CVPR 03-26-14 11am-Noon Coupling & Calcium II - Beam Flashcards
Calcium entry & efflux – Long term
In the long term, Ca2+ entry into myocardial cells from the extracellular space must equal efflux of Ca2+ into the extracellular space, since any continuing imbalance would cause the cells to continuously gain or lose Ca2+.
Calcium entry & efflux – Short term
In the short term, calcium influx can exceed efflux, or short term calcium efflux can exceed influx. Except for these short term increases or decreases, however, it is important that SR calcium content be kept roughly constant.
Consequence of short term Ca2+ influx exceeding efflux
Amount of Ca2+ stored in SR can be increased
Consequence of short term Ca2+ efflux exceeding influx
SR calcium content would decrease
Mechanisms for Ca2+ homeostasis
NCX calcium exchanger…..L-type Ca2+ channel
L-type Ca2+ channel and Ca2+ homeostasis
L-type Ca2+ channel undergoes a form of inactivation that depends on [Ca2+] near its cytoplasmic side = calcium-dependent inactivation (CDI). This helps to maintain a constant SR Ca2+ content.
Calcium dependent inactivation (CDI) depends on…
Depends in part on Ca2+ entering through the channel but also, to a large extent, on Ca2+ released via RyR2 (Increase amount of Ca2+ in SR & thus amount released via RyR2 —> greater CDI causes less Ca2+ to enter via the L-type channel; Decrease Ca2+ in SR/released by RyR2 —> less CDI & greater Ca2+ entry via the L-type channel). Thus, CDI helps to maintain a constant SR Ca2+ content.
Norepinephrine released by sympathetic nerve terminals and circulating epinephrine act to:
- Increase HR (positive chronotropy) by raising firing rate of SA node pacemaker cells …..2. Alter propagation through conduction pathways…..3. Increase Contractile Force (positive inotropy)…..4. Increase Rate of Relaxation (positive lusitropy)
Positive inotropy & lusitropy effects of Norepi/Epi involve…
Involve activation of -adrenergic receptors, elevation of cytoplasmic cAMP, and activation of Protein Kinase A (PKA).
Four important targets for PKA in myocardium are:
- The L-type Ca2+ channel…..2. RyR2…..3. Phospholamban (PLB) [associated w/SERCA pump]…..4. Troponin
Effects of Phosphorylation of L-type Ca2+ channel (DHPR w/Cav1.2 subunit) by PKA in myocardium
increases the amplitude of the L-type Ca2+ current more Ca2+ comes in to both increase the size of the trigger Ca2+ to activation of RyR2 and increases the quantity of Ca2+ stored in the SR. Contributes to Positive inotropy
Effect of Phosphorylation of RyR2 by PKA in myocardium
Causes it to be sensitized to activation by trigger Ca2+; Contributes to Positive inotropy
Association of Phospholamban (PLB) w/SERCA2
Inhibits Ca2+ pumping activity
Effect of Phosphorylation of PLB by PKA in myocardium
Causes inhibitory PLB to dissociate from SERCA2, which relieves the inhibition & thus increases SERCA’s pumping Ca2+ into the SR —> speeds relaxation & increases the quantity of Ca2+ stored in SR; ; Contributes to Positive inotropy & Positive lusitropy
Effect of Phosphorylation of troponin by PKA in myocardium
Speeds the rate of Ca2+ dissociation from thin filaments; Contributes to Positive lusitropy
Timothy Syndrome - presentation
Debilitating disorder resulting in syncope, cardiac arrhythmias and sudden death; besides congenital heart disease, patients display intermittent hypoglycemia, immune deficiency, syndactyly (finger webbing), and cognitive abnormalities including autism
Timothy Disease – mutation site
Linked to recurrent, de novo mutations in CaV1.2 (principle subunit of L-type Ca2+ channel), which is consistent with the multi-system nature of the syndrome given that CaV1.2 is expressed not only in the heart but in many other tissues as well….Location of mutations in Exon 8
TS2 mutations – effects
Profoundly suppress voltage-dependent inactivation
Cardiac manifestation of TS & TS2 patients
AV block, prolonged Q-T intervals (indicative of prolonged ventricular AP) and episodes of polymorphic ventricular tachycardia. Normally, current decays over time, due to voltage & due to Ca2+ entry; In Timothy syndrome, Ca2+ current goes away less slowly, prolonging the plateau of depolarization (prolonged QT interval)
Brugada Syndrome -presentation
Aka Sudden Unexplained Death Syndrome; Associated w/ several ECG alterations, which in some instances are revealed by administration of class IC anti-arrhythmics (sodium channel blockers) including ajmaline.
Brugada syndrome - mutations
Linked to several mutations of the cardiac Na+ channel (NaV1.5), KChip2 (associated w/Kv4.3 to produce IKto, transient outward K+ current), and several other proteins including ankyrin (links NaV1.5 to cytoskeleton)…… A subset of Brugada Syndrome patients either have mutations in the principal subunit CaV1.2 or a mutation in the main accessory subunit 2b of the L-type Ca2+ channel.
Brugada syndrome – effects of mutations
Appear to cause a large reduction in the magnitude of L-type Ca2+ current which (for mutations in Cav1.2) may be a consequence of impaired membrane trafficking —> shortens the plateau of the AP —> significantly SHORTENED QT interval (opposite effect of Timothy syndrome) —> arrhythmias
Cardiac manifestations of Brugada syndrome
Significantly shortened Q-T interval.- arrhythmias
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) – timing of ECG abnormalities
Pts w/ CPVT do not display ECG abnormalities at rest, but do upon exercise or infusion of catecholamines.
Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Dominantly inherited causative mutations have been found in RyR2; Recessively inherited causative mutations have also been found in the lumenal Ca2+ buffer calsequestrin2 (CasQ2; isoform expressed in heart).
RyR2 mutations in CPVT – effects
Thought to increase the resting “leak” of Ca2+ out of the SR and/or render RyR2 more sensitive to activation by Ca2+.
CasQ2 mutations in CPVT – effects
Some in the homozygous condition would result in dramatic loss of lumenal Ca2+ buffering, whereas others would not have such a pronounced effect. However, in addition to buffering lumenal Ca2+, calsequestrin has also been suggested to regulate the function of RyR2 and this regulation may be altered by the CPVT causing mutations.
Cardiac manifestation of CPVT (and mechanism)
CPVT mutations + increased SR Ca2+ content (a consequence of activated -adrenergic receptors) —> releases of Ca2+ that are not directly triggered by the L-type Ca2+ current during the plateau of the AP but instead occur either shortly or long after repolarization……Extrusion of this Ca2+ via NCX results in depolarizations that can trigger ectopic action potentials and thus initiate arrhythmias.
Beta blockers in CPVT
Activation of b-adrenergic receptors is likely pro-arrhythmogenic, partly atleast b/c beta-AR activations causes increase in SR Ca content, as well as phosphorylation of RyR2 (makes more twitchy)…..Beta-blockers are a standard therapy for CPVT.
Heart failure & RyR2
HF has been suggested to lead to “hyperphosphorylation” RyR2 (twitchy) and thus contribute in the increased incidence of arrhythmias in HF patients
Treating CPVT
Beta-blockers & other standard therapies are NOT effective for some CPVT pts; Blocking aberrant Ca2+ release via RyR2 might be effective — as of now, Tetracaine can do this, but at too high doses to be clinically useful; Flecainide (class 1C anti-arrhythmic drug) also can block cardiac Na+ channels as well as RyR2
Flecainide action & CPVT
Only blocks the RyR channels when they are already open (use-dependent) –> so, only hold them closed when they are active for a long time; seems to keep twitchy RyR channels calmed down
