Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial
Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial
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DOI：
10.1161/01.atv.0000121571.78696.dc
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发表时间：
2004-04-01
影响因子：
8.7
通讯作者：
Golub, LM
中科院分区：
文献类型：
--
作者：
Brown, DL;Desai, KK;Golub, LM
背景--易损斑块表现为强烈的炎症，其中巨噬细胞分泌基质金属蛋白酶（MMPs）降解纤维帽，最终导致破裂、原位血栓形成和相关的临床事件。因此，MMP活性的抑制或血管炎症的更普遍的抑制是旨在减少斑块破裂的干预的有吸引力的目标。我们假设，亚抗菌剂量的强力霉素（SDD）（20毫克，每天两次）将有益于冠心病患者减少炎症和MMP活性，从而可能防止冠状动脉斑块破裂events.Methods和结果，我们进行了一项前瞻性，随机，双盲，安慰剂对照的试点研究6个月的SDD或安慰剂治疗，以减少炎症和预防斑块破裂事件。共入组50例患者，其中24例随机分配至安慰剂组，26例随机分配至SDD组。6个月时，SDD组与安慰剂组患者在猝死、致死性心肌梗死（MI）、非致死性MI或肌钙蛋白阳性不稳定型心绞痛的复合终点方面无差异（8.4% vs 0%，P=0.491）。在30例患者中，在研究开始时和治疗6个月后，在血浆中评估炎症的生化标志物。在接受SDD治疗的患者中，高敏C反应蛋白（CRP）从4.8+/-0.6 mug/mL降至2.6+/-0.4 mug/mL，降低了46%（P=0.007），而安慰剂组患者的CRP没有显著降低。在接受SDS治疗的患者中，白细胞介素（IL）-6从基线时的22.1+/-3.7 pg/mL降至6个月时的14.7+/-1.8 pg/mL（P=0.025），但在接受安慰剂治疗的患者中没有显著降低。在酶谱，MMP-9的活性降低50% SDD治疗（P=0.011），而安慰剂treatment.Conclusion-SDD似乎发挥潜在的有益作用，可以促进斑块稳定性的炎症。这些发现应该在更大的研究中进行调查。
Background-Vulnerable plaque demonstrates intense inflammation in which macrophages secrete matrix metalloproteinases (MMPs) that degrade the fibrous cap, ultimately leading to rupture, in situ thrombosis, and an associated clinical event. Thus, inhibition of MMP activity or more general suppression of vascular inflammation are attractive targets for interventions intended to reduce plaque rupture. We hypothesized that subantimicrobial doses of doxycycline (SDD) (20 mg twice daily) would benefit patients with coronary artery disease by reducing inflammation and MMP activity and thus possibly prevent coronary plaque rupture events.Methods and Results-We conducted a prospective, randomized, double-blind, placebo-controlled pilot study of 6 months of SDD or placebo treatment to reduce inflammation and prevent plaque rupture events. A total of 50 patients were enrolled, of whom 24 were randomized to placebo and 26 to SDD. At 6 months, there was no difference in the composite endpoint of sudden death, fatal myocardial infarction (MI), non-fatal MI, or troponin-positive unstable angina in SDD compared with placebo-treated patients (8.4% versus 0%, P=0.491). Biochemical markers of inflammation were assessed in plasma at study entry and after 6 months of therapy in 30 patients. In SDD-treated patients, high-sensitivity C-reactive protein (CRP) was reduced by 46% from 4.8+/-0.6 mug/mL to 2.6+/-0.4 mug/mL (P=0.007), whereas CRP was not significantly reduced in placebo patients. Interleukin (IL)-6 decreased from 22.1+/-3.7 pg/mL at baseline to 14.7+/-1.8 pg/mL at 6 months in SDD-treated patients (P=0.025) but did not decrease significantly in placebo-treated patients. On zymography, pro-MMP-9 activity was reduced 50% by SDD therapy (P=0.011), whereas it was unchanged by placebo treatment.Conclusion-SDD appears to exert potentially beneficial effects on inflammation that could promote plaque stability. These findings should be investigated in a larger study.