Cognitive Impairment and Synaptic Dysfunction in Cardiovascular Disorders: The New Frontiers of the Heart-Brain Axis

Abstract

Within the central nervous system, synaptic plasticity, fundamental to processes like learning and memory, is largely driven by activity-dependent changes in synaptic strength. This plasticity often manifests as long-term potentiation (LTP) and long-term depression (LTD), which are bidirectional modulations of synaptic efficacy. Strong epidemiological and experimental evidence show that the heart-brain axis could be severely compromised by both neurological and cardiovascular disorders. Particularly, cardiovascular disorders, such as heart failure, hypertension, obesity, diabetes and insulin resistance, and arrhythmias, may lead to cognitive impairment, a condition known as cardiogenic dementia. Herein, we review the available knowledge on the synaptic and molecular mechanisms by which cardiogenic dementia may arise and describe how LTP and/or LTD induction and maintenance may be compromised in the CA1 region of the hippocampus by heart failure, metabolic syndrome, and arrhythmias. We also discuss the emerging evidence that endothelial dysfunction may contribute to directly altering hippocampal LTP by impairing the synaptically induced activation of the endothelial nitric oxide synthase. A better understanding of how CV disorders impact on the proper function of central synapses will shed novel light on the molecular underpinnings of cardiogenic dementia, thereby providing a new perspective for more specific pharmacological treatments.

Keywords: NMDA receptors; arrhythmias; cardiogenic dementia; cardiovascular disorders; cognitive impairment; heart failure; heart–brain axis; long-term potentiation; metabolic syndrome; synaptic plasticity.

Figure 1

Cardiogenic dementia: a multifaceted pathway. Cardiogenic dementia can result from cognitive impairment following heart disease. This impairment can occur due to chronic cerebral hypoperfusion (CCH) or independently of it. CCH arises when long-term heart damage reduces cardiac output. This triggers a chain of events involving oxidative stress, local inflammation, immune responses, and blood–brain barrier (BBB) disruption. Cardiogenic dementia can also occur without changes in cerebral blood flow (CBF). This involves systemic inflammation, neurohumoral activation, and the release of exosomes. Increased norepinephrine (NE) and reactive oxygen species (ROS) can result from sympathetic excitation. Additionally, the overactivation of the renin–angiotensin system (RAS) leads to oxidative stress, BBB disruption, and inflammation. In conclusion, heart disease can contribute to amyloid-beta protein (Aβ) deposition, neuronal damage, and neurotoxicity. It can also hinder synaptic plasticity and neurogenesis through both CCH-dependent and -independent mechanisms. These factors collectively worsen cognitive function. Made with BioRender.

Figure 2

Molecular mechanisms of LTP in the hippocampus. The molecular mechanisms underlying LTP, involving signaling pathways mediated by N-methyl-D-aspartate (NMDA) receptors (NMDARs) and calcium ions (Ca²⁺). At excitatory synapses, synaptic plasticity is primarily mediated by alterations in postsynaptic ionotropic glutamate receptors, particularly α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs). NMDARs play a crucial role in initiating LTP by acting as coincidence detectors for pre- and postsynaptic firing patterns. An NMDAR-mediated rise in postsynaptic Ca²⁺ activates the Ca²⁺/Calmodulin (CaM)-dependent protein-kinase II (CaMKII). CaMKII-dependent phosphorylation, in turn, drives AMPAR incorporation to postsynaptic density in a post-synaptic density protein 95 (PSD-95)-dependent manner. Furthermore, CaMKII may phosphorylate cAMP response element-binding protein (CREB), the transcription factor regulating the expression of postsynaptic proteins and driving the physical expansion of dendritic spines. Made with BioRender.