Calcium and arrhythmias

Question 1

Myofilament Ca sensitivityis dynamically regulated by a number of processes:

Answer 1

1. Ca binding to TnC
   
   2. De-inhibition of actin-myosin interaction by the thin filament
   3. Actin-myosin cross-bridge properties

Ca sensitivity changes during each cardiac cycle with sarcomere length, an effect in part responsible for the immediate adaptation in cardiac output during beat-to-beat changes in ventricular filling (frank-starling).

Longer lasting regulation is achieved by phosphorylation of TnI:

Question 2

How can phosphorylation affect Ca sensitivity?

Answer 2

Longer lasting regulation is achieved by phosphorylation of TnI:
The phosphorylation of N-terminal serines by cAMP dependent protein kinase A (PKA) decreases myofilament Ca sensitivity and contributes to postiive lusitropic effects of beta agonists. The same serines are also phosphorylated by PKD, thereby allowing multiple pathways to regulate Ca dependent force production.

Question 3

What is ca sensitivity like in acutely ischaemic myocardium?

Answer 3

During acute myocardial ischaemia, myofilament Ca senisitivity decreases largely due to a combined effect of acidic pH and increased [PO4] - as a consequence of decline in high-energy phosphates.
Myofilament Ca sensitivity remains decreased in stunned myocardium.

Question 4

Myofilament Ca sensitisation may mediate the effect on cardiac excitation via 3 principle pathways:

Answer 4

1) Through effects on the intracellular Ca homeostasis

Energy metabolism (depletion due ^ Demand&utilisation)

Mechanical stretch

Question 5

1) Through effects on the intracellular Ca homeostasis

Answer 5

a. TnC buffers ~50% Ca released from SR -> higher Ca sensitivity -> decreased peak free [Ca]
thus as [Ca] decreases, the Ca dissociation from the myofilaments becomes the rate limiting step for Ca transient decline
b. Ca-dependent inactivation of L-type Ca channels -> if peak [Ca] is lower due to higher Ca sensitivity, this -ve feedback may be affected. However, myofilament effects may not extend to the dydactic cleft between the RYRs and L-channels ->Consistent with experimental findings

Question 6

2) Energy metabolism (depletion due to increased Demand&utilisation)

Answer 6

a. Inefficient energy utilisation
b. Positive inotropy due to higher Ca sensitivity directly leads to higher ATP use for cross-bridge formation -> affects ATP dependent processes:
i. decreases SERCA activity -> higer[Ca] -> increasedIncx
ii. Na/K-ATPase -> increased [K] extracellular -> depolarises the membrane, slows conduction, alters refractoriness (also slow AP upstroke, decreased AP amplitude)èñProbability of reentrant arrhythmias
Also causes Na overload
iii. KATP opening -> may also render the cells non-excitable (above -70mV sodium channels do not recover from inactivation)

Question 7

Increased mechanical stretch

Answer 7

Mechanical stretch
a. Stretch evoked Ca release from SR

When activated muscle is passively stretched, cross-bridges rapidly detach and Ca dissociated from TnC. More Ca is bound to Ca-sensitised myofilaments, thus more can be released -> increases arrhythmogenesis