The causal role of atrial fibrillation in the development of right heart dysfunction: atrial-ventricular cell signaling

We propose to test the paradigm-shifting hypothesis that atrial fibrillation (AF) causes right ventricular dysfunction (RVD). AF and RVD are highly prevalent amongst heart failure (HF) patients, irrespective of their left ventricular ejection fraction (LVEF). The conventional paradigm is that AF and RVD are consequences of left heart disease with either secondary left atrial remodeling or secondary pulmonary hypertension, respectively. However, recent clinical studies have found that AF, not pulmonary arterial systolic pressure (PASP), is independently associated with RVD in HF with either preserved or reduced LVEF (HFpEF or HFrEF). A longitudinal study of RV function in HFpEF patients identified AF to be independently associated with the development of RVD, suggesting that AF itself may cause chronic RVD. Others have previously shown that the cardiac-specific, alpha MHC-Cre driven, liver kinase B1 (LKB1) knockout exhibits spontaneous AF, atrial and ventricular remodeling, and concomitant ventricular dysfunction. This and other existing genetic mouse models of AF cannot determine the causal role of AF in RVD, as their ventricular myocytes harbor the AF-inducing gene modification. Our overall hypothesis is that atrial pathobiology itself induces RV myocardial dysfunction through atrial-ventricular paracrine signaling. To test this hypothesis, we aim: 1) to characterize the effect of chronic AF on RV structure and function in a novel mouse model of AF; and 2) to elucidate the mechanistic details of AF-induced RV remodeling and atrial-ventricular cell signaling. To generate the novel model of pure AF, we will create the atrial myocyte-specific LKB1 deficient mice, using AAV9-mediated delivery of atrial-specific ANF promoter-driven Cre (Addgene) into LKB1 floxed mice (provided by Nabeel El-Bardeesy, PhD, Harvard). We will perform serial in vivo assessment of RV structure and function in these mice using echocardio-graphy. We will examine cross-cell type and atrial-ventricular signaling in these mice using a systems biology approach with single-cell transcriptomic and global proteomic analyses. Our objective is to elucidate the pathophysiologic mechanism of AF-induced RVD. By doing so, we hope to identify potential targets for innovative interventions for RVD and AF that will ultimately improve the lives of those with HF.