Potential common key genes associated with myocardial dysfunction and brain injury following cardiac arrest resuscitation in a rat model

doi:10.5847/wjem.j.1920-8642.2025.055

Abstract

Abstract:

BACKGROUND: Post-cardiac arrest syndrome (PCAS) significantly contributes to mortality after initially successful cardiopulmonary resuscitation (CPR) in cardiac arrest (CA) patients. Effective cardiocerebral protection is essential for improving post-resuscitation survival. This study investigated the mechanisms and common targets of myocardial dysfunction and brain injury after resuscitation.

METHODS: The male Sprague-Dawley rats (10-12 weeks old, 400-500 g) were divided into two groups: the control group (n=6), which received sham surgery, and the CA/CPR group (n=10), which received ventricular fibrillation (VF) followed by CPR. After 24 h, brain and heart tissues were collected for analysis. The sequencing was used to identify differentially expressed genes (DEGs) between control and CA/CPR rats.

RESULTS: At 24 h after resuscitation, CA/CPR rats presented 217 DEGs in the hippocampus and 80 DEGs in the left ventricle (LV) compared to the control group. In the hippocampus, the most notable biological process was the positive regulation of tumor necrosis factor production, with key pathways related to inflammation and the immune response. In the LV, the Gene Ontology (GO) enrichment analysis revealed that gene alterations were primarily associated with amyloid-beta clearance, a pathway that was also relevant in the brain. Eleven common targets were identified in the DEGs of both heart and brain tissues. The reverse transcription-polymerase chain reaction (RT-PCR) validation revealed significant differences in the mRNA expression of Timp1, Apln, Ccl7, and Lgals3 in both LV and hippocampus.

CONCLUSION: This study identified possible key genes and underlying mechanisms involved in PCAS. The differential genes Timp1, Apln, Ccl7, and Lgals3 might serve as common biomarkers for myocardial and neurological injury following resuscitation.

Key words: Cardiac arrest, Myocardial dysfunction, Brain injury, Post-cardiac arrest syndrome, Resuscitation

Jie Chen, Zhonghao Li, Xiaoyu Liu, Tianpeng Hu, Nan Gao, Weijian Zhang, Guoqiang Zhang. Potential common key genes associated with myocardial dysfunction and brain injury following cardiac arrest resuscitation in a rat model[J]. World Journal of Emergency Medicine, 2025, 16(3): 231-238.

Figures/Tables 4

Table 1.

Figure 1.

Figure 2.

Figure 3.

References 32

1	Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020; 141(9): e139-e596.
2	Kang C, You Y, Park JS, Park BK, Lee JK, Lee BK. Utilization of biomarkers for the prognostic prediction of cardiac arrest survivors using a multi-modal approach. World J Emerg Med. 2024; 15(2):131-4. doi: 10.5847/wjem.j.1920-8642.2024.029 pmid: 38476538
3	Punniyakotty B, Ong XL, Ahmad M, Kirresh A. Improving mortality in pediatric out-of-hospital cardiac arrest events requires a multifactorial approach. JACC Asia. 2023; 3(1):166. doi: 10.1016/j.jacasi.2022.11.011 pmid: 36873764
4	Cunningham CA, Coppler PJ, Skolnik AB. The immunology of the post-cardiac arrest syndrome. Resuscitation. 2022; 179: 116-23.
5	Sandroni C, Cronberg T, Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med. 2021; 47(12): 1393-414. doi: 10.1007/s00134-021-06548-2 pmid: 34705079
6	Jentzer JC, Chonde MD, Dezfulian C. Myocardial dysfunction and shock after cardiac arrest. Biomed Res Int. 2015; 2015: 314796.
7	Kohlhauer M, Panel M, Roches MVD, Faucher E, Abi Zeid Daou Y, Boissady E, et al. Brain and myocardial mitochondria follow different patterns of dysfunction after cardiac arrest. Shock. 2021; 56(5): 857-64. doi: 10.1097/SHK.0000000000001793 pmid: 33978607
8	Choudhary RC, Kuschner CE, Kazmi J, McDevitt L, Espin BB, Essaihi M, et al. The role of phospholipid alterations in mitochondrial and brain dysfunction after cardiac arrest. Int J Mol Sci. 2024; 25(9): 4645.
9	Benghanem S, Sharshar T, Gavaret M, Dumas F, Diehl JL, Brechot N, et al. Heart rate variability for neuro-prognostication after CA: insight from the Parisian registry. Resuscitation. 2024; 202: 110294.
10	Endoh H, Kamimura N, Honda H, Nitta M. Early prognostication of neurological outcome by heart rate variability in adult patients with out-of-hospital sudden cardiac arrest. Crit Care. 2019; 23(1): 323.
11	Lamoureux L, Radhakrishnan J, Gazmuri RJ. A rat model of ventricular fibrillation and resuscitation by conventional closed-chest technique. J Vis Exp. 2015(98): 52413.
12	Li RQ, Li YR, Kristiansen K, Wang J. SOAP: short oligonucleotide alignment program. Bioinformatics. 2008; 24(5): 713-4. doi: 10.1093/bioinformatics/btn025 pmid: 18227114
13	Langmead B, Salzberg SL. Fast gapped-read alignment with bowtie 2. Nat Methods. 2012; 9(4): 357-9. doi: 10.1038/nmeth.1923 pmid: 22388286
14	Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12: 323.
15	Ye H, Ye L, Kang H, Zhang D, Tao L, Tang K, et al. HIT: linking herbal active ingredients to targets. Nucleic Acids Res. 2011; 39(database issue): D1055-D1059.
16	Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023:protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023; 51(D1): D638-D646.
17	Pitkin SL, Maguire JJ, Bonner TI, Davenport AP. International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol Rev. 2010; 62(3): 331-42. doi: 10.1124/pr.110.002949 pmid: 20605969
18	Pisarenko OI, Lankin VZ, Konovalova GG, Serebryakova LI, Shulzhenko VS, Timoshin AA, et al. Apelin-12 and its structural analog enhance antioxidant defense in experimental myocardial ischemia and reperfusion. Mol Cell Biochem. 2014; 391(1-2): 241-50. doi: 10.1007/s11010-014-2008-4 pmid: 24599747
19	Khaksari M, Aboutaleb N, Nasirinezhad F, Vakili A, Madjd Z. Apelin-13 protects the brain against ischemic reperfusion injury and cerebral edema in a transient model of focal cerebral ischemia. J Mol Neurosci. 2012; 48(1): 201-8. doi: 10.1007/s12031-012-9808-3 pmid: 22638858
20	Dawkins E, Small DH. Insights into the physiological function of the amyloid-β precursor protein: beyond Alzheimer’s disease. J Neurochem. 2014; 129(5): 756-69. doi: 10.1111/jnc.12675 pmid: 24517464
21	Ishikawa J, Harada K. Heart and brain failure: the vicious cycle of the heart-brain interaction. JACC Asia. 2023; 3(1):120-1. doi: 10.1016/j.jacasi.2022.10.009 pmid: 36873757
22	Greco S, Zaccagnini G, Fuschi P, Voellenkle C, Carrara M, Sadeghi I, et al. Increased BACE1-AS long noncoding RNA and β-amyloid levels in heart failure. Cardiovasc Res. 2017; 113(5): 453-63. doi: 10.1093/cvr/cvx013 pmid: 28158647
23	Stamatelopoulos K, Sibbing D, Rallidis LS, Georgiopoulos G, Stakos D, Braun S, et al. Amyloid-beta (1-40) and the risk of death from cardiovascular causes in patients with coronary heart disease. J Am Coll Cardiol. 2015; 65(9): 904-16. doi: 10.1016/j.jacc.2014.12.035 pmid: 25744007
24	Janata A, Magnet IAM, Uray T, Stezoski JP, Janesko-Feldman K, Tisherman SA, et al. Regional TNFα mapping in the brain reveals the striatum as a neuroinflammatory target after ventricular fibrillation cardiac arrest in rats. Resuscitation. 2014; 85(5): 694-701. doi: 10.1016/j.resuscitation.2014.01.033 pmid: 24530249
25	Bonetti NR, Diaz-Cañestro C, Liberale L, Crucet M, Akhmedov A, Merlini M, et al. Tumour necrosis factor-α inhibition improves stroke outcome in a mouse model of rheumatoid arthritis. Sci Rep. 2019; 9(1): 2173. doi: 10.1038/s41598-019-38670-z pmid: 30778120
26	Van Damme J, Proost P, Lenaerts JP, Opdenakker G. Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family. J Exp Med. 1992; 176(1): 59-65. doi: 10.1084/jem.176.1.59 pmid: 1613466
27	Sun YY, Pinto C, Camus S, Duval V, Alayrac P, Zlatanova I, et al. Splenic marginal zone B lymphocytes regulate cardiac remodeling after acute myocardial infarction in mice. J Am Coll Cardiol. 2022; 79(7): 632-47. doi: 10.1016/j.jacc.2021.11.051 pmid: 35177192
28	Ries C. Cytokine functions of TIMP-1. Cell Mol Life Sci. 2014; 71(4): 659-72. doi: 10.1007/s00018-013-1457-3 pmid: 23982756
29	Barton PJR, Birks EJ, Felkin LE, Cullen ME, Koban MU, Yacoub MH. Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure. J Heart Lung Transplant. 2003; 22(7): 738-44.
30	Angus McQuibban G, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood. 2002; 100(4): 1160-7. pmid: 12149192
31	Venkatraman A, Hardas S, Patel N, Singh Bajaj N, Arora G, Arora P. Galectin-3: an emerging biomarker in stroke and cerebrovascular diseases. Eur J Neurol. 2018; 25(2): 238-46. doi: 10.1111/ene.13496 pmid: 29053903
32	Shirakawa K, Endo J, Kataoka M, Katsumata Y, Yoshida N, Yamamoto T, et al. IL (interleukin)-10-STAT3-galectin-3 axis is essential for osteopontin-producing reparative macrophage polarization after myocardial infarction. Circulation. 2018; 138(18): 2021-35. doi: 10.1161/CIRCULATIONAHA.118.035047 pmid: 29967195

Time	SBP, mmHg	DBP, mmHg	HR, beats/min	MAP, mmHg
Baseline	134.0±3.2	112.5±2.1	424.2±7.2	123.7±2.6
ROSC	97.0±6.8^**	79.1±7.5^**	353.6±21.2^*	87.7±7.4^**
24 hours at PR	111.7±3.0^**	84.8±6.1^**	382.2±3.9^**	98.7±4.1^**

[1]	Lulu Lan, Guo Cheng, Meijie He, Min Min, Chaoyang Tong, Shilin Du, Xin Li, Yi Han. Fluid resuscitation in the early management of acute pancreatitis: a five-year retrospective observational study [J]. World Journal of Emergency Medicine, 2026, 17(3): 230-236.
[2]	Senlin Xia, Zumin Chen, Yanmei He, Yanhan Yang, Mingyang Qin, Lizhao Xu, Hui Peng, He Liu, Sheng Qiu, Lijun Liu. The basal forebrain-DMN/solv cholinergic projection mediates the attenuation of brain injury after cardiopulmonary resuscitation [J]. World Journal of Emergency Medicine, 2026, 17(2): 126-136.
[3]	Sohyeon Chun, Gi Woon Kim, Han Bit Kim. Association between on-scene cardiopulmonary resuscitation duration and outcomes in out-of-hospital cardiac arrest patients [J]. World Journal of Emergency Medicine, 2026, 17(2): 137-145.
[4]	Ping Gong, Hong Zhao, Peijuan Li, Ling Wang, Jin Wang, Rui Yang, Zhangping Sun. Elevated serum osmolarity is associated with 28-day all-cause mortality in patients with cardiac arrest [J]. World Journal of Emergency Medicine, 2026, 17(1): 50-56.
[5]	Xing Luo, Jinzhao Zhang, Fanrong Lin, Siqi Liu, Zhengfei Yang. Beyond the chain of survival: a scoping review of artificial intelligence applications in cardiac arrest [J]. World Journal of Emergency Medicine, 2026, 17(1): 7-14.
[6]	Gannan Wang, Yi Zhu, Hao Zhou, Tao Ding, Yutong Shi, Xiaoquan Xu, Hai Xu, Wei Li, Xufeng Chen. Association between chest computed tomography features and prognosis in patients treated with extracorporeal cardiopulmonary resuscitation [J]. World Journal of Emergency Medicine, 2025, 16(6): 567-572.
[7]	Yi Jiang, Jianyong Wu, Ying Liu, Xianfei Ji, Ping Gong. The association of the plasma iron and neuron-specific enolase combination and the 28-day neurological outcome after cardiopulmonary resuscitation: a prospective study of iron metabolism disturbances [J]. World Journal of Emergency Medicine, 2025, 16(6): 559-566.
[8]	Shin Ae Lee, Jongwon Ha, Ye Rim Chang. Defining optimal volume of inflation for partial resuscitative endovascular balloon occlusion of the aorta in swine hemorrhagic shock model [J]. World Journal of Emergency Medicine, 2025, 16(5): 431-437.
[9]	Xiaodong Huang, Zhihong Xu, Siyao Liu, Xiong Liu, Long Lin, Mandong Pan, Xianwei Huang, Jiyan Lin. Association of fluid balance index with in-hospital mortality in critically ill patients with acute pancreatitis: a multicenter retrospective cohort study [J]. World Journal of Emergency Medicine, 2025, 16(5): 462-468.
[10]	Young Min Kim, Hyun Seok Chai, Gwan Jin Park, Sang Chul Kim, Hoon Kim, Seok Woo Lee, Hyeon Jeong Park, Han Bit Kim, Hyo Been Lee, Ji Han Lee. Effect of bag valve ventilation versus mechanical ventilation after endotracheal intubation during cardiopulmonary resuscitation on outcomes following out-of-hospital cardiac arrest: a propensity score analysis [J]. World Journal of Emergency Medicine, 2025, 16(4): 313-320.
[11]	Ahammed Mekkodathil, Ayman El-Menyar, Talat Chughtai, Ahmed Abdel-Aziz Bahey, Ahmed Labib Shehatta, Ali Ayyad, Abdulnasser Alyafai, Hassan Al-Thani. Initial serum electrolyte imbalances and mortality in patients with traumatic brain injury: a retrospective study [J]. World Journal of Emergency Medicine, 2025, 16(4): 331-339.
[12]	Rui Shao, Chenchen Hang, Xingsheng Wang, Luying Zhang, Fei Shao, Ziren Tang. The “SOOTEST-ICU” bundle for optimizing cerebral hypoxia and reperfusion to minimize brain injury after resuscitation from cardiac arrest [J]. World Journal of Emergency Medicine, 2025, 16(3): 206-211.
[13]	George Briassoulis, Mina Argyrakopoulou, Dafni Korela, Sotiria Labrinaki, Artemis Nikiforou, Antonios Papoutsakis, Panagiotis Briassoulis, Marianna Miliaraki, George Notas, Stavroula Ilia. Lifelong training, retraining, reskilling, upskilling and knowledge gaps in emergency medicine: a cross-sectional survey study [J]. World Journal of Emergency Medicine, 2025, 16(3): 212-219.
[14]	Tingting Xu, Shaokun Wang, Liqiang Zhao, Jiawen Wang, Jihong Xing. A two-sample Mendelian randomization study on the relationship of body weight, body mass index, and waist circumference with cardiac arrest [J]. World Journal of Emergency Medicine, 2025, 16(2): 129-135.
[15]	Wachira Wongtanasarasin, Daniel K. Nishijima, Wanrudee Isaranuwatchai, Jeffrey S. Hoch. Real-world cost-effectiveness of targeted temperature management in out-of-hospital cardiac arrest survivors: results from an academic medical center [J]. World Journal of Emergency Medicine, 2025, 16(1): 28-34.