慢性心力衰竭患者血浆海蟾蜍毒素、Ⅰ型胶原α1链表达水平及其与预后的相关性

doi:10.11958/20252440

摘要/Abstract

摘要：

目的探讨血浆海蟾蜍毒素（MBG）、Ⅰ型胶原α1链（COL1A1）水平在慢性心力衰竭（CHF）患者中的表达及与预后的相关性。方法选取CHF患者（CHF组）126例和同期健康体检志愿者（对照组）63例，CHF患者根据NYHA心功能分级分为Ⅱ级组、Ⅲ级组、Ⅳ级组（48例、44例、34例），根据6个月预后分为不良组和良好组。检测血浆MBG、COL1A1水平，分析CHF患者血浆MBG、COL1A1水平与NYHA心功能分级的关系；并分析血浆MBG、COL1A1水平与CHF患者不良预后的关系及预测能效。结果与对照组比较，CHF组血浆MBG、COL1A1水平升高（P<0.05）。Ⅱ级组、Ⅲ级组、Ⅳ级组血浆MBG、COL1A1水平依次升高（P<0.05）。CHF患者血浆MBG、COL1A1水平与NYHA心功能分级呈正相关（r_s分别为0.715、0.727，P<0.05）。随访6个月，126例CHF患者不良预后率为31.75%（40/126）。NYHA心功能Ⅳ级（OR=4.007，95%CI：1.858~8.643），N末端B型钠尿肽前体（OR=1.001，95%CI：1.000~1.001）、MBG（OR=1.020，95%CI：1.010~1.030）、COL1A1（OR=1.037，95%CI：1.017~1.056）升高为CHF患者不良预后的独立危险因素（P<0.05）。血浆MBG、COL1A1水平联合预测CHF患者不良预后的曲线下面积为0.880（95%CI：0.810~0.931），优于血浆MBG、COL1A1水平单独预测的0.786（95%CI：0.704~0.854）、0.797（95%CI：0.716~0.863）。结论血浆MBG、COL1A1水平升高与CHF患者心功能降低及不良预后有关，二者联合对预后的预测能效较高。

关键词: 心力衰竭, 预后, 胶原Ⅰ型, 海蟾蜍毒素, 心功能

Abstract:

Objective To investigate the expression levels of plasma marinobufagenin (MBG) and type Ⅰ collagen α1 chain (COL1A1) in patients with chronic heart failure (CHF) and their correlation with prognosis. Methods A total of 126 patients with CHF (CHF group) and 63 healthy volunteers (control group) were enrolled. According to the New York Heart Association (NYHA) functional classification, CHF patients were divided into the class Ⅱ (n=48), the class Ⅲ (n=44), and the class Ⅳ (n=34) groups. Based on the 6-month follow-up outcomes, patients were classified into the poor prognosis and the good prognosis groups. Plasma MBG and COL1A1 levels were measured, and their relationships with NYHA classification and prognosis were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate predictive efficacy. Results Plasma MBG and COL1A1 levels were significantly higher in the CHF group than those in the control group (P<0.05). Among CHF patients, plasma MBG and COL1A1 levels increased progressively from NYHA class Ⅱ to Ⅳ (P<0.05) and were positively correlated with NYHA classification (P<0.05). During the 6-month follow-up, the incidence of poor prognosis in CHF patients was 31.75% (40/126). Multivariate logistic regression showed that NYHA class Ⅳ (OR=4.007, 95%CI: 1.858-8.643), N-terminal pro-B-type natriuretic peptide (OR=1.001, 95%CI: 1.000-1.001), MBG (OR=1.020, 95%CI: 1.010-1.030), and COL1A1 (OR=1.037, 95%CI: 1.017-1.056) were independent risk factors for poor prognosis (P<0.05). The area under the ROC curve (AUC) for the combined prediction of MBG and COL1A1 was 0.880 (95%CI: 0.810-0.931), which was superior to MBG (0.786, 95%CI: 0.704-0.854) or COL1A1 (0.797, 95%CI: 0.716-0.863) alone (P<0.05). Conclusion Elevated plasma MBG and COL1A1 levels are associated with impaired cardiac function and poor prognosis in CHF patients, and their combined measurement provides higher predictive value for adverse outcomes.

Key words: heart failure, prognosis, collagen type Ⅰ, marinobufagenin, cardiac function

中图分类号:

R541

图/表 6

参考文献 25

[1]	LIU Z, LI Z, LI X, et al. Global trends in heart failure from 1990 to 2019:an age-period-cohort analysis from the global burden of disease study[J]. ESC Heart Fail, 2024, 11(5):3264-3278. doi:10.1002/ehf2.14915.
[2]	WANG H, LI Y, CHAI K, et al. Mortality in patients admitted to hospital with heart failure in China:a nationwide cardiovascular association database-heart failure centre registry cohort study[J]. Lancet Glob Health, 2024, 12(4):e611-e622. doi:10.1016/S2214-109X(23)00605-8.
[3]	中华医学会心血管病学分会, 中国医师协会心血管内科医师分会, 中国医师协会心力衰竭专业委员会, 等. 中国心力衰竭诊断和治疗指南2024[J]. 中华心血管病杂志, 2024, 52(3):235-275.
	Chinese Society of Cardiology,Chinese Medical Association, Chinese College of Cardiovascular Physician, Chinese Heart Failure Association of Chinese Medical Doctor Association, et al. Chinese guidelines for the diagnosis and trentment of heart failure 2024[J]. Chin J Cardiol, 2024, 52(3):235-275. doi:10.3760/cma.j.cn112148-20231101-00405.
[4]	CARULLO N, FABIANO G, D'AGOSTINO M, et al. New insights on the role of marinobufagenin from bench to bedside in cardiovascular and kidney diseases[J]. Int J Mol Sci, 2023, 24(13):11186. doi:10.3390/ijms241311186.
[5]	KENNEDY D J, SHRESTHA K, SHEEHEY B, et al. Elevated plasma marinobufagenin,an endogenous cardiotonic steroid,is associated with right ventricular dysfunction and nitrative stress in heart failure[J]. Circ Heart Fail, 2015, 8(6):1068-1076. doi:10.1161/CIRCHEARTFAILURE.114.001976.
[6]	DEVOS H, ZOIDAKIS J, ROUBELAKIS M G, et al. Reviewing the regulators of COL1A1[J]. Int J Mol Sci, 2023, 24(12):10004. doi:10.3390/ijms241210004.
[7]	HOU C, HUO J, YAN S, et al. Identification of fibrosis-associated biomarkers in heart failure and human cancers[J]. J Transl Med, 2024, 22(1):1042. doi:10.1186/s12967-024-05759-7.
[8]	中华医学会心血管病学分会心力衰竭学组, 中国医师协会心力衰竭专业委员会, 中华心血管病杂志编辑委员会. 中国心力衰竭诊断和治疗指南2018[J]. 中华心血管病杂志, 2018, 46(10):760-789.
	Heart Failure Group of the Chinese Society of Cardiology, Heart Failure Committee of the Chinese Medical Doctor Association, Editorial Board of Chinese Journal of Cardiology. Chinese guidelines for the diagnosis and trentment of heart failure 2018[J]. Chin J Cardiol, 2018, 46(10):760-789. doi:10.3760/cma.j.issn.0253-3758.2018.10.004.
[9]	ŁABNO-KIRSZNIOK K, KUJAWA-SZEWIECZEK A, WIECEK A, et al. The effects of short-term changes in sodium intake on plasma marinobufagenin levels in patients with primary salt-sensitive and salt-insensitive hypertension[J]. Nutrients, 2021, 13(5):1502. doi:10.3390/nu13051502.
[10]	中国老年医学学会心电及心功能分会, 中国医师协会心血管内科分会, 中国心衰中心联盟专家委员会. 慢性心力衰竭加重患者的综合管理中国专家共识2022[J]. 中国循环杂志, 2022, 37(3):215-225.
	Electrophysiology and Cardiac Function Branch of Chinese Society of Geriatrics, Cardiovascular Medicine Branch of Chinese Physicians Association, Expert Committee of China Heart Failure Center. Chinese expert consensus on comprehensive management of patients with worsening heart failure 2022[J]. Chinese Circulation Journal, 2022, 37(3):215-225. doi:10.3969/j.issn.1000-3614.2022.03.003.
[11]	董玉婷, 龚雪莲, 屈超. 慢性心力衰竭患者血浆IGFBP2、SMOC2水平与心功能及预后的关系[J]. 天津医药, 2025, 53(6):593-598.
	DONG Y T, GONG X L, QU C. Analysis of the relationship between plasma IGFBP2,SMOC2 levels and cardiac function and prognosis in patients with chronic heart failure[J]. Tianjin Med J, 2025, 53(6):593-598. doi:10.11958/20250289.
[12]	中国医师协会心力衰竭专业委员会, 国家心血管病专家委员会心力衰竭专业委员会, 中华心力衰竭和心肌病杂志编辑委员会. 心力衰竭生物标志物临床应用中国专家共识[J]. 中华心力衰竭和心肌病杂志, 2022, 6(3):175-192.
	Chinese Heart Failure Association of Chinese Medical Doctor Association, National Expert Committee on Cardiovascular Diseases and Professional Committee on Heart Failure, Editorial Board of Chinese Journal of Heart Failure and Cardiomyopathy. Chinese expert consensus on clinical application of biomarkers for heart failure[J]. Chin J Heart Fail & Cardiomyopathy, 2022, 6(3):175-192. doi:10.3760/cma.j.cn101460-20220810-00071.
[13]	ORLOV S N, TVERSKOI A M, SIDORENKO S V, et al. Na,K-ATPase as a target for endogenous cardiotonic steroids:What's the evidence?[J]. Genes Dis, 2020, 8(3):259-271. doi:10.1016/j.gendis.2020.01.008.
[14]	HALLER S T, YAN Y, DRUMMOND C A, et al. Rapamycin attenuates cardiac fibrosis in experimental uremic cardiomyopathy by reducing marinobufagenin levels and inhibiting downstream pro-fibrotic signaling[J]. J Am Heart Assoc, 2016, 5(10):e004106. doi:10.1161/JAHA.116.004106.
[15]	DRUMMOND C A, HILL M C, SHI H, et al. Na/K-ATPase signaling regulates collagen synthesis through microRNA-29b-3p in cardiac fibroblasts[J]. Physiol Genomics, 2016, 48(3):220-229.doi:10.1152/physiolgenomics.00116.2015.
[16]	LIU C, BAI Y, CHEN Y, et al. Reduction of Na/K-ATPase potentiates marinobufagenin-induced cardiac dysfunction and myocyte apoptosis[J]. J Biol Chem, 2012, 287(20):16390-16398. doi:10.1074/jbc.M111.304451.
[17]	BOLIGNANO D, DE ROSA S, GRECO M, et al. Marinobufagenin,left ventricular geometry and cardiac dysfunction in end-stage kidney disease patients[J]. Int Urol Nephrol, 2022, 54(10):2581-2589. doi:10.1007/s11255-022-03161-0.
[18]	DHALLA N S, ELIMBAN V, ADAMEOVA A D. Role of Na^＋/K^＋-ATPase alterations in the development of heart failure[J]. Int J Mol Sci, 2024, 25(19):10807. doi:10.3390/ijms251910807.
[19]	SŁABIAK-BŁAŻ N, PIECHA G. Endogenous mammalian cardiotonic steroids-a new cardiovascular risk factor? a mini-review[J]. Life (Basel), 2021, 11(8):727. doi:10.3390/life11080727.
[20]	SELVARAJ V, SEKARAN S, DHANASEKARAN A, et al. Type 1 collagen:synthesis,structure and key functions in bone mineralization[J]. Differentiation, 2024, 136:100757. doi:10.1016/j.diff.2024.100757.
[21]	QIAN L, XU H, YUAN R, et al. Formononetin ameliorates isoproterenol induced cardiac fibrosis through improving mitochondrial dysfunction[J]. Biomed Pharmacother, 2024, 170:116000. doi:10.1016/j.biopha.2023.116000.
[22]	SINGH R, KAUNDAL R K, ZHAO B, et al. Resistin induces cardiac fibroblast-myofibroblast differentiation through JAK/STAT3 and JNK/c-Jun signaling[J]. Pharmacol Res, 2021, 167:105414. doi:10.1016/j.phrs.2020.105414.
[23]	ZHANG P, GENG L, ZHANG K, et al. Identification of shared molecular mechanisms and diagnostic biomarkers between heart failure and idiopathic pulmonary fibrosis[J]. Heliyon, 2024, 10(8):e30086. doi:10.1016/j.heliyon.2024.e30086.
[24]	DONG H, YIN C, XIAO D, et al. Identification of differentially expressed genes to predict the risk of heart failure in older patients with hypertrophic cardiomyopathy[J]. Aging (Albany NY), 2024, 16(13):10860-10867. doi:10.18632/aging.205956.
[25]	NIKOLOV A, POPOVSKI N. Extracellular matrix in heart disease:focus on circulating collagen type I and III derived peptides as biomarkers of myocardial fibrosis and their potential in the prognosis of heart failure:a concise review[J]. Metabolites, 2022, 12(4):297. doi:10.3390/metabo12040297.

组别	n	性别（男/女）	年龄/ 岁	MBG/ （pmol/L）	COL1A1/ （μg/L）
对照组	63	40/23	57.30±13.16	234.22±52.98	147.94±40.28
CHF组	126	73/53	59.77±10.28	504.12±113.83	302.14±62.83
χ²或t		0.539	1.414	22.231^＊＊	20.408^＊＊

组别	n	性别（男/女）	年龄/ 岁	MBG/ （pmol/L）	COL1A1/ （μg/L）
对照组	63	40/23	57.30±13.16	234.22±52.98	147.94±40.28
CHF组	126	73/53	59.77±10.28	504.12±113.83	302.14±62.83
χ²或t		0.539	1.414	22.231^＊＊	20.408^＊＊

组别	n	MBG/（pmol/L）	COL1A1/（μg/L）
Ⅱ级组	48	423.77±93.11	260.27±50.54
Ⅲ级组	44	520.21±87.38^a	305.61±43.12^a
Ⅳ级组	34	596.74±90.63^ab	356.76±57.05^ab
F		72.745^＊＊	74.143^＊＊

组别	n	MBG/（pmol/L）	COL1A1/（μg/L）
Ⅱ级组	48	423.77±93.11	260.27±50.54
Ⅲ级组	44	520.21±87.38^a	305.61±43.12^a
Ⅳ级组	34	596.74±90.63^ab	356.76±57.05^ab
F		72.745^＊＊	74.143^＊＊

组别	n	性别（男/女）		年龄/ 岁		原发疾病（冠心病/ 扩张型心肌病/原发性高血压）		NYHA心功能分级（Ⅱ/Ⅲ/Ⅳ）		糖尿病	高血压		冠心病	心房颤动		高脂血症
良好组	86	48/38		58.74±11.35		33/18/35		46/29/11		22（25.6）	64（74.4）		40（46.5）	24（29.9）		21（24.4）
不良组	40	25/15		61.98±7.12		18/7/15		2/15/23		15（37.5）	31（77.5）		19（47.5）	18（45.0）		13（32.5）
χ²或t		0.501		1.944		0.529		6.053^＊＊		1.870	0.140		0.011	3.590		0.905
组别	吸烟史			饮酒史	收缩压/mmHg		舒张压/mmHg		LVEF	NT-proBNP/（ng/L）			血尿酸/（μmol/L）
良好组	25（29.1）			14（16.3）	137.74±16.68		82.28±13.62		0.50±0.06	2 381.24±914.44			482.28±150.95
不良组	17（42.5）			10（25.0）	143.55±16.31		86.58±16.77		0.48±0.04	3 393.68±1 197.70			502.93±172.52
χ²或t	2.216			1.347	1.516		1.529		1.916	5.227^＊＊			0.682
组别			血红蛋白/（g/L）		白蛋白/（g/L）		血肌酐/（μmol/L）		血尿素氮/（mmol/L）			MBG/（pmol/L）			COL1A1/（μg/L）
良好组			123.64±17.19		36.74±6.01		80.78±33.56		10.98±3.83			468.92±106.62			280.66±52.56
不良组			116.61±23.21		34.98±5.50		91.35±30.21		12.18±4.10			579.81±90.27			348.33±58.54
t			1.711		1.572		1.697		1.602			5.693^＊＊			6.486^＊＊