Comprehensive Physiology Wiley Online Library

Aging and Heart Failure with Preserved Ejection Fraction

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Abstract

Heart failure is a clinical syndrome characterized by the inability of the cardiovascular system to provide adequate cardiac output at normal filling pressures. This results in a clinical syndrome characterized by dyspnea, edema, and decreased exertional tolerance. Heart failure with preserved ejection fraction (HFpEF) is an increasingly common disease, and the incidence of HFpEF increases with age. There are a variety of factors which contribute to the development of HFpEF, including the presence of hypertension, diabetes, obesity, and other pro‐inflammatory states. These comorbid conditions result in changes at the biochemical and cell signaling level which ultimately lead to a disease with a great deal of phenotypic heterogeneity. In general, the physiologic dysfunction of HFpEF is characterized by vascular stiffness, increased cardiac filling pressures, pulmonary hypertension, and impaired volume management. The normal and abnormal processes associated with aging serve as an accelerant in this process, resulting in the hypothesis that HFpEF represents a form of presbycardia. In this article, we aim to review the processes importance of aging in the development of HFpEF by examining the disease and its causes from the biochemical to physiologic level. © 2022 American Physiological Society. Compr Physiol 12: 1–10, 2022.

Figure 1. Figure 1. Aging, hypertension (HTN), diabetes mellitus (DM), and obesity are associated with an increase in cytokines, which lead to activation of NF‐κB, STAT3, and Smads, as well as an ER stress response. The activation of NF‐κB, STAT3, and Smads could produce a change in contractile and regulatory proteins expression, and thus, produce the cardiac and vascular contractility associated with HFpEF, including diastolic dysfunction and an increase in vascular tone as well as a decrease in vascular sensitivity to NO. An ER stress response includes phosphorylation of inositol requiring enzyme 1 (IRE1α) and alternative mRNA splicing of X‐box protein 1 (XBP1), which decreases mitofusin 2 (Mfn2) expression. Mfn1/Mfn2 complex tethers the mitochondria to the ER, which establishes a microdomain of higher cytosolic Ca2+, which is necessary to activate the mitochondrial Ca2+ uniporter (MCU). The decrease in Mfn2 expression will decrease the proximity of the ER and mitochondria and decrease Ca2+‐activation of the MCU and the influx of Ca2+ into the mitochondria, which will decrease ATP production, which could contribute to the energetic abnormalities associated with HFpEF (see text for details).


Figure 1. Aging, hypertension (HTN), diabetes mellitus (DM), and obesity are associated with an increase in cytokines, which lead to activation of NF‐κB, STAT3, and Smads, as well as an ER stress response. The activation of NF‐κB, STAT3, and Smads could produce a change in contractile and regulatory proteins expression, and thus, produce the cardiac and vascular contractility associated with HFpEF, including diastolic dysfunction and an increase in vascular tone as well as a decrease in vascular sensitivity to NO. An ER stress response includes phosphorylation of inositol requiring enzyme 1 (IRE1α) and alternative mRNA splicing of X‐box protein 1 (XBP1), which decreases mitofusin 2 (Mfn2) expression. Mfn1/Mfn2 complex tethers the mitochondria to the ER, which establishes a microdomain of higher cytosolic Ca2+, which is necessary to activate the mitochondrial Ca2+ uniporter (MCU). The decrease in Mfn2 expression will decrease the proximity of the ER and mitochondria and decrease Ca2+‐activation of the MCU and the influx of Ca2+ into the mitochondria, which will decrease ATP production, which could contribute to the energetic abnormalities associated with HFpEF (see text for details).
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Kathryn F. Larson, Awais Malik, Frank V. Brozovich. Aging and Heart Failure with Preserved Ejection Fraction. Compr Physiol 2022, 12: 1-10. doi: 10.1002/cphy.c210035