Introduction: The molecular mechanisms whereby ventricular ectopy results in non-ischemic CM remain largely uncharacterized. Our PVC-cardiomyopathy (PVC-CM) animal model has allowed us to study limited molecular changes (e.g. L-type Ca channel, junctophilin-2 and IK1). Objective: To Identify the transcriptional profile associated to PVC-CM.
Methods: Using a premature pacing algorithm, PVC-CM was induced after 3-months of bigeminal RV apical PVCs at coupling intervals of 200ms in healthy canines. Myocardial tissue from multiple regions of the LV free wall were harvested and total RNA was extracted. 16 ribo-depleted libraries were created including samples from 5 sham controls and 11 PVC-canines. Paired-end massive parallel sequencing of cDNA (RNA-seq) was performed using an Illumina HiSeq platform. Gene models were defined using the UCSD/Broad CanFam3.1 assembly. Gene-level exploratory analysis and differential expression was performed using the DeSeq2 R-package).
Results: 22,652 mapped reads with a >5 total read count were used for downstream analysis. 646 genes (2.9%) were significantly upregulated, whereas 470 (2.1%) were downregulated in PVC myocardium compared to sham controls (FDR <0.1). Gene ontology analysis revealed key molecular pathways associated with high PVCs burden including response to external stimulus, response to wounding, response to cytokine stimulus, inflammation response and response to stress. Indeed, several inflammation-related genes such as IL-33, IL-6, IL-4 receptor, NFKbeta subunits and the leukotriene B4 receptor, as well as genes encoding different tissue metalloproteinases (MMPs 8,9,3,24) were significantly upregulated. Conversely, cation binding and metal ion binding biological processes were downregulated in PVC-CM, including genes encoding potassium voltage-gated channels, as well as CACNA1C, a gene encoding the pore-forming subunit (Cav1.2) of the L-type Ca2+ channel required for adequate T- tubule function.
Conclusions: Ventricular ectopy results in highly specific molecular signatures associated with impaired LV function. Further molecular are warranted. These molecular changes may provide future strategies to prevent and treat PVC-CM.