Response by Vandecasteele et al to Letter Regarding Article, “Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure”

Circulation. 2021;143:e26–e27. DOI: 10.1161/CIRCULATIONAHA.120.051628 e26 Grégoire Vandecasteele , PhD Delphine Mika , PhD Jean Piero Margaria , PhD Alessandra Ghigo , PhD Emilio Hirsch , PhD Jérôme Leroy , PhD Rodolphe Fischmeister , PhD In Response: We thank Drs Hang and Zhao for their interest in our work. Although today we have no evidence that a moderate overexpression of the cyclic nucleotide phosphodiesterase (PDE) type 4B is beneficial in heart failure (HF) induced by chronic myocardial ischemia or in atrial fibrillation, our findings that PDE4B is decreased in cardiac biopsies from patients with ischemic HF1 and that the relative PDE4 activity is decreased in atria from patients with permanent atrial fibrillation2 suggest that this could be the case. Concerning the potential contribution of other PDE isoforms, in particular PDE3, to the cardioprotective effect of PDE4B overexpression, we did not observe modification in the expression of PDE3A or other major PDEs in hearts from PDE4B transgenic mice. In terms of the optimal fold change of PDE4B overexpression for clinical application, according to our study, a 5-fold increase in myocardial PDE4B protein expression attenuated cardiac dysfunction and maladaptive remodeling induced by long-term isoprenaline infusion or transaortic constriction in mice without adversely affecting normal cardiac function.1 However, to what extent this dosage applies to other HF types and to large animal models of HF that are closer to human HF remains to be established. In the pathological models investigated, we observed that cardiac PDE4B overexpression attenuated cardiac fibrosis. This may indeed seem paradoxical when we consider the broad anti-inflammatory and antifibrotic effects of PDE4 inhibitors and the specific role of PDE4B in inflammation.3 However, it should be emphasized that, in our study, PDE4B was overexpressed exclusively (PDE4B transgenic mice) or at least preferentially (adeno-associated virus 9) in cardiomyocytes. In the case of adenoassociated virus 9–mediated overexpression, this was associated with decreased apoptosis. Thus, a reduction in cardiomyocyte death resulting from a PDE4B increase specifically in these cells may explain the overall reduced fibrosis in our experiments. An interesting point to consider here is the possibility that distinct PDE4B isoforms regulate cAMP levels in cardiomyocytes, immune cells, and fibroblasts. Indeed, whereas a short PDE4B isoform (PDE4B2) was shown to be predominant in macrophages3 and mouse embryonic fibroblasts,4 we found a long PDE4B isoform (PDE4B3) in cardiomyocytes. Recently, an allosteric activator of PDE4 that specifically targets long PDE4 forms was reported,5 suggesting that specific modulation of PDE4B in cardiomyocytes, but not in fibroblasts and inflammatory cells, is possible. Future investigations to determine which factors are responsible for the downregulation of PDE4 observed in pathological conditions and the downstream effectors of PDE4B modulated by its overexpression to improve cardiac function are indeed of great interest to develop new therapeutic approaches.