1. Gene annotation for heart rhythm 1.Control of heart rate 2.Action Potential 3.Ion channels and transporters 4.Arrhythmia 5.EC coupling

2. Control of heart rate

3. Autonomic regulation of heart function

4. Autonomic Regulation II Central integration of blood pressure and respiratory control Afferents via baroreceptors, chemoreceptors etc Integrated in brainstem centres

5. Autonomic Regulation III Proteins involved in presynaptic vesicle release Proteins involved in signal transduction in the SA node Effector arm

6. Heart Rate Variability The heart beat is not quite regular subject to small variations e.g. sinus arrhythmia Indicative of health. Correlates inversely with outcome after MI etc Time domain:– Tachograms, SD of R-R or  R-R Frequency domain:- Potentially more revealing. HF=vagal\respiration, LF=sympathetic\BP control

7. What ionic mechanisms are responsible? Intrinsic rhythm set by SA node Modulation of pacemaker depolarisation  receptor activation Gs Adenylate cyclase Increased cAMP I f activation M2 receptor activation Gi\o Adenylate cyclase Decreased cAMP I f inhibition G  liberation I KAch activation

8. What is the intrinsic pacemaker? Spontaneous activity in the absence of innervation (intrinsic heart rate) Actually currently quite controversial Two hypotheses – I f current is centrally important and\or Ca 2+ cycling

9. I f \HCN channels Activated by hyperpolarisation Cation but otherwise nonselective Directly opened by cAMP HCN1-4, mainly HCN4 in heart Largely expressed in SA node Ivabradine used for the treatment of angina

10. Action potential

11. Cardiac Action Potential I

12. Conduction system AP in heart regionsAnatomy

13. Cardiac action potential II I Kur – Kv1.5 I KACh – Kir3.1\3.4 I KATP – SUR1\Kir6.1\Kir6.2 vs SUR2A\Kir6.2 Cx40 in atria. Cx43 in ventricle SK channels

14. Ion Channels and Transporters

15. What is happening at the molecular level? Ion channels predominantly control membrane excitability

16. Sodium channels SCN5A in the heart. Both beta subunits present.

17. Potassium channels

18. Lots of genes underlying K+ channels Also SK channels and twin pore channels

19. K channels in Long QT alphabetacurrent KCNQ1 (KvLQT1) KCNE1 (IsK)Iks HERGKCNE2 (MIRP1)Ikr

20. Na + \K + ATPase Member of the P type ATPase pumps  and  3 subunits.  1 and  2 auxiliary subunits Electrogenic 3Na + for 2K + but transport rate ~4 four fold less than the Na channel (100 ions\second)

21. Arrhythmia

22. Classification of arrhythmia Site of origin e.g. atrial, nodal, ventricular Rate e.g. bradycardia, tachycardia Process\Substrate e.g. fibrillation, heart block, ectopic etc This carefully orchestrated activity can go wrong

23. Electrocardiogram (ECG) The benchmark of clinical diagnosis is the ECG P wave= atrial depolarisation QRS= ventricular depolarisation T wave=ventricular repolarisation

24. Examples Atrial FibrillationVentricular Tachycardia

25. Repolarisation and K + currents

26. Excitation-contractioncoupling

27. Cardiac excitation-contraction coupling

28. Calcium channels Gene = CACNAx for alpha subunits (CACNA1C = Ca v 1.2) Ca v 1 = L-type, Ca v 2 = N-, P\Q and R type and Ca v 3 = T type

29. Ryanodine receptor RyR2 in heart Calcium induced calcium release LTCC and RyR2 opposed in T- tubule Large tetrameric complex Protein interactions

30. Sodium\calcium exchanger Major mechanism for calcium extrusion from the heart Electrogenic – 3 Na + for single Ca 2+ Passive coupled counter transport system NCX1 in the heart (3 isoforms in total) Also P type ATPase Ca 2+ pump present in heart which actively extrudes Ca 2+ (PMCA)

31. SERCA2a and phospholamban Major mechanism for calcium uptake into SR P-type ATPase that transports Ca 2+ actively driven by ATP hydrolysis Regulated by phospholamban