Our laboratory studies the effects of inflammation on the heart. Specifically, we believe that inflammation leads to heart failure with preserved ejection fraction (HFpEF) and arrhythmias. If true, this hypothesis would establish novel anti-inflammatory treatments for arrhythmias and HFpEF. Our working hypothesis is that inflammation-mediated downregulation of ion channels through a distinct set of mechanisms leads to arrhythmogenesis and that this arrhythmic risk can be prevented by interrupting this signaling cascade and maintaining healthy ion channel levels and function. Moreover, interrupting the inflammation cascade can prevent or treat diastolic dysfunction, thereby providing a novel therapeutic strategy for most HFpEF. This innovative hypothesis implies that cardiac inflammation and subsequent ROS underlies arrhythmic risk and HFpEF and interrupting these deleterious pathways can lead to novel therapies for these diseases. The overall goal is to validate novel therapies for arrhythmias and HFpEF that could move into clinical trials.
Unfolded Protein Response and Arrhythmias
Human heart failure is characterized by arrhythmogenic electrical remodeling consisting mostly of ion channel downregulations. Understanding the pathophysiological mechanisms of arrhythmias is crucial for finding the proper treatments. Adult cardiomyocytes, being differentiated and lack of regenerative potential, require a vital balance of its contents such as sarcomeres, membrane ion channel proteins, and mitochondria to maintain its viability and function. Therefore, protein quality control is crucial for cardiomyocyte survival and function. The unfolded protein response (UPR) is one of the important mechanisms of protein quality control in the endoplasmic reticulum (ER) to monitor and regulate misfolded and unfolded proteins. Our group has found that the activated UPR in human heart failure plays important roles on downregulation of cardiac Nav1.5. Recently, we reported that the UPR regulates multiple cardiac ion channels under ER stress in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), indicating an arrhythmogenic role of the UPR in heart disease. Activated UPR is also observed in our mouse models of ischemic and nonischemic heart failure. In preliminary study, we found that inhibiting PERK after myocardial infarction reduced sudden death, reduced spontaneous, nonsustained ventricular tachycardia, reduced QTc interval, and reduced action potential duration without negative consequences to contractile function.
Our studies and literature show that the UPR plays important roles in heart and targeting the UPR seems to be a potentially fruitful approach and clinically beneficial in novel therapeutics for cardiac disease. We will keep investigating the mechanisms of the beneficial effects of PERK inhibition and if the IRE1 and ATF6 branches play important roles in heart failure.
Mg and High Fat Diet-Induced Diabetes
Increased consumption of a high-fat diet (HFD) and a sedentary lifestyle have been implicated in the global epidemic of obesity. Obesity and diabetes mellitus (DM) are important risk factors for the development of cardiovascular disease, including cardiac diastolic dysfunction (DD). Cardiac DD underlies heart failure with preserved ejection fraction. Altered myocardial metabolism and increased oxidative stress accompany DM-associated DD. Recently, we have reported that cardiac mitochondrial oxidative stress can cause DD and heart failure with preserved ejection fraction by oxidatively modifying cardiac myosin binding protein C.
Magnesium (Mg) is an essential element for mitochondrial function, especially for ATP production. Mg deficiency is found commonly in cardiovascular disease, type II DM, hypertension, heart failure, and ventricular arrhythmia patients. A low serum Mg level is associated with increased cardiovascular mortality, while dietary Mg intake is associated with a decreased risk of developing type II DM and heart failure.
Our recent study shows that oral Mg supplementation improve mitochondrial function and cardiac DD/hypertrophy in a HFD mouse model of type II DM. Therefore, dietary Mg supplementation may be an inexpensive therapy for DD and subsequent heart failure with preserved ejection fraction. We will keep investigating the mechanisms of how Mg reverses cardiac DD/hypertrophy and mitochondrial dysfunction.
The Contribution of Mitochondrial Ca2+ Handling to Arrhythmia in Heart Failure
Recently, we have shown that mitochondrial Ca2+ handling can play roles in automaticity, action potential prolongation, and triggered arrhythmias. This suggests that mitochondrial dysfunction may be a central process in the generation of arrhythmias in cardiac disease and that altering mitochondrial Ca2+ flux may be a new therapeutic antiarrhythmic target.
Molecular Mechanisms of Sodium Channel (SCN5A) Regulation in Heart Disease
Downregulated sodium currents in heart failure (HF) has been linked to increased arrhythmic risk. Various factors may be contribute to the downregulation of sodium channel gene SCN5A mRNA. Currently, we are focusing on the role of alternative splicing factors and 3' UTR mediated mRNA stability factors in regulation of SCN5A. Furthermore, we are studying the role of specific miRNA on regulation of SCN5A in hypoxia which is a common pathogenic factor in HF. This allows us to build and understand the gene network for SCN5A regulatory and identify targets that may be applied to therapy.
Full list of publications at Experts@Minnesota.
1. Xie A, Gallant B, Guo H, Gonzalez A, Clark M, Madigan A, Feng F, Chen HD, Cui Y, Dudley SC Jr, Wan Y. Functional cardiac Na(+) channels are expressed in human melanoma cells. Oncol Lett. 2018 Aug;16(2):1689-1695.
2. Xie A, Zhou A, Liu H, Shi G, Liu M, Boheler KR, Dudley SC Jr. Mitochondrial. Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes. PLoS One. 2018 Jul 12;13(7):e0200448.
3. Zhou A, Shi G, Kang GJ, Xie A, Liu H, Jiang N, Liu M, Jeong EM, Dudley SC Jr. RNA Binding Protein, HuR, Regulates SCN5A Expression Through Stabilizing MEF2C transcription factor mRNA. J Am Heart Assoc. 2018 Apr 20;7(9).
4. Xie A, Song Z, Liu H, Zhou A, Shi G, Wang Q, Gu L, Liu M, Xie LH, Qu Z, Dudley SC Jr. Mitochondrial Ca(2+) Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy. J Am Heart Assoc. 2018 Apr 7;7(8).
5. Liu M, Shi G, Zhou A, Rupert CE, Coulombe KLK, Dudley SC Jr. Activation of the unfolded protein response downregulates cardiac ion channels in human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2018 Apr;117:62-71.
6. Zhang X, Yoon JY, Morley M, McLendon JM, Mapuskar KA, Gutmann R, Mehdi H, Bloom HL, Dudley SC, Ellinor PT, Shalaby AA, Weiss R, Tang WHW, Moravec CS, Singh M, Taylor AL, Yancy CW, Feldman AM, McNamara DM, Irani K, Spitz DR, Breheny P, Margulies KB, London B, Boudreau RL. A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality. J Clin Invest. 2018 Mar 1;128(3):1154-1163.
7. Zhou A, Xie A, Kim TY, Liu H, Shi G, Kang GJ, Jiang N, Liu M, Jeong EM, Choi BR, Dudley SC Jr. HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure. Heart Rhythm. 2018 Jul;15(7):1072-1080.
8. Noyes AM, Zhou A, Gao G, Gu L, Day S, Andrew Wasserstrom J, Dudley SC. Abnormal sodium channel mRNA splicing in hypertrophic cardiomyopathy. Int J Cardiol. 2017 Dec 15;249:282-286.
9. Vang A, Clements RT, Chichger H, Kue N, Allawzi A, O'Connell K, Jeong EM, Dudley SC Jr, Sakhatskyy P, Lu Q, Zhang P, Rounds S, Choudhary G. Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: a mechanism underlying RV fibrosis associated with cigarette smoke exposure. Am J Physiol Lung Cell Mol Physiol. 2017 May 1;312(5):L748-L759.
10. Kim TY, Terentyeva R, Roder KH, Li W, Liu M, Greener I, Hamilton S, Polina I, Murphy KR, Clements RT, Dudley SC Jr, Koren G, Choi BR, Terentyev D. SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR. Cardiovasc Res. 2017 Mar 1;113(3):343-353.
Full list of publications at Experts@Minnesota.
Director, Lillehei Heart Institute
Chief, Cardiovascular Division
Fred C. and Katherine B. Andersen Chair - Adult Cardiology
Assistant Professor of Medicine, Cardiovascular Division
Gyeoung-Jin Kang, Ph.D.