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BackgroundCurrent heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures.ResultsRNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets.ConclusionsOur results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5213-9) contains supplementary material, which is available to authorized users.

Aims: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT. Methods and Results:We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT. Conclusions:Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.

Cardiac resynchronisation therapy (CRT) may fail in up to one third of patients, mainly due to anatomical and procedural issues. In the daily practice, ECG optimisation is largely used to address CRT delivery. Ineffective CRT can be related to non-optimal pacing timing as well as inadequate pacing-capture. A rate-competitive atrial fibrillation (AF) or a high daily burden of premature ventricular contractions (PVC) may also affect CRT by means of fusion or pseudo-fusion captures. Growing observations suggest that in a subset of patients with typical left bundle branch block (LBBB), selected LV pacing may be more effective, producing a complete fusion between the left pacing and the intrinsic right bundle activation. The His-ventricular (HV) interval is an invasive measurement (derived from electrophysiological study), which mainly reflects the RV activation (and its contribution to QRS timing) and has been proposed by some authors when addressing LV-paced–RV-sensed fusion. In sinus rhythm CRT patients, with baseline typical LBBB criteria and preserved AV conduction, the “dromotropic” management to achieve RV intrinsic activation with LV fusion is also “AV delay dependent”. In this regard, the RV intrinsic activation (detected by RV sensing) and the A (paced/sensed)-RV (sensed) interval are also influenced by the RV lead position within the RV. The current families of CRT devices have implemented automatic algorithms to optimise AV and VV timing intervals. The proof of principle is again the evidence that fusion of an LV-paced beat with intrinsic rhythm may be more beneficial than standard biventricular pacing, provided a preserved AV conduction. In the present review, all the above issues are discussed.