Abstract 12370: Atrial Fibrillation and Atrial Remodeling Deteriorates Right Heart Function With Preserved LV Function in LKB1 f/f /ANF Cre+ Mice

Abstract

Introduction: Atrial fibrillation (AF) and right ventricular dysfunction(RVD) are each highly prevalent in heart failure (HF) patients; their co-existence represents a severe HF phenotype. AF and RVD in HF are respectively attributed to left atrial remodeling and pulmonary hypertension due to left heart disease. Yet clinical studies have found that AF, not pulmonary pressure, is independently associated with RVD in HF. These findings suggest the possibility that AF can cause RV dysfunction. Hypothesis: Atrial fibrillation can cause progressive RV dysfunction even in the absence of pulmonary hypertension. Methods: We created an atrial-specific LKB1 knockdown (atrial-LKB1 KD) by injecting AAV9-ANF-Cre retro-orbitally into adult male LKB1 fl/fl mice (age 8 wks). Echocardiography and telemetry were performed at 4- and 12- weeks post AAV9-ANF-Cre. At 12-weeks post-AAV injection, both right ventricular and left ventricular pressure- volume loop recordings were performed. Histological and molecular analyses were also performed at study endpoint. LKB1 fl/fl mice (Cre-) were used as controls (CTL). Results: At 12 wks post-injection, the incidence of AF with atrial remodeling was 100% in atrial-LKB1 KD. Echocardiography revealed RV systolic dysfunction by RV FAC (50.72% vs. 60.45%, p<0.05) and TAPSE (0.89mm vs. 1.15mm, p<0.05) in atrial-LKB1 KD vs. CTL. In contrast, LV FS were comparable between atrial-LKB1 KD and CTL. (40.4% vs. 42%, p=0.38). Atrial-LKB1 KD demonstrated abnormal RV-pulmonary arterial coupling, increased RV systolic pressure, and preserved LV function following atrial remodeling. Expression of genes related to remodeling and inflammation were upregulated in the RV of atrial-LKB1 KD. Compared to that of CTL, RV expression level of Nppb was 3.4-fold higher (p<0.05) and IL1β was 7.1 fold higher (p<0.05) in atrial-LKB1 KD. Conclusions: Our findings strongly suggest that atrial fibrillation alone can cause RV dysfunction with concomitant preserved LV function. Remodeling and inflammation of the RV but not LV in the atrial-LKB1 KD also suggests that the right heart is more vulnerable than the left heart to AF-induced dysfunction.