Expression of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN4) is increased in hypertrophic cardiomyopathy

Abstract 

Objective

Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium with uncertain etiology and often leads to sudden death as the result of arrhythmia. Pacemaker hyperpolarization-activated current I_f was altered in hypertrophic hearts and was probably responsible for arrhythmia. I_f channels are compose\d of four hyperpolarization-activated cyclic nucleotide-gated cation subunits (HCN1–4). A previous study found significantly high levels of HCN2 and HCN4 mRNA in hypertrophic hearts compared to control hearts in septum and left ventricles in rats. No studies, however, have investigated the HCN gene expression in the myocardium from human HCM heart.

Methods

The left ventricular tissue from four patients who died of HCM and six healthy patients who died of motor vehicle accidents was included in this study. The fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay was used to detect HCN4 mRNA. The expression of HCN4 mRNA of the two groups was detected on the assay.

Results

In the HCM hearts, disorganization of the hypertrophic myofibers and interstitial fibrosis were observed in all four patients, although absent in healthy control hearts. By quantitative polymerase chain reaction, the mean copy number of HCN4 mRNA was 2.2×10⁷ (range, 6.8×10⁶ to 4.55×10⁷) in HCM hearts and 8.17×10³ (range, 8.76×10¹ to 3.5×10⁴) in control hearts (P=.0318).

Conclusion

Higher HCN4 mRNA levels in the HCM hearts suggest that up-regulation of HCN4 gene expression might be responsible for ventricular arrhythmia that leads to sudden death.

Keywords: FQ-RT-PCR, Gene expression, HCN4, Hypertrophic cardiomyopathy, Sudden death