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Neurocognitive Disorders in Heart Failure: Novel Pathophysiological Mechanisms Underpinning Memory Loss and Learning Impairment

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Abstract

Heart failure (HF) is a major public health issue affecting more than 26 million people worldwide. HF is the most common cardiovascular disease in elder population; and it is associated with neurocognitive function decline, which represent underlying brain pathology diminishing learning and memory faculties. Both HF and neurocognitive impairment are associated with recurrent hospitalization episodes and increased mortality rate in older people, but particularly when they occur simultaneously. Overall, the published studies seem to confirm that HF patients display functional impairments relating to attention, memory, concentration, learning, and executive functioning compared with age-matched controls. However, little is known about the molecular mechanisms underpinning neurocognitive decline in HF. The present review round step recent evidence related to the possible molecular mechanism involved in the establishment of neurocognitive disorders during HF. We will make a special focus on cerebral ischemia, neuroinflammation and oxidative stress, Wnt signaling, and mitochondrial DNA alterations as possible mechanisms associated with cognitive decline in HF. Also, we provide an integrative mechanism linking pathophysiological hallmarks of altered cardiorespiratory control and the development of cognitive dysfunction in HF patients.

Main molecular mechanisms involved in the establishment of cognitive impairment during heart failure. Heart failure is characterized by chronic activation of brain areas responsible for increasing cardiac sympathetic load. In addition, HF patients also show neurocognitive impairment, suggesting that the overall mechanisms that underpin cardiac sympathoexcitation may be related to the development of cognitive disorders in HF. In low cardiac output, HF cerebral infarction due to cardiac mural emboli and cerebral ischemia due to chronic or intermittent cerebral hypoperfusion has been described as a major mechanism related to the development of CI. In addition, while acute norepinephrine (NE) release may be relevant to induce neural plasticity in the hippocampus, chronic or tonic release of NE may exert the opposite effects due to desensitization of the adrenergic signaling pathway due to receptor internalization. Enhanced chemoreflex drive is a major source of sympathoexcitation in HF, and this phenomenon elevates brain ROS levels and induces neuroinflammation through breathing instability. Importantly, both oxidative stress and neuroinflammation can induce mitochondrial dysfunction and vice versa. Then, this ROS inflammatory pathway may propagate within the brain and potentially contribute to the development of cognitive impairment in HF through the activation/inhibition of key molecular pathways involved in neurocognitive decline such as the Wnt signaling pathway.

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Acknowledgments

Figures were designed with elements provided by Servier Medical Art (https://smart.servier.com).

Funding

This work was supported by the Fondo de Desarrollo Científico y Tecnológico (Fondecyt) (grant number 1180172), the Basal Center of Excellence in Aging and Regeneration (AFB 170005), and the special grant “Lithium in Health and Disease” from the Sociedad Química y Minera de Chile (SQM).

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  1. C. Toledo and D. C. Andrade contributed equally to this work

Authors and Affiliations

  1. Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile

    C. Toledo, D. C. Andrade, H. S. Díaz & R. Del Rio

  2. Center for Aging and Regeneration (CARE-UC), Pontificia Universidad Católica de Chile, Santiago, Chile

    C. Toledo, N. C. Inestrosa & R. Del Rio

  3. Centro de investigación en fisiología del ejercicio, Universidad Mayor, Santiago, Chile

    D. C. Andrade

  4. Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

    N. C. Inestrosa & R. Del Rio

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Toledo, C., Andrade, D.C., Díaz, H.S. et al. Neurocognitive Disorders in Heart Failure: Novel Pathophysiological Mechanisms Underpinning Memory Loss and Learning Impairment. Mol Neurobiol 56, 8035–8051 (2019). https://doi.org/10.1007/s12035-019-01655-0

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