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Samuel Dudley Ruth and Paul Levinger Professor of Cardiology, Professor of Medicine

Brown Affiliations

Research Areas

scholarly work

5. JEONG, E.M., MONASKY, M.M., GU, L., TAGLIERI, D.M., PATEL, B.G., LIU, H., WANG, Q., GREENER, I., DUDLEY, S.C., SOLARO, R.J. Tetrahydrobiopterin Improves Diastolic Dysfunction by Reversing Changes in Myofilament Properties. (2013). J Mol Cell Cardiol. 56: 44-54. PMID: 23247392.

4. LIU, M., GU, L., SULKIN, MS., LIU, H., JEONG, EM., GREENER, I., XIE, A., EFIMOV, IR., DUDLEY, SC., Mitochondrial Dysfunction Causing Cardiac Sodium Channel Downregulation in Cardiomyopathy. (2013). J Mol Cell Cardiol. 54:25–34. PMID: 23123323. PMCID: PMC3595554.

3. GAO, G., DUDLEY, SC., RBM25/LUC7L3 Function in Cardiac Sodium Channel Splicing Regulation of Human Heart Failure. (2013). Trends Cardiovasc Med. 23(1):5-8. PMID: 22939879. PMCID: PMC3532530.

2. SIMPSON, DL., DUDLEY, SC., Modulation of human mesenchymal stem cell function in a three-dimensional matrix promotes attenuation of adverse remodelling after myocardial infarction. (2013). J Tissue Eng Regen Med. 7(3): 192–202. PMID: 22095744.

1. SOVARI, A., RUTLEDGE, C., JEONG, EM., DOLMATOVA, E., ARASU, D., LIU, H. VADANI, N., GU, L., ZANDIEH, S., XIAO, L., BONINI, MG., DUFFY, HS., DUDLEY, SC. Mitochondria Oxidative Stress, Connexin43 Remodeling, and Sudden Arrhythmic Death. (2013). Circ Arrhythm Electrophysiol. PMID: 23559673.

17. ABREU-VELEZ, AM., SMOLLER, BR., GAO, W., GROSSNIKLAUS, HE., JIAO, Z., ARIAS, LF., DUDLEY, SC., HOWARD, MS. Varicella-zoster virus (VZV) and alpha 1 antitrypsin: a fatal outcome in a patient affected by endemic pemphigus foliaceus. (2012). Int J Dermatol. 51(7):809–816. PMID: 22715825.

16. WANG, T., LANG, G., MORENO-VINASCO, L., HUANG, Y., GOONEWARDENA, S., PENG, Y., SVENSSON, E., NATARAJAN, V., LANG, R., LINARES, J., BREYSSE, P., GEYH, A., SAMET, J., LUSSIER, Y., DUDLEY, SC., PRABHAKAR, N., GARCIA., J.. Particulate Matter Induces Cardiac Arrhythmias via Dysregulation of Carotid Body Sensitivity and Cardiac Sodium Channels. (2012). Am J Respir Cell Mol Biol. 46(4):524-531. PMID: 22108299.

15. SIMPSON, D.L., BOYD, N.L., STICE, S.L., DUDLEY, SC. Use of Human Embryonic Stem Cell Derived-Mesenchymal Cells for Cardiac Repair. (2012). Biotechnol Bioeng. 109(1):274-83. PMID: 21837664. PMCID: PMC3220775.

14. REFAAT, M., LUBITZ, S., SEIKO, S., ISLAM, Z., FRANGISKAKIS, M., MEHDI, H., GUTMANN, R., ZHANG, M., BLOOM, H., MACRFAE C., DUDLEY, SC., SHALABY, A., WEISS, R., MCNAMARA, D., LONDON, B., ELLINOR, P. Genetic Variation in the Alternative Splicing Regulator, RBM20, is associated with Dilated Cardiomyopathy. (2012). Heart Rhythm. 9(3):390-6. PMID: 22004663. PMCID: PMC3516872.

13. NEGI, S., JEONG, EM., SHUKRULLAH, I., RAICU, M., DUDLEY, SC. Association of Low Plasma Adiponectin with Early Diastolic Dysfunction. (2012). Congest Heart Fail. 18(4):187–191. PMID: 22809257. PMC3646250.

12. LOVELOCK, J., MONASKY, M.M., JEONG, E.M., LARDIN, H.A., LIU, H.,PATEL, B.G., TAGLIERI, D.M., GU, L., KUMAR, P., POKHREL, N., ZENG, D., BELARDINELLI, L., SORESCU, D., SOLARO, R.J., DUDLEY, SC. Ranolazine Improves Cardiac Diastolic Dysfunction through Modulation of Myofilament Calcium Sensitivity. (2012). Ci. Res. 110:841-850. PMID: 22343711. PMCID: PMC3314887.

10. LIANG, Y., ROEDE, J., DIKALOV, S., MILLER, N., DUDLEY, SC., QUYYUMI, A., JONES D., Determination of Ebselen-Sensitive Reactive Oxygen Metabolites (ebROM) in Human Serum Based Upon N,N' –Diethyl-1,4-Phenylenediamine Oxidation, (2012). Clinica Chemica Acta. 414: 1–6. PMID: 22687643. PMCID: PMC3662006.

9. SOVARI, A., DUDLEY, SC., Antioxidant Therapy for Atrial Fibrillation: Lost in Translation? (2012). Heart. 98(22):1615-1616. PMID: 22895646. PMCID: PMC3651833.

8. SOVARI, A., DUDLEY, SC., Reactive Oxygen Species-Targeted Therapeutic Interventions for Atrial Fibrillation. (2012). Front Physiol. 3:311. PMID: 22934062. PMCID: PMC3429082.

7. SOVARI, A., DUDLEY, SC., Gene and Cell Therapies for the Failing Heart to Prevent Sudden Arrhythmic Death. (2012). Minerva Cardioangiol. 60(4):363-373. PMID: 22858914. PMCID: PMC3655203.

6. BLANCO, R.R., AUSTIN, H., VEST, R.N., VALADRI, R., LI, W., LASSEGUE, B., SONG, Q., LONDON, B., DUDLEY, S.C., BLOOM, H.L., SEARLES, C.D., ZAFARIM, A.M., Angiotensin receptor type 1 single nucleotide polymorphism 1166A/C is associated with malignant arrhythmias and altered circulating miR-155 levels in patients with chronic heart failure. (2012). J Card Fail. 18(9):717-723. PMID: 22939041. PMCID: PMC3640363.

11. JEONG, EM., LIU, M., STURDY, M., VARGHESE, S., SOVARI, A., DUDLEY, SC. Metabolic stress, reactive oxygen species, and arrhythmia. (2012). J Mol Cell Cardiol. 52(2): 545-463. PMID: 21978629. PMCID: PMC3264827.

27. GAO, G., XIE, A., HUANG, S. , ZHOU, A., ZHANG, J., HERMAN, A., GHASSEMZADEH, S., JEONG, E.M., SOBIESKI, M., BHAT, G., TATOOLES, A., BENZ, E., KAMP, T., DUDLEY, S.C. JR. The Role of the RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure. (2011). Circulation. 124:1124-1131. PMID: 21859973. PMCID: PMC3172047.

26. NEGI, S., SHUKRULLAH, I., VELEDAR, E., BLOOM, H.L., JONES, D.P., DUDLEY, S.C., JR., Satin Therapy for the Prevention of Atrial Fibrillation Trial (SToP AF trial). (2011). J Cardiovasc Electrophysiol. 22:414-419. PMID: 20946227. PMCID: PMC3022954

25. ABREU-VALEZ, AM., HOWARD, M., JIO, Z., GAO, W., GROSSNIKLAUS, H., DUQUE-RAMIREZ, M., DUDLEY, SC. Cardiac autoantibodies from patients affected by a new variant of endemic pemphigus foliaceus in Colombia, South America. (2011). J of Clin Immunol. 31(6):985-97. PMID: 21796504. PMCID: PMC3380437.

23. MISHRA, R., VIJAYAN, K., COLLETTI, E.J., HARRINGTON, D.A., MATTHIESEN, T.S., SIMPSON, D., GOH, S.K., WALKER, B., ALMEIDA-PORADA, G., WANG, D., BACKER, C.L., DUDLEY, S.C. JR, WOLD, L.E,. KAUSHAL, S., Characterization and Functionality of Cardiac Progenitor Cells in Congenital Heart Patients. (2011). Circulation. 4:364-373. PMID: 21242485. PMCID: PMC3320857.

22. IRAVANIAN, S., B.S. HARRIS, H.D. XIAO, Z. JIAO, E.A. WITHAM,R.G. GOURDIE, K.E. BERNSTEIN, DUDLEY, SC. Connexin43 (Cx43) Phosphorylation State Correlates with Ventricular Tachycardia Risk in a Model of Cardiac Renin-Angiotensin System (RAS) Activation. (2011). J Mol Med. 89:677-687. PMID: 21724869.

21. NEGI, S., SOVARI, A., DUDLEY, SC. Atrial Fibrillation: The Emerging Role of Inflammation and Oxidative. (2011). Cardiovasc Haematol Disord Drug Targets. 10(4):262-268. PMID: 20932266.

20. SOVARI, A., BONINI, M., DUDLEY, SC. Effective Antioxidant Therapy for the Management of Arrhythmia, (2011). Expert Rev Cardiovas Ther. 9:797-800. PMID: 21809958.

19. SOVARI, A., IRAVANIAN, S., DOLMATOVA, E., JIAO, Z., LIU, H., ZANHIEH, S., KUMAR, V., WNAG, K., BERNSTEIN K., BONINI, M., DUFFY, H., DUDLEY, SC. Inhibition of c-Src Tyrosine Kinase Prevents Angiotensin II-Mediated Connexin43 Remodeling and Sudden Cardiac Death. (2011). J Am Coll Cardiol. 58 (22):2332-9. PMID: 22093512. PMCID: PMC3226807.

18. REED, A., TANAKA, A., SORESCU, D., LIU, H., JEONG, EM., STURDY, M., WALP, E, DUDLEY, SC., SUTLIFF, RL. Diastolic Dysfunction is Associated with Cardiac Fibrosis in the Senescence-Accelerated Mouse. (2011). Am J Physiol Heart Circ Physiol. 301(3):H824-831. PMID: 21724869. PMCID: PMC3191096.

24. IRAVANIAN, S., SOVARI, A.A., LARDIN, H.A., LIU, H., XIAO, H.D., DOLMATOVA, E., JIAO, Z., HARRIS, B.S., WITHAM, E.A., GOURDIE, R.G., DUFFY, H.S., BERNSTEIN, K.E., DUDLEY, S.C., JR. Inhibition of Renin-Angiotensin System (RAS) Reduces Ventricular Tachycardia Risk by Altering Connexin43. (2011). J Mol Med. 89(7):677-687. PMID: 21553032. PMCID: PMC3156477.

31. SILBERMAN, G.A., T.M. FAN, H. LIU, Z. JIAO, H.D. XIAO, J.D. LOVELOCK, B.M. BOULDEN, J. WIDDER, S. FREDD, K.E. BERNSTEIN, B. WOLSKA, S. DIKALOV, D.G. HARRISON, S.C. DUDLEY, Jr. Uncoupled Cardiac Nitric Oxide Synthase Mediates Diastolic Dysfunction. (2010). Circulation. 121:519-528. PMID: 20083682. PMCID: PMC2819317.

29. LIU, M., LIU, H., DUDLEY, S.C. Reactive Oxygen Species Originating from Mitochondria Regulate the Cardiac Sodium Channel. (2010). Cir Res. 107:967-974. PMID: 20724705. PMCID: PMC2955818.

28. DUDLEY, S.C., JR., Ion channelopathies: A tapped out mine? (2010). Am. J. Physi - Heart Circ. Physiol. 300:H716-H717. PMID: 21193585.

34. GAO, G. S.C. DUDLEY, Jr. Redox regulation, NF-B, and atrial fibrillation. (2009). Antioxidants & Redox Signaling. 11:2265-2277. PMID: 19309257. PMCID: PMC2819799.

33. SIMPSON, D., S.C. DUDLEY, Jr. Lost in Translation: What is Limiting Cardiomyoplasty and Can Tissue Engineering Help? (2009). Curr. Stem. Cell Res Ther. 4:210-23. PMID: 19492979. PMCID: PMC3164232.

30. BLOOM, H.L., I. SHUKRULLAH, E. VELEDAR, R. GUTTMAN, B. LONDON, S.C. DUDLEY, Jr. Statins Decrease Oxidative Stress and ICD Therapies. (2009). Cardiology Research and Practice. Cardiol Res Pract. 2010:253803. PMID: 20369058. PMCID: PMC2847377.

32. LIU, M., S. SANYAL, I. GURUNG, X. ZHU, G. GACONNET, L. KERCHNER, L. SHANG, C. HUANG, A. GRACE, B. LONDON, S.C DUDLEY, Jr. Cardiac Na+ Current Regulation by Pyridine Nucleotides. (2009). Circ. Res. 105:737-45. PMID: 19745168. PMCID: PMC2773656.

research overview

The research in Dudley lab spans from basic science targeting fundamental mechanisms underlying cardiovascular diseases, to translational medicine aiming at advancing the diagnosis and treatment of arrhythmias and cardiomyopathy. Specific projects include exploring the mechanisms of the transcriptional and post-translational regulation of Na+ channel in heart failure, AngII-mediated cardiac connexon regulation, redox-sensitive Ca2+ handling and myofilament-dependent diastolic heart failure.

research statement

Cardiac sodium channel splicing regulation in human heart failure
Alternative splicing is a posttranscriptional mechanism that can substantially change the pattern of gene expression. Up to 95% of human genes have multiexon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases. Our lab has been investigating the SCN5A splicing abnormalities in heart failure (HF), and has found that 47 of 181 known splicing regulators were upregulated in HF compared to controls, which indicates that splicing regulation may play a key role in HF. Our results show that angiotensin II and hypoxia, signals common to HF, result in increased LUC7L3 and RBM25 splicing regulators, increased binding of RBM25 to SCN5A mRNA, increased SCN5A splice variant abundances, decreased full-length SCN5A mRNA and protein, and decreased Na+ current. These observations may shed light on a mechanism whereby cardiac function and arrhythmic risk are associated and allow for refined predictions of which patients may be at highest arrhythmic risk or suffer from Na+ channel blocking anti-arrhythmic drug complications.

Reactive oxidative stress-mediated cardiac sodium channel regulation
It is well recognized that increasing severity of HF parallels sudden death risk, reduced INa increases arrhythmic risk, and myopathic conditions are associated with reduced INa. Previously, we have worked one of the mechanisms whereby INa is downregulated in heart failure. We have observed that NADH downregulates Nav1.5 through PKC activation and mitochondrial reactive oxygen species (ROS) overproduction. NAD + , in a redox couple with NADH, can reverse the reduction of cardiac Nav1.5 currents and mitochondrial ROS overproduction through PKA. We have also found that NAD + reduces antiarrhythmic risk in SCN5A +/- hearts. This implies that NAD + can potentially be given to humans to raise INa in HF and reduce sudden death risk. Since heart failure is the most common admitting diagnosis to a hospital, heart failure has the same prognosis as lung cancer, and sudden death accounts for half of all heart failure deaths, this potential new therapy could have a large impact on human health. Moreover, this therapy represents a completely new antiarrhythmic paradigm of raising, rather than blocking, channels to treat arrhythmic risk.

Mechanisms linking renin-angiotensin system activation, cardiac connexon regulation and ventricular arrhythmias
Activation of the cardiac renin-angiotensin system (RAS) is the hallmark of cardiomyopathy and is associated with increased risk of ventricular arrhythmia and sudden cardiac death. Increased cardiac RAS activity leads to conduction block and spontaneous ventricular arrhythmias as a result of connexin 43 (Cx43) downregulation. We have demonstrated in a transgenic mouse model of cardiac-specific overexpression of angiotensin converting enzyme (ACE8/8) that RAS activation-induced Cx43 degradation is mediated by the activation of redox-sensitive tyrosine kinase c-Src signaling. We have also shown that RAS-induced c-Src activation and Cx43 degradation is dependent on the increase in mitochondrial reactive oxygen species (mito-ROS). Our recent data suggest that this RAS-induced mito-ROS-dependent c-Src activation results from the post-translational regulation of the scaffolding protein caveolin 1 (Cav1). These findings may explain the genetic association of Cav1 with arrhythmias and suggests that targeted regulation of Cav1 or antioxidant therapy may reduce arrhythmic risk during RAS activation.

Role of c-Src kinase in cardiac arrhythmias with ischemic heart disease
Ischemic heart disease (IHD) is associated with decreased electrical current conductance in the heart, which increases the risk for arrhythmia and sudden cardiac death. Connexin43 (Cx43) is the principal gap junction protein responsible for propagating current through the cardiomyocytes in the ventricles. Cx43 expression is known to be reduced in the left ventricle following IHD. Recently, we showed that production of reactive oxygen species (ROS) stimulates phosphorylation of the tyrosine kinase c-Src, allowing c-Src to bind the scaffolding protein zonula occludens-1 (ZO-1), which is responsible for stabilizing Cx43. Binding of c-Src to ZO-1 results in destabilization and degradation of Cx43, reducing the heart's ability to propagate current. In this project, we are exploring the roles of mitochondrial-specific ROS scavenging and Src inhibition in the prevention of Cx43 remodeling following IHD.

Role of mitochondria Ca 2+ flux in calcium handling and cardiac arrhythmogenesis
Mitochondria participate in Ca 2+ homeostasis and Ca 2+ oscillations are thought to be involved in arrhythmogenesis. Nevertheless, the role of mitochondria in arrhythmogenesis is unclear. We investigated the role of mitochondrial Ca 2+ handling in arrhythmias using a mouse model of nonischemic cardiomyopathy (unilateral nephrectomy followed by deoxycorticosterone acetate, DOCA, treatment), as well as a cellular model of ventricular-like cardiomyocytes derived from mouse embryonic stem cells. We demonstrated that mitochondrial Ca 2+ uptake plays a critical role in regulating myocyte membrane excitability through inhibiting Na + /Ca 2+ exchanger (NCX), thereby modulating arrhythmic risk in vivo. In addition, our recent data also suggest that the increased arrhythmic risk with reduced SR Ca 2+ release upon ryanodine receptor2 (RYR2) observed in heart failure is dependent on mitochondrial Ca 2+ uptake.

Role of myofilament modification in diastolic heart failure
Despite the increasing prevalence of heart failure with preserved left ventricular function, there are no specific treatments, partially because the mechanism of impaired relaxation is incompletely understood. Evidence indicates that cardiac relaxation may depend on nitric oxide (NO), generated by NO synthase (NOS) requiring the co-factor tetrahydrobiopterin (BH4). Recently, we reported that hypertension-induced diastolic dysfunction was accompanied by cardiac BH4 depletion, NOS uncoupling, a depression in myofilament cross-bridge kinetics, and S-glutathionylation of myosin binding protein C (MyBP-C). We hypothesized that the mechanism by which BH4 ameliorates diastolic dysfunction is by preventing glutathionylation of MyBP-C and thus reversing changes of myofilament properties that occur during diastolic dysfunction. We used the deoxycorticosterone acetate (DOCA)-salt mouse model, which demonstrates mild hypertension, myocardial oxidative stress, and diastolic dysfunction. Mice were divided into two groups that received control diet and two groups that received BH4 supplement for 7days after developing diastolic dysfunction at post-operative day 11. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH4 treatment. Diastolic sarcomere length and relengthening were also restored to control by BH4 treatment. pCa50 for tension increased in DOCA-salt compared to sham but reverted to sham levels after BH4 treatment. Maximum ATPase rate and tension cost (ΔATPase/ΔTension) decreased in DOCA-salt compared to sham, but increased after BH4 treatment. Cardiac MyBP-C glutathionylation increased in DOCA-salt compared to sham, but decreased with BH4 treatment. MyBP-C glutathionylation correlated with the presence of diastolic dysfunction. Our results suggest that by depressing S-glutathionylation of MyBP-C, BH4 ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins. Our recent data also indicate that post-translational modification of myofilament proteins also plays a critical role in mediating the diastolic dysfunction observed with diabetes mellitus, suggesting a potential novel therapeutic approach to prevent or treat diabetes-induced cardiac dysfunction.

funded research

1. P.I.
A blood test to predict sudden death risk

2. P.I.
Na+ channel mRNA splicing in heart failure

3. P.I.
Metabolic regulation of sodium channels

4. P.I.
VA Merit
Renin angiotensin system and connexin43

5. Co Inv. on NIH P01 (PI Harrison)
R01 within P01 (PI Dudley)
Oxidative stress and left ventricular dysfunction
04/01/2009 -11/30/2013

6. P.I.
Training in the Mechanisms of Cardiovascular Disease
08/01/2009 - 07/31/2014

1. P.I.
UIC – Office of Technology Management (Proof of Concept)
A Blood Test to Differentiate Systolic from Diastolic Heart Failure

1. P.I.
Stem cell therapy and arrhythmia
04/01/2005 - 03/31/2010

2. P.I.
Oxidative Stress and Diastolic Dysfunction
4/1/2008 -3/31/2009 (overlapped with P01 above, relinquished by PI)

3. P.I.
Angiotensin converting enzyme, angiotensin II, and arrhythmia
07/01/2007 - 06/30/2011

4. P.I.
VA Merit
Nitric Oxide and the Pathogenesis of Atrial Fibrillation
04/01/2003 - 03/31/2007

5. P.I.
VA MERIT - declined
Evaluation of the Sodium Channel Outer Vestibule
01/01/2000 – 12/31/2004

6. P.I.
VA MERIT - declined
Angiotensin converting enzyme, angiotensin II, and arrhythmia
04/01/2007 - 03/31/2011

7. Co-P.I.
Regulation of Vascular Function by the Endothelium
01/01/2001 - 01/01/2006

8. P.I.
Evaluation of the Sodium Channel Outer Vestibule
06/10/2000 - 05/31/2005

9. P.I.
Environmental Protection Agency
A Mechanistic Study of Halocarbon/Epinephrine Induced Arrhythmias
08/01/2004 - 07/31/2004

1. P.I.
Takeda Pharmaceuticals
Educational Grant
10/01/2009 - 12/31/2010

2. P.I.
American Heart Association
Established Investigator
01/01/2004 - 12/31/2009

3. P.I.
Pfizer Pharmaceuticals
Atorvastatin therapy for the prevention of atrial fibrillation

4. Co- P.I.
The Relationship Between Angiotensin Converting Enzyme (ACE insertion/deletion [I/D]) and the Angiotensin II Type 1 Receptor (AGTR1 A1166C) Polymorphisms and Ventricular Arrhythmias in a Large Patient Cohort Treated With Implantable Cardiac Defibrillators
07/09/2006 - 07/09/2007

5. P.I.
Procter and Gamble
Development of differentiated mouse embryonic stem cells for the study of arrhythmia
01/01/1998 - 01/01/2002

6. P.I.
Southeast Affiliate American Heart Association
Experimental Evaluation of a Molecular Model of the Na Channel Outer Vestibule
07/01/1998 - 06/30/2000

7. P.I.
Atlanta Research and Education Foundation
A Model of Idiopathic Ventricular Fibrillation
09/21/1998 - 09/21/1999

8. P.I.
A Differentiated Embryonic Stem Cell Model of an Inherited Arrhythmia
07/01/1998 - 07/01/1998