Phosphodiesterase-9 inhibitors for the treatment of heart failure?

Phosphodiesterase-9 inhibitors for the treatment of heart failure?

Phosphodiesterase-9 (PDE9) has the highest binding affinity among phosphodiesterases with cyclic guanosine monophosphate [1]. Cardioprotective effects of natriuretic peptides released in response to ventricular stretch in heart failure are mediated by the second messenger cyclic guanosine monophosphate (cGMP) [2]. Intracellular levels of cGMP and cAMP are governed by the activity of cyclic nucleotide phosphodiesterases. 11 phosphodiesterases with varying tissue selectivity and substrate affinity for cGMP and cAMP have been identified (PDE1 to PDE11) so far.

Increased mortality with high doses of PDE3 inhibitors milrinone, vesnarinone, and enoximone in chronic heart failure with reduced ejection fraction (HFrEF) is thought to be secondary to the preferential affinity of PDE3 for cAMP relative to cGMP. This can lead to increase in the risk of ventricular arrhythmias as a result of increased intracellular levels of cAMP [2].

A metanalysis of PDE5 inhibitor sildenafil in the treatment of heart failure reported on 9 randomized controlled trials enrolling 612 heart failure patients. A pacifying finding was there was no significant differences in adverse events between sildenafil group and placebo group. Sildenafil improved hemodynamic parameters, particularly in HFrEF. Treatment was well tolerated and had no impact on quality of life [3].

PDE9 with greatest affinity for cGMP has specific affinity for the natriuretic peptide/cGMP signaling pathway, with no effect on the nitric oxide/cGMP pathway [4]. Protein expression and activity of PDE9 is increased in human heart with HFrEF, HFpEF and left ventricular hypertrophy secondary to aortic stenosis [2].

PDE9 inhibition, by increasing transduction of natriuretic peptide/cGMP signaling pathway may maximize the beneficial natriuretic, diuretic, arterial and venous vasodilatory, and antifibrotic/apoptotic effects of natriuretic peptides in heart failure [2].

An experimental study evaluated the effect of PDE9 inhibition in pacing induced heart failure in an ovine model. It was shown that PDE9 inhibition improves natriuretic peptide efficacy in conjunction with beneficial hemodynamic and renal effects in experimental heart failure [5].

PDE9a expression is reported to be upregulated in human myocardium with heart failure with preserved ejection fraction (HFpEF). The effect of chronic PDE9a inhibition in murine models of diastolic dysfunction have been evaluated. The study showed that PDE9a inhibition lowers ventricular chamber stiffness. But the required dose also impaired systolic function.  Due to this negative impact on systolic function, authors suggested combination treatment with a strategy to reduce effective arterial elastance [6].

Yet another murine study of PDE9 inhibition has been published in heart failure caused by pressure overload induced by transverse aortic constriction.  The study showed improvement in key hallmarks of heart failure including left ventricular hypertrophy, left ventricular dysfunction, left atrial dilation, and pulmonary edema. There was significant improvement in left ventricular ejection fraction (P=0.009) [7].

These studies are just concept generating and we need further studies and clinical trials later to decide on whether the PDE9 inhibitors in development will finally qualify as novel drugs for the treatment of heart failure.

References

1. Wu Y, Wang Q, Jiang MY, Huang YY, Zhu Z, Han C, Tian YJ, Zhang B, Luo HB. Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis. J Med Chem. 2021 Jul 8;64(13):9537-9549. doi: 10.1021/acs.jmedchem.1c00862. Epub 2021 Jun 18. PMID: 34142552.
2. McMurray JJV, Docherty KF. Phosphodiesterase-9 Inhibition in Heart Failure: A Further Opportunity to Augment the Effects of Natriuretic Peptides? J Am Coll Cardiol. 2019 Aug 20;74(7):902-904. doi: 10.1016/j.jacc.2019.07.008. PMID: 31416534.
3. Zhuang XD, Long M, Li F, Hu X, Liao XX, Du ZM. PDE5 inhibitor sildenafil in the treatment of heart failure: a meta-analysis of randomized controlled trials. Int J Cardiol. 2014 Apr 1;172(3):581-7. doi: 10.1016/j.ijcard.2014.01.102. Epub 2014 Jan 24. PMID: 24534379.
4. Lee DI, Zhu G, Sasaki T, Cho GS, Hamdani N, Holewinski R, Jo SH, Danner T, Zhang M, Rainer PP, Bedja D, Kirk JA, Ranek MJ, Dostmann WR, Kwon C, Margulies KB, Van Eyk JE, Paulus WJ, Takimoto E, Kass DA. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature. 2015 Mar 26;519(7544):472-6. doi: 10.1038/nature14332. Epub 2015 Mar 18. PMID: 25799991; PMCID: PMC4376609.
5. Scott NJA, Rademaker MT, Charles CJ, Espiner EA, Richards AM. Hemodynamic, Hormonal, and Renal Actions of Phosphodiesterase-9 Inhibition in Experimental Heart Failure. J Am Coll Cardiol. 2019 Aug 20;74(7):889-901. doi: 10.1016/j.jacc.2019.05.067. PMID: 31416533.
6. Methawasin M, Strom J, Borkowski T, Hourani Z, Runyan R, Smith JE 3rd, Granzier H. Phosphodiesterase 9a Inhibition in Mouse Models of Diastolic Dysfunction. Circ Heart Fail. 2020 May;13(5):e006609. doi: 10.1161/CIRCHEARTFAILURE.119.006609. Epub 2020 May 18. PMID: 32418479; PMCID: PMC7895451.
7. Richards DA, Aronovitz MJ, Liu P, Martin GL, Tam K, Pande S, Karas RH, Bloomfield DM, Mendelsohn ME, Blanton RM. CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure. Circ Heart Fail. 2021 Jan;14(1):e007300. doi: 10.1161/CIRCHEARTFAILURE.120.007300. Epub 2021 Jan 19. PMID: 33464954; PMCID: PMC8451972.