慢性心力衰竭患者血清脯氨酸脱氢酶水平与左心收缩功能的关联性分析

doi:10.13481/j.1671-587X.20240626

摘要/Abstract

摘要：

目的探讨不同射血分数型慢性心力衰竭（CHF）患者血清脯氨酸脱氢酶（ProDH）水平差异，阐明ProDH水平对心功能的影响。方法回顾性分析118例CHF患者的临床资料，将其分为射血分数减低型心力衰竭组（HFrEF）组（n=39）、射血分数中间值型心力衰竭（HFmrEF）组（n=42）和射血分数保留型心力衰竭组（HFpEF）组（n=37）。收集同期住院的非CHF患者45例，作为对照组。收集各组研究对象一般资料，检测各组研究对象血清中生化指标水平和心脏结构指标，患者血清中ProDH水平与各生化指标的相关性采用Spearman相关性分析和点二列相关性分析，HFrEF和HFmrEF的影响因素采用多因素Logistic回归分析。结果与对照组比较，HFpEF组患者β受体阻滞剂类药物使用率明显升高（P<0.05）；HFmrEF组男性患者百分率、他汀类药物使用率和β受体阻滞剂类药物使用率均明显升高（P<0.05）；HFrEF组患者年龄和收缩压（SBP）均明显降低（P<0.05），他汀类药物使用率和β受体阻滞剂类药物使用率均明显升高（P<0.05）。与HFpEF组比较，HFmrEF组患者年龄明显降低（P<0.05），男性患者百分率和他汀类药物使用率均明显升高（P<0.05）；HFrEF组患者年龄明显降低（P<0.05），他汀类药物使用率明显升高（P<0.05）。与HFmrEF组比较，HFrEF组患者SBP明显降低（P<0.05）。与对照组比较，HFpEF组和HFmrEF组患者血清中低密度脂蛋白胆固醇（LDL-c）水平均明显降低（P<0.05），N末端脑利钠肽前体（NT-proBNP）水平均明显升高（P<0.05）；HFrEF组患者血清中肾小球滤过率（GFR）和ProDH水平均明显降低（P<0.05），空腹血糖（FBG）和NT-proBNP水平均明显升高（P<0.05）。与HFpEF组比较，HFmrEF组患者血清中血红蛋白（Hb）水平明显升高（P<0.05）；HFrEF组患者血清中NT-proBNP水平明显升高（P<0.05），ProDH水平明显降低（P<0.05）。与HFmrEF组比较，HFrEF组患者血清中NT-proBNP水平明显升高（P<0.05）。与对照组比较，HFpEF组、HFmrEF组和HFrEF组患者左心房内径（LAD）和左心室舒张早期二尖瓣血流速度（E）/二尖瓣环舒张早期运动速度（Em）比值均明显升高（P<0.05）；HFmrEF组和HFrEF组患者左心室舒张末期内径（LVEDD）均明显升高（P<0.05），左心室射血分数（LVEF）均明显降低（P<0.05）；与HFpEF组比较，HFmrEF组和HFrEF组患者LVEDD均明显升高（P<0.05），LVEF均明显降低（P<0.05），HFrEF组患者LAD明显升高（P<0.05）。与HFmrEF组比较，HFrEF组患者E/Em比值明显升高（P<0.05），LVEF明显降低（P<0.05）。患者血清中ProDH水平与LVEDD呈负相关关系（r=－0.210，P=0.007），与LVEF呈正相关关系（r=0.220，P=0.005）。男性和FBG水平升高为心脏功能的危险因素，血清中GFR和ProDH水平升高为心脏功能的保护因素。结论 ProDH在不同射血分数型CHF患者间存在差异，心功能较差的患者血清ProDH水平较低，较高水平的ProDH可能有利于CHF患者左心收缩功能的提高。

关键词: 脯氨酸脱氢酶, 慢性心力衰竭, 射血分数减低型心力衰竭, 射血分数中间值型心力衰竭, 射血分数保留型心力衰竭

Abstract:

Objective To discuss the differences in serum proline dehydrogenase （ProDH） levels among chronic heart failure （CHF） patients with different ejection fraction types， and to clarify the effect of ProDH levels on cardiac function. Methods A retrospective analysis of clinical data of 118 CHF patients was conducted. These patients were divided into heart failure with reduced ejection fraction （HFrEF） group （n=39）， heart failure with mid-range ejection fraction group （HFmrEF）（n=42）， and heart failure with preserved ejection fraction （HFpEF） group （n=37）. A total of 45 non-CHF patients hospitalized during the same period were collected as control group. The general data of all the subjects in various groups were collected， and the levels of biochemical indicators and cardiac structure indicators in serum of all the subjects were detected. Spearman correlation analysis and point-biserial correlation analysis were used to analyze the correlation between serum ProDH levels and various biochemical indicators； multivariate Logistic regression analysis was used to analyze the factors influencing HFrEF and HFmrEF. Results Compared with control group， the usage rate of beta-blockers of the patients in HFpEF group was significantly increased （P<0.05）； in HFmrEF group， the percentage of male patients， the usage rate of statins， and the usage rate of beta-blockers were all significantly increased （P<0.05）； in HFrEF group， the age and systolic blood pressure （SBP） of the patients were significantly decreased （P<0.05）， while the usage rates of statins and beta-blockers of the patients were significantly increased （P<0.05）. Compared with HFpEF group， the age of the patients in HFmrEF group was significantly decreased （P<0.05）， and the percentage of male patients and the usage rate of statins were significantly increased （P<0.05）； the age of the patients in the HFrEF group was significantly decreased （P<0.05）， and the usage rate of statins was significantly increased （P<0.05）. Compared with HFmrEF group， the SBP of the patients in HFrEF group was significantly decreased （P<0.05）.Compared with control group， the serum levels of low-density lipoprotein cholesterol （LDL-c） of the patients in HFpEF and HFmrEF groups were significantly decreased （P<0.05）， while the levels of N-terminal pro-brain natriuretic peptide （NT-proBNP） were significantly increased （P<0.05）； the serum levels of glomerular filtration rate （GFR） and ProDH of the patients in HFrEF group were significantly decreased （P<0.05）， and the levels of fasting blood glucose （FBG） and NT-proBNP were significantly increased （P<0.05）. Compared with HFpEF group， the serum hemoglobin （Hb） level of the patients in HFmrEF group was significantly increased （P<0.05）； the serum NT-proBNP level of the patients in HFrEF group was significantly increased （P<0.05）， while the ProDH level was significantly decreased （P<0.05）. Compared with HFmrEF group， the serum NT-proBNP level of the patients in HFrEF group was significantly increased （P<0.05）.Compared with control group， the left atrial diameter （LAD） and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity （E/Em） of the patients in HFpEF， HFmrEF， and HFrEF groups were significantly increased （P<0.05）； the left ventricular end-diastolic diameter （LVEDD） of the patients in HFmrEF and HFrEF groups were significantly increased （P<0.05）， and the left ventricular ejection fraction （LVEF） were significantly decreased （P<0.05）. Compared with HFpEF group， the LVEDD of the patients in HFmrEF and HFrEF groups were significantly increased （P<0.05）， and the LVEF were significantly decreased （P<0.05）； the LAD of the patients In HFrEF group was significantly increased （P<0.05）. Compared with HFmrEF group， the E/Em ratio of the patients in HFrEF group was significantly increased （P<0.05）， and the LVEF was significantly decreased（P<0.05）. The serum ProDH levels of the patients were negatively correlated with LVEDD （r=-0.210， P=0.007） and positively correlated with LVEF （r=0.220， P=0.005）. Male and elevated FBG levels were the risk factors for cardiac function， while the increasing serum GFR and ProDH levels were the protective factors for cardiac function. Conclusion There are differences in ProDH levels among the CHF patients with different ejection fraction types. The patients with poorer cardiac function have lower serum ProDH levels， and higher ProDH levels may be beneficial for improving the left ventricular systolic function in the CHF patients.KEDWORDS Proline dehydrogenase； Chronic heart failure； Heart failure with reduced ejection fraction； Heart failure with mid-range ejection fraction； Heart failure with preserved ejection fraction

中图分类号:

R541.6

杨凯同,和丽丽,左庆娟,于鑫伟,郭艺芳. 慢性心力衰竭患者血清脯氨酸脱氢酶水平与左心收缩功能的关联性分析[J]. 吉林大学学报(医学版), 2024, 50(6): 1719-1727.

Kaitong YANG,Lili HE,Qingjuan ZUO,Xinwei YU,Yifang GUO. Correlation analysis on serum proline dehydrogenase levels and left ventricular systolic function in patients with chronic heart failure[J]. Journal of Jilin University(Medicine Edition), 2024, 50(6): 1719-1727.

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参考文献 26

1	马丽媛，王增武，樊静，等. 《中国心血管健康与疾病报告2022》要点解读［J］. 中国全科医学， 2023， 26（32）： 3975-3994.
2	XI X R， ZHANG M， LI Y H， et al. Identification of PRODH as a mitochondria- and angiogenesis-related biomarker for lung adenocarcinoma［J］. Transl Cancer Res， 2024， 13（5）： 2073-2093.
3	HUYNH T Y L， ZAREBA I， BASZANOWSKA W， et al. Understanding the role of key amino acids in regulation of proline dehydrogenase/proline oxidase （prodh/pox）-dependent apoptosis/autophagy as an approach to targeted cancer therapy［J］. Mol Cell Biochem， 2020， 466（1/2）： 35-44.
4	PENG H M， XU J， YANG X P， et al. N-acetyl-seryl-aspartyl-lysyl-proline treatment protects heart against excessive myocardial injury and heart failure in mice［J］. Can J Physiol Pharmacol， 2019， 97（8）： 753-765.
5	WANG J C， XUE Z M， LIN J， et al. Proline improves cardiac remodeling following myocardial infarction and attenuates cardiomyocyte apoptosis via redox regulation［J］. Biochem Pharmacol， 2020， 178： 114065.
6	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.
7	PALKA J， OSCILOWSKA I， SZOKA L. Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy［J］. Amino Acids， 2021， 53（12）： 1917-1925.
8	CHEN C， LIU Q Y， CHEN W J， et al. PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production［J］. EMBO Rep， 2024， 25（4）： 2015-2044.
9	XU X Y， ZHANG G T， CHEN Y J， et al. Can proline dehydrogenase-a key enzyme involved in proline metabolism-be a novel target for cancer therapy？［J］. Front Oncol， 2023， 13： 1254439.
10	TANNER J J. Structural biology of proline catabolic enzymes［J］. Antioxid Redox Signal， 2019， 30（4）： 650-673.
11	LEWONIEWSKA S， OSCILOWSKA I， HUYNH T Y L， et al. Troglitazone-induced PRODH/POX-dependent apoptosis occurs in the absence of estradiol or ERβ in ER-negative breast cancer cells［J］. J Clin Med， 2021， 10（20）： 4641.
12	HANCOCK C N， LIU W， ALVORD W G， et al. Co-regulation of mitochondrial respiration by proline dehydrogenase/oxidase and succinate［J］. Amino Acids， 2016， 48（3）： 859-872.
13	KAZBERUK A， ZAREBA I， PALKA J， et al. A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells： the implication of proline oxidase and peroxisome proliferator-activated receptor［J］. Pharmacol Rep， 2020， 72（5）： 1152-1160.
14	WANG J C， XUE Z M， HUA C T， et al. Metabolomic analysis of the ameliorative effect of enhanced proline metabolism on hypoxia-induced injury in cardiomyocytes［J］. Oxid Med Cell Longev， 2020， 2020： 8866946.
15	LV Q B， LI D B， ZHAO L D， et al. Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart［J］. Sci Adv， 2024， 10（19）： eadl3549.
16	蔡美莲，钟国强. 慢性心力衰竭治疗进展［J］. 中国实用内科杂志， 2023， 43（11）： 944-949， 954.
17	ZAREBA I， SURAZYNSKI A， CHRUSCIEL M， et al. Functional consequences of intracellular proline levels manipulation affecting PRODH/POX-dependent pro-apoptotic pathways in a novel in vitro cell culture model［J］. Cell Physiol Biochem， 2017， 43（2）： 670-684.
18	ZAREBA I， CELINSKA-JANOWICZ K， SURAZYNSKI A， et al. Proline oxidase silencing induces proline-dependent pro-survival pathways in MCF-7 cells［J］. Oncotarget， 2018， 9（17）： 13748-13757.
19	GAO G Y， CHEN W W， YAN M J， et al. Rapamycin regulates the balance betweencardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling［J］. Int J Mol Med， 2020， 45（1）： 195-209.
20	GROSSI S， BERNO E， CHIOFALO P， et al. Proline dehydrogenase （PRODH） is expressed in lung adenocarcinoma and modulates cell survival and 3D growth by inducing cellular senescence［J］. Int J Mol Sci， 2024， 25（2）： 714.
21	SCIOMER S， MOSCUCCI F， SALVIONI E， et al. Role of gender， age and BMI in prognosis of heart failure［J］. Eur J Prev Cardiol， 2020， 27（）： 46-51.
22	LEE D P H. Impact of sex and diabetes in patients with heart failure with mildly reduced ejection fraction［J］. Ann Acad Med Singap， 2022， 51（8）： 458-459.
23	MILLER R J H， HOWLETT J G. Untying the Gordian knot of sex and heart failure therapy［J］. Eur J Heart Fail， 2021， 23（9）： 1485-1487.
24	AJIBOWO A O， OKOBI O E， EMORE E， et al. Cardiorenal syndrome： a literature review［J］. Cureus， 2023， 15（7）： e41252.
25	GEMBILLO G， VISCONTI L， GIUSTI M A， et al. Cardiorenal syndrome： new pathways and novel biomarkers［J］. Biomolecules， 2021， 11（11）： 1581.
26	WANG Y Y， ZHOU J D， QI W W， et al. Visit-to-visit variability in fasting blood glucose predicts the new-onset heart failure： results from two large Chinese cohorts［J］. Curr Probl Cardiol， 2023， 48（9）： 101842.

Group	n	Age(year)	Male(η/%)	SBP(P/mmHg)	DBP(P/mmHg)	BMI(kg·m^－2)
Control	45	67.6±6.0	21(46.7)	139(122,156)	79(71,90)	25.39(23.24,26.61)
HFpEF	37	68.6±12.2	16(43.2)	138(114,158)	72(67,91)	25.39(21.60,28.19)
HFmrEF	42	63.4±10.7^△	32(76.2)^*△	137(124,154)	79(72,90)	25.50(22.97,28.65)
HFrEF	39	62.4±12.4^*△	27(69.2)	119(109,141)^*#	80(70,90)	24.22(22.13,29.30)
χ²/F/H		3.421	13.434	10.823	2.193	0.979
P		0.021	0.004	0.013	0.533	0.806

Group	n	Alb[ρ_B/(g·L^-1)]	ALT[λ_B/(U·L^-1)]	AST[λ_B/(U·L^-1)]	CK-MB[ρ_B/(mg·L^-1)]
Control	45	40.38±3.50	16.10(11.50,23.70)	20.10(16.40,25.20)	13.30(11.90,15.00)
HFpEF	37	38.62±3.53	17.70(11.40,29.20)	21.30(18.40,31.80)	14.40(11.90,16.60)
HFmrEF	42	39.45±4.23	19.60(12.50,24.20)	19.10(17.10,27.40)	13.10(11.10,15.20)
HFrEF	39	39.07±4.27	20.00(13.80,32.85)	20.70(17.65,31.80)	11.40(8.30,15.15)
H/F		1.537	3.381	2.517	6.870
P		0.207	0.337	0.472	0.076

Group	n	LAD(l/mm)	IVST(l/mm)	LVPWT(l/mm)	LVEDD(l/mm)	E/Em(m·s^-1)	LVEF(η/%)
Control	45	36(34,39)	10(9,10)	9(9,10)	46(43,48)	9.75(7.68,11.75)	64(61,68)
HFpEF	39	42(38,45)^*	10(9,11)	10(9,10)	47(43,50)	15.19(13.55,22.35)^*	61(56,65)
HFmrEF	42	43(40,46)^*	10(9,11)	10(9,10)	55(52,59)^*△	12.74(10.33,18.33)^*	44(43,47)^*△
HFrEF	37	47(42,50)^*△	9(8,10)	9(8,10)	61(55,68)^*△	21.11(15.48,28.75)^*#	33(30,36)^*△#
H/F		66.576	5.702	4.765	87.620	65.312	139.556
P		<0.01	0.127	0.190	<0.01	<0.001	<0.01

Factor	Age	Gender	SBP	GFR	LDL-c	FBG	Hb	NT-proBNP	LAD	LVEDD	E/Em	LVEF
r	－0.089	0.008	0.028	0.015	－0.078	－0.065	－0.018	－0.133	－0.119	－0.210	－0.066	0.220
P	0.261	0.923	0.724	0.852	0.320	0.409	0.819	0.091	0.129	0.007	0.403	0.005

Influencing factor	B	SE	Wald	P	OR(95%CI)
Age(year)	-0.085	0.027	9.845	0.002	0.919(0.871—0.969)
Gender	1.260	0.496	6.449	0.011	3.526(1.333—9.327)
SBP(mmHg)	-0.006	0.009	0.405	0.525	0.994(0.977—1.012)
Statins	1.347	0.502	7.211	0.007	3.847(1.439—10.285)
Beta-blockers	0.370	0.484	0.585	0.444	1.448(0.560—3.743)
CK-MB(μg·L^-1)	-0.104	0.046	5.004	0.025	0.901(0.823—0.987)
Na(mmol·L^-1)	0.137	0.077	3.145	0.076	1.146(0.986—1.333)
GFR(mL·min^-1)	-0.045	0.013	11.512	0.001	0.956(0.931—0.981)
LDL-c(mL·min^-1)	0.197	0.267	0.542	0.462	1.217(0.721—2.054)
FBG(mL·min^-1)	0.333	0.136	5.999	0.014	1.395(1.069—1.820)
Hb(g·L^-1)	0.023	0.016	2.060	0.151	1.024(0.992—1.057)
ProDH(ng·L^-1)	-0.186	0.062	9.067	0.003	0.830(0.736—0.937)