%) individuals. At 90 days, substantial reductions in serum LDL-C, triglycerides (TG), and total cholesterol:HDL-C (TC:HDL-C) were observed in both the primary and secondary prevention groups, and both FH and non-FH individuals. In the primary prevention group, median (interquartile range) reduction in LDL-C was 43.7% (10.8%; 63.0%); TG, 15.0% (7.2%; 35.3%); and TC:HDL-C, 31.5% (11.1%; 46.0%). In the secondary prevention group, median (interquartile range) reduction in LDL-C was 48.3% (22%; 70%); TG, 19.6% (1.2%; 32.5%); and TC:HDL-C, 32.6% (14.6%; 46.3%) (all, P < 0.0001). American College of Cardiology/American Heart Association LDL-C targets were consistently achieved in 114 (62.3%) patients during a follow-up of 359 (79-639) days. Nonattainment of the LDL-C target was attributed to nonadherence in 36 (52.2%) patients and discontinuation of treatment in 14 (20.3%) patients. Evolocumab was discontinued in 4 patients because of adverse events. IMPLICATIONS: This study is the first from the Middle East and North Africa region that reports the real-world efficacy of evolocumab in a mixed risk population of individuals with FH and other non-FH indications. Clinically meaningful and sustained reductions in LDL-C, TG, and cholesterol ratios were observed after evolocumab initiation. Few adverse events were reported in this predominantly Arabic population, consistent with previous safety reports for evolocumab. Notable strengths of this study include a relatively large cohort, patient heterogeneity and high retention, and a minimum follow-up of 1 year. Despite these strengths, the study has some limitations, including the selection bias due to the retrospective design and absence of comparative group.
77Effectiveness and safety of PCSK9 inhibitor therapy in patients with familial hypercholesterolemia within a therapeutic program in Poland: Preliminary multicenter data.PubMed
Krzysztof Chlebus, Barbara Cybulska, Piotr Dobrowolski, et al.
Cardiol J. 2022;29(1):62-71. doi: 10.5603/CJ.a2022.0003. Epub 2022 Feb 11.
BACKGROUND: In Poland, treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has become available free of charge in a therapeutic program. Assessed herein, is the efficacy and safety of alirocumab and evolocumab in patients with heterozygous familial hypercholesterolemia (FH). METHODS: Data of 55 adult FH patients who participated in the program were analyzed upon meeting the criteria established by the Ministry of Health (low density lipoprotein cholesterol [LDL-C] above 160 mg/dL on max. tolerated statin dose and ezetimib). The efficacy of PCSK9 inhibitors in reducing LDL-C with drug administration every 2 weeks was assessed after 3 months and 1 year of therapy. A safety profile evaluation was performed at each visit. 48 patients completed the 3-month and 21 for the 1-year observation periods (34 patients treated with alirokumab and 14 with evolocumab). RESULTS: The mean concentration of direct-measured LDL-C decreased from the initial level of 215.1 ± 74.5 mg/dL to 75.3 ± 64.1 mg/dL, i.e., by 65 ± 14% following 3 months of treatment. This effect was stable in 1-year observation (77.7 ± 72.8 mg/dL). Adverse effects were flu-like symptoms (13.0%), injection site reactions (11.1%), fatigue (5.6%) and musculoskeletal symptoms (5.6%). Seven patients failed to complete the 3-month treatment period due to side effects or non-compliance, and 1 patient failed to complete the 1-year treatment due to myalgia. CONCLUSIONS: This study confirmed high effectiveness of PCSK9 inhibitors in reducing LDL-C levels in patients with FH. Due to restrictive inclusion criteria with LDL-C threshold level > 160 mg/dL (> 4.1 mmol/L) required for participation in the therapeutic program, a relatively small number of FH patients were eligible for treatment.
78Real-world effectiveness of monoclonal antibody inhibitors of PCSK9 in patients with heterozygous familial hypercholesterolemia: A retrospective cohort study.PubMed
Rebecca Siemens, Mark Pryjma, Susan Buchkowsky, et al.
Pharmacotherapy. 2024 Sep;44(9):730-737. doi: 10.1002/phar.4609. Epub 2024 Sep 6.
BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is a genetic condition that is associated with a high risk of atherosclerotic cardiovascular disease (ASCVD) due to elevated lipid levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody inhibitors have been shown to reduce low-density lipoprotein cholesterol (LDL-C) substantially. This study aimed to assess the real-world effectiveness of PCSK9 inhibitor therapy among patients with HeFH. METHODS: Retrospective cohort study of patients with probable or definite HeFH on a PCSK9 inhibitor at a specialized lipid clinic between 2015 and 2022. The primary objective was the proportion of patients who attained a ≥50% reduction in LDL-C after 12 months of treatment. RESULTS: In total, 141 patients were screened and 95 were included. Mean age was 63 years, 51% were female, and mean baseline LDL-C level was 4.0 mmol/L (155 mg/dL). A majority of patients (60%) had statin intolerance, and 73% were on ezetimibe. The most common PCSK9 inhibitor was evolocumab (94%). Overall, 74% of patients achieved a ≥50% reduction in LDL-C after 12 months of therapy. Mean LDL-C concentration decreased to 1.7 mmol/L (66 mg/dL) (approximately 59% reduction from baseline) after 12 months of follow-up but increased to 1.9 mmol/L (73 mg/dL) after ≥24 months of follow-up. Similar trends were observed in non-high-density lipoprotein cholesterol and apolipoprotein B. Lipoprotein(a) was significantly reduced by 45% over 12 months. Twelve percent of patients permanently discontinued therapy. Barriers to PCSK9i use were mostly related to cost. CONCLUSIONS: In a real-world cohort of HeFH patients, most of which were intolerant to statins, a high majority were able to achieve a ≥50% reduction in LDL-C after 12 months of PCSK9 inhibitor therapy (mean reduction of approximately 59%), which is similar to clinical trial data of patients with ASCVD. A significant reduction in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) were also observed.
79Safety and Effectiveness of Low-Density Lipoprotein Cholesterol-Lowering Therapy With Evolocumab for Familial Hypercholesterolemia/Hypercholesterolemia in Japan: A Real-World, Postmarketing, Single-Arm Study.PubMed
Koutaro Yokote, Junya Ako, Kazuo Kitagawa, et al.
J Am Heart Assoc. 2024 Nov 5;13(21):e035809. doi: 10.1161/JAHA.124.035809. Epub 2024 Oct 29.
BACKGROUND: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 approved in Japan for familial hypercholesterolemia (FH) and hypercholesterolemia; however, data on its safety and effectiveness in the real-world setting in Japan are limited. METHODS AND RESULTS: This real-world, postmarketing, single-arm study assessed the safety and effectiveness of low-density lipoprotein cholesterol lowering with evolocumab in patients with homozygous/heterozygous familial hypercholesterolemia and hypercholesterolemia with high risk in Japan (668 sites). The primary safety end point was the incidence (percentage) and number of patients with adverse drug reactions and serious adverse events during the 104-week follow-up. Primary effectiveness end points included the percentage change in low-density lipoprotein cholesterol levels from baseline to week 12, assessed using 2-sided paired tests. The safety and effectiveness sets comprised 3724 (homozygous FH, n=108; heterozygous FH, n=2009; hypercholesterolemia with high risk, n=1607) and 2797 (homozygous FH, n=91; heterozygous FH, n=1615; hypercholesterolemia with high risk, n=1091) patients, respectively. Overall, mean age and disease duration were 63.2 and 12.3 years, respectively. Serious adverse drug reactions and serious adverse events were experienced by 0.5% and 10.3% of patients; the incidence rates of myocardial infarction and stroke were 0.7% and 0.3%, respectively. A significant mean±SD percentage change in low-density lipoprotein cholesterol levels was observed at week 12 among patients with homozygous FH (-45.7%±28.2; <0.001), heterozygous FH (-55.9%±28.8; <0.001), and hypercholesterolemia with high risk (-63.3%±23.7; <0.001). CONCLUSIONS: Evolocumab was well tolerated, and real-world patients with familial hypercholesterolemia and hypercholesterolemia with high risk in Japan had sustained low-density lipoprotein cholesterol reduction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02808403.
80Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial.PubMed
Daniel Gaudet, Denes Pall, Gerald F Watts, et al.
JAMA Cardiol. 2024 Jul 1;9(7):620-630. doi: 10.1001/jamacardio.2024.0959.
IMPORTANCE: Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains. OBJECTIVE: To determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering-RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG. DESIGN, SETTING, AND PARTICIPANTS: The Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 centers across the US, Europe, New Zealand, Australia, and Canada from May 31, 2021, to August 31, 2023. Eligible patients had fasting triglyceride levels in the range of 500 to 4000 mg/dL (to convert to millimoles per liter, multiply by 0.0113) while receiving stable lipid-lowering treatment. INTERVENTIONS: Participants received 2 subcutaneous doses of plozasiran (10, 25, or 50 mg) or matched placebo on day 1 and at week 12 and were followed up through week 48. MAIN OUTCOMES AND MEASURES: The primary end point evaluated the placebo-subtracted difference in means of percentage triglyceride change at week 24. Mixed-model repeated measures were used for statistical modeling. RESULTS: Of 229 patients, 226 (mean [SD] age, 55 [11] years; 176 male [78%]) were included in the primary analysis. Baseline mean (SD) triglyceride level was 897 (625) mg/dL and plasma APOC3 level was 32 (16) mg/dL. Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose. Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL. Plozasiran was associated with dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) level, which was significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001). However, apolipoprotein B (ApoB) levels did not increase, and non-high-density lipoprotein cholesterol (HDL-C) levels decreased significantly at all doses, with a placebo-adjusted change of -20% at the highest dose. There were also significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48. Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of patients with sHTG, plozasiran decreased triglyceride levels, which fell below the 500 mg/dL threshold of acute pancreatitis risk in most participants. Other triglyceride-related lipoprotein parameters improved. An increase in LDL-C level was observed but with no change in ApoB level and a decrease in non-HDL-C level. The safety profile was generally favorable at all doses. Additional studies will be required to determine whether plozasiran favorably modulates the risk of sHTG-associated complications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04720534.
81Updates in Drug Treatment of Severe Hypertriglyceridemia.PubMed
Ioanna Gouni-Berthold, Jonas Schwarz, Heiner K Berthold
Curr Atheroscler Rep. 2023 Oct;25(10):701-709. doi: 10.1007/s11883-023-01140-z. Epub 2023 Aug 29.
PURPOSE OF REVIEW: To provide an insight into the new pharmacological options for the treatment of severe hypertriglyceridemia (sHTG). RECENT FINDINGS: sHTG is difficult to treat. The majority of the traditional pharmacological agents available have limited success in both robustly decreasing triglyceride levels and/or in reducing the incidence of acute pancreatitis (AP), the most severe complication of sHTG. Therapeutic options with novel mechanisms of action have been developed, such as antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeting APOC3 and ANGPTL3. The review discusses also 2 abandoned drugs for sHTG treatment, evinacumab and vupanorsen. The ASO targeting APOC3, volanesorsen, is approved for use in patients with familial chylomicronemia syndrome (FCS) in Europe. Olezarsen, an N-acetylgalactosamine (GalNAc)-conjugated ASO with the same target, seems to have a better safety and efficacy profile. siRNA targeting APOC3 and ANGPTL3, namely ARO-APOC3 and ARO-ANG3, are also promising for the treatment of sHTG. However, the ultimate clinical goal of any sHTG treatment, the decrease in the risk of AP, has not been definitively achieved till now by any pharmacotherapy, either approved or in development.
82APOC3 siRNA and ASO therapy for dyslipidemia.PubMed
Jasmine Chebli, Miriam Larouche, Daniel Gaudet
Curr Opin Endocrinol Diabetes Obes. 2024 Apr 1;31(2):70-77. doi: 10.1097/MED.0000000000000857. Epub 2024 Feb 9.
PURPOSE OF REVIEW: The aim of this review is to present the clinical indications of apolipoprotein C-III (apoC3) inhibition in the therapeutic arsenal for the treatment of lipid disorders and associated risks and to compare the most advanced modalities of apoC3 inhibition currently available or in development, specifically APOC3 antisense oligonucleotides (ASO) and small interfering RNA (siRNA). RECENT FINDINGS: ApoC3 inhibition significantly decreases triglyceride levels by mechanisms coupling both lipoprotein lipase (LPL) upregulation and LPL-independent mechanisms. The main apoC3 inhibitors in advanced clinical development are the GalNAc-ASO olezarsen and the GalNAc-siRNA plozasiran. Clinical studies conducted with volanesorsen, the olezarsen precursor, showed a favorable effect on hepatic steatosis (nonalcoholic fatty liver disease, NAFLD). Olezarsen does not appear to be associated with the main side effects attributed to volanesorsen including thrombocytopenia. Plozasiran is in advanced clinical development and requires subcutaneous injection every 3 months and present to-date an efficacy and safety profile comparable to that of the monthly ASO. SUMMARY: Inhibition of apoC3 is effective across all the spectrum of hypertriglyceridemia, might have a favorable effect on hepatic steatosis (NAFLD) and the effect of apoC3 inhibition on cardiovascular risk is not limited to its effect on plasma triglycerides. APOC3 GalNAc-conjugated ASO and siRNA are both effective in decreasing plasma apoC3 and triglyceride levels.
83Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia.PubMed
Christie M Ballantyne, Szilard Vasas, Masoud Azizad, et al.
N Engl J Med. 2024 Sep 12;391(10):899-912. doi: 10.1056/NEJMoa2404143. Epub 2024 May 28.
BACKGROUND: Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase. METHODS: We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24. RESULTS: A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose. CONCLUSIONS: In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.).
84Potentials of artificial intelligence in familial hypercholesterolemia: Advances in screening, diagnosis, and risk stratification for early intervention and treatment.PubMed
Mohammad Athar
Int J Cardiol. 2024 Oct 1;412:132315. doi: 10.1016/j.ijcard.2024.132315. Epub 2024 Jul 6.
Familial hypercholesterolemia (FH) poses a global health challenge due to high incidence rates and underdiagnosis, leading to increased risks of early-onset atherosclerosis and cardiovascular diseases. Early detection and treatment of FH is critical in reducing the risk of cardiovascular events and improving the long-term outcomes and quality of life for affected individuals and their families. Traditional therapeutic approaches revolve around lipid-lowering interventions, yet challenges persist, particularly in accurate and timely diagnosis. The current diagnostic landscape heavily relies on genetic testing of specific LDL-C metabolism genes, often limited to specialized centers. This constraint has led to the adoption of alternative clinical scores for FH diagnosis. However, the rapid advancements in artificial intelligence (AI) and machine learning (ML) present promising solutions to these diagnostic challenges. This review explores the intricacies of FH, highlighting the challenges that are encountered in the diagnosis and management of the disorder. The revolutionary potential of ML, particularly in large-scale population screening, is highlighted. Applications of ML in FH screening, diagnosis, and risk stratification are discussed, showcasing its ability to outperform traditional criteria. However, challenges and ethical considerations, including algorithmic stability, data quality, privacy, and consent issues, are crucial areas that require attention. The review concludes by emphasizing the significant promise of AI and ML in FH management while underscoring the need for ethical and practical vigilance to ensure responsible and effective integration into healthcare practices.
85Algorithms for Treating Dyslipidemia in Youth.PubMed
Grace K Kim, Jennifer K Yee, Nidhi Bansal
Curr Atheroscler Rep. 2023 Aug;25(8):495-507. doi: 10.1007/s11883-023-01122-1. Epub 2023 Jul 31.
PURPOSE OF REVIEW: The goal of this article is to review algorithms for treating dyslipidemia in youth, discuss pitfalls, propose enhanced algorithms to address pitfalls, and consider future directions. RECENT FINDINGS: The presence of modifiable and non-modifiable cardiovascular disease (CVD) risk factors during childhood is associated with CVD-related events in adulthood. Recent data has shown that childhood initiation of statin therapy in youth < 18 years of age with familial hypercholesterolemia reduces the risk of adult CVD. However, pediatric dyslipidemia remains undertreated in part due to a lack of primary health care providers with adequate understanding of screening guidelines and pediatric lipidologists with experience in treatment and follow-up of this unique population. Management algorithms have been published by the National Heart, Lung, and Blood Institute and American Heart Association as tools to empower clinicians to manage dyslipidemia. We propose enhanced algorithms, which incorporate recently approved pharmacotherapy to address the management gaps. Future algorithms based upon clinical risk scores may enhance treatment and improve outcomes. Algorithms for dyslipidemia management which target youth < 18 years of age are tools which empower clinicians to manage dyslipidemia in this unique population. Enhanced algorithms may help address pitfalls. We acknowledge the need for further risk assessment tools in pediatrics for tailored dyslipidemia management.
86The functions of apolipoproteins and lipoproteins in health and disease.PubMed
Zijun Ma, Jixin Zhong, Wei Tu, et al.
Mol Biomed. 2024 Oct 28;5(1):53. doi: 10.1186/s43556-024-00218-7.
Lipoproteins and apolipoproteins are crucial in lipid metabolism, functioning as essential mediators in the transport of cholesterol and triglycerides and being closely related to the pathogenesis of multiple systems, including cardiovascular. Lipoproteins a (Lp(a)), as a unique subclass of lipoproteins, is a low-density lipoprotein(LDL)-like particle with pro-atherosclerotic and pro-inflammatory properties, displaying high heritability. More and more strong evidence points to a possible link between high amounts of Lp(a) and cardiac conditions like atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis (AS), making it a risk factor for heart diseases. In recent years, Lp(a)'s role in other diseases, including neurological disorders and cancer, has been increasingly recognized. Although therapies aimed at low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) have achieved significant success, elevated Lp(a) levels remain a significant clinical management problem. Despite the limited efficacy of current lipid-lowering therapies, major clinical advances in new Lp(a)-lowering therapies have significantly advanced the field. This review, grounded in the pathophysiology of lipoproteins, seeks to summarize the wide-ranging connections between lipoproteins (such as LDL-C and HDL-C) and various diseases, alongside the latest clinical developments, special emphasis is placed on the pivotal role of Lp(a) in cardiovascular disease, while also examining its future potential and mechanisms in other conditions. Furthermore, this review discusses Lp(a)-lowering therapies and highlights significant recent advances in emerging treatments, advocates for further exploration into Lp(a)'s pathogenic mechanisms and its potential as a therapeutic target, proposing new secondary prevention strategies for high-risk individuals.
87Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention.PubMed
Daniel Tobias Michaeli, Julia Caroline Michaeli, Sebastian Albers, et al.
Am J Cardiovasc Drugs. 2023 Sep;23(5):477-495. doi: 10.1007/s40256-023-00594-5. Epub 2023 Jul 24.
Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.
88The evolving landscape of targets for lipid lowering: from molecular mechanisms to translational implications.PubMed
Christie M Ballantyne, Giuseppe D Norata
Eur Heart J. 2025 Nov 21;46(44):4737-4750. doi: 10.1093/eurheartj/ehaf606.
Cardiovascular disease remains a major global health challenge, with dyslipidaemia being a key modifiable risk factor. While low density lipoprotein cholesterol (LDL-C) is the primary target for lipid-lowering therapies, recent evidence highlights the importance of triglycerides, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] for residual cardiovascular risk. Current lipid-lowering therapies target key enzymes and proteins involved in cholesterol and lipid metabolism. Statins inhibit HMG-CoA reductase, reducing cholesterol biosynthesis and increasing LDL receptor (LDLR) expression in the liver. Bempedoic acid inhibits ATP citrate lyase, the enzyme upstream of HMG-CoA reductase in the mevalonate pathway, offering an alternative to statins by selectively acting in the liver, minimizing muscle-related side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide decanoate (MK0616)] prevent LDLR degradation, while ezetimibe limits intestinal cholesterol absorption. Emerging lipid-lowering targets include angiopoietin-like 3 protein (ANGPTL3) and apolipoprotein C-III (apoC-III). Inhibiting ANGPTL3 reduces both triglycerides and LDL-C independently of LDL receptor. Inhibition of apoC-III unleashes lipoprotein lipase (LPL) activity, promoting triglyceride-rich particle catabolism, even in complete LPL deficiency. Cholesteryl ester transfer protein (CETP) inhibition also increases the catabolism of apoB-containing lipoproteins. Ongoing research into strategies to reduce Lp(a), primarily but not exclusively through antisense therapies, aims to demonstrate the cardiovascular benefits of targeting this lipoprotein. In summary, the field of targets for lipid and lipoprotein lowering is constantly evolving and offers new strategies for patients resistant to current therapies or with specific lipid profile abnormalities.
89Nutrition and Lifestyle Interventions in Managing Dyslipidemia and Cardiometabolic Risk.PubMed
Hygerta Berisha, Reham Hattab, Laura Comi, et al.
Nutrients. 2025 Feb 23;17(5):776. doi: 10.3390/nu17050776.
Dyslipidemia, characterized by abnormal blood lipid levels, is a major public health concern due to its association with atherosclerotic cardiovascular disease (ASCVD) and other cardiometabolic disorders. In this context, appropriate nutrition patterns are pivotal as they represent the basic approach for providing a wide range of substantial advantages. The best evidence for dyslipidemia management is offered by the Mediterranean Diet, the Plant-Based Diet, the High-Fiber Diet and the Anti-inflammatory Diet, while the DASH Diet and the Ketogenic Diet have also been shown to target additional pathological features like hypertension and other comorbidities. The bioactive compounds that are enriched in these nutrition patterns and able to manage dyslipidemia include monounsaturated fatty acids such as ω-3, polyphenols such as oleuropein, resveratrol, flavonoids, and catechins, carotenoids, phytosterols and soluble and unsoluble fibers. Diets rich in these compounds can improve lipid profile by mitigating oxidative stress, reducing low-grade chronic inflammation, modulating macronutrient absorption and other mechanisms, thereby supporting cardiovascular health. Additionally, lifestyle interventions such as regular physical activity, weight loss, reduced alcohol consumption and smoking cessation further ameliorate lipid metabolism and manage circulated lipid profile. Furthermore, emerging insights from nutrigenomics underscore the potential for proper diet to address genetic factors and optimize treatment outcomes. The pivotal role of nutrition interventions in the context of dyslipidemia and its cardiometabolic implications is discussed in this review, emphasizing evidence-based and personalized approaches.
90Nutrition interventions for adults with dyslipidemia: A Clinical Perspective from the National Lipid Association.PubMed
Carol F Kirkpatrick, Geeta Sikand, Kristina S Petersen, et al.
J Clin Lipidol. 2023 Jul-Aug;17(4):428-451. doi: 10.1016/j.jacl.2023.05.099. Epub 2023 Jun 2.
Lifestyle habits can have a profound impact on atherosclerotic cardiovascular disease (ASCVD) risk. The National Lipid Association previously published recommendations for lifestyle therapies to manage dyslipidemia. This Clinical Perspective provides an update with a focus on nutrition interventions for the three most common dyslipidemias in adults: 1) low-density lipoprotein cholesterol (LDL-C) elevation; 2) triglyceride (TG) elevation, including severe hypertriglyceridemia with chylomicronemia; and 3) combined dyslipidemia, with elevations in both LDL-C and TG levels. Lowering LDL-C and non-high-density lipoprotein cholesterol are the primary objectives for reducing ASCVD risk. With severe TG elevation (≥500 mg/dL), the primary objective is to prevent pancreatitis and ASCVD risk reduction is secondary. Nutrition interventions that lower LDL-C levels include reducing cholesterol-raising fatty acids and dietary cholesterol, as well as increasing intakes of unsaturated fatty acids, plant proteins, viscous fibers, and reducing adiposity for patients with overweight or obesity. Selected dietary supplements may be employed as dietary adjuncts. Nutrition interventions for all patients with elevated TG levels include restricting intakes of alcohol, added sugars, and refined starches. Additional lifestyle factors that reduce TG levels are participating in daily physical activity and reducing adiposity in patients with overweight or obesity. For patients with severe hypertriglyceridemia, an individualized approach is essential. Nutrition interventions for addressing concurrent elevations in LDL-C and TG include a combination of the strategies described for lowering LDL-C and TG. A multidisciplinary approach is recommended to facilitate success in making and sustaining dietary changes and the assistance of a registered dietitian nutritionist is highly recommended.
91Firefighter health and fitness assessment: a call to action.PubMed
Thomas W Storer, Brett A Dolezal, Marlon L Abrazado, et al.
J Strength Cond Res. 2014 Mar;28(3):661-71. doi: 10.1519/JSC.0b013e31829b54da.
Sudden cardiac deaths experienced by firefighters in the line of duty account for the largest proportion of deaths annually. Several fire service standards for fitness and wellness have been recommended but currently only 30% of U.S. fire departments are implementing programs for this purpose. The Department of Homeland Security Science and Technology Directorate has initiated the Physiological Health Assessment System for Emergency Responders (PHASER) program aiming to reduce these line-of-duty deaths through an integration of medical science and sensor technologies. Confirming previous reports, PHASER comprehensive risk assessment has identified lack of physical fitness with propensity for overexertion as a major modifiable risk factor. We sought to determine if current levels of fitness and cardiovascular disease (CVD) risk factors in a contemporary cohort of firefighters were better than those reported over the past 30 years. Fifty-one firefighters from a Southern California department were characterized for physical fitness and CVD risk factors using standard measures. Overall, physical fitness and risk factors were not different from previous reports of firefighter fitness and most subjects did not achieve recommended fitness standards. Considering the lack of widespread implementation of wellness/fitness programs in the U.S. fire service together with our findings that low physical fitness and the presence of CVD risk factors persist, we issue a call to action among health and fitness professionals to assist the fire service in implementing programs for firefighters that improve fitness and reduce CVD risk factors. Fitness professionals should be empowered to work with fire departments lending their expertise to guide programs that achieve these objectives, which may then lead to reduced incidence of sudden cardiac death or stroke.
92Exercise and diabetes.PubMed
M Bergman, C Auerhahn
Am Fam Physician. 1985 Oct;32(4):105-11.
Exercise has variable effects on diabetes control. It may cause deterioration in diabetes regulation if patients are hyperglycemic, whereas it may reduce blood glucose levels in well-controlled patients. Factors influencing the magnitude of blood glucose reduction include timing of meal ingestion, peak of insulin activity and whether the extremity injected is exercised. Plasma cholesterol and triglyceride levels decrease while high-density lipoprotein levels may increase with activity.
93Activity Tracker-Based Metrics as Digital Markers of Cardiometabolic Health in Working Adults: Cross-Sectional Study.PubMed
Yuri Rykov, Thuan-Quoc Thach, Gerard Dunleavy, et al.
JMIR Mhealth Uhealth. 2020 Jan 31;8(1):e16409. doi: 10.2196/16409.
BACKGROUND: Greater adoption of wearable devices with multiple sensors may enhance personalized health monitoring, facilitate early detection of some diseases, and further scale up population health screening. However, few studies have explored the utility of data from wearable fitness trackers in cardiovascular and metabolic disease risk prediction. OBJECTIVE: This study aimed to investigate the associations between a range of activity metrics derived from a wearable consumer-grade fitness tracker and major modifiable biomarkers of cardiometabolic disease in a working-age population. METHODS: This was a cross-sectional study of 83 working adults. Participants wore Fitbit Charge 2 for 21 consecutive days and went through a health assessment, including fasting blood tests. The following clinical biomarkers were collected: BMI, waist circumference, waist-to-hip ratio, blood pressure, triglycerides (TGs), high-density lipoprotein (HDL) and low-density lipoprotein cholesterol, and blood glucose. We used a range of wearable-derived metrics based on steps, heart rate (HR), and energy expenditure, including measures of stability of circadian activity rhythms, sedentary time, and time spent at various intensities of physical activity. Spearman rank correlation was used for preliminary analysis. Multiple linear regression adjusted for potential confounders was used to determine the extent to which each metric of activity was associated with continuous clinical biomarkers. In addition, pairwise multiple regression was used to investigate the significance and mutual dependence of activity metrics when two or more of them had significant association with the same outcome from the previous step of the analysis. RESULTS: The participants were predominantly middle aged (mean age 44.3 years, SD 12), Chinese (62/83, 75%), and male (64/83, 77%). Blood biomarkers of cardiometabolic disease (HDL cholesterol and TGs) were significantly associated with steps-based activity metrics independent of age, gender, ethnicity, education, and shift work, whereas body composition biomarkers (BMI, waist circumference, and waist-to-hip ratio) were significantly associated with energy expenditure-based and HR-based metrics when adjusted for the same confounders. Steps-based interdaily stability of circadian activity rhythm was strongly associated with HDL (beta=5.4 per 10% change; 95% CI 1.8 to 9.0; P=.005) and TG (beta=-27.7 per 10% change; 95% CI -48.4 to -7.0; P=.01). Average daily steps were negatively associated with TG (beta=-6.8 per 1000 steps; 95% CI -13.0 to -0.6; P=.04). The difference between average HR and resting HR was significantly associated with BMI (beta=-.5; 95% CI -1.0 to -0.1; P=.01) and waist circumference (beta=-1.3; 95% CI -2.4 to -0.2; P=.03). CONCLUSIONS: Wearable consumer-grade fitness trackers can provide acceptably accurate and meaningful information, which might be used in the risk prediction of cardiometabolic disease. Our results showed the beneficial effects of stable daily patterns of locomotor activity for cardiometabolic health. Study findings should be further replicated with larger population studies.