Albert Oh

Background:  Heart failure with preserved ejection fraction (HFpEF) is defined as heart failure with ejection fraction ≥ 50% and now accounts for approximately 50% of the total number of patients with heart failure in the community, with heart failure itself remaining a leading cause of morbidity and mortality globally^1,2. HFpEF is difficult to manage due to its high pathophysiological heterogeneity and lack of evidence based clinically effective pharmacological treatment^3,4. This review aims to bring together some recent promising research in pharmacologic treatments for this disease.

Methods:  A thorough literature review was done through the PubMed literature database to identify recent influential primary research in HFpEF. Search terms used included “Heart Failure with Preserved Ejection Fraction” combined with “Treatments” as well as “Epidemiology” to obtain comprehensive background knowledge as well as current work on this disease. MeSH subheadings within PubMed were also utilized to obtain a more focused set of search results.

Results:  One study by Schiattarella et al. has identified the inducible nitric oxide synthase (iNOS) to IRE1a-Xbp1s axis – which is part of the unfolded protein response (UPR) – as a potential target for therapy⁵. Specifically, it was shown that ablation of the gene NOS2 which encodes iNOS allows for restoration of IRE1a-Xbp1s activity and subsequent amelioration of the HFpEF phenotype⁵. Another study by Tong et al. demonstrated how NAD+ repletion in cardiac myocyte mitochondria using Nicotinamide Riboside ameliorates the HFpEF phenotype⁶. A study by Rosas et al. outlined how maintenance of cardiac myosin binding protein-c (cMyBP-C) phosphorylation promotes myocyte cross-bridge cycling which in turn promotes the heart’s ability to contract and relax⁷. Two other studies by Bayes-Genis et al. and Anker et al., respectively, outlined the biomechanical pathway of the Sodium/glucose cotransporter-2 inhibitor (SGLT2i) Empagliflozin and researched its efficacy in treating HFpEF^8,9. Anker et al. specifically concluded that Empagliflozin reduces risk of cardiovascular death or hospitalization due to HFpEF⁹.

Conclusion:  There is active and fruitful research in treatments for HFpEF. Some have identified potential new targets for HFpEF therapy such as the iNOS to IRE1a-Xbp1s axis in the UPR, NAD+ repletion therapy, and maintenance of cMyBP-C phosphorylation. Other researchers have shown the utility of existing pharmaceuticals such as the SGLT2i Empagliflozin in treating HFpEF. Questions for further research could include what new therapies can come out of these recent findings as well as what other existing therapies for other cardiovascular conditions could be applied to HFpEF.

Works Cited:

1. Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nature Reviews Cardiology. 2017/10/01 2017;14(10):591-602. doi:10.1038/nrcardio.2017.65
2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. May 3 2022;145(18):e895-e1032. doi:10.1161/cir.0000000000001063
3. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. Sep 2020;17(9):559-573. doi:10.1038/s41569-020-0363-2
4. Omote K, Verbrugge FH, Borlaug BA. Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies. Annu Rev Med. Jan 27 2022;73:321-337. doi:10.1146/annurev-med-042220-022745
5. Schiattarella GG, Altamirano F, Tong D, et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature. Apr 2019;568(7752):351-356. doi:10.1038/s41586-019-1100-z
6. Tong D, Schiattarella GG, Jiang N, et al. NAD(+) Repletion Reverses Heart Failure With Preserved Ejection Fraction. Circ Res. May 28 2021;128(11):1629-1641. doi:10.1161/circresaha.120.317046
7. Rosas PC, Warren CM, Creed HA, Trzeciakowski JP, Solaro RJ, Tong CW. Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Age-Related Cardiac Dysfunction: Hope for Better Aging? JACC Basic Transl Sci. Nov 2019;4(7):817-830. doi:10.1016/j.jacbts.2019.06.003
8. Bayes-Genis A, Iborra-Egea O, Spitaleri G, et al. Decoding empagliflozin’s molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence. Sci Rep. Jun 8 2021;11(1):12025. doi:10.1038/s41598-021-91546-z
9. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. Oct 14 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038