Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.

中文翻译：

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橄榄苦苷、羟基酪醇、油棘醛及其组合的心脏保护潜力：揭示对急性心肌梗死和代谢综合征的互补作用


临床研究此前已经确定了橄榄产品在预防心血管疾病（CVD）方面的作用，但其有益作用的主要成分仍有待确定。我们试图评估和比较橄榄苦苷 (OL)、羟基酪醇 (HT)、齐墩果醛 (OC) 和齐墩果酸 (OA) 在缓解缺血/再灌注损伤 (IRI) 和 CVD 危险因素方面的心脏保护潜力。该研究的范围是通过实验室到临床的方法为高心血管风险患者设计一种有效且安全的组合疗法。我们在患有代谢综合征 (MS) 的健康小鼠中评估了 OL、HT、OC 或 OA 营养剂量 6 周治疗的 IRI 限制潜力。设计了三种组合方案，与分离的化合物相比，混合物具有显着的益处（OL-HT-OC，组合 2），包括梗塞预防和抗血糖功效，并进一步研究了其抗动脉粥样硬化作用。体内实验表明，Combo 2 的联合方案在限制梗塞面积和高血糖方面表现出最有利的效果，选择该方案在慢性冠状动脉综合征 (CCAS) 患者的临床环境中进行进一步研究。在临床研究中，在基线和使用 OL-HT-OC 补充剂治疗 4 周后对心脏功能、炎症标志物和氧化应激进行了评估。我们发现，与对照组相比，OL、OC 和 OA 显着减少了体内梗塞面积。 OL 表现出抗高血糖特性，而 OA 则减弱高胆固醇血症。 OL-HT-OA、OL-HT-OC 和 OL-HT-OC-OA 联合方案具有心脏保护作用，而只有 OL-HT-OC 可以减轻高血糖。 Combo 2 的心脏保护作用归因于细胞凋亡抑制、抗氧化作用增强和抗氧化酶上调。此外，它还减少了体内动脉粥样硬化斑块的程度。在小规模临床研究中，补充 OL-HT-OC 可改善心脏、血管和内皮功能。总之，OL-HT-OC 联合疗法在体内发挥有效的心脏保护、降血糖和抗动脉粥样硬化特性，对高危患者具有显着且可临床转化的心血管益处。