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CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure
Daniel A Richards1, Mark J Aronovitz1, Peiwen Liu2
1Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (D.A.R., M.J.A., G.L.M., K.T., S.P., R.H.K., R.M.B.).
Circulation. Heart Failure
|January 19, 2021
Summary
The novel PDE9 inhibitor CRD-733 reversed heart failure symptoms in mice, including left ventricular hypertrophy and dysfunction. Elevated cyclic guanosine monophosphate (cGMP) levels indicate its effectiveness as a potential heart failure treatment.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biomedical Science
Background:
- Natriuretic peptide (NP) receptor and cyclic guanosine monophosphate (cGMP) signaling augmentation is a therapeutic strategy for heart failure (HF).
- cGMP-specific phosphodiesterase 9 (PDE9) inhibition enhances cGMP signaling and reduces stress-induced hypertrophic heart disease.
- CRD-733 is a novel cGMP-specific PDE9 inhibitor undergoing clinical trials.
Purpose of the Study:
- To investigate the effects of chronic PDE9 inhibition using CRD-733 in a mouse model of pressure overload-induced heart failure.
- To evaluate CRD-733's impact on cardiac structure and function in the transverse aortic constriction (TAC) model.
Main Methods:
- Adult male mice underwent TAC to induce left ventricular (LV) hypertrophy.
- Mice received daily treatment with CRD-733 (600 mg/kg/day) or vehicle, alongside sham-operated controls.
- Serial echocardiography assessed LV hypertrophy, ejection fraction, and left atrial dimensions.
Main Results:
- CRD-733 treatment reversed established LV hypertrophy and improved LV ejection fraction.
- The inhibitor attenuated left atrial dilation, reduced LV end-diastolic pressures, and decreased lung weights.
- CRD-733 increased plasma cGMP levels and cardiac myosin binding protein-C phosphorylation.
Conclusions:
- CRD-733 effectively improves key heart failure indicators, including LV hypertrophy, dysfunction, and pulmonary edema, in a pressure overload mouse model.
- Elevated plasma cGMP may serve as a biomarker for target engagement by CRD-733.
- These findings support further clinical investigation of CRD-733 for human heart failure treatment.
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