Efficacy and Safety of Xinmailong Injection for Chronic Heart Failure: A Systematic Review and Meta-Analysis for Randomized Clinical Trials

Abstract

Introduction:

Xinmailong injection (XMLI) is a common Traditional Chinese Medicine for treating chronic heart failure (CHF) in China. However, strong evidence-based medical evidence for XMLI is lacking.

Purpose:

To evaluate the efficacy and safety of XMLI in patients with CHF.

Methods:

PubMed, the Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Database, VIP Database for Chinese Technical Periodicals, and Chinese Biomedical Literature Database were searched to identify randomized controlled trials (RCTs) of XMLI for CHF from the inception of the databases to November 2, 2024. The Cochrane risk of bias tool for randomized trials (RoB 2) was used to evaluate the quality of studies, and STATA 17.0 software was used to perform a meta-analysis of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-min walking distance (6-MWD), and adverse reactions. The quality of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Results:

Twenty-three RCTs comprising 2643 patients were included. Meta-analysis showed that compared with those under conventional Western drug treatment (CWT), combined XMLI and CWT effectively increased LVEF (mean difference [MD] = 6.66, 95% confidence interval [CI] [5.23, 8.09], Z = 9.12, p < 0.001) and 6-MWD (MD = 44.01, 95% CI [28.63,59.38], Z = 5.61, p < 0.001) and reduced LVEDD (MD = −4.19, 95% CI [−5.55, −2.83], Z = −6.05, p < 0.001), BNP (MD = −178.84, 95% CI [−230.29, −127.40], Z = −6.81, p < 0.001), and NT-proBNP (MD = −490.95, 95% CI [−729.40, −252.50], Z = −4.04, p < 0.001). There were no statistically significant differences between the two adverse reactions (risk ratio [RR] = 1.47, 95% CI [0.73,2.99], Z = 1.08, p = 0.28). The GRADE assessment rated adverse reactions as moderate-quality evidence, while LVEDD, BNP, NT-proBNP, and 6-MWD were classified as low-quality evidence, and LVEF was categorized as very low-quality evidence.

Conclusions:

This systematic review demonstrates that combining XMLI with CWT is effective and safe for managing CHF and offers an evidence-based adjunctive therapeutic strategy. Further high-quality clinical trials are required to investigate the prognostic implications and long-term outcomes.

Introduction

Heart failure (HF) is the end stage of various cardiac diseases. It is a complex clinical syndrome resulting from structural or functional cardiac abnormalities, characterized by dyspnea, fatigue, pulmonary congestion, and peripheral edema.¹ The global incidence of HF increases with age. Among individuals aged >45 years old, the incidence rate is 0.8%. As age increases by 20 years, the incidence may intensify by 1.3%. The five-year mortality rate following diagnosis is as high as 67%, causing a large economic burden on the global health care system.² In clinical practice, the treatment agents for chronic heart failure (CHF) primarily include diuretics, β-blockers, angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors. However, despite high-dose diuretic therapy, volume overload persists in some patients after discharge. In advanced HF, even with optimal pharmacological treatments, systolic and diastolic dysfunctions persist, and HF symptoms remain unresolved.³ Therefore, CHF treatment remains highly challenged.

Traditional Chinese Medicine (TCM) has a long history in the treatment of CHF, and the use of TCM alone or combined with Western medicine improves patient prognosis.^4
–6 Xinmailong injection (XMLI) is a bioactive peptide preparation extracted from Periplaneta americana. The primary active ingredients are adenosine, inosine, protocatechuic acid, and pyroglutamate dipeptides.⁷ Clinical studies have demonstrated the therapeutic potential of XMLI in CHF. However, current studies are limited by small sample sizes and insufficient evidence, and the systematic analysis lacks literature updates and fails to reveal the influence of baseline indicators on outcomes.⁸ This study aims to systematically evaluate the efficacy and safety of XMLI in CHF treatment.

Materials and Methods

The protocol for this meta-analysis has been registered in PROSPERO (no. CRD42024574757) and reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (2020).⁹

Search strategy

Two reviewers (S.-W.Z. and J.-P.C.) searched PubMed, the Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Database, VIP Database for Chinese Technical Periodicals, and Chinese Biomedical Literature Database, from the database inception to November 2, 2024. The search terms included “Xinmailong Injection,” “Xinmailong,” “heart failure,” “chronic heart failure,” “randomized controlled trial (RCT),” “RCT,” and “randomized.” The search algorithm focused on the search terms mentioned in the title, abstract, and keywords. No language restrictions were imposed. The detailed search strategies are presented in Supplementary Table S2.

Inclusion and exclusion criteria

The inclusion criteria were (1) population: patients diagnosed with CHF; (2) intervention: the combination of XMLI with conventional Western drug therapy (CWT); (3) control: CWT alone based on HF guidelines^1,2; (4) outcome: primary: left ventricular ejection fraction (LVEF); secondary: left ventricular end-diastolic diameter (LVEDD), brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-min walking distance (6-MWD), and adverse reactions. Studies reporting at least one outcome measure were included; (5) study design: RCTs, regardless of blinding or allocation concealment.

The excluded criteria were (1) animal experiments or cellular studies, (2) literature reviews or meta-analyses, (3) case reports, (4) literature with inconsistent data or incomplete access to key information, (5) clinical studies with clearly erroneous designs, and (6) duplicate publications.

Data extraction and literature quality assessment

Two trained reviewers (S.-W.Z. and H.-Q.Z.) independently conducted a literature search and screening. Disputed studies were discussed or assessed for inclusion by a third author (H.-X.L.). Excel was used to organize the required information. If essential information in the original article was unclear, erroneous, or ambiguous, the corresponding author was contacted via email. Studies were excluded if the actual effective original data were unavailable.

According to the Cochrane Handbook,¹⁰ two evaluators (S.-W.Z. and X.L.) independently assessed the quality of the included studies using the Cochrane risk of bias tool for randomized trials (RoB 2). The assessment included seven domains, such as the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Differences in opinion were resolved through the involvement of a third author (H.-X.L.), if necessary.

Statistical analysis

The meta-analysis was conducted using STATA 17.0 software. Risk ratio (RR) was used as the effect size for dichotomous variables. For continuous variables, the means and standard deviations of the differences before and after treatment were used, with the mean difference (MD) serving as the effect size. Each effect size was reported with a 95% confidence interval (CI).^11,12 According to the recommendations of the Cochrane Handbook and study design characteristics, a random-effects model using the DerSimonian–Laird method was adopted by default for the meta-analysis. The heterogeneity of the included studies was analyzed. I ² ≤ 50% indicated low heterogeneity, and I ² > 50% indicated substantial heterogeneity. Subgroup analyses were performed to investigate the sources of heterogeneity. Sensitivity analyses were performed to assess the robustness of the results. A funnel plot and Egger’s test were performed to analyze publication bias when the number of studies exceeded ten. p-Value <0.05 was considered statistically significant.

Evaluation of the quality of evidence

Two evaluators (S.-W.Z. and J.-P.C.) assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The quality of evidence rating for each outcome was assessed based on the risk of bias, inconsistency, indirectness, imprecision, and other considerations.

Results

Literature screening results

According to the search strategy, 766 studies were examined. After removing the duplicates, 266 studies remained. A total of 208 studies that did not meet the inclusion criteria were excluded after reading the titles and abstracts. Twenty-three studies were included after reading the full text, comprising 2643 patients. Figure 1 illustrates the literature search process. Table 1 summarizes the basic characteristics of the included studies.

FIG. 1.

Studies screening flowchart.

Table 1.

Characteristics of Included Studies

Study	Samplesize		Age		Male/female		Intervention		XMLI dose	Country of origin (XMLI)	Treatment course（day）	LVEF （%）	Outcome indicator
Study	T	C	T	C	T	C	T	C	XMLI dose	Country of origin (XMLI)	Treatment course（day）	LVEF （%）	Outcome indicator
Lin Du, 2016¹³	49	49	NR	NR	NR	NR	XMLI + CWT	CWT	5 mg/kg bid	China	10	≥40	①③④⑤⑥
Quan Fan, 2017¹⁴	44	34	64.2 ± 7.6	63.8 ± 6.8	28/16	20/14	XMLI + CWT	CWT	5 mg/kg bid	China	5	<40	②③
Shengmin Guo, 2016¹⁵	104	52	70.0 ± 7.0	68.0 ± 5.0	53/51	28/24	XMLI + CWT	CWT	250 mg bid	China	10	<40	①③④⑤⑥
Yi Jiang, 2019¹⁶	56	52	63.1 ± 7.2	62.7 ± 7.6	31/25	29/23	XMLI + CWT	CWT	5 mg/kg bid	China	10	<40	②③④⑤⑥
Haibin Li, 2015¹⁷	35	30	62.0 ± 10.0	58.0 ± 8.0	20/15	18/12	XMLI + CWT	CWT	400 mg qd	China	15	<40	③④
Junfeng Li, 2018¹⁸	36	36	77.9 ± 9.4	77.4 ± 9.6	21/15	23/13	XMLI + CWT	CWT	5 mg/kg bid	China	5	<40	①③⑤⑥
Qian Liu, 2020¹⁹	65	65	57.0 ± 4.5	56.3 ± 5.8	40/25	37/40	XMLI + CWT	CWT	5 mg/kg bid	China	10	<40	③④⑥
Hongyu Qu, 2017²⁰	114	106	69.0 ± 10.0	68.0 ± 11.0	92/22	88/18	XMLI + CWT	CWT	5-10 mg/kg bid	China	14	<40	①③⑤
Wuxia Quan, 2017²¹	51	51	67.6 ± 10.5	65.8 ± 11.4	35/16	38/13	XMLI + CWT	CWT	5 mg/kg bid	China	10	<40	②③⑤⑥
Wenyu Shen, 2017²²	58	58	62.8 ± 7.1	61.6 ± 7.8	34/24	24/22	XMLI + CWT	CWT	200 mg bid	China	14	<40	②③④⑤
Xianjun Si, 2021²³	51	51	75.4 ± 8.2	74.8 ± 9.7	25/26	23/28	XMLI + CWT	CWT	5 mg/kg bid	China	14	<40	①③
Nan Wang, 2019²⁴	58	58	59.5 ± 7.8	59.4 ± 7.9	27/31	28/30	XMLI + CWT	CWT	5 mg/kg bid	China	14	≥40	①③⑤
Yong Xu, 2016²⁵	76	76	NR	NR	50/26	48/28	XMLI + CWT	CWT	5 mg/kg bid	China	14	<40	③④⑤
Jingui Xue, 2015²⁶	115	120	63.1 ± 9.8	63.9 ± 9.0	69/46	60/60	XMLI + CWT	CWT	5 mg/kg bid	China	5	≥40	③⑤⑥
Haiyan Yang, 2014²⁷	49	43	77.5 ± 6.2	75.2 ± 5.5	33/16	31/12	XMLI + CWT	CWT	300 mg qd	China	14	NR	②⑤
Jing Yang, 2012²⁸	57	53	79.0 ± 10.0	78.0 ± 11.0	46/11	44/9	XMLI + CWT	CWT	200 mg bid	China	14	<40	①③
Enhui Yao, 2014²⁹	52	52	64.0 ± 4.0	62.0 ± 7.0	27/25	28/24	XMLI + CWT	CWT	200 mg qd	China	7	≥40	①③④⑥
Kefeng Ye, 2017³⁰	63	63	71.3 ± 11.4	74.0 ± 13.2	39/24	43/20	XMLI + CWT	CWT	5 mg/kg bid	China	14	<40	②③⑥
Haibo Yu, 2018³¹	30	30	63.9 ± 6.9	62.3 ± 6.7	13/17	16/14	XMLI + CWT	CWT	300 mg bid	China	10	<40	③④⑤⑥
Guili Yuan, 2015³²	54	34	51.5 ± 5.6	52.3 ± 6.0	30/24	19/15	XMLI + CWT	CWT	5 mg/kg bid	China	5	NR	②⑤⑥
Haiyan Zhang, 2015³³	59	58	NR	NR	26/33	30/28	XMLI + CWT	CWT	5 mg/kg bid	China	10	<40	②③⑥
Airong Zhao, 2022³⁴	48	48	66.0 ± 5.3	65.9 ± 4.6	27/21	26/22	XMLI + CWT	CWT	5 mg/kg qd	China	7	<40	②③④⑥
Xiaochao Zhou, 2020³⁵	50	50	66.6 ± 3.2	65.7 ± 3.3	27/23	29/21	XMLI + CWT	CWT	5 mg/kg bid	China	14	≥40	③④⑥

① BNP；② NT-proBNP；③ LVEF；④ LVEDD；⑤ 6-MWD；⑥ adverse reactions.

6-MWD, 6-min walking distance; BNP, brain natriuretic peptide; C, control group; CWT, conventional Western drug therapy; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NR, data not reported in the original study; NT-proBNP, N-terminal pro-brain natriuretic peptide; T, treatment group; XMLI, Xinmailong injection.

Risk of bias assessment

Ten studies described the randomization method, whereas 13 only mentioned randomization without specifying the method. Only one study mentioned allocation concealment. Two studies reported double blinding. No studies mentioned statistical blinding. Overall, one study was classified as low risk, while 22 were rated as having some concerns. The bias analyses are presented in Figure 2.

FIG. 2.

Risk of bias summary (A) and risk of bias diagram (B).

Primary outcome

A total of 21 studies that explored LVEF and comprised 2445 patients were included. A random-effects model was adopted for the analysis based on a priori methodological considerations. The XMLI group was more effective in increasing LVEF compared with CWT (MD = 6.66, 95% CI [5.23,8.09], Z = 9.12, p < 0.001) (Fig. 3). The heterogeneity test suggested significant heterogeneity (I ² = 90.97%, p < 0.001). No significant sources of heterogeneity were identified in subgroup analyses stratified by mean age, LVEF, treatment course, and sample size (Table 2). No outliers were observed in the sensitivity analysis (Supplementary Fig. S1).

FIG. 3.

Forest plots for left ventricular ejection fraction (LVEF).

Table 2.

Subgroup Analysis of LVEF

Grouping criteria	Subgroups	n	I ² (%)	MD (95% CI)
Mean age	<65 years	9	90.1	5.93 (3.67, 8.19)
Mean age	≥65 years	12	91.5	7.19 (5.25, 9.13)
LVEF	<40%	16	92.5	6.56 (4.89, 8.23)
LVEF	≥40%	5	66.2	7.14 (4.92, 9.36)
Treatment course	>7 days	5	96.1	7.67 (0.91, 14.43)
Treatment course	≤7 days	16	85.7	6.31 (5.09, 7.53)
Sample size	≥100	14	82.8	5.72 (4.52, 6.91)
Sample size	<100	7	94.4	8.61 (4.54, 12.67)

CI, confidence interval; LVEF, left ventricular ejection fraction; MD, mean difference.

Secondary outcomes

Left ventricular end-diastolic diameter

Eleven studies explored LVEDD, including 1185 patients. A random-effects model indicated that the XMLI group was more effective in reducing LVEDD levels compared with CWT (MD = −4.19, 95% CI [−5.55, −2.83], Z = −6.05, p < 0.001) (Fig. 4). Significant heterogeneity existed (I ² = 81.87%, p < 0.001). Subgroup analyses stratified by mean age, LVEF, treatment course, and sample size revealed no significant sources of heterogeneity (Table 3). Sensitivity analysis showed that there were no data outliers (Supplementary Fig. S2).

FIG. 4.

Forest plot for left ventricular end-diastolic diameter (LVEDD).

Table 3.

Subgroup Analysis of LVEDD

Grouping criteria	Subgroups	n	I ² (%)	MD (95% CI)
Mean age	<65 years	6	88.9	−4.66 (−7.02, −2.29)
Mean age	≥65 years	5	44.6	−3.59 (−479, −2.39)
LVEF	<40%	8	87.1	−4.12 (−5.96, −2.28)
LVEF	≥40%	3	0	−4.44 (−5.73, −3.16)
Treatment course	>7 days	9	83.2	−4.50 (−6.05, −2.94)
Treatment course	≤7 days	2	60.4	−2.68 (−5.19, −0.18)
Sample size	≥100	7	73.5	−3.61 (−5.03, −2.19)
Sample size	<100	4	89.3	−5.25 (−8.34, −2.16)

CI, confidence interval; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; MD, mean difference.

Brain natriuretic peptide and N-terminal pro-brain natriuretic peptide

Eight studies, including 978 patients, considered the BNP levels. A random-effects model was adopted. Combined XMLI and CWT more effectively reduced BNP levels than did CWT alone (MD = −178.84, 95% CI [−230.29, −127.40], Z = −6.81, p < 0.001) (Fig. 5). Heterogeneity tests showed I ² = 96.16% (p < 0.001), indicating the presence of substantial heterogeneity. No significant sources of heterogeneity were identified in subgroup analyses stratified by mean age, LVEF, treatment course, and sample size (Table 4). Sensitivity analysis revealed that there were no data outliers (Supplementary Fig. S3).

FIG. 5.

Forest plots for brain natriuretic peptide (BNP).

Table 4.

Subgroup Analysis of BNP

Grouping criteria	Subgroups	n	I ² (%)	MD (95% CI)
Mean age	<65 years	2	60.3	−241.33 (−319.83, −162.82)
Mean age	≥65 years	6	95.1	−160 (−208.86, −112.61)
LVEF	<40%	5	96.0	−164.27 (−219.63, −108.92)
LVEF	≥40%	3	92.0	−202.80 (−296.99, −108.61)
Treatment course	>7 days	6	95.1	−169.18 (−221.45, −116.91)
Treatment course	≤7 days	2	96.9	−201.86 (−335.55, −68.17)
Sample size	≥100	6	97.3	−194.43 (−260.80, −128.05)
Sample size	<100	2	96.3	−140.10 (−167.24, −112.96)

BNP, brain natriuretic peptide; CI, confidence interval; LVEF, left ventricular ejection fraction; MD, mean difference.

Nine studies explored the NT-proBNP levels in 915 patients. A random-effects model indicated a greater improvement in NT-proBNP levels in the XMLI group (MD = −490.95, 95% CI [−729.40, −252.50], Z = −4.04, p < 0.001) (Fig. 6). The heterogeneity test suggested significant heterogeneity (I ² = 90.44%, p < 0.001). Subgroup analyses stratified by mean age, LVEF, treatment course, and sample size revealed no significant sources of heterogeneity (Table 5). Similarly, the sensitivity analysis showed no outliers (Supplementary Fig. S4).

FIG. 6.

Forest plot for N-terminal pro-brain natriuretic peptide (NT-proBNP).

Table 5.

Subgroup Analysis of NT-proBNP

Grouping criteria	Subgroups	n	I ² (%)	MD (95% CI)
Mean age	<65 years	4	88.5	−679.76 (−1129.20, −230.33)
Mean age	≥65 years	5	73.4	−288.28 (−497.80, −78.76)
LVEF	<40%	9	90.44	−729.40 (−729.40, −252.50)
LVEF	≥40%	0	—	—
Treatment course	>7 days	6	69.4	−256.19 (−426.17, −86.12)
Treatment course	≤7 days	3	96.9	−720.41 (−1073.02, −367.80)
Sample size	≥100	4	13.6	−292.94 (−429.96, −155.91)
Sample size	<100	5	94.2	−577.43 (−1030.57, −124.30)

CI, confidence interval; LVEF, left ventricular ejection fraction; MD, mean difference; NT-proBNP, N-terminal pro-brain natriuretic peptide.

6-min walking distance

Thirteen studies involving 1606 patients mentioned the 6-MWD. A random-effects model indicated that the XMLI group had a longer 6-MWD (MD = 44.01, 95% CI [28.63,59.38], Z = 5.61, p < 0.001) (Fig. 7). There was significant heterogeneity among the included studies (I ² = 92.90%, p < 0.001). No sources of heterogeneity were identified in the subgroup analyses (Table 6). Sensitivity analysis revealed that there were no data outliers (Supplementary Fig. S5).

FIG. 7.

Forest plot for 6-min walking distance (6-MWD).

Table 6.

Subgroup Analysis of 6-MWD

Grouping criteria	Subgroups	n	I ² (%)	MD (95% CI)
Mean age	<65 years	6	93.8	41.80 (18.53, 65.07)
Mean age	≥65 years	7	91.0	45.86 (23.94, 67.77)
LVEF	<40%	8	92.5	45.96 (28.92, 63.00)
LVEF	≥40%	5	93.1	38.69 (2.26, 75.12)
Treatment course	>7 days	10	93.9	47.67 (30.03, 65.30)
Treatment course	≤7 days	3	6.3	31.67 (17.76, 45.58)
Sample size	≥100	7	94.5	57.19 (37.11, 77.28)
Sample size	<100	6	22.2	23.76 (14.14, 33.38)

6-MWD, 6-min walking distance; CI, confidence interval; LVEF, left ventricular ejection fraction; MD, mean difference.

Adverse reactions

Fifteen studies investigated adverse reactions, nine of which reported no adverse reactions. Six studies reported adverse reactions, including hepatic dysfunction, skin itching, palpitations, and other conditions (Supplementary Table S3). The incidences of adverse reactions were 1.9% and 1.3% in the XMLI and CWT groups, respectively. A random-effects model indicated no statistically significant difference in adverse reaction rates between the XMLI and CWT groups (RR = 1.47, 95% CI [0.73,2.99], Z = 1.08, p = 0.28) (Fig. 8). The studies showed no heterogeneity (I ² = 0.00%, p = 0.99).

FIG. 8.

Forest plot for adverse reactions.

Publication bias

Funnel plots, including LVEF, LVEDD, and 6-MWD, were used to assess publication bias for the outcomes in more than 10 included studies (Supplementary Figs. S6–S8). Egger’s test showed that there was a publication bias for LVEF (p = 0.032), and no significant publication bias for LVEDD (p = 0.477) or 6-MWD (p = 0.946).

GRADE quality grading of evidence

The quality of evidence for all outcomes was assessed using GRADE. Adverse reactions were rated as moderate-quality evidence; LVEDD, BNP, NT-proBNP, and 6-MWD were classified as low-quality evidence; and LVEF was rated as very low-quality evidence. The results are presented in Supplementary Table S4.

Discussion

XMLI is a new national Class II drug with independent intellectual property rights for treating patients with CHF with qi and yang deficiency, as well as blood stasis.³⁶ Cluster and factor analysis of TCM patterns in 768 patients with CHF revealed qi deficiency, yang deficiency, and blood stasis as the primary syndromes.³⁷ This systematic review included 23 RCTs with 2643 patients, evaluating the efficacy and safety of XMLI for CHF treatment based on LVEF, LVEDD, BNP, NT-proBNP, 6-MWD, and adverse reactions.

The LVEF and LVEDD reflect systolic and diastolic cardiac functions, respectively. Based on the LVEF, CHF is classified into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction, and HF with preserved ejection fraction.³⁸ Studies have demonstrated that patients with HFrEF had a higher risk for cardiovascular mortality, rehospitalization, and sudden cardiac death. Prognosis improved significantly when the LVEF increased by ≥10% and exceeded 40%.² Adam et al. found that even slight increases in the LVEF (5% and 10%) correlate with significant improvements in quality of life.³⁹ The LVEDD reflects cardiac volume loading and is associated with cardiac remodeling.⁴⁰ Research indicated that LVEDD was negatively correlated with quality of life in patients with HF.⁴¹ Our study showed that the combination of XMLI with CWT resulted in a 6.66% increase in LVEF and a 4.19 mm reduction in LVEDD compared with those under CWT alone, suggesting a potential improvement in prognosis and quality of life.

BNP and NT-proBNP are biochemical markers of CHF that are primarily produced by cardiomyocytes. Their levels increase when cardiomyocytes are subjected to stress, volume loading, and certain hormonal stimuli, reflecting the severity of HF.⁴² The European Society of Cardiology uses BNP and NT-proBNP as exclusion criteria for CHF.¹ BNP and NT-proBNP reflect the prognosis of patients with CHF. A systematic review of 19 studies showed that each 100 ng/L increase in admission BNP levels was associated with a 35% higher relative all-cause mortality risk.⁴³ A study involving 7039 patients reported that a 1-unit increase in the log-transformed discharge BNP value was correlated with a 34% increased risk of 1-year mortality.⁴⁴ At discharge, patients with a <50% reduction in NT-proBNP had a 57% higher rehospitalization or death risk.⁴⁵ In a study of 599 patients with dyspnea, those with NT-proBNP levels of >986 pg/mL had a 2.88-fold higher mortality rate than did those with NT-proBNP levels of ≤986 pg/mL.⁴⁶ Our study suggested that, compared with CWT alone, the combination of XMLI and CWT reduced BNP and NT-proBNP levels by 178.84 and 490.95 ng/L, respectively, potentially improving prognosis and disease progression in patients with CHF.

The 6-min walk test is a simple and effective method for assessing cardiac function and activity capacity in patients with CHF. Patients walking ≤200 m had an approximately 20% higher all-cause mortality rate than those walking >200 m. A 25-m improvement in 6-MWD may be clinically significant, while a 50-m improvement may indicate a more improved health status.^47,48 In this study, the combination of XMLI and CWT increased the 6-MWD by 44.01 m compared with that under CWT alone, potentially improving patients’ health status.

Our study indicated that the incidence of adverse reactions was slightly higher in the XMLI group (1.9%) than in the CWT group (1.3%), but there was no statistically significant difference between the two groups. Adverse reactions associated with XMLI combined with CWT primarily included hepatic dysfunction, skin itching, palpitations, and headaches, whereas those in the CWT group primarily included headaches, hepatic dysfunction, and skin itching. No severe adverse events were observed in either group. The available evidence suggests that the combination of XMLI and CWT may be considered safe. However, owing to limitations in the reported adverse reaction data (e.g., 8 out of 23 studies did not assess safety outcomes), further research is required to confirm its safety profile.

The use of insect medicines has a long history worldwide.⁴⁹ In Brazil, ants are used to treat asthma, impotence, and arthritis, whereas in Japan, bees and their products aid in treating conditions such as freckles, hemorrhoids, and constipation. Because of their resilience and widespread presence, cockroaches have also garnered attention.⁵⁰ In Europe, cockroaches are used to treat strokes, and in South India, wine containing cockroach ashes is used to treat bladder stones. P. americana is a cockroach species considered significant in complementary and alternative medicine. TCM believes that P. americana invigorates blood and reduces swelling.³⁶ Modern research has revealed that P. americana extracts exert multicomponent, multitarget effects and are used to treat ulcerative colitis, cancer, wound healing, cardiovascular disease, and other conditions.^51

–54

With the advancements in modern scientific research methodologies and the refinement of evidence-based medical frameworks, the clinical value of herbal compound formulations and monomeric components in the prevention and treatment of cardiovascular diseases is garnering attention. Their multicomponent, multitarget regulatory networks have been progressively elucidated.^55

–61 XMLI, extracted from P. americana, was approved by the Chinese State Food and Drug Administration in 2006 for CHF treatment and exerts therapeutic effects on CHF through multiple mechanisms.

Ventricular remodeling is the core pathological mechanism underlying the onset and progression of CHF. When the heart suffers pathological injuries such as myocardial ischemia or pressure overload, the ventricles undergo adaptive changes in structure, morphology, and function. Although these changes transiently maintain cardiac output in the early stages, prolonged progression causes decompensatory alterations, including diminished myocardial contractility and reduced ventricular compliance, triggering a vicious HF cycle. Ventricular remodeling involves multiple pathological mechanisms, such as cardiomyocyte hypertrophy, myocardial fibrosis, inflammation, and oxidative stress.^62
–64 Excessive cardiomyocyte hypertrophy leads to energy metabolism disorders and contractile dysfunction. Previous studies have demonstrated that GATA binding protein 4 (GATA4), a key pro-hypertrophic transcription factor, can activate multiple HF-associated genes.⁶⁵ XMLI inhibits the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (AKT), and glycogen synthase kinase-3β, as well as suppresses the protein expression of GATA4, reversing cardiac structural remodeling and contractile dysfunction.⁶⁶ Cyclic guanosine monophosphate (cGMP), an intracellular second messenger molecule synthesized by guanylyl cyclase, regulates cellular growth, fibrosis, myocardial contraction, and cardiac remodeling through the activation of its downstream effector, cGMP-dependent protein kinase G (PKG).⁶⁷ Studies have shown that Sacubitril/valsartan can improve diastolic left ventricular stiffness by activating the cGMP-PKG signaling pathway and may serve as a therapeutic target for HF.⁶⁸ Similarly, XMLI regulates the cGMP-PKG pathway and improves myocardial fibrosis.⁶⁹ Autophagy, a lysosome-dependent process, degrades damaged organelles, misfolded proteins, and other harmful components to sustain cellular homeostasis and metabolic balance, playing a crucial role in myocardial fibrosis.^70
–72 XMLI can regulate autophagy and ameliorate cardiac fibrotic remodeling and LVEF by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and inhibiting the ERK1/2 and p38 mitogen-activated protein kinase signaling pathways.⁷³ Inflammation and oxidative stress contribute significantly to the pathogenesis and progression of CHF.^74
–76 XMLI reduces pro-inflammatory markers such as tumor necrosis factor-α and interleukin-6 and increases superoxide dismutase levels, inhibiting ventricular remodeling.^77,78 Additionally, XMLI can directly modulate Ca²⁺ channels to promote Ca²⁺ influx into cardiomyocytes, which is similar to the action of positive inotropic agents.⁷⁹ In summary, XMLI inhibits ventricular remodeling by regulating cardiomyocyte hypertrophy, myocardial fibrosis, inflammation, and oxidative stress and enhances myocardial contractile function by promoting Ca²⁺ influx, exerting therapeutic effects in CHF.

Strengths and Limitations

Our study suggests that the combination of XMLI and CWT effectively improves laboratory indices, cardiac function, and exercise tolerance in patients with CHF, potentially contributing to a better prognosis. Recent studies have demonstrated that XMLI combined with CWT has a satisfactory safety profile. This study provides new evidence-based support for XMLI as a complementary therapeutic option for patients with CHF. However, this study had some limitations.

First, the quality of the included studies was poor. Only 10 studies (43.4%) mentioned the randomization methods, 1 (4.34%) mentioned allocation concealment, 2 (8.69%) mentioned double blinding, and none mentioned blinded evaluation of personnel conducting statistical analyses, indicating a risk of selection bias. Second, the original studies did not comprehensively report the specific drug names or dosages used in the CWT. Third, heterogeneity persisted despite the subgroup analyses, possibly because of variations in the detection equipment and differences in CWT protocols. Fourth, Egger’s test suggested a publication bias in the LVEF results, possibly because studies with positive findings were more frequently published. Fifth, this study investigated the effect of combining XMLI with CWT on the prognosis of patients with CHF; however, the conclusions were based solely on clinical physicochemical indices without a direct analysis of rehospitalization or all-cause mortality rates.

Future studies should focus on the following aspects to further investigate the efficacy of XMLI in CHF. First, high-quality clinical trials should be conducted with a randomized, triple-blind, placebo-controlled design. Second, clinical trial reports should follow standardized protocols and provide detailed documentation of baseline characteristics, including specific medications and dosages used in CWT. Finally, in addition to existing outcome measures, prognostic indicators, such as rehospitalization rates, cardiovascular mortality, and all-cause mortality, should be evaluated.

Conclusions

This study demonstrates the efficacy and safety of combining XMLI with CWT for CHF treatment, providing an additional therapeutic option for patients with CHF. However, further high-quality clinical trials focusing on long-term prognoses are required to validate these findings.

Footnotes

Authors’ Contributions

S.-W.Z. conceptualized the study, searched and screened qualified studies, assessed the risk of bias, analyzed data, and drafted the article. J.-P.C. conceptualized the study, searched qualified studies, and drafted the article. H.-Q.Z. screened qualified studies, analyzed data, and visualized images. X.L. conceptualized the study, assessed the risk of bias, and corrected the article. H.-X.L. supervised the data search and analysis process and corrected the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the National Natural Science Foundation of China (grant numbers: 82205098) and Scientific Research Program Project of Hebei Provincial Administration of Traditional Chinese Medicine (grant numbers: B2025055).

Supplementary Material

Supplementary Data

References

McDonagh

, Metra

, Adamo

, et al.; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J, 2021; 42(36):3599–3726; doi: 10.1093/eurheartj/ehab368

National Center for Cardiovascular Diseases. China National Heart Failure Society, Chinese Heart Failure Association of Chinese Medical Doctor Association. China National Heart Failure Guideline 2023. Chin J Heart Fail & Cardiomyopathy, 2023; 07(04):215–311; doi: 10.3760/cma.j.issn.101460-20231209-00052

Llorens

, Herrero

, Miró

. Diuretic strategies in patients with acute heart failure. N Engl J Med, 2011; 364(21):2068–2069; author reply 2069; doi: 10.1056/NEJMc1103708

Zhao

, Wang

, Zhao

, et al. Research progress of traditional Chinese medicine diagnosis and treatment of heart failure with normal ejection fraction. China J Tradit Chin Med Pharm, 2022; 37(6):3343–3345.

Xing

, Shang

, Liu

, et al. Shenyuan Yiqi Huoxue Capsules interfere with quality of life of patients with ischemic heart failure: A clinical randomized controlled trial. World Chin Med, 2022; 17(7):1013–1017.

Lai

, Shang

, Liu

, et al. Treatment of chronic ischemic heart failure with qi deficiency and blood stasis pattern by xiefei lishui mixture combined with western medicine routine therapy: A real-world multicenter cohort study. J Tradit Chin Med, 2022; 63(6):544–550; doi: 10.1328/8/j.11-2166/r.2022.06.010

Wang

, Ye

, Wan

, et al. Xinmailong modulates platelet function and inhibits thrombus formation via the platelet αIIbβ3-mediated signaling pathway. Front Pharmacol, 2019; 10:923; doi: 10.3389/fphar.2019.00923

, Zhang

, Wang

, et al. Clinical efficacy and safety of Xinmailong injection for the treatment of chronic heart failure: A meta-analysis. Front Pharmacol, 2018; 9:810; doi: 10.3389/fphar.2018.00810

Page

, Moher

, Bossuyt

, et al. PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews. BMJ, 2021; 372:n160; doi: 10.1136/bmj.n160

10.

Sterne

JAC

, Savović

, Page

, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ, 2019; 366:l4898; doi: 10.1136/bmj.l4898

11.

Xing

, Wu

, Chen

. Sample size estimation strategies in the absence of information on the standard deviation of differences in paired designs. Chin J Health Statistics, 2021; 38(2):181–182.

12.

Cao

, Zhou

, Liu

, et al. Clinical efficacy and safety of Shensong Yangxin Capsule-Amiodarone combination on heart failure complicated by Ventricular Arrhythmia: A meta-analysis of randomized controlled trials. Front Pharmacol, 2021; 12:613922; doi: 10.3389/fphar.2021.613922

13.

, Wu

, Li

, et al. Clinical efficacy of Xinmailong injection for chronic heart failure and its effect on cardiac function and BNP. Chin J Integr Med Cardio-Cerebrovasc Dis, 2016; 14(22):2656–2658.

14.

Fan

, Wang

, Cai

, et al. The effect of Xinmailong injection on serum lipocalin levels and cardiac function in patients with chronic heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2017; 15(13):1598–1600.

15.

Guo

, Ren

. Effects of Xinmailong injection at different dosages on the cardiac function and BNP level in elderly patients with chronic heart failure. Her Med, 2016; 35(1):54–57.

16.

Jiang

, Li

, Tang

, et al. Clinical study on Xinmailong injection in the treatment of senile chronic heart failure. China Pharm, 2019; 28(15):53–55.

17.

, Li

. Clinical observation of Xinmailong injection for chronic heart failure. Hebei Med J, 2015; 37(5):713–714.

18.

. The effect of Xinmailong injection on serum cystatin C and cardiac function in elderly patients with chronic heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2018; 16(24):3651–3653.

19.

Liu

, Song

, Chang

. Therapeutic effect of Xinmailong injection on elderly chronic heart failure and its influence on neuroendocrine hormones. Chin J Evid-Based Cardiovasc Med, 2020; 12(8):999–1001.

20.

, Zhao

, Yu

. Clinical observation of Xinmailong injection for chronic heart failure. Stud Trace Elem Health, 2017; 34(4):28–29.

21.

Quan

, Miao

. The clinical effect of Xinmailong injection on chronic heart failure. Chin J New Clin Med, 2017; 10(4):353–356.

22.

Shen

, Li

, Yang

. The influence of Xinmailong injection on cardiac function and plasma NT-proBNP level in patients with coronary heart disease with chronic heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2017; 15(7):833–835.

23.

. Clinical efficacy observation of Xinmailong injection in the treatment of chronic heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2017; 15(14):1736–1738.

24.

Wang

. Effects of Xinmailong injection combined with western drugs on cardiac function and myocardial damage in patients with chronic heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2019; 17(16):2483–2486.

25.

, Xu

. Clinical efficacy observation of Xinmailong injection for chronic heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2016; 14(20):2413–2414.

26.

Xue

, Wang

, Xu

, et al. Treatment of chronic heart failure patients with Qi-Yang deficiency and blood stasis resistance syndrome by Xinmailong injection: A multi-center randomized control study. Chin J Integr Tradit West Med, 2015; 35(7):796–800.

27.

Yang

, Cao

, Fu

. Effects of Xinmailong injection on pro-brain natriuretic peptide and troponinI in elderly patients with chronic heart failure. China Pharm, 2014; 23(17):30–32.

28.

Yang

, Chen

, Jiang

, et al. Observation of curative effect on Xinmailong Injection in the treatment of 110 patients with chronic heart failure. China Med Her, 2012; 9(14):93–94.

29.

Yao

, Li

, Wang

. Effects of Xinmailong injection on cardiac function and plasma BNP level in the patients with chronic heart failure. Chin Gen Pract, 2014; 17(27):3239–3241.

30.

, Sun

, Zhang

, et al. Observations on the efficacy of Xinmailong injection in the treatment of chronic cardiac insufficiency in elderly people. Chin J Integr Med Cardio-Cerebrovasc Dis, 2017; 15(19):2428–2430.

31.

, Li

, Yu

. The effect of Xinmailong injection on reticulin-1 and interleukin-17 in patients with heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2018; 16(21):3192–3194.

32.

Yuan

, Zhao

, Li

, et al. Observation of Xinmailong injection on the treatment of chronic heart failure. Hebei J Tradit Chin Med, 2015; 37(10):1545–1548.

33.

Zhang

. Clinical observation on Xinmailong injection in treatment of 59 patients with chronic heart failure. Chin J Integr Med Cardio-Cerebrovasc Dis, 2015; 13(2):218–220.

34.

Zhao

. Xinmailong injection combined with sacubitril valsartan sodium tablets in chronic heart failure. Chin Health Care, 2022; 40(4):142–145.

35.

Zhou

, Xu

. Effect of Xinmailong injection on cardiac function and inflammatory factors in patients with chronic heart failure. Clin J Tradit Chin Med, 2020; 32(2):344–346; doi: 10.1644/8/j.cjtcm.2020.0238

36.

Liu

, Zhu

, Mao

, et al. Expert consensus on the standardised application of Xinmailong injection in the treatment of chronic heart failure. Chin J Integr Tradit West Med, 2016; 36(3):280–284.

37.

, Wang

, Hu

, et al. Study on syndromes regularity of chronic heart failure based on data mining technology. Shandong J Tradit Chin Med, 2023; 42(11):1186–1191; doi: 10.1629/5/j.cnki.0257-358x.2023.11.009

38.

Writing Committee Members, ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA Guideline for the management of heart failure. J Card Fail, 2022; 28(5):e1–e167; doi: 10.1016/j.cardfail.2022.02.010

39.

DeVore

, Hellkamp

, Thomas

, et al. The association of improvement in left ventricular ejection fraction with outcomes in patients with heart failure with reduced ejection fraction: Data from CHAMP-HF. Eur J Heart Fail, 2022; 24(5):762–770; doi: 10.1002/ejhf.2486

40.

Huang

, Xu

, Liu

, et al. Effects of new hypoglycemic drugs on cardiac remodeling: A systematic review and network meta-analysis. BMC Cardiovasc Disord, 2023; 23(1):293; doi: 10.1186/s12872-023-03324-6

41.

Ferreira

, Shah

, Claggett

, et al. Cardiac structure and function and quality of life associations in HFpEF: An analysis from TOPCAT-Americas. Int J Cardiol, 2022; 352:78–83; doi: 10.1016/j.ijcard.2022.01.053

42.

Nishikimi

, Nakagawa

. B-Type Natriuretic Peptide (BNP) Revisited-Is BNP still a biomarker for heart failure in the angiotensin receptor/neprilysin inhibitor era? Biology (Basel), 2022; 11(7):1034; doi: 10.3390/biology11071034

43.

Castiglione

, Aimo

, Vergaro

, et al. Biomarkers for the diagnosis and management of heart failure. Heart Fail Rev, 2022; 27(2):625–643; doi: 10.1007/s10741-021-10105-w

44.

Kociol

, Horton

, Fonarow

, et al. Admission, discharge, or change in B-type natriuretic peptide and long-term outcomes: Data from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims. Circ Heart Fail, 2011; 4(5):628–636; doi: 10.1161/CIRCHEARTFAILURE.111.962290

45.

Michtalik

, Yeh

H-C

, Campbell

, et al. Acute changes in N-terminal pro-B-type natriuretic peptide during hospitalization and risk of readmission and mortality in patients with heart failure. Am J Cardiol, 2011; 107(8):1191–1195; doi: 10.1016/j.amjcard.2010.12.018

46.

Januzzi

, Sakhuja

, O’donoghue

, et al. Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department. Arch Intern Med, 2006; 166(3):315–320; doi: 10.1001/archinte.166.3.315

47.

Curtis

, Rathore

, Wang

, et al. The association of 6-minute walk performance and outcomes in stable outpatients with heart failure. J Card Fail, 2004; 10(1):9–14.

48.

Jain

, Cohen

, Zhang

, et al. Defining a clinically important change in 6-minute walk distance in patients with heart failure and mitral valve disease. Circ Heart Fail, 2021; 14(3):e007564; doi: 10.1161/CIRCHEARTFAILURE.120.007564

49.

Namba

, Ma

, Inagaki

. Insect-derived crude drugs in the Chinese Song dynasty. J Ethnopharmacol, 1988; 24(2–3):247–285; doi: 10.1016/0378-8741(88)90157-2

50.

Meyer-Rochow

. Therapeutic arthropods and other, largely terrestrial, folk-medicinally important invertebrates: A comparative survey and review. J Ethnobiol Ethnomed, 2017; 13(1):9; doi: 10.1186/s13002-017-0136-0

51.

Zhang

, Sun

, Liu

, et al. The ethanol extract of Periplaneta Americana L. improves ulcerative colitis induced by a combination of chronic stress and TNBS in rats. Acta Cir Bras, 2022; 37(5):e370505; doi: 10.1590/acb370505

52.

Wang

, He

, Song

, et al. Chemotherapeutic effects of bioassay-guided extracts of the American cockroach, Periplaneta americana. Integr Cancer Ther, 2011; 10(3):NP12–NP23; doi: 10.1177/1534735411413467

53.

Zhang

, Dong

, Wang

, et al. N-acetyldopamine oligomers from Periplaneta americana with anti-inflammatory and vasorelaxant effects and their spatial distribution visualized by mass spectrometry imaging. J Ethnopharmacol, 2024; 318(Pt B):116989; doi: 10.1016/j.jep.2023.116989

54.

Chen

, Hu

, Li

, et al. A feasible biocompatible hydrogel film embedding Periplaneta americana extract for acute wound healing. Int J Pharm, 2019; 571:118707; doi: 10.1016/j.ijpharm.2019.118707

55.

Wang

, Zhuang

, Yang

, et al. Exploring the mechanism of ferroptosis induction by Sappanone A in cancer: Insights into the mitochondrial dysfunction mediated by NRF2/xCT/GPX4 Axis. Int J Biol Sci, 2024; 20(13):5145–5161; doi: 10.7150/ijbs.96748

56.

, Zhang

, Liu

, et al. Ginsenoside Rb1 ameliorates heart failure through DUSP-1-TMBIM-6-mediated mitochondrial quality control and gut flora interactions. Phytomedicine, 2024; 132:155880; doi: 10.1016/j.phymed.2024.155880

57.

, Yu

, Li

, et al. New insights into the role of mitochondrial metabolic dysregulation and immune infiltration in septic cardiomyopathy by integrated bioinformatics analysis and experimental validation. Cell Mol Biol Lett, 2024; 29(1):21; doi: 10.1186/s11658-024-00536-2

58.

Chang

, Zhang

, Huang

, et al. Quercetin inhibits necroptosis in cardiomyocytes after ischemia-reperfusion via DNA-PKcs-SIRT5-orchestrated mitochondrial quality control. Phytother Res, 2024; 38(5):2496–2517; doi: 10.1002/ptr.8177

59.

Chang

, Li

, Liu

, et al. ß-tubulin contributes to Tongyang Huoxue decoction-induced protection against hypoxia/reoxygenation-induced injury of sinoatrial node cells through SIRT1-mediated regulation of mitochondrial quality surveillance. Phytomedicine, 2023; 108:154502; doi: 10.1016/j.phymed.2022.154502

60.

Chang

, Zhou

, Liu

, et al. Zishen Tongyang Huoxue decoction (TYHX) alleviates sinoatrial node cell ischemia/reperfusion injury by directing mitochondrial quality control via the VDAC1-β-tubulin signaling axis. J Ethnopharmacol, 2024; 320:117371; doi: 10.1016/j.jep.2023.117371

61.

Chang

, Zhou

, Liu

, et al. Zishenhuoxue decoction-induced myocardial protection against ischemic injury through TMBIM6-VDAC1-mediated regulation of calcium homeostasis and mitochondrial quality surveillance. Phytomedicine, 2024; 132:155331; doi: 10.1016/j.phymed.2023.155331

62.

Tanai

, Frantz

. Pathophysiology of heart failure. Compr Physiol, 2015; 6(1):187–214; doi: 10.1002/cphy.c140055

63.

Chang

, Liu

, Li

, et al. Molecular mechanisms of mitochondrial quality control in ischemic cardiomyopathy. Int J Biol Sci, 2023; 19(2):426–448; doi: 10.7150/ijbs.76223

64.

Xiong

, Yang

. Revising the hemodynamic criteria for pulmonary hypertension: A perspective from China. J Transl Int Med, 2023; 11(1):1–3; doi: 10.2478/jtim-2022-0023

65.

Cheng

, Xu

, Chen

, et al. DEC1 represses cardiomyocyte hypertrophy by recruiting PRP19 as an E3 ligase to promote ubiquitination-proteasome-mediated degradation of GATA4. J Mol Cell Cardiol, 2022; 169:96–110; doi: 10.1016/j.yjmcc.2022.05.005

66.

, Yu

, Tan

, et al. Mechanisms of Chinese Medicine Xinmailong’s protection against heart failure in pressure-overloaded mice and cultured cardiomyocytes. Sci Rep, 2017; 7:42843; doi: 10.1038/srep42843

67.

Nakamura

, Tsujita

. Current trends and future perspectives for heart failure treatment leveraging cGMP modifiers and the practical effector PKG. J Cardiol, 2021; 78(4):261–268; doi: 10.1016/j.jjcc.2021.03.004

68.

Furukawa

, Matsui

, Sunaga

, et al. Sacubitril/valsartan improves diastolic left ventricular stiffness with increased titin phosphorylation via cGMP-PKG activation in diabetic mice. Sci Rep, 2024; 14(1):25081; doi: 10.1038/s41598-024-75757-8

69.

Xue

, Lv

, Jin

, et al. Study on the mechanism of Xinmailong injection against chronic heart failure based on transcriptomics and proteomics. J Pharm Biomed Anal, 2025; 253:116529; doi: 10.1016/j.jpba.2024.116529

70.

Wang

, Yuan

, Zheng

, et al. Chikusetsu saponin IVa attenuates isoprenaline-induced myocardial fibrosis in mice through activation autophagy mediated by AMPK/mTOR/ULK1 signaling. Phytomedicine, 2019; 58:152764; doi: 10.1016/j.phymed.2018.11.024

71.

Zhang

, Zhou

, Chang

. Involvement of mitochondrial dynamics and mitophagy in diabetic endothelial dysfunction and cardiac microvascular injury. Arch Toxicol, 2023; 97(12):3023–3035; doi: 10.1007/s00204-023-03599-w

72.

Wang

, Zhuang

, Jia

, et al. Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy. Int J Biol Sci, 2024; 20(11):4458–4475; doi: 10.7150/ijbs.95853

73.

, Mao

, Zhang

, et al. Xinmailong mitigated epirubicin-induced cardiotoxicity via inhibiting autophagy. J Ethnopharmacol, 2016; 192:459–470; doi: 10.1016/j.jep.2016.08.031

74.

Murphy

, Kakkar

, McCarthy

, et al. Inflammation in heart failure: JACC state-of-the-art review. J Am Coll Cardiol, 2020; 75(11):1324–1340; doi: 10.1016/j.jacc.2020.01.014

75.

van der Pol

, van Gilst

, Voors

, et al. Treating oxidative stress in heart failure: Past, present and future. Eur J Heart Fail, 2019; 21(4):425–435; doi: 10.1002/ejhf.1320

76.

Pang

, Dong

, Pang

, et al. Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: Focus on mitochondrial dysfunction. Angiogenesis, 2024; 27(4):623–639; doi: 10.1007/s10456-024-09938-4

77.

Jiang

, Liu

, Xiao

, et al. Xinmailong attenuates Doxorubicin-induced lysosomal dysfunction and oxidative stress in H9c2 Cells via HO-1. Oxid Med Cell Longev, 2021; 2021:5896931; doi: 10.1155/2021/5896931

78.

Wei

. Effect of Xinmailong injection on levels of inflammatory factors in patients with heart failure after acute myocardial infarction. Mod Med Health Res Electronic J, 2023; 7(6):92–94.

79.

, Li

, Hu

, et al. Mechanisms underlying action of Xinmailong injection, a traditional Chinese medicine in cardiac function improvement. Afr J Tradit Complement Altern Med, 2017; 14(2):241–252; doi: 10.2101/0/ajtcam.v14i2.26

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