Cedric Robinson

Introduction. Heart failure with a preserved ejection fraction (HFpEF) is growing in prevalence, at least 50% of 6 million cases in the United States and possesses little to no treatment options.^1,2 The pathophysiology and treatment for HFpEF remain an enigma. At the center of these many hypotheses lies the sarcomeric proteins and their associated kinases or phosphatases.^3,4 Additionally, clinical studies have shown that Isosorbide Mononitrate treatment worsened symptoms of HFpEF.^2,5 Nevertheless, exploration of this pathway has continued with compounds associated with the Nitric Oxide (NO) pathway. Reactive nitrogen species are produced by the inducible nitric oxide synthase (iNOS) or the uncoupling of endothelial nitric oxide synthase (eNOS) – results of metabolic dysfunction.⁷ Nitrosylation, or the association of nitric oxide group – particularly tyrosine and cysteine residues, may result in unfolded proteins.⁶ The IRE1 Alpha – XBP1 signaling pathway is a relevant to stress regulation. This represents an intriguing pathway for the HFpEF solution.⁷ Methods. Mouse models were split into four groups: high fat diet (HFD), L-Name, HFD+L-Name (two-hit), and standard chow diet.⁷ L-Name was used to model vasoconstriction and HFD for the typical metabolic presentation of HFpEF. Variables assessing diastolic dysfunction were measured at 5- and 15-week time points. Notable variables measuring diastolic dysfunction included: Lung Weights, Running distance, and cardiac relaxation. Of note, the E/e’ ratio one of the criteria for doppler filling pressure measurements – mimicking human HFpEF.^1,3,7 Following the observational evaluation, the disease states effect on the IRE1 Alpha – XBP1 signaling pathway, involved with cardiomyocyte stress. – Using the ZSF-1 obese rat as a control and the double hit, protein isolation of IRE1 Alpha and using gel electrophoresis to assess phosphorylation.⁷ Results. Results varied across the HFpEF models with the two-hit model showing the most disease progression. Notably, the greatest indication of diastolic dysfunction or hypertrophic response was the lung weight – representing pulmonary edema.^1,4,7 Upon harvesting of cardiac tissue only the double-hit model was seen to have abnormal relaxation.⁷ The mice in the L-NAME group displayed hypertension and High fat diet group gained weight impacting exercise performance. In two-hit HFpEF mice models eNOS suppression and iNOS upregulation.⁷ The iNOS upregulation led to global protein nitrosylation, which decreased the phosphorylation of IRE1 alpha and no expression of XBP1.⁷ Conclusion. These are intriguing findings perhaps provide a glimpse into HFpEF.^7,8 Future works should focus on closing the knowledge gap of this disease process and providing further pathways for pharmacologic targets and disease prevention.¹

1. Writing Committee M, Members AAJC. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Card Fail. Mar 14 2022;doi:10.1016/j.cardfail.2022.02.010
2. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. Feb 22 2022;145(8):e153-e639. doi:10.1161/CIR.0000000000001052
3. Rosas PC, Liu Y, Abdalla MI, et al. Phosphorylation of cardiac Myosin-binding protein-C is a critical mediator of diastolic function. Circ Heart Fail. May 2015;8(3):582-94. doi:10.1161/CIRCHEARTFAILURE.114.001550
4. Soetkamp D, Gallet R, Parker SJ, et al. Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure. Circ Res. Dec 3 2021;129(12):1125-1140. doi:10.1161/CIRCRESAHA.119.316311
5. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. Dec 10 2015;373(24):2314-24. doi:10.1056/NEJMoa1510774
6. Perez-Torres I, Manzano-Pech L, Rubio-Ruiz ME, Soto ME, Guarner-Lans V. Nitrosative Stress and Its Association with Cardiometabolic Disorders. Molecules. May 31 2020;25(11)doi:10.3390/molecules25112555
7. 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
8. Redfield MM, Jacobsen SJ, Burnett JC, Jr., Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. Jan 8 2003;289(2):194-202. doi:10.1001/jama.289.2.194