Abstract
Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date.
Highlights
The Brugada syndrome, first described by the Brugada brothers in 1992 [1], is a life-threatening arrhythmogenic disease characterized by an abnormal electrocardiogram (Figure 1) with ST segment elevation in the right precordial leads V1 to V3 and right bundle-branch block
The transmural voltage gradient is caused by depression or loss of the epicardial action potential dome. Their results indicated that phase 2 reentry (P2R) could cause extra-systolic activity in the right ventricular wall which could serve as a substrate for ventricular arrhythmias
The results from a right ventricular wedge preparation perfused with verapamil, a sodium and calcium channel blocker, indicated that T-wave alternans could be caused by the loss of the action potential dome and by a concealed P2R which both lead to transmural dispersion of repolarization
Summary
The Brugada syndrome, first described by the Brugada brothers in 1992 [1], is a life-threatening arrhythmogenic disease characterized by an abnormal electrocardiogram (Figure 1) with ST segment elevation in the right precordial leads V1 to V3 and right bundle-branch block. It is responsible for 4 to 12% of sudden cardiac deaths in the general population. Patients often present with symptoms of ventricular tachycardia, bradycardia, or atrial-ventricular (AV) node conduction disorder. These symptoms are more often present in males than in females. Remleuvtaanttiomnsutuastiinognsdairreectthseenquinetnrcoidnugcwedithinatocavnedctiodrastecagrernyeinagptphreoagcehn.eRoefleinvtaenrtesmt uutsaintigonssitaer-deitrheecnted muintatrgoednuesciesd, anindtosuvbescetqouresntclayrrtryainnsgfetchteedginentoeaohfosint cteerlle(set.gu.,stinsAg20si1tec-edllisr)eoctreidn vmiturotatgreannescsrisib, eadnadnd injseucbtesdeqiunetontXlyentroapnussfeocotecdytienst.oCaarhdoisotmcyelolc(yet.egs.,ftrsoAm20In1dcuelcles)doPrluinripvoittreonttrSatnesmcri(biPedS)aCnedllsin: jDecetremd al fibirnotbolaXsetsnoapreusisooloacteydte,sc. uCltaurrdeidomanydoctyrtaenssffercotmedIwndituhcethdePplluurripipootetenntcyStefamcto(irPsSO) cCt3e/l4ls, :KDlfe4r,mSoalx, anfdibcr-oMbylacs. tTsraarnesifseoctleadtefidb, rcoubltluasrtesdaarendthternancusfletuctred winihthumthaenpelumrbipryootennicystfeamctcoerlsl Oseclet3c/t4io, nKmlf4e,dSioaxu2n,til coalonndiecs-MofyiPc.STcreallnssaferectdedetefcibterdob. lSaesltesctaerde itPhSenceclluslthuerendunindehrugmo acanrdemiombryyoocnyictesdteiffmerceenltliasteiloenctuiosning eitmheerduianguunitdilecdo(lsopnoienstaonfeioPuSs)cedlilffsearreentdiaettieocnte, dg.uSideeledctdeidffeiPreSntciealtlisonth(ecnytuonkdineersg,ogrcoawrdtihomfaycotocryst)eor thrdoiuffgehrecnot-icautilotunreu. sTinheg peairtahmereteurnsgauniadleydzed(sapnodntkaenyeofiunsd)indgisffeorreenatciahtimono,deglusiydsetedmdairfefesruemntmiaatiroizned at the bottom of each panel
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