Introduction: The co-existence of atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) results in worse clinical outcomes than for either individual disorder, and the presence of AF blunts or eliminates the favorable response of HFrEF to beta-blocker therapy.
Hypothesis: The presence of AF in HFrEF fundamentally changes the biology and the therapeutic phenotype of the failing left ventricle, which can be detected by myocardial gene expression measurements.
Methods: We measured mRNA expression profiles by RTqPCR for 50 candidate genes normalized to GAPDH and by a pan-genomic microarray (19,673 genes) in RV septal biopsies in 47 patients sampled before and after 12 months of treatment with beta-blocker combinations (carvedilol or metoprolol) that had in common beta-1 adrenergic receptor (AR) blockade (ClinicalTrials.gov NCT01798992), in HFrEF/IDC patients with and without AF.
Results: At baseline LVEF in the 10 patients with permanent AF (LVEF median (IQR) 0.24 (0.20,0.29)) did not differ from the 37 (LVEF 0.24 (0.19,0.33)) in sinus rhythm (SR). The only candidate gene with differential baseline expression was GNAQ (1.43 fold higher in AF-HFrEF, p =0.006). Microarray analysis yielded 1378 (7%) genes with differential (p <0.05) baseline expression between AF- and SR-HFrEF. Using a definition of reverse remodeling response of an increase at 12 months of at least 8 absolute % (EFU), AF-HFrEF patients exhibited a trend (p = 0.051) for a lower response rate (40% vs. 73% in SR-HFrEF), but the median LVEF change was not different (in ΔEFU, AF 0.06 (0.03,0.13), SR 0.14 (0.05,0.26) p = 0.11). Eight candidate (3 adrenergic signal transduction, ATP2A2 and PLN, NPPA and NPPB, IL6) and 2687 (14%) microarray measured genes exhibited significant (p <0.05) fold changes in AF vs. SR HFrEF. Moreover, 49% of genes within a previously identified N= 87 gene network related to beta-1 AR signaling (beta-1 GSN) were differentially changed with beta-blocker treatment in AF vs. SR HFrEF, compared to 14% of genes outside this network (p <0.0001).
Conclusions: In AF vs. SR HFrEF ventricular myocardial gene expression is: 1) similar at baseline; 2) substantially different with beta-blocker therapy; 3) Markedly different for genes within the beta-1 GSN.