structure and function correlations in electrophysiology Flashcards
functional consequences of differential gap jucntion/ion channel distribution
SAN Atrium His-purkinje AVN Ventricle
SA Node
• Prominent Phase 4 for pacemaker activity1
• If encoding cDNA transcripts 140 times higher than ventricle2
• Longest APD in the centre to prevent entrance of ectopics3
• More atrial like at periphery4
• Cx45
Atrium
• APD ¯ from crista terminalis to the pectinate muscles to “stream” the impulses from the SAN to the AVN.5,6
• Cx43/ Cx40
His-Purkinje
Cx43/ Cx40/ Cx45
AV node
• Low excitability limits max. no. of impulses to prevent rapid ventricular rates7
• Cx45
Ventricle
• No significant phase 4 depolarisation
• Endo-epi AP differences give rise to ECG T wave8
• Cx43
Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused by Tachycardia-Induced Atrial Electrical Remodeling
Fareh et al. Circulation. 1998;98:2202–2209.
• Atrial fibrillation leads to electrophysiological changes
• What is the effect of non-uniform changes?
• Pacemaker implanted into adult mongrel dogs
• 12 underwent rapid pacing (400bpm)/ 12 left inactivated for 24 hrs
• Chest was opened and a 240 bipolar electrode array sutured to atrial epicardium
• Linear conduction velocities were measured
• Effective refractory period measured by premature extrastimuli
• Rapid atrial pacing in dogs ® Pathological heterogeneous ion channel changes ® Heterogeneous refractory period ® short ERP adjacent to long ERP ® conduction block AF vulnerability
Altered Pattern of Connexin40 Distribution in Persistent
Atrial Fibrillation in the Goat
Van der Velden et al. J Cardiovasc Electrophysiol.1998 Jun;9(6):596-607
Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goa
- Gap junctional remodelling occurs in atrial fibrillaton
- What is the timing and localisation of these changes?
- 36 goats were implanted with pacemakers to deliver 50 Hz bursts lasting 2s on detection of SR
- Maintained in AF for up to 16 weeks
- On sacrifice RAA and LAA were fixed and labelled for Cx40 and Cx43
- Atrial fibrillation is associated with heterogenous loss of Cx40 in a goat model
Remodelling of cardiac repolarization: how homeostaticresponses can lead to arrhythmogenesis
Multiple ion channel changes occur in congestive heart failure:
- Late INa due to slow inactivation, contributes to APD prolongation.
- Sarcoplasmic reticulum (SR) Ca2+ stores reduced, SERCA downregulated, slow relaxation of the systolic Ca2+ transient and diastolic Ca2+ may be increased.
- NCX is upregulated and may compensate for cytosolic Ca2+ removal impairments
- Changes in NCX may affect repolarization
- Voltage-dependent K+ currents are downregulated leading to APD prolongation
Disturbed Connexin43 Gap Junction Distribution Correlates With the Location of Reentrant Circuits in the Epicardial Border Zone of Healing Canine Infarcts That Cause Ventricular Tachycardia
- Gap junctional changes occur after infarct
- Does the localisation of these changes affect conduction properties?
- MI induced in 6 mongrel dogs by LAD ligation
- 292 bipolar electrode array sutured onto epicardial LV over infarct area for mapping of conduction
- Tissue underlying the array was fixed and stained for Cx43 in sections from epicardium to endocardium
- Immunohistochemistry for Cx43
- Abnormalities in gap junction distribution in the canine healing infarct border zone correlates with re-entrant arrhythmias
Characterization of Conduction in the Ventricles of Normal and Heterozygous Cx43 Knockout Mice Using Optical Mapping
- Gap junctions are a pathway for cell to cell conduction
- Does a lack of Cx43 lead to slow conduction?
- 14 WT and 7 Cx43+/- were used
- Hearts were removed and Langendorff perfused with oxygenated Tyrodes
- Pacing was carried out at CL 80 – 150ms
- Fluorescence intensity recordings were taken after staining with voltage sensitive dye Di-4-ANEPPS
- CV were calculated
- Things aren’t always as it seems it should be.
- Cx43 KO does not slow conduction.
Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes.
- Neonatal rat myocytes were cultured in 1-d strands
- Fluorescence intensity recordings were taken after staining with voltage sensitive dye RH-237
Conduction in a 1-d chain of myocytes is regular
Anisotropic conduction block and reentry in neonatal rat ventricular myocyte monolayers
- Cells in whole heart are elongated
- What happens if cultured cells are patterned in this way?
- Neonatal rat ventricular myocytes were seeded on culture dishes either direct or after abrasion
- Fluorescence intensity recordings were taken after staining with voltage sensitive dye RH-237
- Conduction in a 2-d layer of round cells is isotropic
- Conduction in a 2-d layer of elongated cells is isotropic
fibre orientation in the whole heart
- Fibre orientation is complex in the whole heart
- There is a difference in orientation from endo ® epi
- This leads to a specific pattern of activation
Total Excitation of the Isolated Human Heart
Durrer Circulation. 1970;41:899-912
• What is the pattern of excitation in the normal human heart?
- 7 hearts were excised from patients who died from cerebral conditions
- Epicardial and intramural activity recorded from 660 electrode array or 20 multi-electrode needles
Pattern of activation was calculated
Functional effect of changes in anisotropy and fibre direction in a 2D monolayer
• Conduction block in an anisotropic monolayer can lead to re-entry
Change in fibre direction can be a point of initiation of re-entry
Functional consequences of dissociation of fibre layers in atrial fibrillation
Time course and mechanisms of endo-epicardial electrical dissociation during atrial fibrillation in the goat
Eckstein et al Cardiovascular Research (2011) 89, 816–824
• Muscle bundles are dissociated in atrial fibrillation
• Is activation between layers of the atrial wall seperated?
• Goats were induced into atrial fibrillation for 3 weeks or 6 months (7 in each group)
• A double-sided eno/epi 256 channel mapping array was placed on the left atrium
• Double-sided activation maps were calculated
• Endo- and epi-cardial layers can be dissociated in atrial fibrillation
• This leads to fibrillatory wavefronts
Functional consequences in changes in fibre orientation after infarction
Towards predictive modelling of the electrophysiology of the heart
- Fibre orientation is disrupted in the infarct border zone due to scar
- This is a substrate for re-entry
- Vigmond et al Exp Physiol Volume 94, Issue 5, pages 563–577, May 2009
- Cellular location and expression of ion channels and gap junctional channels are specific to the normal functioning of each cell type in different regions of the heart.
- Abnormal localisation/ expression of channels can be pro-arrhythmic
- Specific tissue structure and orientation allows for normal conduction propagation through the heart
- Loss of tissue structure can be pro-arrhythmic
