Background—: Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD). Methods and Results—: Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing human LV (n=8) was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ≈10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes ICM from NICM. Further analysis suggests that cis -gene regulation represents a major mechanism of action of human cardiac lncRNAs. Conclusions—: The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

Fibroblast growth factor 14 (FGF14) belongs to the intracellular FGF homologous factor subfamily of FGF proteins (iFGFs) that are not secreted and do not activate tyrosine kinase receptors. The iFGFs, however, have been shown to interact with the pore-forming (α) subunits of voltage-gated Na⁺(Na_v) channels. The neurological phenotypes seen inFgf14^−/−mice and the identification of anFGF14missense mutation (FGF14^F145S) in a Dutch family presenting with cognitive impairment and spinocerebellar ataxia suggest links between FGF14 and neuronal functioning. Here, we demonstrate that the expression of FGF14^F145Sreduces Na_vα subunit expression at the axon initial segment, attenuates Na_vchannel currents, and reduces the excitability of hippocampal neurons. In addition, and in contrast with wild-type FGF14, FGF14^F145Sdoes not interact directly with Na_vchannel α subunits. Rather, FGF14^F145Sassociates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Na_vα subunits, suggesting that the mutant FGF14^F145Sprotein acts as a dominant negative, interfering with the interaction between wild-type FGF14 and Na_vchannel α subunits and altering neuronal excitability.

Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ⁺ channel remodeling was examined in a mouse model of pressure overload–induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT _c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance ( C _m ) was higher, and I _to,f , I _K,slow , I _ss , and I _K1 densities were lower in TAC, than in sham, LV myocytes. Although the primary determinant of the reduced current densities is the increase in C _m , I _K,slow amplitudes were decreased and I _ss amplitudes were increased in TAC LV cells. Further experiments revealed regional differences in the effects of LVH. Cellular hypertrophy and increased I _ss amplitudes were more pronounced in TAC endocardial LV cells, whereas I _K,slow amplitudes were selectively reduced in TAC epicardial LV cells. Consistent with the similarities in I _to,f and I _K1 amplitudes, Kv4.2, Kv4.3, and KChIP2 ( I _to,f ), as well as Kir2.1 and Kir2.2 ( I _K1 ), transcript and protein expression levels were similar in TAC and sham LV. Unexpectedly, expression of I _K,slow channel subunits Kv1.5 and Kv2.1 was increased in TAC LV. Biochemical experiments also demonstrated that, although total protein was unaltered, cell surface expression of TASK1 was increased in TAC LV. Functional changes in repolarizing K ⁺ currents with LVH, therefore, result from distinct cellular (cardiomyocyte enlargement) and molecular (alterations in the numbers of functional channels) mechanisms.

This is the second of the two White Papers from the fourth UC Davis Cardiovascular SymposiumSystems Approach to Understanding Cardiac Excitation–Contraction Coupling and Arrhythmias(3–4 March 2016), a biennial event that brings together leading experts in different fields of cardiovascular research. The theme of the 2016 symposium was ‘K⁺channels and regulation’, and the objectives of the conference were severalfold: (1) to identify current knowledge gaps; (2) to understand what may go wrong in the diseased heart and why; (3) to identify possible novel therapeutic targets; and (4) to further the development of systems biology approaches to decipher the molecular mechanisms and treatment of cardiac arrhythmias. The sessions of the Symposium focusing on the functional roles of the cardiac K⁺channel in health and disease, as well as K⁺channels as therapeutic targets, were contributed by Ye Chen‐Izu, Gideon Koren, James Weiss, David Paterson, David Christini, Dobromir Dobrev, Jordi Heijman, Thomas O'Hara, Crystal Ripplinger, Zhilin Qu, Jamie Vandenberg, Colleen Clancy, Isabelle Deschenes, Leighton Izu, Tamas Banyasz, Andras Varro, Heike Wulff, Eleonora Grandi, Michael Sanguinetti, Donald Bers, Jeanne Nerbonne and Nipavan Chiamvimonvat as speakers and panel discussants. This article summarizes state‐of‐the‐art knowledge and controversies on the functional roles of cardiac K⁺channels in normal and diseased heart. We endeavour to integrate current knowledge at multiple scales, from the single cell to the whole organ levels, and from both experimental and computational studies.