Epigenetic Mechanism of Heart Failure with Preserved Ejection Fraction (HFpEF).
- 1Department of Physiology, School of Medicine, University of Louisville, HSC-A-1115, 500 South Preston Street, Louisville, KY 40202, USA.
- 2Department of Neurological Surgery, School of Medicine, University of Louisville, 220 Abraham Flexner Way, Suite 1512, Louisville, KY 40202, USA.
- 3Kentucky Spinal Cord Injury Research Center, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a primary cause in patients with metabolic dysfunction and hypertension. A chronic high fat diet (HFD) creates metabolic dysfunction and dysregulation of epigenetic folate 1-carbon metabolism (FOCM), elevating the homocysteine levels (Hcy, characteristic of homocystinuria or HHcy). Homocystinuria has been associated with an increase in blood pressure (via abrogation eNOS pathways) and hypertension. It is unclear whether HFD and homocystinuria contribute synergistically to HFpEF. The HFD may increase the method of transportation via the SLC25A transporter and dysregulate FOCM, creating homocystinuria. The inhibition of SLC25A by suramin could attenuate the FOCM, DNMT1, and TET2 levels, and cardiac dysfunction during HFD and homocystinuria. Because HFD increases methionine and decreases homocysteine transsulfuration via the SLC7A transporter, we hypothesize that the induction of SLC7A will increase homocysteine transport into the mitochondrial transsulfuration, and will produce H₂S during HFD and homocystinuria. The overall hypothesis to be tested is that a HFD increases methionine transport by SLC25A and induces epigenetic FOCM, homocystinuria, and decreases mitochondrial transsulfuration by SLC7A, CBS/CSE/3MST and H₂S, causing HFpEF. This review introduces a novel framework to understand how diet-induced epigenetic disruptions contribute to HFpEF through altered homocysteine metabolism and hypertension. Additionally, it explores the therapeutic potential of SLC25A inhibition via suramin to counteract these effects. Insights gained from those studies will underscore the critical role of HFD-induced HFpEF and open pathways for new interventions.
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BibTeX
@article{tyagi2026epigenetic,
title = {{Epigenetic Mechanism of Heart Failure with Preserved Ejection Fraction (HFpEF).}},
author = {Suresh C Tyagi and Alexander V Ovechkin},
journal = {Journal of cardiovascular development and disease},
year = {2026},
month = sep,
doi = {10.3390/jcdd13100489},
url = {https://europepmc.org/article/MED/42930885},
note = {CC BY},
}
RIS
TY - JOUR
TI - Epigenetic Mechanism of Heart Failure with Preserved Ejection Fraction (HFpEF).
AU - Suresh C Tyagi
AU - Alexander V Ovechkin
PY - 2026
DA - 2026/09/29
JO - Journal of cardiovascular development and disease
DO - 10.3390/jcdd13100489
UR - https://europepmc.org/article/MED/42930885
AB - Heart failure with preserved ejection fraction (HFpEF) is a primary cause in patients with metabolic dysfunction and hypertension. A chronic high fat diet (HFD) creates metabolic dysfunction and dysregulation of epigenetic folate 1-carbon metabolism (FOCM), elevating the homocysteine levels (Hcy, characteristic of homocystinuria or HHcy). Homocystinuria has been associated with an increase in blood pressure (via abrogation eNOS pathways) and hypertension. It is unclear whether HFD and homocystinuria contribute synergistically to HFpEF. The HFD may increase the method of transportation via the SLC25A transporter and dysregulate FOCM, creating homocystinuria. The inhibition of SLC25A by suramin could attenuate the FOCM, DNMT1, and TET2 levels, and cardiac dysfunction during HFD and homocystinuria. Because HFD increases methionine and decreases homocysteine transsulfuration via the SLC7A transporter, we hypothesize that the induction of SLC7A will increase homocysteine transport into the mitochondrial transsulfuration, and will produce H₂S during HFD and homocystinuria. The overall hypothesis to be tested is that a HFD increases methionine transport by SLC25A and induces epigenetic FOCM, homocystinuria, and decreases mitochondrial transsulfuration by SLC7A, CBS/CSE/3MST and H₂S, causing HFpEF. This review introduces a novel framework to understand how diet-induced epigenetic disruptions contribute to HFpEF through altered homocysteine metabolism and hypertension. Additionally, it explores the therapeutic potential of SLC25A inhibition via suramin to counteract these effects. Insights gained from those studies will underscore the critical role of HFD-induced HFpEF and open pathways for new interventions.
SN - 2308-3425
ER -