Yiqi Huoxue formula (益气活血方) relieves heart failure with reduced ejection fraction in calcium/calmodulin-dependent protein kinase Ⅱ delta B isoform and calcium/calmodulin-dependent protein kinase Ⅱ delta C isoform transgenic mice by inhibiting myocardial remodeling and enhancing calcium homeostasis

doi:10.19852/j.cnki.jtcm.20260214.001

Journal of Traditional Chinese Medicine ›› 2026, Vol. 46 ›› Issue (3): 530-543.DOI: 10.19852/j.cnki.jtcm.20260214.001

• Original Articles • Previous Articles Next Articles

Yiqi Huoxue formula (益气活血方) relieves heart failure with reduced ejection fraction in calcium/calmodulin-dependent protein kinase Ⅱ delta B isoform and calcium/calmodulin-dependent protein kinase Ⅱ delta C isoform transgenic mice by inhibiting myocardial remodeling and enhancing calcium homeostasis

XU Jianglin¹, SHI Xiaolu², LI Yan³, ZHOU Kun³, LI Peng⁴, LI Sinai⁵, LU Jinjin³, CHEN Yajun⁴, ZHAN Nannan⁴, ZHANG Ruotong⁴, CHENG Bairu⁴, LIN Qian⁴, WAN Jie³(), LIU Jing³()

¹ Department of Cardiology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
² Beijing Key Laboratory of TCM Basic Research on Prevention and Treatment of Major Disease, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
³ Department of Cardiology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China
⁴ Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100010, China
⁵ Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China

Received:2025-01-11 Accepted:2025-09-29 Online:2026-06-15 Published:2026-02-14
Contact: LIU Jing, Department of Cardiology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China. liujingth@sina.com, Telephone: +86-13161161811;
WAN Jie, Department of Cardiology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100078, China. yuezhijie1226@sina.com, Telephone: +86-19047159498
About author:First author contact:
XU Jianglin and SHI Xiaolu are co-first authors and contributed equally to this work
Supported by:
Natural Science Foundation-funded Project: Underlined Mechanism of Calcium/calmodulin-dependent Protein Kinase II Regulating Heart Failure With Preserved Ejection Fraction and the Effect of Yiqi-Huoxue Formula(81903993);Investigation on the Mechanism of Yiqi-Huoxue Method on Heart Failurebased on Mitochondrial Calcium/calmodulin-dependent Protein Kinase II Overexpression Mediated Energy Shuttle Disturbance-calcium Homeostasis Disorder(82305170);Fundamental Research Funds for the Central Public Welfare Research Institutes National Traditional Chinese: High-throughput Detection Technology for the Study of Excitation-contraction-coupled Calcium Transport(JBGS2021006);National High Level Chinese Medicine Hospital Clinical Research Funding: Mechanism Study on the Reduction of Post-Percutaneous Coronary Intervention Microvascular Obstruction by Yiqi Liangxue Shengji Formula: Exploring the Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2/Peptidylarginine Deiminase 4 Pathway-mediated Neutrophil Extracellular Trap Formation(DFG2RB2024GJR013)

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Abstract

Abstract:

OBJECTIVE: To confirm the efficacy of Yiqi Huoxue formula (益气活血方, YQHX) on heart failure with reduced ejection fraction (HFrEF), and elucidate its potential effect on calcium homeostasis.

METHODS: Cardiac specific calcium/calmodulin-dependent protein kinase II delta C isoform (CaMKⅡδC)-overexpression transgenic mice (C-CaMKⅡδC^+/- Tg mice) and calcium/calmodulin-dependent protein kinase II delta B isoform (CaMKⅡδB)-overexpression transgenic mice (C-CaMKⅡδB^+/- Tg mice) were established by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 technique, and their genotypes and phenotypes were identified thereafter. C57BL/6 mice and transgenic mice were divided into seven groups in random, each containing eight mice. The groups were Control group, CaMKⅡδB model group, CaMKⅡδB treatment group (B Treated), CaMKⅡδB inhibitor group (B Inhibitor), CaMKⅡδC model group (C Model), CaMKⅡδC treatment group (C Treated), CaMKⅡδC inhibitor group (C Inhibitor). B and C Treated groups were given YQHX once a day for 4 weeks by gavage. The cardiac function and structure were evaluated using echocardiogram. The myocardial cellular status and fibrosis were detected by hematoxylin and eosin staining and Masson staining. Calcium transients and calcium leakage from cardiac ventricular myocytes were detected to reflect calcium homeostasis, and the expressions of CaMKⅡδB, CaMKⅡδC, hypertrophy factors, calcium pathway-related genes, and the level of calcium handling proteins were assessed by western blotting and reverse transcription-quantitative polymerase chain reaction.

RESULTS: We found CaMKⅡδB and CaMKⅡδC transgenic mice showed HFrEF phenotype. YQHX improved the systolic function of the CaMKⅡδB transgenic mice, reduced the cross-sectional area of cardiomyocytes, inhibited the overexpression of CaMKⅡδB and hypertrophy-related genes (B-type natriuretic peptide, myocyte enhancer factor 2, and atrial natriuretic factor), and increased calcium handling protein sarcoendoplasmic reticulum Ca²⁺ adenosine triphosphatase 2a (SERCA2a) and calcium capacity. YQHX improved the cardiac systolic function of CaMKⅡδC transgenic mice, reduced the ventricular diameter and cardiomyocyte cross-sectional area, alleviated myocardial fibrosis, increased SERCA2a expression and calcium capacity, and reduced calcium leakage.

CONCLUSION: Our results suggest that YQHX improved HFrEF by inhibiting CaMKIIδB overexpression, which may be related to reduced expression of hypertrophy-related factors, and increased SERCA2a expression to increase calcium reserve. In addition, YQHX improved HFrEF by inhibiting CaMKIIδC overexpression, which may be related to reduce calcium leakage, and increase SERCA2a expression to increase calcium reserve.

Key words: heart failure, systolic, calcium homeostasis, Yiqi Huoxue formula, calcium/calmodulin-dependent protein kinase II delta C isoform overexpression, calcium/calmodulin-dependent protein kinase II delta B isoform overexpression

XU Jianglin, SHI Xiaolu, LI Yan, ZHOU Kun, LI Peng, LI Sinai, LU Jinjin, CHEN Yajun, ZHAN Nannan, ZHANG Ruotong, CHENG Bairu, LIN Qian, WAN Jie, LIU Jing. Yiqi Huoxue formula (益气活血方) relieves heart failure with reduced ejection fraction in calcium/calmodulin-dependent protein kinase Ⅱ delta B isoform and calcium/calmodulin-dependent protein kinase Ⅱ delta C isoform transgenic mice by inhibiting myocardial remodeling and enhancing calcium homeostasis[J]. Journal of Traditional Chinese Medicine, 2026, 46(3): 530-543.

Figures/Tables 5

Table 1 Components identification in YQHX

No.	Compounds	RT (min)	Formula	Mode	Molecular weight
1	Puerarin	0.76	C₂₁H₂₀O₉	Negative	416.38
2	Gentisinic acid	1.00	C₇H₆O₄	Negative	154.12
3	Catechol	1.16	C₆H₆O₂	Negative	110.11
4	Isoimperatorin	1.26	C₁₆H₁₄O₄	Negative	270.28
5	4-Methylesculetin	1.82	C₁₀H₈O₄	Positive	192.17
6	Naringenin	2.12	C₁₅H₁₂O₅	Positive	282.33
7	Genistein	2.14	C₁₅H₁₀O₅	Positive	270.24
8	3',4',7-Trihydroxyflavanone	2.16	C₁₅H₁₂O₅	Negative	282.33
9	Liquiritigenin	2.80	C₁₅H₁₂O₄	Positive	256.25
10	Cuminyl alcohol	3.01	C₁₀H₁₄O	Positive	150.22
11	Dioscin	3.04	C₄₅H₇₂O₁₆	Negative	869.04
12	Glycitein	3.21	C₁₆H₁₂O₅	Negative	284.27
13	o-Veratraldehyde	3.23	C₉H₁₀O₃	Positive	166.17
14	Oroxylin A-7-O-beta-D-glucuronide	3.28	C₂₂H₂₀O₁₁	Negative	460.40
15	Gal(alpha1-6)Glc(alpha1-2beta)Fruf	4.26	C₁₈H₃₂O₁₆	Positive	504.44
16	Muricarpone B	4.35	C₁₉H₂₂O₅	Positive	330.38
17	Formononetin	4.76	C₁₆H₁₂O₄	Positive	268.26
18	Resveratrol	4.91	C₁₄H₁₂O₃	Positive	228.24
19	Marmesin	4.91	C₁₄H₁₄O₄	Positive	246.26
20	Pyocyanin	4.98	C₁₃H₁₀N₂O	Positive	210.23
21	Soyasapogenol M1	4.98	C₃₀H₄₈O₂	Positive	440.71
22	Matairesinol	5.25	C₂₀H₂₂O₆	Positive	358.39
23	Demethoxycurcumin	5.48	C₂₀H₁₈O₅	Positive	338.35
24	Glabridin	5.56	C₂₀H₂₀O₄	Positive	324.37
25	Ginsenoside Re	5.61	C₄₈H₈₂O₁₈	Positive	947.16
26	Dehydronuciferin	5.80	C₁₉H₁₉NO₂	Positive	293.36
27	Licoflavone A	5.84	C₂₀H₁₈O₄	Positive	322.35
28	Cabreuvin	5.98	C₁₈H₁₆O₅	Positive	312.32
29	Cycloastragenol	6.14	C₃₀H₅₀O₅	Positive	490.72
30	Oxoglaucine	6.15	C₂₀H₁₇NO₅	Positive	351.35
31	Betulin	6.50	C₃₀H₅₀O₂	Positive	442.72
32	Alisol B 23-acetate	6.77	C₃₂H₅₀O₅	Positive	514.74
33	Bavachin	6.94	C₂₀H₂₀O₄	Positive	324.37
34	Dehydrotrametenolic acid	7.21	C₃₀H₄₆O₃	Positive	454.68
35	Acetyl-11-keto-beta-boswellic acid	7.23	C₃₂H₄₈O₅	Positive	512.72
36	Quillaic acid	7.48	C₃₀H₄₆O₅	Positive	486.68
37	(+)-Chalepin	7.89	C₁₉H₂₂O₄	Positive	314.38
38	Tanshinone ⅡA	9.92	C₁₉H₁₈O₃	Positive	394.35
39	Steviol-19-O-glucoside	13.03	C₂₆H₄₀O₈	Positive	480.60

Table 1 Components identification in YQHX

No.	Compounds	RT (min)	Formula	Mode	Molecular weight
1	Puerarin	0.76	C₂₁H₂₀O₉	Negative	416.38
2	Gentisinic acid	1.00	C₇H₆O₄	Negative	154.12
3	Catechol	1.16	C₆H₆O₂	Negative	110.11
4	Isoimperatorin	1.26	C₁₆H₁₄O₄	Negative	270.28
5	4-Methylesculetin	1.82	C₁₀H₈O₄	Positive	192.17
6	Naringenin	2.12	C₁₅H₁₂O₅	Positive	282.33
7	Genistein	2.14	C₁₅H₁₀O₅	Positive	270.24
8	3',4',7-Trihydroxyflavanone	2.16	C₁₅H₁₂O₅	Negative	282.33
9	Liquiritigenin	2.80	C₁₅H₁₂O₄	Positive	256.25
10	Cuminyl alcohol	3.01	C₁₀H₁₄O	Positive	150.22
11	Dioscin	3.04	C₄₅H₇₂O₁₆	Negative	869.04
12	Glycitein	3.21	C₁₆H₁₂O₅	Negative	284.27
13	o-Veratraldehyde	3.23	C₉H₁₀O₃	Positive	166.17
14	Oroxylin A-7-O-beta-D-glucuronide	3.28	C₂₂H₂₀O₁₁	Negative	460.40
15	Gal(alpha1-6)Glc(alpha1-2beta)Fruf	4.26	C₁₈H₃₂O₁₆	Positive	504.44
16	Muricarpone B	4.35	C₁₉H₂₂O₅	Positive	330.38
17	Formononetin	4.76	C₁₆H₁₂O₄	Positive	268.26
18	Resveratrol	4.91	C₁₄H₁₂O₃	Positive	228.24
19	Marmesin	4.91	C₁₄H₁₄O₄	Positive	246.26
20	Pyocyanin	4.98	C₁₃H₁₀N₂O	Positive	210.23
21	Soyasapogenol M1	4.98	C₃₀H₄₈O₂	Positive	440.71
22	Matairesinol	5.25	C₂₀H₂₂O₆	Positive	358.39
23	Demethoxycurcumin	5.48	C₂₀H₁₈O₅	Positive	338.35
24	Glabridin	5.56	C₂₀H₂₀O₄	Positive	324.37
25	Ginsenoside Re	5.61	C₄₈H₈₂O₁₈	Positive	947.16
26	Dehydronuciferin	5.80	C₁₉H₁₉NO₂	Positive	293.36
27	Licoflavone A	5.84	C₂₀H₁₈O₄	Positive	322.35
28	Cabreuvin	5.98	C₁₈H₁₆O₅	Positive	312.32
29	Cycloastragenol	6.14	C₃₀H₅₀O₅	Positive	490.72
30	Oxoglaucine	6.15	C₂₀H₁₇NO₅	Positive	351.35
31	Betulin	6.50	C₃₀H₅₀O₂	Positive	442.72
32	Alisol B 23-acetate	6.77	C₃₂H₅₀O₅	Positive	514.74
33	Bavachin	6.94	C₂₀H₂₀O₄	Positive	324.37
34	Dehydrotrametenolic acid	7.21	C₃₀H₄₆O₃	Positive	454.68
35	Acetyl-11-keto-beta-boswellic acid	7.23	C₃₂H₄₈O₅	Positive	512.72
36	Quillaic acid	7.48	C₃₀H₄₆O₅	Positive	486.68
37	(+)-Chalepin	7.89	C₁₉H₂₂O₄	Positive	314.38
38	Tanshinone ⅡA	9.92	C₁₉H₁₈O₃	Positive	394.35
39	Steviol-19-O-glucoside	13.03	C₂₆H₄₀O₈	Positive	480.60

Figure 1 Effect of YQHX on cardiac function and dilation in mice A, B: representative M-mode echocardiographic images; C: representative macrograph of HE-stained sections of hearts; A1, B1, C1: Control group; A2, B2, C2: B Model group; A3, B3, C3: B Treated group; A4, B4, C4: B Inhibitor group; A5, B5, C5: C Model group; A6, B6, C6: C Treated group; A7, B7, C7: C Inhibitor group; D: LVEF; E: FS; F: LVEDd. Control group: male C57BL/6J mice received 0.9% saline solution (0.1 mL/10 g daily); B Model group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); B Treated group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); B Inhibitor group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;); C Model group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); C Treated group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); C Inhibitor group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;). YQHX: Yiqi Huoxue formula; HE: hematoxylin and eosin; CaMKIIδB: calcium/calmodulin-dependent protein kinase Ⅱ delta B isoform; CaMKⅡδC: calcium/calmodulin-dependent protein kinase Ⅱ delta C isoform;KN-93: N-[2-[[[(2E)-3-(4-Chlorophenyl)-2-propenyl]methylamino]methyl] phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide; LVEF: left ventricular ejection fraction; FS: fraction shortening; LVEDd: left ventricular internal diameter of diastole. Statistical analyses were conducted using one-way analysis of variance for comparisons among multiple groups. All data are expressed as mean ± standard deviation (the sample sizes were 8-11 for A, B and D, and 4 for C). aP < 0.05, compared with the Control group; bP < 0.05, compared with the B Model group; cP < 0.05, compared with the C Model group.

Figure 2 Effect of YQHX on cardiac histopathological changes A : representative HE staining images (× 20); B: representative Masson staining images (× 20); A1, B1: Control group; A2, B2: B Model group; A3, B3: B Treated group; A4, B4: B Inhibitor group; A5, B5: C Model group; A6, B6: C Treated group; A7, B7: C Inhibitor group; C: CCSA; D: CVF. Control group: male C57BL/6J mice received 0.9% saline solution (0.1 mL/10 g daily); B Model group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); B Treated group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); B Inhibitor group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;); C Model group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); C Treated group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); C Inhibitor group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;). YQHX: Yiqi Huoxue formula; HE: hematoxylin and eosin; CaMKIIδB: calcium/calmodulin-dependent protein kinase II delta B isoform; CaMKIIδC: calcium/calmodulin-dependent protein kinase II delta C isoform; KN-93: N-[2-[[[(2E)-3-(4-Chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide; CCSA: cross-sectional area of cardiomyocytes; CVF: collagen volume fraction. Statistical analyses were conducted using one-way analysis of variance for comparisons among multiple groups. All data are expressed as mean ± standard deviation (n = 4 in each group). aP < 0.05, compared with the Control group; bP < 0.05, compared with the B Model group; cP < 0.05, compared with the C Model group.

Figure 3 Effect of YQHX on calcium homeostasis A: calcium transient amplitude; B: [Ca2+]SR; C: SR leak ratio. Control group: Male C57BL/6J mice received 0.9% saline solution (0.1 mL/10 g daily); B Model group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); B Treated group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); B Inhibitor group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;); C Model group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); C Treated group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); C Inhibitor group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;). YQHX: Yiqi Huoxue formula; CaMKⅡδB: calcium/calmodulin-dependent protein kinase II delta B isoform; CaMKIIδC: calcium/calmodulin-dependent protein kinase Ⅱ delta C isoform; KN-93: N-[2-[[[(2E)-3-(4-Chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide; SR: sarcoplasmic reticulum. Statistical analyses were conducted using one-way analysis of variance for comparisons among multiple groups. All data are expressed as mean ± standard deviation (n = 3 in each group). aP < 0.05, compared with the Control group; bP < 0.05, compared with the B Model group; cP < 0.05, compared with the C Model group.

Figure 4 Effect of YQHX on CaMKⅡδB, CaMKⅡδC expression and genes associated with cardiac hypertrophy and calcium homeostasis expression A: mRNA expression of CaMKⅡδB; B: protein expression of CaMKⅡδB; B1: Western blot was used to detect the protein levels of CaMKⅡδB in rat heart tissue; B2: biochemical analysis was used to detect the levels of CaMKⅡδB; C: mRNA expression of CaMKⅡδC; D: protein expression of CaMKⅡδC; D1: Western blot was used to detect the protein levels of CaMKⅡδC in rat heart tissue; D2: biochemical analysis was used to detect the levels of CaMKⅡδC; E: protein expression of SERCA2a; E1: Western blot was used to detect the protein levels of SERCA2a in rat heart tissue; E2: biochemical analysis was used to detect the levels of SERCA2a; Control group: male C57BL/6J mice received 0.9% saline solution (0.1 mL/10 g daily); B Model group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); B Treated group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); B Inhibitor group: male Rosa26-LSL-CaMKⅡδB+/-; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;); C Model group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received 0.9% saline solution (0.1 mL/10 g daily); C Treated group: male Rosa26-LSL-CaMKⅡδC+/- ;Myh6-CreER+ mice received YQHX (0.1 mL/10 g daily); C Inhibitor group: male Rosa26-LSL-CaMKⅡδC+/- ; Myh6-CreER+ mice received KN-93 (10 μmoL·kg-1;·d-1;). YQHX: Yiqi Huoxue formula; CaMKIIδB: calcium/calmodulin-dependent protein kinase II delta B isoform; CaMKIIδC: calcium/calmodulin-dependent protein kinase Ⅱ delta C isoform; KN-93: N-[2-[[[(2E)-3-(4-Chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide; SERCA2a: sarco/endoplasmic reticulum Ca2+-ATPase 2a. Statistical analyses were conducted using one-way analysis of variance for comparisons among multiple groups. All data are expressed as mean ± standard deviation (n = 3 in each group). aP < 0.05, compared with the Control group; bP < 0.05, compared with the B Model group; cP < 0.05, compared with the C Model group.

References 53.

1.	McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2022; 24: 4-131.
2.	Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2023 update: a report from the american heart association. Circulation 2023; 147: e93-621. DOI PMID
3.	Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the american ccollege of cardiology/american heart association joint committee on cclinical practice guidelines. Circulation 2022; 14: e895-1032.
4.	Zhou J, Liew D, Kaye DM, Zoungas S, Stub D. Cost-effectiveness of empagliflozin in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Qual Outcomes 2022; 15: e008638.
5.	Chen J, Wei X, Zhang Q, et al. The Traditional Chinese Medicines treat chronic heart failure and their main bioactive constituents and mechanisms. Acta Pharm Sin B 2023; 13: 1919-55. DOI PMID
6.	Hao P, Jiang F, Cheng J, Ma L, Zhang Y, Zhao Y. Traditional Chinese Medicine for cardiovascular disease: evidence and potential mechanisms. J Am Coll Cardiol 2017; 69: 2952-66. DOI PMID
7.	Li X, Zhang J, Huang J, et al. A multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the effects of Qili Qiangxin capsules in patients with chronic heart failure. J Am Coll Cardiol 2013; 62: 1065-72. DOI PMID
8.	Wang J, Yang R, Zhang F, et al. The effect of Chinese herbal medicine on quality of life and exercise tolerance in heart failure with preserved ejection fraction: a systematic review and Meta-analysis of randomized controlled trials. Front Physiol 2018; 9: 1420. DOI PMID
9.	Liu X, Fu J, Fan T, et al. The efficacy and safety of Shen Guo Lao Nian granule for common old of Qi-deficiency syndrome: study protocol for a randomized, double-blind, placebo-controlled, multicenter, pphase Ⅱ clinical trial. Evid Based Complement Alternat Med 2017; 2017: 1806461. DOI URL
10.	He X, Jiang Y, Li S, et al. Efficacy and safety of Qishen Yiqi dripping pills in the treatment of coronary heart disease complicating chronic heart failure (syndrome of Qi deficiency with blood stasis): study protocol for a randomized, placebo-controlled, double-blind and multi-centre phase Ⅱ clinical trial. Int J Gen Med 2023; 16: 6177-88. DOI URL
11.	Zang Y, Wan J, Zhang Z, Huang S, Liu X, Zhang W. An updated role of astragaloside IV in heart failure. Biomed Pharmacother 2020; 126: 110012. DOI PMID
12.	Zhang Z, Zhang M, Xu Y, Lu M, Zhang L, Li C. Effect of astragaloside IV on improving cardiac function in rats with heart failure: a preclinical systematic review and Meta-analysis. Front Pharmacol 2023; 14: 1226008. DOI URL
13.	Wang JN, Kan CD, Lee LT, et al. Herbal extract from codonopsis pilosula (Franch.) Nannf. enhances cardiogenic differentiation and improves the function of infarcted rat hearts. Life (Basel) 2021; 11: 422.
14.	Wang X, Jiang Y, Zhang Q, et al. Autophagy as a novel insight into mechanism of Danqi pill against post-acute myocardial infarction heart failure. J Ethnopharmacol 2021; 266: 113404. DOI URL
15.	Zhang B, Yu P, Su E, et al. Sodium Tanshinone ⅡA sulfonate improves adverse ventricular remodeling post-MI by reducing myocardial necrosis, modulating inflammation, and promoting angiogenesis. Curr Pharm Des 2022; 28: 751-59. DOI URL
16.	Chen J, Xue R, Li L, et al. Panax notoginseng saponins protect cardiac myocytes against endoplasmic reticulum stress and associated apoptosis through mediation of intracellular calcium homeostasis. Front Pharmacol 2019; 10: 1013. DOI PMID
17.	Gao S, Zhang Q, Tian C, et al. The roles of Qishen granules recipes, Qingre Jiedu, Wenyang Yiqi and Huo Xue, in the treatment of heart failure. J Ethnopharmacol 2020; 249: 112372. DOI URL
18.	Mao J, Zhang J, Lam CSP, et al. Qishen Yiqi dripping pills for chronic ischaemic heart failure: results of the CACT-IHF randomized clinical trial. ESC Heart Fail 2020; 7: 3881-90.
19.	Zhang GQ, Li Y, Lin Q. Clinical research of Yiqi Huoxue Lishui recipe in the treatment of heart failure disease with Qi deficiency, blood stasis and fluid retention syndrome. Zhong Xi Yi Jie He Xin Nao Xue Guan Bing Za Zhi 2020; 19: 3148-52.
20.	Shankar TS, Ramadurai DKA, Steinhorst K, et al. Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis. Nat Commun 2021; 12: 4583. DOI PMID
21.	Morciano G, Rimessi A, Patergnani S, et al. Calcium dysregulation in heart diseases: targeting calcium channels to achieve a correct calcium homeostasis. Pharmacol Res 2022; 177: 106119. DOI URL
22.	Rostas JAP, Skelding KA. Calcium/calmodulin-stimulated protein kinase Ⅱ (CaMKⅡ): different functional outcomes from activation, depending on the cellular microenvironment. Cells 2023; 12: 401. DOI URL
23.	Hegyi B, Bers DM, Bossuyt J. CaMKⅡ signaling in heart diseases: emerging role in diabetic cardiomyopathy. J Mol Cell Cardiol 2019; 127:246-59. DOI
24.	Liu J, Xu J, Shi X, et al. Effects of Qi-nourishing and blood- activating method on myocardium calcium homeostasis in rats with diastolic heart failure. Beijing Zhong Yi Yao Da Xue Xue Bao 2022; 45: 165-75.
25.	Li S, Nong Y, Gao Q, et al. Astragalus granule prevents Ca⁽²⁺⁾ current rremodeling in heart failure by the downregulation of CaMKII. Evid Based Complement Alternat Med 2017; 2017: 7517358. DOI URL
26.	Reyes Gaido OE, Nkashama LJ, Schole KL, et al. CaMKⅡ as a therapeutic target in cardiovascular disease. Annu Rev Pharmacol Toxicol 2023; 63: 249-72. DOI URL
27.	Dunn WB, Broadhurst D, Begley P, et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat Protoc 2011; 6: 1060-83. DOI PMID
28.	Fan J, Li H, Xie R, et al. LncRNA ZNF593-AS alleviates contractile dysfunction in dilated cardiomyopathy. Circ Res 2021; 128: 1708-23. DOI PMID
29.	Cui T, Liu W, Yu C, et al. Protective effects of allicin on acute myocardial infarction in rats via hydrogen sulfide-mediated regulation of coronary arterial vasomotor function and myocardial calcium transport. Front Pharmacol 2021; 12: 752244. DOI URL
30.	Zhang M, Gao H, Liu D, et al. CaMKII-δ9 promotes cardiomyopathy through disrupting UBE2T-dependent DNA repair. Nat Cell Biol 2019; 21: 1152-63. DOI PMID
31.	Lebek S, Caravia XM, Chemello F, et al. Elimination of CaMKIIδ autophosphorylation by CRISPR-Cas9 base editing improves survival and cardiac function in heart failure in mice. Circulation 2023; 148: 1490-504. DOI PMID
32.	Hegyi B, Pölönen RP, Hellgren KT, et al. Cardiomyocyte Na⁽⁺⁾ and Ca⁽²⁺⁾ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors. Basic Res Cardiol 2021; 116: 58. DOI
33.	Colomer JM, Mao L, Rockman HA, Means AR. Pressure overload selectively up-regulates Ca²⁺/calmodulin-dependent protein kinase Ⅱ in vivo. Mol Endocrinol 2003; 17: 183-92. DOI PMID
34.	Gratz SJ, Cummings AM, Nguyen JN, et al. Genome engineering of drosophila with the CRISPR RNA-guided Cas9 nuclease. Genetics 2013; 194: 1029-35. DOI PMID
35.	Porteus MH, Baltimore D. Chimeric nucleases stimulate gene targeting in human cells. Science 2003; 300: 763. DOI PMID
36.	Ma Y, Yu L, Pan S, et al. CRISPR/Cas9-mediated targeting of the Rosa26 locus produces Cre reporter rat strains for monitoring Cre-loxP-mediated lineage tracing. Febs J 2017; 284: 3262-77. DOI PMID
37.	Smedley D, Salimova E, Rosenthal N. Cre recombinase resources for conditional mouse mutagenesis. Methods 2011; 53: 411-6. DOI PMID
38.	McLellan MA, Rosenthal NA, Pinto AR. Cre-loxP-Mediated recombination: general principles and experimental considerations. Curr Protoc Mouse Biol 2017; 7: 1-12. DOI PMID
39.	Maier LS, Zhang T, Chen L, DeSantiago J, Brown JH, Bers DM. Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca²⁺ handling: reduced SR Ca²⁺ load and activated SR Ca²⁺ release. Circ Res 2003; 92: 904-11. PMID
40.	Zhang T, Johnson EN, Gu Y, et al. The cardiac-specific nuclear delta(B) isoform of Ca²⁺/calmodulin-dependent protein kinase Ⅱ induces hypertrophy and dilated cardiomyopathy associated with increased protein phosphatase 2A activity. J Biol Chem 2002; 277: 1261-7. DOI PMID
41.	Zhang T, Maier LS, Dalton ND, et al. The deltaC isoform of CaMKⅡI is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ Res 2003; 92: 912-9. DOI PMID
42.	Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. CaM kinase Ⅱ selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest 2006; 116: 1853-64. DOI URL
43.	Little GH, Bai Y, Williams T, Poizat C. Nuclear calcium/calmodulin-dependent protein kinase Ⅱdelta preferentially transmits signals to histone deacetylase 4 in cardiac cells. J Biol Chem 2007; 282: 7219-31. DOI URL
44.	Zhang T, Kohlhaas M, Backs J, et al. CaMKⅡdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses. J Biol Chem 2007; 282: 35078-87. DOI PMID
45.	Ljubojevic-Holzer S, Herren AW, Djalinac N, et al. CaMKⅡδC drives early adaptive Ca⁽²⁺⁾ change and late eccentric cardiac hypertrophy. Circ Res 2020; 127: 1159-78. DOI URL
46.	Zhu W, Woo AY, Yang D, Cheng H, Crow MT, Xiao RP. Activation of CaMKⅡdeltaC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis. J Biol Chem 2007; 282: 10833-9. DOI URL
47.	Dupont S, Maizel J, Mentaverri R, et al. The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension. Am J Physiol Heart Circ Physiol 2012; 302: H1524-32. DOI URL
48.	Baier MJ, Klatt S, Hammer KP, Maier LS, Rokita AG. Ca²⁺/ calmodulin-dependent protein kinase Ⅱ is essential in hyperacute pressure overload. J Mol Cell Cardiol 2020; 138: 212-21. DOI URL
49.	Valverde CA, Agüero R, Wehrens X, Vila Petroff M, Mattiazzi A, Gonano LA. RyR2 phosphorylation at serine-2814 increases cardiac tolerance to arrhythmogenic Ca⁽²⁺⁾ alternans in mice. J Mol Cell Cardiol 2025; 200: 40-4. DOI PMID
50.	Luczak ED, Wu Y, Granger JM, et al. Mitochondrial CaMKⅡ causes adverse metabolic reprogramming and dilated cardiomyopathy. Nat Commun 2020; 11: 4416. DOI
51.	Xi YD, Zhang DD, Ding J, et al. Genistein Inhibits Aβ25-35-Induced synaptic toxicity and regulates CaMKII/CREB pathway in SH-SY5Y Cells. Cell Mol Neurobiol 2016; 36: 1151-9. DOI URL
52.	Lin X, Cheng C, Zhong J, et al. Resveratrol inhibits angiotensin Ⅱ‑induced proliferation of A7r5 cells and decreases neointimal hyperplasia by inhibiting the CaMKII‑HDAC4 signaling pathway. Mol Med Rep 2018; 18: 1007-14.
53.	Ge L, Li C, Wang Z, Zhang Y, Chen L. Suppression of oxidative stress and apoptosis in electrically stimulated neonatal rat cardiomyocytes by resveratrol and underlying mechanisms. J Cardiovasc Pharmacol 2017; 70: 396-404. DOI PMID

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