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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Expression of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN4) is increased in hypertrophic
Huang Wei-qing1, Kong Qing-nuan, Xu Lin
1Department of Pathology, Qingdao Municipal Hospital, Qingdao 266071, Shandong, China.
Insights
Hypertrophic cardiomyopathy (HCM) hearts show significantly higher HCN4 mRNA levels compared to healthy hearts. This suggests increased HCN4 gene expression may contribute to fatal ventricular arrhythmias in HCM patients.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) is a myocardial disease with unknown causes, often leading to sudden cardiac death due to arrhythmia.
- The hyperpolarization-activated current I(f) is altered in hypertrophic hearts and implicated in arrhythmias.
- I(f) channels are formed by HCN1-4 subunits; previous studies indicated elevated HCN2 and HCN4 mRNA in rat hypertrophic hearts.
Purpose of the Study:
- To investigate HCN gene expression in human hypertrophic cardiomyopathy (HCM) myocardium.
- To determine if HCN4 mRNA levels are altered in human HCM hearts compared to healthy controls.
Main Methods:
- Left ventricular tissue samples were obtained from four HCM patients and six healthy individuals.
- Fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR) was employed to quantify HCN4 mRNA expression levels.
Main Results:
- HCM hearts exhibited myofiber disorganization and interstitial fibrosis, absent in controls.
- Quantitative PCR revealed significantly higher mean HCN4 mRNA copy numbers in HCM hearts (2.2×10^7) compared to control hearts (8.17×10^3).
Conclusions:
- Elevated HCN4 mRNA levels in human HCM hearts were observed.
- Up-regulation of HCN4 gene expression is suggested as a potential mechanism contributing to ventricular arrhythmia and sudden death in HCM.
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 2.2×10(7) (range, 6.8×10(6) to 4.55×10(7)) in HCM hearts and 8.17×10(3) (range, 8.76×10(1) to 3.5×10(4)) 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.
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