review article cellular and molecular mechanisms...

Review ArticleCellular and Molecular Mechanisms of Arrhythmia byOxidative Stress

Ali A Sovari

Cardiac Electrophysiology Section Heart Institute Cedars Sinai Medical Center 127 S San Vicente BoulevardA3308 Los Angeles CA 90048 USA

Correspondence should be addressed to Ali A Sovari alisovarigmailcom

Received 30 November 2015 Accepted 10 January 2016

Academic Editor Yi-Gang Li

Copyright copy 2016 Ali A Sovari This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Current therapies for arrhythmia using ion channel blockade catheter ablation or an implantable cardioverter defibrillator havelimitations and it is important to search for new antiarrhythmic therapeutic targets Both atrial fibrillation and heart failure acondition with increased arrhythmic risk are associated with excess amount of reactive oxygen species (ROS) There are severalpossible ways for ROS to induce arrhythmia ROS can cause focal activity and reentry ROS alter multiple cardiac ionic currentsROS promote cardiac fibrosis and impair gap junction function resulting in reduced myocyte coupling and facilitation of reentryIn order to design effective antioxidant drugs for treatment of arrhythmia it is essential to explore the molecular mechanismsby which ROS exert these arrhythmic effects Activation of Ca2+CaM-dependent kinase II c-Src tyrosine kinase protein kinaseC and abnormal splicing of cardiac sodium channels are among the recently discovered molecular mechanisms of ROS-inducedarrhythmia

1 Scope of the Problem inTreatment of Arrhythmias

Cardiovascular disorders are the most common cause ofdeath in the United States and most of the developedcountries [1] Ventricular fibrillation (VF) and ventriculartachycardia (VT) are the most common cause of suddencardiac death (SCD) [2] Atrial fibrillation (AF) althoughusually not life threatening is associated with higher throm-boembolism increased mortality and high healthcare costand its incidence is increasing [3ndash8]

Current therapies for treatment of arrhythmias are antiar-rhythmic drugs catheter ablation and implantable car-dioverter defibrillators (ICDs) for VTVF Although thesetherapies have had some success they have limitations Ionchannel blockade has important limitations for chronic treat-ment and prevention of those arrhythmias For example theCardiac Arrhythmia Suppression Trial (CAST) showed thattreatment of premature ventricular contractions (PVCs) withclass IC antiarrhythmic drugs may increase cardiovascularmortality in patients with myocardial infarction (MI) [9]Chronic treatment of AF with current antiarrhythmic drugs

has not been more effective than a rate control strategyin reducing thromboembolism [10] which may suggest theineffectiveness of the antiarrhythmic drugs in maintainingthe sinus rhythm Paradoxically a common adverse effect ofall currently available antiarrhythmic drugs is proarrhythmia[11 12] Catheter ablation therapy is based on creating ananatomically fixed lesion in the heart in order to block thereentrant circuit or propagation of the focal activity Studiesusing optical mapping of the heart have shown ectopic fociand reentrant circuits are usually multiple and dynamic incomplex arrhythmias such as VF and AF [13ndash15] Catheterablation forVT is primarily an adjuvant therapy for reductionof symptoms in patients with ICD [16] and cannot providea reliable method for prevention of SCD Defibrillation hasshown success in terminating VTVF Nevertheless it doesnot prevent the occurrence of arrhythmia and frequent ICDshocks worsen the quality of life and may even increasemortality [16] ICDs are relatively expensive A study thatevaluated data from multiple randomized clinical trials esti-mated that the cost of the ICD-related primary prevention ofSCD ranged from$34000 to $70200 for each life-year [17] Inaddition about 70 of the patients who receive an ICD never

Hindawi Publishing CorporationCardiology Research and PracticeVolume 2016 Article ID 9656078 7 pageshttpdxdoiorg10115520169656078

2 Cardiology Research and Practice

have any appropriate defibrillation and only 30 of patientswith sudden cardiac arrest (SCA) meet current criteria forimplantation of ICD [18]

Many of the aforementioned limitations of current thera-pies for arrhythmia arise from the fact that these therapies donot address the underlying pathophysiology of arrhythmiaA more successful therapeutic approach may arise fromtargeting upstream pathologies that result in abnormalitiesin ionic currents and emergence of reentry and focal activityOxidative stress which is an imbalance between productionand neutralization of reactive oxygen species (ROS) is anexample of a possible upstream therapeutic target Mostclinical risk factors of AF such as hypertension age andcardiothoracic surgeries are conditions that are associatedwith oxidative stress [19] Serum markers of oxidative stresshave been shown to be elevated in patients with AF [20ndash22] AF in human is associated with a significant reduc-tion in the expression of antioxidant genes as well as asignificant increase in the expression of five genes relatedto ROS supporting a shift toward prooxidation state in AF[23] Cardiomyopathy which is associated with significantlyhigher risk of VTVF is associated with oxidative stressand increased oxidation and carbonylation of proteins [24]Perfusion of H

2O2of hearts in the Langendorff setting

induces VTVF and AF [13ndash15 25] providing evidence thatROS elevation can be a cause of arrhythmia

Despite considerable evidence that ROS play an impor-tant role in the genesis of arrhythmia limited clinical stud-ies using conventional antioxidants have shown conflictingresults [26] The biology of ROS is complex and designingan effective antioxidant therapy for arrhythmia requires anin-depth understanding of the cardiac sources of ROS theROS molecules structures and properties triggers of ROSproduction and the downstream effects of ROS which resultin arrhythmia The study of mechanisms by which ROSelevation may result in arrhythmia may lead to the discoveryof novel therapeutic targets for treatment of arrhythmia

2 Oxidative Stress Facilitating FocalActivity and Reentry

ROS can lead to focal activity It has been shown that ROSprolong action potential duration (APD) in rat and guinea pigmyocytes and induce early afterdepolarizations (EADs) anddelayed afterdepolarization (DADs) [27] Consistent withthat finding ROS has been shown to facilitate ventriculararrhythmia in aged and hypertensive rat hearts mainly via anEAD mechanism [25 28]

ROS can also provide substrate for reentry One possiblemechanism for reentry in oxidative stress is via heteroge-neous APD prolongation in which at a moment one area withshorter APD is excitable while the area with prolonged APDis not excitable [15 25 29] In an angiotensin II activationmousemodelwith elevatedROS levels and in amitochondrialoxidative stress mouse model conduction velocity (CV) isdecreased and inducible VTs are mainly caused by reentry[30ndash32]

The results from mathematical modeling studies havesupported both reentry via decreased in conduction CV and

focal activity via EADDAD mechanisms for ROS-mediatedarrhythmias [13 33] It is not clear in which conditions and atwhat levels ROS may promote one of the two mechanismsfocal activity and reentry Nevertheless ROS can promoteboth

3 Arrhythmogenic Ionic Effects ofOxidative Stress

ROS elevation affects several ionic currents in cardiomy-ocytes The effect of ROS on total and late Na+ current isimportant and can be arrhythmogenic One of the mecha-nisms of H

2O2-induced APD prolongation and EAD forma-

tion is by promoting an enhanced late sodium (Na+) current[34] Ranolazine a late Na+ current blocker can suppressROS-mediated EADs and arrhythmia which suggests a rolefor the increased late Na+ current in the pathogenesis ofROS-mediated arrhythmia [25] Treatments with H

2O2and

angiotensin II enhance the late Na+ current however thosetreatments decrease the overall Na+ current in isolatedmyocytes partially through the downregulation of SCN5Atranscription [35] While an increase in late Na+ current mayresult in arrhythmia via an EAD mechanism the reductionin total Na+ current seen by ROS may cause a reduction inCV and provide substrate for reentry ROS can downregulatecardiac sodium channels andmitochondrial antioxidants canreverse this effect [36] This can also provide a substrate forarrhythmia in a similar fashion that happens in Brugadasyndrome [37ndash39]

ROS may also alter intracellular Ca2+ handling in a waythat generates arrhythmia ROS may stimulate the L-typeCa2+ current which can facilitate EAD [40] In additionhydroxyl radicals increase the open probability of cardiacryanodine receptors which control the Ca2+ release from thesarcoplasmic reticulum (SR) to the cytoplasm [41] AbnormalCa2+ release from SR during diastole may result in formationand propagation of DADs [42 43] Even a brief exposureto OHminus significantly decreases SR Ca2+ uptake which leadsto an increased Ca2+ level in myocytes during diastole [44]This short-term effect on Ca2+ transport is likely due tothe OHminus-mediated peroxidation of lipid membranes andprotein sulfhydryl formation which leads to an indirect effecton the SR Ca2+ transporter [44] Increase in intracellularlevels of Ca2+ can then translate to an inward current bysodium-calcium exchanger (NCX) action In addition ROSmay increase directly NCX activity [43]

In addition to the cardiac Na+ current and intracellularCa2+ handling oxidative stress affects also cardiac potassiumcurrents ROS may inhibit KATP channels [45] and down-regulates 119868to [46 47] These effects of ROS and its possiblesuppression of 119868Kr and 119868Ks [48] can potentially decreasethe repolarization reserve prolong the APD and facilitatetriggered activity

In summary ROS can affect all major ionic currentswith increases in the late Na+ current L-type Ca2+ currentleak of Ca2+ from SR and NCX activity ROS decrease peaksodium current and SERCA-mediated SR Ca2+ uptake Allthese changes are likely to increase intracellular Ca2+ levels

Cardiology Research and Practice 3

prolong the APD reduce of CV and facilitate triggeredactivity and reentry

4 Oxidative Stress and Cell Coupling

Oxidative stress promotes myocardial fibrosis [49 50] Bio-physical properties of the extracellular matrix (ECM) areimportant factors that can affect the propagation of theaction potential in the heart For example increased collagendeposition in the ECMwhich is seen in increasedmyocardialfibrosis and scar tissue formation after myocardial infarctionmay provide a barrier to the AP propagation and contributeto reentry [51] In addition collagen deposition may reduceelectrical coupling between myocytes and facilitate focalactivities by reducing the sink-to-source effect in the regionof the heart [14] Proliferation of fibroblasts and their trans-formation tomyofibroblastsmay be associatedwithmyocyte-fibroblast coupling which is potentially arrhythmogenic viaincreased ectopic activity [52]

Another important factor that affects electrical couplingof myocytes is gap junction function and oxidative stressimpairs gap junction conduction [30 53 54] Gap junctionsare channels in all compartments of the heart that form theconduction pathways between cells allowing for an electricalsyncytium Connexin 43 (Cx43) is the major component ofgap junctions in the ventricular myocytes and it is one of theimportant connexins in the atria Cx43 is decreased in humanheart failure a condition that is associated with significantlyincreased ROS levels and increased risk of arrhythmia [2455ndash57] In cardiac angiotensin II activation and mitochon-drial oxidative stress mouse models ROS elevation signifi-cantly decreases Cx43 levels impairs gap junction conduc-tion and results in spontaneous and pacing induced arrhyth-mia [31 32 58 59] Treatments with a mitochondria-targetedantioxidant and angiotensin receptor blockers prevent thegap junctional remodeling and arrhythmias supporting a keyrole for oxidative stress in Cx43 remodeling and impairingelectrical coupling between myocytes [30ndash32]

5 Molecular Mechanisms ofROS-Induced Arrhythmia

While ROS seems to be able to cause arrhythmias atleast when externally supplied and there are some possiblealterations that can explain the arrhythmogenic substratecreated by ROS more effort and focus are required to explorethe molecular mechanisms by which ROS result in thoseabnormalities These mechanisms may involve the effect ofROS on genes transcriptional regulation protein traffickingand posttranslational modifications There are examples ofstudies that described novel molecular mechanisms for ROS-induced arrhythmia which may result in discovering poten-tially new antiarrhythmic targets however there are muchmore research needed in this area

The molecular mechanism by which ROS affect thecardiac Na+ current and how the Na+ current reductioncan be prevented will be important steps toward designingnew and effective antiarrhythmic drugs Abnormal splicing

of cardiac sodium channel mRNA is a possible mechanismfor the decreased sodium current in arrhythmiaThe splicingfactors RBM25 and LUC7L3 are elevated in human heartfailure tissue and mediate truncation of SCN5A mRNA inboth Jurkat cells and human embryonic stem cell-derivedcardiomyocytes [60] RBM25LUC7L3-mediated abnormalSCN5A mRNA splicing reduces Na+ channel current to arange known to cause sudden cardiac death [61] It has beenshown that angiotensin II and hypoxia known to causeelevation in ROS levels [62ndash64] are associated with the afore-mentioned splicing factor abnormalities resulting in a Na+current reduction in the heart [60] Another mechanism bywhich ROSmay affect cardiac sodium current is probably viaprotein kinaseC (PKC) It has been shown thatmitochondrialROS causes a reduction in cardiac sodium current and thateffect can be prevented by inhibition of PKC [36] In additionc-Src inhibition can recover cardiac Na+ current to normal ina mouse model of manganese superoxide dismutase deficientwith elevated mitochondrial ROS which suggests that c-Srcpartially mediates the effect of ROS on cardiac Na+ currentreduction [59]

Ca2+CaM-dependent kinase II (CaMKII) can be acti-vated by ROS and its activation probably mediates severalof the ROS-induced arrhythmogenic effects [65] If CaMKIIis activated under prooxidant conditions two methionineresidues become oxidized and the sustained activation ofCaMKII independent of its binding to Ca2+CaM occurs[66] Pretreatment of hypertensive rat hearts with a CaMKII-inhibitor KN-93 prevents VT inducibility during oxidativestress [67] These findings are supported by both patch-clamp and Ca2+-imaging studies which demonstrate thatthe oxidative-stress-induced activation of CaMKII causesarrhythmias [68] Several recent studies have linked the useof CaMKII inhibitors to a decrease in catecholaminergicpolymorphic ventricular tachycardia [69 70]

Other possible arrhythmogenic mechanisms by whichCaMKII activation exerts arrhythmic effects include RyRphosphorylation and activation under oxidative stress [7172] An increase in the open probability of RyR is thoughtto be mediated by CaMKII activation [42] In additionCaMKII has been shown to shift the voltage dependence ofNa+ channel availability by approximately +5mV to hastenrecovery from inactivation and to increase late Na+ currentin cardiomyocytes [73] CaMKII plays an important role in L-type Ca2+ channel facilitation the Ca2+-dependent augmen-tation of Ca2+ current (119868CaL) exhibited during rapid repeateddepolarization [74] In addition CaMKII has been identifiedrecently as one of the mediators of fibroblast proliferationin response to angiotensin II [75] Because CaMKII is arelatively indiscriminate kinase it is very possible that othermechanisms are involved in the genesis of arrhythmia byCaMKII activation under oxidative stress

6 Conclusion

Ventricular and atrial arrhythmias place considerable burdenon the healthcare system Currently available therapies forarrhythmia have certain limitations In order to identify


Table 1 A summary of mechanisms of oxidative stress induced arrhythmia and potential therapeutic targets

Affected ion channels

Na+ current reduction (via PKC and c-Src also via abnormal splicing)rArr reduction inconduction velocityKATP inhibitionrArr repolarization abnormalityNCX activationrArr increasing inward current and facilitating afterdepolarization119868to 119868Kr 119868Ks inhibitionrArr abnormal repolarizationIncrease in inward Ca++ current (direct or via CaMKII activation)rArr facilitatingafterdepolarizationIncrease in late Na+currentrArr facilitating afterdepolarization

Effect on intracellular Ca++ handling

Impairment of SERCArArr increase intracellular Ca++ levelsrArr facilitatingafterdepolarizationAffecting RyR receptor (via CaMKII activation)rArr leakiness of SRrArr increaseintracellular Ca++ levelsrArr facilitating afterdepolarization

Effect on myocyte-myocyte coupling Affecting assembling of Cx43 at gap junctionsrArr reduction in conduction velocity

Effect on extracellular matrix Activating fibrotic process (via TGF-120573)rArr reduction in conduction velocity and impairedmyocyte-myocyte coupling due to collagen deposition

CaMKII Ca2+calmodulin-dependent protein kinases II Cx43 connexin 43 NCX Na+Ca2+ exchanger RyR ryanodine receptor SERCA sarco-endoplasmic reticulum Ca++ - ATPase TGF-120573 Transforming Growth Factor-120573

5998400

5998400

5998400

5998400

39984003998400

NH

NH

NH

NH

SH

O

O

OH

OHO

O

m7GAAAAAAAA

CH3

CH3

CH2

H2 C

Transcription

Splicing

mRNA

microRNATranslation

RYR

PLB

ZO-1ZO-1

P

ROS

PKC

CaMKIIactivation

Cx43 reductionCx43

Cx43

reduction

NCX activation

C-Srcactivation

Increase in

Increase in L-type

reduction

Fibroblasts activation and collagen deposition

SERCA impairment

TGF-120573

late Na+ current

Na+ current

Na+ current

Ca+ current

Ito IΚs and IΚr inhibition

ΚATP inhibition

Splici

mRNA

Figure 1 Schematic reviewof someof the important knownmechanisms bywhich excess ROSmay induce arrhythmia Activation ofCaMKIIc-Src and PKC may mediate several important effects of ROS on ionic currents resulting in arrhythmia In addition ROS adversely affectsplicing of mRNA of cardiac sodium channels resulting in abnormal truncated cardiac sodium channel proteins and a reduction in normalsodium channels ROS also increase fibrosis and impair gap junction conduction resulting in reduced myocyte coupling Abnormal splicingactivation of CaMKII c-Src and PKC are among emerging new antiarrhythmic therapeutic targets CaMKII Ca2+calmodulin-dependentprotein kinases II CX43 connexin 43 NCX Na+Ca2+ exchanger PLB phospholamban ROS reactive oxygen species RYR ryanodinereceptor SERCA sarco-endoplasmic reticulum Ca2+-ATPase TGF-120573 Transforming Growth Factor-120573 ZO-1 Zonula Occludens-1


new effective therapeutic targets for treatment of arrhyth-mia mechanisms of the genesis of arrhythmia should befurther explored One possible upstream therapeutic targetfor treatment of arrhythmia is oxidative stress It has beenshown that excess amount of ROS can result in both reentryand focal activity by modifying many of the ionic currentsin cardiomyocytes cardiomyocyte coupling and importantelements of the extracellular matrix (Figure 1 and Table 1)Molecular mechanisms by which ROS exert those effects arethe key areas under investigation Activation of CaMKII c-Src PKC and abnormal splicing of cardiac sodium channelsare among the emerging new therapeutic targets

List of Abbreviations

AF Atrial fibrillationAPD Action potential durationCaMKII Ca2+calmodulin-dependent protein kinases IICx43 Connexin 43CV Conduction velocityDAD Delayed afterdepolarizationEAD Early afterdepolarizationICD Implantable cardioverter defibrillatorNCX Na+Ca2+ exchangerPLB PhospholambanROS Reactive oxygen speciesRyR Ryanodine receptorSERCA Sarco-endoplasmic reticulum Ca2+-ATPaseSCA Sudden cardiac arrestSCD Sudden cardiac deathTGF-120573 Transforming Growth Factor-120573VT Ventricular tachycardiaVF Ventricular fibrillationZO-1 Zonula Occludens-1

Conflict of Interests

Ali A Sovari has the pending patent Mitochondria Antiox-idants for Prevention of Sudden Death by Raising Connexin43 Levels (Application no 61503096)

References

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[2] M Rubart and D P Zipes ldquoMechanisms of sudden cardiacdeathrdquo The Journal of Clinical Investigation vol 115 no 9 pp2305ndash2315 2005

[3] W M Feinberg J L Blackshear A Laupacis R Kronmal andR G Hart ldquoPrevalence age distribution and gender of patientswith atrial fibrillation Analysis and implicationsrdquo Archives ofInternal Medicine vol 155 pp 469ndash473 1995

[4] P A Wolf R D Abbott andW B Kannel ldquoAtrial fibrillation asan independent risk factor for stroke the Framingham StudyrdquoStroke vol 22 no 8 pp 983ndash988 1991

[5] C D Furberg B M Psaty T A Manolio J M Gardin V ESmith and P M Rautaharju ldquoPrevalence of atrial fibrillation

in elderly subjects (the Cardiovascular Health Study)rdquo TheAmerican Journal of Cardiology vol 74 no 3 pp 236ndash241 1994

[6] B M Psaty T A Manolio L H Kuller et al ldquoIncidence of andrisk factors for atrial fibrillation in older adultsrdquoCirculation vol96 no 7 pp 2455ndash2461 1997

[7] P A Wolf R D Abbott and W B Kannel ldquoAtrial fibrillationa major contributor to stroke in the elderly The Framinghamstudyrdquo Archives of Internal Medicine vol 147 no 9 pp 1561ndash1564 1987

[8] A D Krahn J Manfreda R B Tate F A L Mathewson and TE Cuddy ldquoThe natural history of atrial fibrillation incidencerisk factors and prognosis in themanitoba follow-up studyrdquoTheAmerican Journal of Medicine vol 98 no 5 pp 476ndash484 1995

[9] The Cardiac Arrhythmia Suppression Trial (CAST) Investiga-tors ldquoPreliminary report effect of encainide and flecainide onmortality in a randomized trial of arrhythmia suppression aftermyocardial infarctionrdquo The New England Journal of Medicinevol 321 pp 406ndash412 1989

[10] K K Anthony and V F Mauro ldquoRate versus rhythm control inatrial fibrillationrdquo Annals of Pharmacotherapy vol 38 no 5 pp839ndash844 2004

[11] D M Roden ldquoAntiarrhythmic drugs from mechanisms toclinical practicerdquo Heart vol 84 no 3 pp 339ndash346 2000

[12] R Lazzara ldquoAntiarrhythmic drugs and torsade de pointesrdquoEuropean Heart Journal vol 14 supplement H pp 88ndash92 1993

[13] D Sato L-H Xie A A Sovari et al ldquoSynchronization ofchaotic early afterdepolarizations in the genesis of cardiacarrhythmiasrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 106 no 9 pp 2983ndash29882009

[14] N Morita A A Sovari Y Xie et al ldquoIncreased susceptibility ofaged hearts to ventricular fibrillation during oxidative stressrdquoThe American Journal of PhysiologymdashHeart and CirculatoryPhysiology vol 297 no 5 pp H1594ndashH1605 2009

[15] N Ono H Hayashi A Kawase et al ldquoSpontaneous atrial fibril-lation initiated by triggered activity near the pulmonary veinsin aged rats subjected to glycolytic inhibitionrdquo The AmericanJournal of PhysiologymdashHeart and Circulatory Physiology vol292 no 1 pp H639ndashH648 2007

[16] EWissnerWG Stevenson andK-HKuck ldquoCatheter ablationof ventricular tachycardia in ischaemic and non-ischaemic car-diomyopathy where are we today A clinical reviewrdquo EuropeanHeart Journal vol 33 no 12 pp 1440ndash1450 2012

[17] G D Sanders A M Bayoumi V Sundaram et al ldquoCost-effectiveness of screening for HIV in the era of highly activeantiretroviral therapyrdquo The New England Journal of Medicinevol 352 no 6 pp 570ndash585 2005

[18] R J Myerburg R Mitrani A Interian Jr and A CastellanosldquoInterpretation of outcomes of antiarrhythmic clinical trialsdesign features and population impactrdquo Circulation vol 97 no15 pp 1514ndash1521 1998

[19] A A Sovari and S C Dudley ldquoAtrial fibrillation and oxidativestressrdquo in Studies in Cardiovascular Disorders H Sauer M SAjay and F R Laurindo Eds pp 373ndash389 Humana Press NewYork NY USA 1st edition 2010

[20] R B Neuman H L Bloom I Shukrullah et al ldquoOxidativestress markers are associated with persistent atrial fibrillationrdquoClinical Chemistry vol 53 no 9 pp 1652ndash1657 2007

[21] C A Carnes M K Chung T Nakayama et al ldquoAscorbateattenuates atrial pacing-induced peroxynitrite formation and


electrical remodeling and decreases the incidence of postoper-ative atrial fibrillationrdquo Circulation research vol 89 no 6 ppE32ndashE38 2001

[22] M Ozaydin O Peker D Erdogan et al ldquoN-acetylcysteine forthe prevention of postoperative atrial fibrillation a prospectiverandomized placebo-controlled pilot studyrdquo European HeartJournal vol 29 no 5 pp 625ndash631 2008

[23] Y H Kim J H Lee D S Lim et al ldquoGene expression profilingof oxidative stress on atrial fibrillation in humansrdquoExperimentaland Molecular Medicine vol 35 no 5 pp 336ndash349 2003

[24] M Canton SMenazza F L Sheeran P P de Laureto F Di Lisaand S Pepe ldquoOxidation of myofibrillar proteins in human heartfailurerdquo Journal of the American College of Cardiology vol 57no 3 pp 300ndash309 2011

[25] N Morita J H Lee Y Xie et al ldquoSuppression of re-entrant andmultifocal ventricular fibrillation by the late sodium currentblocker ranolazinerdquo Journal of the American College of Cardi-ology vol 57 no 3 pp 366ndash375 2011

[26] H D Sesso J E Buring W G Christen et al ldquoVitamins Eand C in the prevention of cardiovascular disease in men thePhysiciansrsquo Health Study II randomized controlled trialrdquo TheJournal of the AmericanMedical Association vol 300 no 18 pp2123ndash2133 2008

[27] A Beresewicz and M Horackova ldquoAlterations in electrical andcontractile behavior of isolated cardiomyocytes by hydrogenperoxide possible ionic mechanismsrdquo Journal of Molecular andCellular Cardiology vol 23 no 8 pp 899ndash918 1991

[28] N Morita A A Sovari Y Xie et al ldquoIncreased susceptibility ofaged hearts to ventricular fibrillation during oxidative stressrdquoAmerican Journal of PhysiologymdashHeart and Circulatory Physiol-ogy vol 297 no 5 pp H1594ndashH1605 2009

[29] A A Sovari N Vahdani N Morita K Roos J N Weissand H S Karagueuzian ldquoOxidative stress promotes ventricularfibrillation at early stages of hypertension role of Ca2+CaMkinase-IIrdquo Heart Rhythm vol 7 supplement pp PO3ndashPO922010

[30] A A Sovari S Iravanian D Mitchell et al ldquoMitochondria-targeted antioxidant mito-tempo prevents angiotensin IImediated connexin 43 remodeling and sudden cardiac deathrdquoJournal of Investigative Medicine vol 59 pp 692ndash730 2011

[31] S Iravanian A A Sovari H A Lardin et al ldquoInhibition ofrenin-angiotensin system (RAS) reduces ventricular tachycar-dia risk by altering connexin43rdquo Journal of Molecular Medicinevol 89 no 7 pp 677ndash687 2011

[32] A A Sovari S Iravanian E Dolmatova et al ldquoInhibition of c-Src tyrosine kinase prevents angiotensin II-mediated connexin-43 remodeling and sudden cardiac deathrdquo Journal of theAmerican College of Cardiology vol 58 no 22 pp 2332ndash23392011

[33] M D Christensen W Dun P A Boyden M E AndersonP J Mohler and T J Hund ldquoOxidized calmodulin kinaseII regulates conduction following myocardial infarction acomputational analysisrdquoPLoS Computational Biology vol 5 no12 Article ID e1000583 2009

[34] Y Song J C Shryock SWagner L SMaier and L BelardinellildquoBlocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunctionrdquoJournal of Pharmacology and Experimental Therapeutics vol318 no 1 pp 214ndash222 2006

[35] L L Shang S Sanyal A E Pfahnl et al ldquoNF-120581B-dependenttranscriptional regulation of the cardiac scn5a sodium channel

by angiotensin IIrdquo The American Journal of PhysiologymdashCellPhysiology vol 294 no 1 pp C372ndashC379 2008

[36] M Liu H Liu and S C Dudley Jr ldquoReactive oxygen speciesoriginating from mitochondria regulate the cardiac sodiumchannelrdquo Circulation Research vol 107 no 8 pp 967ndash974 2010

[37] P Brugada ldquoCommentary on the Brugada ECG pattern amarker of channelopathy structural heart disease or neitherToward a unifying mechanism of the Brugada syndromerdquoCirculation Arrhythmia and Electrophysiology vol 3 no 3 pp280ndash282 2010

[38] A A Sovari M A Prasun and A G Kocheril ldquoST segmentelevation on electrocardiogram the electrocardiographic pat-tern of Brugada syndromerdquo MedGenMed Medscape GeneralMedicine vol 9 no 3 article 59 2007

[39] A A Sovari M A Prasun A G Kocheril and R BrugadaldquoBrugada syndrome unmasked by pneumoniardquo Texas HeartInstitute Journal vol 33 no 4 pp 501ndash504 2006

[40] G P Thomas S M Sims M A Cook and M KarmazynldquoHydrogen peroxide-induced stimulation of L-type calciumcurrent in guinea pig ventricular myocytes and its inhibition byadenosine A1 receptor activationrdquo Journal of Pharmacology andExperimental Therapeutics vol 286 no 3 pp 1208ndash1214 1998

[41] K Anzai K Ogawa A Kuniyasu T Ozawa H Yamamotoand H Nakayama ldquoEffects of hydroxyl radical and sulfhydrylreagents on the open probability of the purified cardiac ryan-odine receptor channel incorporated into planar lipid bilayersrdquoBiochemical and Biophysical Research Communications vol 249no 3 pp 938ndash942 1998

[42] X Ai J W Curran T R Shannon D M Bers and S M Pog-wizd ldquoCa2+calmodulin-dependent protein kinase modulatescardiac ryanodine receptor phosphorylation and sarcoplasmicreticulum Ca2+ leak in heart failurerdquo Circulation Research vol97 pp 1314ndash1322 2005

[43] DM Bers and S Despa ldquoCardiacmyocytes Ca2+ andNa+ regu-lation in normal and failing heartsrdquo Journal of PharmacologicalSciences vol 100 no 5 pp 315ndash322 2006

[44] T E Morris and P V Sulakhe ldquoSarcoplasmic reticulum Ca2+-pump dysfunction in rat cardiomyocytes briefly exposed tohydoxyl radicalsrdquo Free Radical Biology amp Medicine vol 22 no1-2 pp 37ndash47 1997

[45] Y Yang W Shi N Cui Z Wu and C Jiang ldquoOxidative stressinhibits vascular KATP channels by S-glutathionylationrdquo TheJournal of Biological Chemistry vol 285 no 49 pp 38641ndash38648 2010

[46] M Seddon Y H Looi and A M Shah ldquoOxidative stressand redox signalling in cardiac hypertrophy and heart failurerdquoHeart vol 93 no 8 pp 903ndash907 2007

[47] C X C Santos N Anilkumar M Zhang A C Brewer and AM Shah ldquoRedox signaling in cardiac myocytesrdquo Free RadicalBiology and Medicine vol 50 no 7 pp 777ndash793 2011

[48] Y Zhang J Xiao H Wang et al ldquoRestoring depressed HERGK+ channel function as a mechanism for insulin treatmentof abnormal QT prolongation and associated arrhythmias indiabetic rabbitsrdquo American Journal of PhysiologymdashHeart andCirculatory Physiology vol 291 no 3 pp H1446ndashH1455 2006

[49] A Cui Q Ye R Sarria S Nakamura J Guzman and UCostabel ldquoN-acetylcysteine inhibits TNF-120572 sTNFR and TGF-120573 1 release by alveolar macrophages in idiopathic pulmonaryfibrosis in vitrordquo Sarcoidosis Vasculitis and Diffuse Lung Dis-eases vol 26 no 2 pp 147ndash154 2009

[50] K Koli M Myllarniemi J Keski-Oja and V L KinnulaldquoTransforming growth factor-120573 activation in the lung focus on


fibrosis and reactive oxygen speciesrdquo Antioxidants and RedoxSignaling vol 10 no 2 pp 333ndash342 2008

[51] J M T de Bakker F J L van Capelle M J Janse et alldquoReentry as a cause of ventricular tachycardia in patientswith chronic ischemic heart disease electrophysiologic andanatomic correlationrdquo Circulation vol 77 no 3 pp 589ndash6061988

[52] M Miragoli N Salvarani and S Rohr ldquoMyofibroblasts induceectopic activity in cardiac tissuerdquo Circulation Research vol 101no 8 pp 755ndash758 2007

[53] E-M Jeong M Liu M Sturdy et al ldquoMetabolic stress reactiveoxygen species and arrhythmiardquo Journal of Molecular andCellular Cardiology vol 52 no 2 pp 454ndash463 2012

[54] V M Berthoud and E C Beyer ldquoOxidative stress lens gapjunctions and cataractsrdquoAntioxidants and Redox Signaling vol11 no 2 pp 339ndash353 2009

[55] C Banfi M Brioschi S Barcella et al ldquoOxidized proteinsin plasma of patients with heart failure role in endothelialdamagerdquo European Journal of Heart Failure vol 10 no 3 pp244ndash251 2008

[56] A F Bruce S Rothery E Dupont and N J Severs ldquoGapjunction remodelling in human heart failure is associated withincreased interaction of connexin43 with ZO-1rdquoCardiovascularResearch vol 77 no 4 pp 757ndash765 2008

[57] R R Kaprielian M Gunning E Dupont et al ldquoDownreg-ulation of immunodetectable connexin43 and decreased gapjunction size in the pathogenesis of chronic hibernation in thehuman left ventriclerdquo Circulation vol 97 no 7 pp 651ndash6601998

[58] A A Sovari S Iravanian D Mitchell et al ldquoMitochondria-targeted antioxidant Mito-TEMPO prevents angiotensin IImediated connexin 43 remodeling and sudden cardiac deathrdquoJournal of Investigative Medicine vol 59 pp 692ndash730 2011

[59] A A Sovari E-M Jeong E Dolmatova et al ldquoc-Src tyrosinekinase mediates the effect of mitochondrial oxidative stresson gap junctional remodeling and ventricular tachycardiardquoCirculation vol 124 Article ID A14385 2011

[60] G Gao A Xie S-C Huang et al ldquoRole of RBM25LUC7L3 inabnormal cardiac sodium channel splicing regulation in humanheart failurerdquo Circulation vol 124 no 10 pp 1124ndash1131 2011

[61] E Burashnikov R Pfeifer M Borggrefe et al ldquoMutations inthe cardiac L-type calcium channel associated with inheritedsudden cardiac death syndromesrdquo Circulation vol 120 articleS573 2009

[62] R S Stearman L Dwyer-Nield L Zerbe et al ldquoAnalysisof orthologous gene expression between human pulmonaryadenocarcinoma and a carcinogen-inducedmurinemodelrdquoTheAmerican Journal of Pathology vol 167 no 6 pp 1763ndash17752005

[63] RM A van deWal HWM Plokker D J A Lok et al ldquoDeter-minants of increased angiotensin II levels in severe chronicheart failure patients despite ACE inhibitionrdquo InternationalJournal of Cardiology vol 106 no 3 pp 367ndash372 2006

[64] L Koslashber C Torp-Pedersen J E Carlsen et al ldquoA clinical trialof the angiotensin-converting-enzyme inhibitor trandolaprilin patients with left ventricular dysfunction after myocardialinfarctionrdquo The New England Journal of Medicine vol 333 no25 pp 1670ndash1676 1995

[65] B Hoch R Meyer R Hetzer E-G Krause and P KarczewskildquoIdentification and expression of 120575-isoforms of the multifunc-tional Ca2+calmodulin-dependent protein kinase in failing and

nonfailing human myocardiumrdquo Circulation Research vol 84pp 713ndash721 1999

[66] J R Erickson M-L A Joiner X Guan et al ldquoA dynamicpathway for calcium-independent activation of CaMKII bymethionine oxidationrdquo Cell vol 133 no 3 pp 462ndash474 2008

[67] A A Sovari N Morita J N Weiss and H KaragueuzianldquoOxidative stress promotes ventricular fibrillation in sponta-neously hypertensive rats by a Ca2+CaM dependent kinase-IIsignaling pathwayrdquo Journal of the American College of Cardiol-ogy vol 53 pp A101ndashA102 2009

[68] L-H Xie F Chen H S Karagueuzian and J N WeissldquoOxidative stress-induced afterdepolarizations and calmodulinkinase II signalingrdquo Circulation Research vol 104 no 1 pp 79ndash86 2009

[69] J Ke C-T Zhang Y-X Ma et al ldquoThe effects of calmodulinkinase II inhibitor on ventricular arrhythmias in rabbits withcardiac hypertrophyrdquo Zhonghua Xin Xue Guan Bing Za Zhi vol35 no 1 pp 33ndash36 2007

[70] U Mohamed C Napolitano and S G Priori ldquoMolecular andelectrophysiological bases of catecholaminergic polymorphicventricular tachycardiardquo Journal of Cardiovascular Electrophys-iology vol 18 no 7 pp 791ndash797 2007

[71] D B Witcher R J Kovacs H Schulman D C Cefali and L RJones ldquoUnique phosphorylation site on the cardiac ryanodinereceptor regulates calcium channel activityrdquo The Journal ofBiological Chemistry vol 266 no 17 pp 11144ndash11152 1991

[72] X H T Wehrens S E Lehnart S R Reiken and A R MarksldquoCa2+calmodulin-dependent protein kinase II phosphoryla-tion regulates the cardiac ryanodine receptorrdquo CirculationResearch vol 94 pp e61ndashe70 2004

[73] T Aiba G G Hesketh T Liu et al ldquoNa+ channel regulationby Ca2+calmodulin and Ca2+calmodulin-dependent proteinkinase II in guinea-pig ventricular myocytesrdquo CardiovascularResearch vol 85 no 3 pp 454ndash463 2010

[74] Y L Hashambhoy R L Winslow and J L GreensteinldquoCaMKII-induced shift in modal gating explains L-type Ca2+current facilitation a modeling studyrdquo Biophysical Journal vol96 no 5 pp 1770ndash1785 2009

[75] F Bellocci L M Biasucci G F Gensini et al ldquoPrognostic roleof post-infarction C-reactive protein in patients undergoingimplantation of cardioverter-defibrillators design of the C-reactive protein Assessment after Myocardial Infarction toGUide Implantation of DEfibrillator (CAMI GUIDE) studyrdquoJournal of Cardiovascular Medicine vol 8 no 4 pp 293ndash2992007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


have any appropriate defibrillation and only 30 of patientswith sudden cardiac arrest (SCA) meet current criteria forimplantation of ICD [18]

Many of the aforementioned limitations of current thera-pies for arrhythmia arise from the fact that these therapies donot address the underlying pathophysiology of arrhythmiaA more successful therapeutic approach may arise fromtargeting upstream pathologies that result in abnormalitiesin ionic currents and emergence of reentry and focal activityOxidative stress which is an imbalance between productionand neutralization of reactive oxygen species (ROS) is anexample of a possible upstream therapeutic target Mostclinical risk factors of AF such as hypertension age andcardiothoracic surgeries are conditions that are associatedwith oxidative stress [19] Serum markers of oxidative stresshave been shown to be elevated in patients with AF [20ndash22] AF in human is associated with a significant reduc-tion in the expression of antioxidant genes as well as asignificant increase in the expression of five genes relatedto ROS supporting a shift toward prooxidation state in AF[23] Cardiomyopathy which is associated with significantlyhigher risk of VTVF is associated with oxidative stressand increased oxidation and carbonylation of proteins [24]Perfusion of H

2O2of hearts in the Langendorff setting

induces VTVF and AF [13ndash15 25] providing evidence thatROS elevation can be a cause of arrhythmia

Despite considerable evidence that ROS play an impor-tant role in the genesis of arrhythmia limited clinical stud-ies using conventional antioxidants have shown conflictingresults [26] The biology of ROS is complex and designingan effective antioxidant therapy for arrhythmia requires anin-depth understanding of the cardiac sources of ROS theROS molecules structures and properties triggers of ROSproduction and the downstream effects of ROS which resultin arrhythmia The study of mechanisms by which ROSelevation may result in arrhythmia may lead to the discoveryof novel therapeutic targets for treatment of arrhythmia

2 Oxidative Stress Facilitating FocalActivity and Reentry

ROS can lead to focal activity It has been shown that ROSprolong action potential duration (APD) in rat and guinea pigmyocytes and induce early afterdepolarizations (EADs) anddelayed afterdepolarization (DADs) [27] Consistent withthat finding ROS has been shown to facilitate ventriculararrhythmia in aged and hypertensive rat hearts mainly via anEAD mechanism [25 28]

ROS can also provide substrate for reentry One possiblemechanism for reentry in oxidative stress is via heteroge-neous APD prolongation in which at a moment one area withshorter APD is excitable while the area with prolonged APDis not excitable [15 25 29] In an angiotensin II activationmousemodelwith elevatedROS levels and in amitochondrialoxidative stress mouse model conduction velocity (CV) isdecreased and inducible VTs are mainly caused by reentry[30ndash32]

The results from mathematical modeling studies havesupported both reentry via decreased in conduction CV and

focal activity via EADDAD mechanisms for ROS-mediatedarrhythmias [13 33] It is not clear in which conditions and atwhat levels ROS may promote one of the two mechanismsfocal activity and reentry Nevertheless ROS can promoteboth

3 Arrhythmogenic Ionic Effects ofOxidative Stress

ROS elevation affects several ionic currents in cardiomy-ocytes The effect of ROS on total and late Na+ current isimportant and can be arrhythmogenic One of the mecha-nisms of H

2O2-induced APD prolongation and EAD forma-

tion is by promoting an enhanced late sodium (Na+) current[34] Ranolazine a late Na+ current blocker can suppressROS-mediated EADs and arrhythmia which suggests a rolefor the increased late Na+ current in the pathogenesis ofROS-mediated arrhythmia [25] Treatments with H

2O2and

angiotensin II enhance the late Na+ current however thosetreatments decrease the overall Na+ current in isolatedmyocytes partially through the downregulation of SCN5Atranscription [35] While an increase in late Na+ current mayresult in arrhythmia via an EAD mechanism the reductionin total Na+ current seen by ROS may cause a reduction inCV and provide substrate for reentry ROS can downregulatecardiac sodium channels andmitochondrial antioxidants canreverse this effect [36] This can also provide a substrate forarrhythmia in a similar fashion that happens in Brugadasyndrome [37ndash39]

ROS may also alter intracellular Ca2+ handling in a waythat generates arrhythmia ROS may stimulate the L-typeCa2+ current which can facilitate EAD [40] In additionhydroxyl radicals increase the open probability of cardiacryanodine receptors which control the Ca2+ release from thesarcoplasmic reticulum (SR) to the cytoplasm [41] AbnormalCa2+ release from SR during diastole may result in formationand propagation of DADs [42 43] Even a brief exposureto OHminus significantly decreases SR Ca2+ uptake which leadsto an increased Ca2+ level in myocytes during diastole [44]This short-term effect on Ca2+ transport is likely due tothe OHminus-mediated peroxidation of lipid membranes andprotein sulfhydryl formation which leads to an indirect effecton the SR Ca2+ transporter [44] Increase in intracellularlevels of Ca2+ can then translate to an inward current bysodium-calcium exchanger (NCX) action In addition ROSmay increase directly NCX activity [43]

In addition to the cardiac Na+ current and intracellularCa2+ handling oxidative stress affects also cardiac potassiumcurrents ROS may inhibit KATP channels [45] and down-regulates 119868to [46 47] These effects of ROS and its possiblesuppression of 119868Kr and 119868Ks [48] can potentially decreasethe repolarization reserve prolong the APD and facilitatetriggered activity

In summary ROS can affect all major ionic currentswith increases in the late Na+ current L-type Ca2+ currentleak of Ca2+ from SR and NCX activity ROS decrease peaksodium current and SERCA-mediated SR Ca2+ uptake Allthese changes are likely to increase intracellular Ca2+ levels












6 Conclusion











5998400

5998400

5998400

5998400

39984003998400

NH

NH

NH

NH

SH

O

O

OH

OHO

O

m7GAAAAAAAA

CH3

CH3

CH2

H2 C

Transcription

Splicing

mRNA

microRNATranslation

RYR

PLB

ZO-1ZO-1

P

ROS

PKC

CaMKIIactivation

Cx43 reductionCx43

Cx43

reduction

NCX activation

C-Srcactivation

Increase in

Increase in L-type

reduction


SERCA impairment

TGF-120573

late Na+ current

Na+ current

Na+ current

Ca+ current


ΚATP inhibition

Splici

mRNA








References
























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























6 Conclusion











5998400

5998400

5998400

5998400

39984003998400

NH

NH

NH

NH

SH

O

O

OH

OHO

O

m7GAAAAAAAA

CH3

CH3

CH2

H2 C

Transcription

Splicing

mRNA

microRNATranslation

RYR

PLB

ZO-1ZO-1

P

ROS

PKC

CaMKIIactivation

Cx43 reductionCx43

Cx43

reduction

NCX activation

C-Srcactivation

Increase in

Increase in L-type

reduction


SERCA impairment

TGF-120573

late Na+ current

Na+ current

Na+ current

Ca+ current


ΚATP inhibition

Splici

mRNA








References
























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























5998400

5998400

5998400

5998400

39984003998400

NH

NH

NH

NH

SH

O

O

OH

OHO

O

m7GAAAAAAAA

CH3

CH3

CH2

H2 C

Transcription

Splicing

mRNA

microRNATranslation

RYR

PLB

ZO-1ZO-1

P

ROS

PKC

CaMKIIactivation

Cx43 reductionCx43

Cx43

reduction

NCX activation

C-Srcactivation

Increase in

Increase in L-type

reduction


SERCA impairment

TGF-120573

late Na+ current

Na+ current

Na+ current

Ca+ current


ΚATP inhibition

Splici

mRNA








References
























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















References
























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article cellular and molecular mechanisms...

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