Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF
Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF
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DOI：
10.1016/j.jacc.2020.05.072
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发表时间：
2020-08-04
影响因子：
24
通讯作者：
Zile, Michael R.
中科院分区：
文献类型：
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作者：
Cunningham, Jonathan W.;Claggett, Brian L.;Zile, Michael R.
背景心肌纤维化可能是射血分数正常的心力衰竭的病理生理学原因。鉴于沙库巴曲/缬沙坦的生化靶点，本研究假设，与缬沙坦单独给药相比，沙库巴曲/缬沙坦改变了反映细胞外基质稳态机制的循环生物标志物。本研究调查了沙库巴曲/缬沙坦对细胞外基质稳态生物标志物的影响，以及生物标志物与主要终点之间的相关性。方法在基线时测定I型和III型胶原N末端前肽、基质金属蛋白酶1组织抑制剂、I型胶原羧基末端肽和可溶性ST 2随机化后16周（n = 1，113）和48周（n = 1，016）。将沙库巴曲/缬沙坦对这些生物标志物的作用与单独缬沙坦的作用进行比较。结果基线时，所有5种生物标志物均高于已发表的参考对照值。随机分组后16周，沙库巴曲/缬沙坦使基质金属蛋白酶组织抑制因子1降低8%，（95%置信区间[CI]：6%至10%; p < 0.001），可溶性ST 2增加4%（95% CI：1%-7%; p = 0.002），III型胶原蛋白N-末端前肽降低3%（95% CI：0%-6%; p = 0.04），I型胶原羧基末端肽增加4%（95% CI：1%-8%; p = 0.02）与缬沙坦单药相比，在男性和女性以及左心室射血分数高于或低于中位数57%的患者中一致。较高水平的基质金属蛋白酶1和可溶性ST 2的组织抑制剂在基线和增加这些标志物在16周与较高的主要终点事件rates.CONCLUSIONS反映细胞外基质稳态的生物标志物升高心力衰竭保留射血分数，有利地改变沙库比曲/缬沙坦，并具有重要的预后价值。（ARNI与ARB在射血分数保留的HF中的全球结局的前瞻性比较[PARAGON-HF]; NCT 01920711）（c）2020作者。由爱思唯尔代表美国心脏病学会基金会出版。这是一个在CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
BACKGROUND Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone. OBJECTIVES This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).METHODS N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.RESULTS At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.CONCLUSIONS Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711) (c) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).