Jesper Jiang

Introduction. Heart failure (HF) is a clinical syndrome that disproportionately affects older individuals. Heart failure with preserved ejection fraction (HFpEF), where the left ventricular ejection fraction is greater than 50%, is the most common form of HF and accounts for at least 50% of all diagnosed HF.^1-4 Age is the major risk factor for HFpEF, and incidence of HFpEF increases with age. However, several recent studies have indicated a microvascular driven etiology and pathophysiology of the condition.^{1-3, 5, 6} While there is no current effective treatment for HFpEF, these studies are hopeful and indicate a potential treatment option by targeting the microvascular dysfunction involved in HFpEF.^1-6 One of the dysregulated signaling pathways involved is the nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway, which has shown to be significantly decreased in HFpEF patients and leads to decreased phosphorylation of titin that then causes increased cardiomyocyte stiffness. ^1-3 Studies have shown that targeting this specific pathway may provide a novel treatment for HFpEF patients.^{2, 3} Methods. To measure the impact of the NO-cGMP-PKG pathway, HFpEF was induced in an animal model through pressure overload left ventricular hypertrophy by performing abdominal aortic constriction (AAC) at the suprarenal level in NO sensitive guanylyl cyclase 1 a knockout mice (GC-1 a -/-). The effect of increasing the NO-cGMP-PKG pathway was observed through administration of an inhibitor of phosphodiesterase-2 (PDE2), a cGMP degrading enzyme. ² In another animal model, HFpEF was developed by inducing hypertension and diastolic dysfunction in rats with a 10-week high salt diet, and the effect of increasing the NO-cGMP-PKG pathway was compared with HFpEF patient myocardial biopsy samples prior to and after the administration of an activator of sGC, the cGMP generating enzyme.³ Results. PDE2 inhibition increased the NO-cGMP-PKG pathway by elevating cGMP levels. This treatment also increased ejection fraction and decreased left ventricular posterior wall diameter at end systole, left ventricular internal diameter at end systole, left ventricular/body weight ratio, and fibrosis percentage, which collectively indicate a reversal of the induced HFpEF.² Using an sGC activator, the NO-cGMP-PKG signaling pathway was improved by stimulation of the NO-sGC portion of the pathway. This stimulation increased cGMP, which then elevated PKG activity that eventually led to improved cardiomyocyte function through enhanced titin phosphorylation and decreased cardiomyocyte stiffness.³ Conclusion. There is no current effective treatment for HFpEF¹, but targeting the NO-cGMP-PKG pathway through PDE2 inhibition and sGC activation may provide a novel therapeutic approach to benefit HFpEF patients.

1. Franssen C, Chen S, Unger A, et al. Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. Apr 2016;4(4):312-24. doi:10.1016/j.jchf.2015.10.007
2. Baliga RS, Preedy MEJ, Dukinfield MS, et al. Phosphodiesterase 2 Inhibition Preferentially Promotes NO/Guanylyl Cyclase/cGMP Signaling to Reverse the Development of Heart Failure. Proc Natl Acad Sci U S A. Jul 31 2018;115(31):E7428-E7437. doi:10.1073/pnas.1800996115
3. Kolijn D, Kovacs A, Herwig M, et al. Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator. Front Physiol. 2020;11:345. doi:10.3389/fphys.2020.00345
4. D’Amario D, Migliaro S, Borovac JA, et al. Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction. Front Physiol. 2019;10:1347. doi:10.3389/fphys.2019.01347
5. Kolijn D, Pabel S, Tian Y, et al. Empagliflozin Improves Endothelial and Cardiomyocyte Function in Human Heart Failure with Preserved Ejection Fraction via Reduced Pro-inflammatory-Oxidative Pathways and Protein Kinase Galpha Oxidation. Cardiovasc Res. Jan 21 2021;117(2):495-507. doi:10.1093/cvr/cvaa123
6. Shah SJ, Lam CSP, Svedlund S, et al. Prevalence and Correlates of Coronary Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction: PROMIS-HFpEF. Eur Heart J. Oct 1 2018;39(37):3439-3450. doi:10.1093/eurheartj/ehy531