Abstract 11099: Transcriptome Profiling of Surgical Myectomy Tissue from Patients with Hypertrophic Cardiomyopathy Reveals Marked Overexpression of ACE2
Introduction. Hypertrophic cardiomyopathy (HCM) is one of the leading causes of sudden cardiac death in the young, and the underlying molecular mechanisms are poorly understood. Herein, we aimed to perform transcriptome profiling of human HCM tissues to better define its pathogenetic basis. Methods. RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy from 106 patients with HCM (54 males, mean age at myectomy 40.5 ± 20.2 years). Tissues from 39 healthy donor hearts served as controls. Expression profiling of 37,846 genes was performed using the Illumina HumanHT-12 v3 Expression BeadChip. A false discovery rate q-value < 0.05 was considered significant. Results were technically validated by quantitative real-time PCR (qRT-PCR) in random samples (n=18 versus 13). Western blot was used to quantify expression (n=31 versus 13) and immunohistochemistry (IHC) to quantify intensity and distribution (n=14 versus 8) of myocyte staining of the ACE2 protein. Autopsy controls were used for the IHC analysis. PCR, Western blot, and IHC results were compared between HCM and controls with T-test or Fisher’s exact test as appropriate, with p< 0.05 considered significant. Results. Overall, 8443 transcripts (22% of the transcriptome) were expressed differentially in mRNA derived from HCM myectomy tissue compared to control myocardial tissue. Notably, ACE2 was up-regulated in HCM 3.53-fold compared to healthy controls (q = 9.72x10-24). This result was confirmed with qRT-PCR (fold-change 3.78; p < 0.001). Western blot demonstrated a 5.34-fold (p = 1.66x10-6) increase in ACE2 protein, and IHC demonstrated increased intensity (100% versus 38% scored 2/2, p = 0.0021) and distribution (43% versus 0% scored 3/3, p = 0.0001) of ACE2 myocyte staining in HCM patients versus controls. Conclusions. In this first large-scale transcriptome analysis of human HCM, we discover marked up-regulation of the gene encoding ACE2, a negative regulator of the angiotensin system thought to suppress pathologic hypertrophy and fibrosis. Thus, ACE2 up-regulation in HCM is counterintuitive. We speculate it is an inadequate compensatory response that perhaps carries novel deleterious consequences such as predisposition to sudden death.
- © 2012 by American Heart Association, Inc.