CVPR 03-25-14 10am-Noon Molecular Mechanisms of Arrhythmias and Anti-Arrhythmin Drugs - Sather Flashcards
Acquired cardiac arrhythmias…from what?
Acquired arrhythmias are much mroe common than congenital, and arise subsequent to MI, ischemia, acidosis, alkalosis, electrolyte abnormalities, or excessive catecholaminexposure
Antiarrhythmic Drug toxicity often causes
Arrhythmic activity, as well as greater mortality when used prophylatically post-MI….EX: Cardiac glycosides (digoxin), some antihistamines (astemizole, terfenadine), and antibiotics (sulfamethoxazole)
Common replacements for antiarrhythmic drugs
Catheter ablation of ectopic foci, Implantable cardioverter-debrillator devices (ICDs)
Uses for antiarrhythmic drugs
1) 1st line for certain arrhythmias…..2) Often used in conjunction w/ICDs (decrease frequency of arrhythmic episodes –> prolong battery life. reduce # of painful shocks)…..3) May be useful if elsewhere once research give more info on mechanisms/molecular targets.
Primary targets of antiarrhythmic drugs
Cardiac Na+ channels (INa), Ca2_ channels (ICa-L), K+ channels (IKs, IKr), and beta-adrenergic receptors (all are direct drug targets)
Indirect targets of antiarrhymthmic drug action
Via beta-adrenergic receptor pathways, pacemaker current, If, and ICa-L, and IKs
Only drug demonstrated to reduce incidence of sudden cardiac death
Beta blockers
Sudden cardiac death
Occurs during episodes of increased sympathetic tone/increased adrenergic receptor activation; Often have family members that suddenly died before the age of 40 (most likely also from sudden cardiac death)
Familial long QT syndrome - overview
Prolongation of the duration of cardiac action potential (QT interval –> can lead to ventricular arrhythmia and sudden death
Mechanism of long QT syndrome problems
Prolongation of the plateau phase (phase 2) of the fast response AP in ventricular myocytes –> torsades de pointes (polymorphic V tach) –> degenerates into V fib –> syncope & sudden cardiac death.
Triggering of Torsades de pointes in Familial long QT syndrome & reasoning for treatment
Typically triggered by an abrupt increase in sympathetic tone (emotional excitement, fright, or physical activity)… For this reason, current clinical practice includes treating long QT patients with β-adrenergic receptor blockers (β-blockers)
Constellation of Symptoms in Long QT syndrome
The Na+ and K+ channels involved in long QT syndrome are also found in other areas of the body, and thus can cause other problems than with the heart
Finding the underlying causes of long QT syndrome
Extensive human pedigrees were screened for families w/Hx of sudden death early in life —>Genetic linkage analysis of IDed pedigrees revealed variety of different mutations, depending upon pedigree, but nearly all were found in cardiac ion channels
Romano-Ward syndrome (RWS)
Autosomal dominant form of long QT syndrome; Genetically heterogeneous: more than 200 mutations IDed, with the most prevalent ones found in slow cardiac K+ channel IKs (LQT1), rapid cardiac K+ channel IKr (LQT2), and cardiac Na+ channel INa (LQT3).
Jervell-Lange-Nielson syndrome (JLNS)
Autosomal recessive form of long QT syndrome; Homozygous carriers of mutations in IKs (LQT1) suffer in addition from congenital deafness, while the heterozygous carriers are asymptomatic.
2 ways QT interval is lengthened in Long QT syndrome
- Loss of function mutation in K+ channel (not enough Phase 2 K+ release, leading to reduced current amplitude)…..2. Gain of function mutations in Na+ channel (incomplete inactivation)….May not see an ECG difference (must sequence), but they are two opposite problems (over and under activation)! So, must make sure drugs match specific problem in long QT syndrome.
Long QT mutations in cardiac K+ channel subunits
Generally reduce the number of K+ channels expressed in the myocyte plasma membrane (loss of function mutations), thereby reducing the size of the K+ current (IKr + IKs) that helps terminate the plateau phase of the fast response and return the membrane to resting potential during diastole.
Long QT mutations in the cardiac Na+ channel (INa)
Prevent Na+ channels from inactivating completely (gain of function mutations), thereby prolonging phase 2 of the fast response.
Long QT mutations in cardiac channels & antiarrhythmia treatment
Long QT mutations have been IDed in almost all of major kinds of cardiac ion channels; Thus, antiarrhythmic drugs should be selected based on specific molecular basis of long QT syndrome…. For patients with the LQT3 mutations, drugs that block Na+ channels should be used…. For patients with LQT1 or LQT2 mutations, drugs that open K+ channels ought to be used, ideally (none are currently approved)
Brugada syndrome
Congenital arrhythmia linked to cardiac Na+ channel mutations (different than in long QT syndrome), in which ventricular fibrillation develops… very poor prognosis (40% die by age 5);
Na+ channel abnormalities in Brugada syndrome
Rather than prolonged activation of I-Na as in long QT syndrome, Brugada syndrome reduces the amount of inward Na+ current that drives the AP upstroke in ventricular myocytes
2 types of arrhythmia problems:
(1) inappropriate impulse initiation in SA node or elsewhere (ectopic focus), and (2) disturbed impulse conduction in nodes, conduction cells (Purkinje cells) or myocytes.
Inappropriate impulse initiation in arrhythmias – identified by…
IDed by abnormally depolarized diastolic membrane potential
Inappropriate impulse initiation in arrhythmias – 2 Causes:
a.) Ectopic Foci, b) triggered afterdepolarizations
Ectopic Focis initiating inappropriate impulses in arrhythmias
B/c normal SA nodal pacemaker is abnormally slow, or ectopic focus is abnormally fast; Infarct causes membrane to depolarize (decrease in [K+]i occurs as Na/K-ATPase fails)
Triggered Afterdepolarizations
Lead to too much Ca2+ inside cardiac myocytes; may be early (EAD) or late/delayed (DAD); Both can trigger fatal arrhythmias
