Research Paper Volume 16, Issue 13 pp 10882—10904

Disorder of neuroplasticity aggravates cognitive impairment via neuroinflammation associated with intestinal flora dysbiosis in chronic heart failure

Jie Chen1, *, , Xiaohong Wei1, *, , Xuefen Wu1, *, , Qian Zhang1, , Guiyang Xia1, , Huan Xia1, , Hongcai Shang1, , Sheng Lin1, ,

  • 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
* Equal contribution

Received: December 12, 2023       Accepted: March 28, 2024       Published: July 1, 2024
How to Cite

Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Chronic heart failure (CHF) impairs cognitive function, yet its effects on brain structure and underlying mechanisms remain elusive. This study aims to explore the mechanisms behind cognitive impairment.

Methods: CHF models in rats were induced by ligation of the left anterior descending coronary artery. Cardiac function was analyzed by cardiac ultrasound and hemodynamics. ELISA, immunofluorescence, Western blot, Golgi staining and transmission electron microscopy were performed on hippocampal tissues. The alterations of intestinal flora under the morbid state were investigated via 16S rRNA sequencing. The connection between neuroinflammation and synapses is confirmed by a co-culture system of BV2 microglia and HT22 cells in vitro.

Results: CHF rats exhibited deteriorated cognitive behaviors. CHF induced neuronal structural disruption, loss of Nissl bodies, and synaptic damage, exhibiting alterations in multiple parameters. CHF rats showed increased hippocampal levels of inflammatory cytokines and activated microglia and astrocytes. Furthermore, the study highlights dysregulated PDE4-dependent cAMP signaling and intestinal flora dysbiosis, closely associated with neuroinflammation, and altered synaptic proteins. In vitro, microglial neuroinflammation impaired synaptic plasticity via PDE4-dependent cAMP signaling.

Conclusions: Neuroinflammation worsens CHF-related cognitive impairment through neuroplasticity disorder, tied to intestinal flora dysbiosis. PDE4 emerges as a potential therapeutic target. These findings provide insightful perspectives on the heart-gut-brain axis.


Ang II: angiotensin II; BDNF: brain-derived neurotrophic factor; BNP: brain natriuretic peptide; cAMP: cyclic adenosine monophosphate; CHF: chronic heart failure; CNS: central nervous system; cTnT: cardiac troponin T; DMEM: Dulbecco’s modified Eagle’s medium; ELISA: enzyme-linked immunosorbent assay; IL-1β: interleukin-1β; IL-10: interleukin-10; LDA: linear discriminant analysis; LEfSe: linear discriminant analysis effect size; LPS: lipopolysaccharide; LTP: long-term potentiation; LVEDP: left ventricular end diastolic pressure; LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; LVSP: left ventricular systolic pressure; MI: myocardial infarction; MWM: Morris water maze; NO: nitric oxide; NT-proBNP: N-terminal pro-B-type natriuretic peptide; OFT: open field test; PCoA: principal coordinates analysis; PSD95: postsynaptic density protein 95; sST2: soluble ST2; TEM: transmission electron microscopy; TNF-α: tumor necrosis factor-α; +dp/dtmax: the maximal upstroke velocity of left ventricle; −dp/dtmax: the maximal descent velocity of left ventricle.