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Yu Lab

Han-Gang Yu, Principal Investigator

Project Name:  Profiling gene expression in obese human cardiac hypertrophy

Description: Using advanced next-generation sequencing techniques, this project is to investigate what genes are linked to development of human cardiac hypertrophy under obesity condition. We focus on genes that have similar alterations in the hearts of an obese rat model and obese humans. We can then study the altered functions of those genes and answer the question as to how these genes contribute to clinical manifestations in cardiac hypertrophy.

Statement of Importance:The importance of this project is to develop a new strategy for effective intervention of hypertrophy, an early indicator of heart failure, which causes most deaths and disabilities in the US.

Students: Mackenzie Newman

Collaborators: Robert Hull, MD; Mary Davis, PhD; James Coad, MD


Project Name: Mechanisms of leptin local actions in bradycardia-tachycardia and ventricular arrhythmia in obesity

Description: Leptin is a peptide released from adipocytes and known to regulate food intake and energy expenditure. How does leptin affect cardiac electrical properties is unknown. We have discovered that leptin can directly inhibit sinus node pacing rate, increase ventricular action potential and QT interval through its receptor. This direct local action of leptin is independent of an indirect leptin signaling via sympathetic tone.  We are currently studying how leptin regulates surface expression of leptin receptor and ion channels that lead to altered electrical properties of the heart.

Statement of Importance: Sudden cardiac death occurs ten-fold higher in obese patients compared to lean subjects. Obesity has now been recognized as an independent risk factor in ventricular arrhythmias which can trigger sudden cardiac death. Findings of fat infiltration within the cardiac myocardium has raised an important question that concerns how fat accumulation in myocardium affects cardiac functions. Investigating how leptin modulates sinus node and ventricular electrical properties simultaneously should inform us of novel strategies to effectively treat bradycardia-tachycardia and associated ventricular arrhythmias, particularly in obesity population.

Students: Mackenzie Newman

Collaborators: Yen-Chang Lin, PhD, Taiwan


Project Name:  Mechanisms of Slow Heart Rate (Braydycardia)

Description: We are investigating the HCN4 pacemaker channel protein. This channel controls the resting heart rate. Mutations in HCN4 cause deep bradycardia which can lead to prolonged QT interval and ventricular tachycardia, requiring implantation of electronic pacemaker. Most HCN4 mutations caused defective membrane trafficking leading to the reduction of channels expressed at the cell surface expression for normal function. We are studying ways to increase the surface expression of mutated HCN4 channels and restore their normal function and thus to maintain the normal heart rate.

Statement of Importance: Normal resting heart rate ranges from 60 to 100 beats per minute (bpm). Tachycardia (fast heart rate >100bpm) can be effectively treated by beta-blockers, but bradycardia (slow heart rate <60 bmp) has no effective pharmacological treatment. Without treatment, bradycardia can lead to atrial fibrillation, the most common arrhythmia in clinic. This bradycardia-tachycardia syndrome can sometime be evolved into ventricular arrhythmias, the less common but lethal leading to sudden cardiac death. Currently, the only effective treatment is the implantation of an electronic pacemaker, which requires surgery. Our findings can provide basis for developing novel pharmaceutical therapy for patients with bradycardia-tachycardia syndrome.

Students: Mackenzie Newman

Collaborators: Robert Hull, MD