Akash Kakkilaya

Introduction: 6 million Americans from 2015-2018 had heart failure (HF).¹ HFpEF is a HF subtype characterized by diastolic dysfunction and a preserved ejection fraction 50%. About 50% of America’s 6 million HF patients have HFpEF, and the prevalence of this subtype is increasing 1% annually.² Risk factors for HFpEF include old age, hypertension, obesity, and diabetes.³ These comorbidities are believed to cause microvascular and endothelial dysfunction leading to HFpEF.⁴ Associated dysfunctional nitric oxide metabolism has been implicated in playing a role as well.⁵ Since the treatments for HFpEF are currently limited to SGLT2 inhibitors, exploring the effects of microvascular and nitric oxide dysfunction on HFpEF is crucial to the development of new HFpEF therapies.⁵ Methods: Schiattarella et al⁴ developed a HFpEF mouse model by feeding mice a high fat diet to induce metabolic stress and L-NAME, a nitric oxide synthase (NOS) antagonist, to induce mechanical stress in the form of hypertension.⁴ The goal was to identify molecular mechanisms that may drive HFpEF. Another study crossed a diabetic rat and hypertensive rat to identify changes in nitric oxide metabolism in HFpEF.⁶ Kitakata et al⁷ used a model similar to Schiattarella et al⁴ to test the effects of imeglimin, a type 2 diabetes drug, on HFpEF. Lastly, Veitch et al⁵ used obese type 2 diabetic mice and rats as their HFpEF model to identify prognostic microRNA’s. Results: Schiattarella et al⁴ replicated the phenotypes seen in patients with HFpEF in their mouse model. They also found that nitrosative stress from iNOS activation and resulting deactivation of IRE1α–XBP1 pathway, a cardiomyocte stress regulator, drove HfpEF.⁴ Büttner et al⁶ found that inflammatory macrophages in the heart and blood divert Arg and hARG away from NOS for use as substrates for arginase and iNOS, two enzymes involved in inflammation. In Kitakata et al’s⁷  study, imeglimin improved glucose tolerance, reduced body and visceral fat, reduced iNOS expression, and restored the Xbp1 pathway in their HFpEF mouse model. Veitch et al⁵ found that extravesicular levels of MicroRNA-30 (MiR-30) increased during microvascular dysfunction but prior to diastolic dysfunction. Conclusion: These results show that the role of systemic inflammation and nitric oxide dysfunction on the pathophysiology of HFpEF is still an enigma. Future clinical trials should focus on inhibiting iNOS, increasing Arg and hArg levels, and further evaluating the effects of imeglimin, to treat HFpEf and considering MiR-30 as a prognostic indicator for the disease.

1. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association. Circulation. 2022;doi:10.1161/cir.0000000000001052
2. Shah SJ, Kitzman DW, Borlaug BA, et al. Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction. Circulation. 2016;134(1):73-90. doi:doi:10.1161/CIRCULATIONAHA.116.021884
3. Mishra S, Kass DA. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nature Reviews Cardiology. 2021;18(6):400-423. doi:10.1038/s41569-020-00480-6
4. Schiattarella GG, Altamirano F, Tong D, et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature. 2019/04/01 2019;568(7752):351-356. doi:10.1038/s41586-019-1100-z
5. Veitch S, Njock M-S, Chandy M, et al. MiR-30 promotes fatty acid beta-oxidation and endothelial cell dysfunction and is a circulating biomarker of coronary microvascular dysfunction in pre-clinical models of diabetes. Cardiovascular Diabetology. 2022/02/24 2022;21(1):31. doi:10.1186/s12933-022-01458-z
6. Büttner P, Werner S, Baskal S, et al. Arginine metabolism and nitric oxide turnover in the ZSF1 animal model for heart failure with preserved ejection fraction. Scientific Reports. 2021/10/19 2021;11(1):20684. doi:10.1038/s41598-021-00216-7
7. Kitakata H, Endo J, Hashimoto S, et al. Imeglimin prevents heart failure with preserved ejection fraction by recovering the impaired unfolded protein response in mice subjected to cardiometabolic stress. Biochemical and Biophysical Research Communications. 2021/10/01/ 2021;572:185-190. doi:https://doi.org/10.1016/j.bbrc.2021.07.090