Dick - Genetic Disorders of the Cardiac Impulse
Genetic Disorders of the Cardiac Impulse - Dick18
For all Genetic d/o of cardiac impulse
-ensure good FHx, draw pedigree to clarify...
-most common pattern is auto dom, so 50% chance a 1st degr relative is affected
--> should check all first degree relatives of a pt w an auto dom heritable d/o, maybe w provocative testing (!)
-even if you wouldn't Tx these pts bc they are ASx otherwise, you'd want to know so you know who else must be screened.
ION CHANNELOPATHIES
Ion Channelopathies that Prolong the Action Potential
Long QT Syndrome
-can be auto dom or auto rec inheritance
-of the 6 identified genes that cause it, 4 involve K ch subunits, one Na ch SCN5A, one ankyrin-B membrane protein that works w the ion channels
-diff gene xx--> diff effects
IKs Defects = KCNQ1 & KCNE1 genes--> subunits of K Ch for the slow K current; both auto dom & re
-if homogenous xx--> sev LQTS Sx and SN deaf
-IKs current--> slowly activating outward K current that allows myocyte to return to RMP after depol
-greatest risk of arrhyth/sudden death w adrenergic surgers- e.g. w fright/anger/symp discharge
--> b-blockade Rx improves survival
-high risk with swimming, so don't swim alone or w/o floatation device
-some mutations--> abNl K channels, while others --> decr amt of K channels ==> diff phenotypes...
IKr Defects = KCNH2 & KCNE2 genes --> subunits of K Ch for the rapid K current; auto dom
-IKr current--> initiate cardiac repol after excitation-contraction
-incr risk to arrhyth p auditory stimuli -alarm clock, phone...
-IKr ch very Sn to extracel [K+]; the ch's ability to conduct K outward depends directly on [K+]extracell, & as the [K+]extrecell increases, the outward K current increases (??Why)
-thus these pts are very Sn to low K levels
-?if K supp, spironolactone,or K ch openers (nicorandil) will help
SCN5A Defects = defect in Na Ch; make up <10% of LQTS reported; auto dom
-incr risk for arrhyth/sudden death w bradycardia- often die in sleep
-arrhyth is less common than w K ch xx, but more deadly bc unobserved (pt sleeping)
--> Na ch unable to completely inactivate after depolarization--> persistent Na leak into cell, w repeated opening of the ch during sustained depol--> small sustained inward depolarizing current--> "gain of fx" mutation (K ch xx has a loss of fx), --> prolonged plateau of cardiac depol--> delay repol onset--> excess Ca loading of myocyte--> high intracell Ca allows for dvp of early after-depolzarizations --> ventric arrhythmias, especially at lower HR.
-thus ? Tx w pacing atrium to prevent brady + mexiletine- Na ch blocker
-note that other xx to SCN5A that --> loss of fx cause Brugada synd & conduction xx, and not LQTS
Drug-Induced LQTS
-many affected pts actually have a subclinical LQTS mutation that become apparent when the Rx compromises the repoln.
-can be more pronounced if P450 system is needed for metab & is inhibited...
-can be more pronounced w hypOK+ which inhibs Kr current...
Dx
-check QTc
-some pts w LQTS by genetics had QTc within Nl range (!) despite incr risk of death
-EP studies don't help Dx
-Holter, provocative testing w epi, and exercise ECG are more useful to check for repol xx if ECG negative, but they arent consistent either
-There is a scoring sytem baesd on ECG findings, FHx/Hx
-Genetic testing- limited still, but do test for the more common causes (top 5)
-only 50-75% of pts get a dx to date...
Mgt
-not all pts w LQTS have same risk or Tx response
-prevent adrenergic surges
-avoid Rx that are QT prolonging
-limit risk- avoid competitive sports, closely watch when swimming, no bedside alarm clocks or phones
-avoid hypO K- eat high K foods
-beta blockers - 1st line Tx, does improve mortality
-ICD- c/s if signif cardiac arrest, persistent Sx despite b-blocker, or strong FHx of sudden cardiac death
-What if gene +, but pt ASx & Nl ECG?
-1/3 of LQTS + pts have ASx/Nl QT and Nl provocative testing; ?who will remain ASx and pt may present w sudden death, so ? if need Rx or not...
Brugada Syndrome
= ST elevation in R precordials: V1-V3
-without ischemia, electrolyte xx, structural cardiopulm dz
-incr risk of sudden death fr polymorphic VT--> VF
-auto dom; 5-66/100K ppl have it
-higher in SE Asia; male >>female
-mutation in SCN5A Na ch (loss of fx, ddx LQTS which is gain of fx xx) --> decr Na current bc reduced # or reduced fx of Na ch's.
--> decr inward Na current, so there is a transient outward K in RV epicardium(via Ito ch)--> epicardial to endocardial voltage gradient--> ST elevation seen in R precordials, which may --> re-exciation in ventricle w triggered VT/VF
Dx
-ECG- not very Sn or Sp
-Type I BrS = prominent coved J pt pk w ST elevation of >0.2mV, then negative T wave w no intervening isoelectric phase
-Type II BrS = prominent J pt elevation (>0.2mV), then biphasic T wave w saddleback look
-Type III BrS = less prominent J pt elevation (>0.1mV), w either cove or saddleback look
-ECG may mimic RBBB, espec in Type I
-DDx fr RBBB bc absence of wide S wave in lead I and in L lat precordials
-Can unmask it with Na ch blocker infusion- ajmaline, flecainide, procainamide- ?Sn/Sp
-may ppt a VT/VF
-?benign course if +testing in ASx pt
-Genetics
-limited use bc only one of the genes are ID'd...
-ID's gene in only 15-20% of pts
Mgt
-If Sx--> Tx, but Rx aren't proven to work
-Quinidine at low ds- inhibits the Ito of K that causes the re-excitation
-Mexiletine- Na ch blocker- ? if it works
-ICD only proven way to prevent sudden death
-if Syncope--> clear indication for ICD; otherwise ? if appropriate if ASx pt
-but 30% of ASx ppl will have VF/VT within 3 yrs of evaluation, same as Sx pts ==> currently rec ICD for ASx ppl w +sustained ventric arrhyth on EP study
Anderson Syndrome
=K Sn periodic paralysis, ventric ectopy, dysmorphisms
--> variable phenotype- short, mandib hypoplasia, low set ears, clinodactyly
-w low, Nl or high k can have paralysis, usually responds to K+ admin
-+/- long QT
-may see bidirectional ventric tachy; may --> syncope/sudden death
-KCNJ2 gene xx in at least some- decr strength of ch interaction w phosphatidulinositol 4,5 biphosphate
-Tx w amio & acetazolamide can relieve cardiac and skel muscle Sx
Ion Channelopathies that Enhance Automaticity
Catecholaminergic Polymorphic VT / Familial VT / Arrhythmogenic RV Dysplasia Type 2
-CPVT, FVT, and ARVD2 - due to abNl ca release fr SR, bc of mutations in cardiac ryanodine R type 2, which is the ch for releasing Ca fr SR stores.
-rare, inheritable
-adrenergic induced VT & sudden death
-1/3 of CPVT is fr auto dom mutation in RYR2 (cardiac ryan R' type 2)
-rest are auto rec, bc mutation in calsequestrin, which sequesters Ca in SR
-ARVD2 & FVT are both fr xx of RYR2
-FVT= loose dx, = inherited disposition to VT/VF (can be applied to ARVD, BrS, CPVT)
-QT interval and heart strucutre are usually Nl in CPVT, FVT, and ARVD2, though some pts w ARVD2 have mild thinning/fibrous fatty replacement of RV myocardium (less than other ARVD forms)
-CPVT pts get syncope/sudden death around 8yrs old, earlier if more severe Sx
-Sx usually w stress/exercise; 30-50% incidence of sudden death by 20-30yo if untreated
-isolated PVCs and atrial arrhythmias will occur early after exercise onset, then get runs of monomorphic or bidirectional VT then degen to polymorphic VT, and then VF
-pts have resting bradycardia
-ARVD2 - similar Sx/presentation as CPVT, w stress induced ventric arrhyth
-BUT, ARVD2 pts may have mild path changes to RV ...
Dx
-must see the ventric arrhyth elicited/exercbated by exercise testing ni pt w/o structural hrt dz or LQTS
-Do perform exercise stress testing to check for it if pt has h/o exericse induced syncope w Nl ECG and echo
-& in ASx pt if +FHx, including FHx of exercise nduced syncope or sudden death of ? etiology
-No genetic testing avail
Mgt
-beta-blockers highly effective to reduce M&M
-some pts w persistent stress induce arrhyth despite b-blocker should get ICD too
Familial Ventricular Fibrillation
-several reports of FVF, one bc of SCN5A gene xx without BrS on ECG
Familial Atrial Fibrillation
-rare to have FAF, no definite genetic cause shown
Cardiomyopathies
-due to abNl structural components of myocytes- sarcomeric & cytoskeletal prtns
HCM
-...
-incr risk w Noonan, LEOPARD, Costello syndromes, and w lysosomal storage dz, mito dz
-mutations.. in variety of genes for b-myosin heavy chaine, cardiac troponin T, myosin bindign prtn C, and others...
Dx
-echo...
-...
-arrhythmia risk not shown to correlate well w degree of hypertrophy, so even if mild can still have sudden death
-Genetics....
Mgt
-Tx Sx...
-b-blocekr & CCB to slow progression of hypertrophy by stoping hypercontractile states
-Antiarrhythmic Tx hasnt been shown to improve the outcome of pts w Sx arrhythmias
-ICD indicated if aborted sudden death, unexplaiend syncope espec if child, strong sudden death FHx, VT on Holter or exercise test, absence of a rise in systolic BP w exercise, and severe IVS thickening (>30mm)
-LVOTO related ischemia is a risk for ventric arrhythmia...
HCM w WPW
-PRKAG3 and AMPK gene xx
DCM
-...
-now 30-50% are thought to be genetic in etiology
-Isolated DCM- alpaha tropmysinc, alpha cardaic acting, b-mMHC, troponin T xx
-DCM w skeletal myopathy- seen w xx to dystrophin, sarcoglycan, and desmin which stabilize sarcomere and assist in force transduction...
-Barth Syndrome w DCM- x linked syndrome w CHF as infant and hypotonia, cyclic neutropenia; if survive infancy the ventric fx usually improves, but then may get HF again later
-xx in Tafazzin gene; see elevated 3methylglutaconic acid in urine
-DCM w Systemic Dz- Emery-Dreifuss muscular Dystrophy- early contractures of elbows & Achilles tendons, slow progressive muscle wasting, DCM, & conduction block
-auto dom, auto rec, or x linked; due to lamin A/C gene xx in atutosomal form, and emerin in x linked... all 3 prtns are for nuclear lamina...
Dx
-...echo....
Mgt
-...
-medical Rx for HF...
-ventric arrhythmias--> poor Px (?)
Arrhythmogenic RV Dysplasia
-fatty infiltrate and fibrosis of RV
-#1 cause of sudden death in Italy - 17% of them
-Auto dom
-9 genes involved, ...
Dx
-hard to dx at times, even if FHx
-first sx might be sudden death, but usually after teens
-ECG- inverted T wave at R precordial leads
-RV arrhythmia w LBBB pattern
-may have arrhyth after adrenergic stim/exercise, or induced by EP stim
-Can Dx w RV Bx, but bc fibrosis usually starts at RV fee wall, then goes to septum, you can get lots of false negative
-can Dx based on Euro criteria based on MRI/echo, fibrofatty infiltrate by Bx, RV origin VT/VF...
Mgt
-Rx
-EP ablation
-ICD
-genetic counseling bc 50% chance to pass it on...
-limited knowledge overall...
Conduction System Abnormalities
Complete Heart Block
-Nkx2.5 gene may b involved w CHB, seen w ASD TOF, conotruncal xx, Ebsteins, APVR; also --> progressive AV block
Kearns-Sayre Syndrome
-external ophthalmoplegia, retina pigmentary degeneration, premature dementia, DCM, progressive conduction block
-mitochondrial DNA xx
-may also show facial, pharyngeal, trunk/limb weakness, deafness, shortness, incr CSF fluid prtn- d/o size & location of the mito DN A deletion
Progressive Cardiac Conduction Defect
-aka Lenegre or LEv dz
-#1 conduction xx in adults
--> progressive HPS conduction slowing, --> RBBB or LBBB or complete AVB, syncope, sudden death
-some may have SCN5A mutation, but dont show LQTS or BrS Si/Sx
Short QT Syndrome
-w QTc <320msec
-assoc w a-fib
-c/s it strongly in young pt w isolated a-fib
-high incidence of syncope & sudden death due to ventric tachyarrhythmias
-heterogeneous..., fr gain of fx mutations ...HERG, KvLQT1, KCNJ2