Question 23

College Answer

To achieve a good pass in this question, candidates needed to outline the ionic events
associated with Phase 0 to phase 4 of the ventricular action potential followed by a description of
excitation – contraction coupling. The second part of the question was best answered using a
ventricular pressure-volume loop and overlaying the phases of the ventricular action potential.
Description of the ionic events associated with the action potential phases was generally well
done, but this was as far as many answers went in answering this question. Few candidates
included a description of excitation-contraction coupling in there answer and few candidates
considered an answer to the second part of the question. The use of illustrations helped answer
this question.
Syllabus: C1b
References: Guyton and Hall Textbook of Medical Physiology, Chp 9

Discussion

It is in fact surprising that as many as 27% of the candidates passed this question, considering that "draw a ventricular PV loop with overlaid phases of the ventricular action potential" does not emerge naturally from "outline how the action potential relates with the mechanical events of the cardiac cycle". Most people would also not immediately assume that the examiners wanted ionic and mechanical events to be joined via excitation-contraction coupling. So vastly different is the question wording from the examiner's expectations, that one has difficulty with presenting a model answer. Does one answer the question as it was asked, or does one produce an answer which the examiners appear to have wanted? 

Thus

Ionic events during the action potential:

• Phase 0: rapid depolarisation by fast voltage-gated sodium channels
• Phase 1: Early repolarisation back to a membrane potential close to 0 mV
  • Mediated by outward potassium current (Ito) and the Na⁺/Ca²⁺ exchanger (INCX) which is a current pumping calcium into the cells, in exchange for sodium.
• Phase 2: Plateau 
  • Mediated mainly by inward calcium current, through L-type voltage gated calcium channels
  • This triggers the release of calcium from the sarcoplasmic reticulum, and initiates muscle contraction
• Phase 3: Repolarisation by Ikr, Iks and Ik1 currents
  • Slowly returns the cell to the resting membrane potential (-90 mV)
• Phase 4: Resting potential
  •  Mediated by the Ik1 inward rectifying potassium current, which stabilises the membrane potential at around -90 mV

Excitation – contraction coupling

• Inward calcium current during Phase 2 activates calcium-gated calcium channels on the sarcoplasmic reticulum
• This produces the release of calcium from the sarcoplasmic reticulum
• Free calcium binds to troponin-C/troponin I regulatory complex, which exposes the active sites of actin and myosin to each other
• This produces the "ratcheting" movement between the myosin heads and the actin, which continues as long as intracellular calcium remains available.

Relationship of the action potential to the mechanical events in the ventricle

They asked for a PV loop. Though the college felt this SAQ was "best answered using a ventricular pressure-volume loop and overlaying the phases of the ventricular action potential", no such loop exists anywhere in the literature, and what is offered here is a total confabulation. Moreover, one is puzzled as to how this is supposed to be better than simply plotting the ventricular pressure and volume over time, together with the action potential.  

Antoni, H. "Electrophysiology of the heart at the single cell level and cardiac rhythmogenesis." Comprehensive Human Physiology. Springer, Berlin, Heidelberg, 1996. 1825-1842.

Pinnell, Jeremy, Simon Turner, and Simon Howell. "Cardiac muscle physiology." Continuing Education in Anaesthesia, Critical Care and Pain 7.3 (2007): 85-88.

Bers, Donald M. "Cardiac excitation–contraction coupling." Nature 415.6868 (2002): 198-205.

Cooper, Patricia J., Christian Soeller, and Mark B. Cannell. "Excitation–contraction coupling in human heart failure examined by action potential clamp in rat cardiac myocytes." Journal of molecular and cellular cardiology 49.6 (2010): 911-917.

Santana, Luis F., Edward P. Cheng, and W. Jonathan Lederer. "How does the shape of the cardiac action potential control calcium signaling and contraction in the heart?." Journal of molecular and cellular cardiology 49.6 (2010): 901.