Transcript Introduzione alla modellistica del potenziale d`azione cardiaco

Stefano Severi
C3MIG 7 maggio 2009
Introduzione
• It is well known that changes in serum calcium influence
the cardiac electrical activity particularly affecting
ventricular repolarization
• The primary electrocardiographic manifestation of
hypocalcaemia is QTc prolongation, which is associated
with increased risk of early after-depolarizations and
triggered arrhythmias
• hypercalcaemia exerts an opposite effect on the ECG
with the hallmark of abnormal shortening of the QTc
interval
Introduzione
• Ca2+-dependency of repolarization is particularly relevant
in dialysis, when plasma Ca2+ levels may vary widely
• During dialysis, QTc was found to inversely correlate
with plasma Ca2+
RELATION BETWEEN CALCIUM CONCENTRATION AND
ACTION POTENTIAL (AP)
Calcium currents
influence the plateau
duration: in particular
the QT interval
increases when
decreasing [Ca2+] is
observed.
4
Background
Effects of rise in [Ca2+]o on APD
Bai, C.-X. et al. Circ Res 2005;96:64-72
Copyright ©2005 American Heart Association
Aim
The aim of the present study was to identify the ionic
mechanism/s likely to underlie the APD dependency
on [Ca2+]o by using an in silico approach.
To this purpose, new formulations of the Ca2+dependency of IKs, IKr and ICaL were incorporated
in the TNNP model of the human ventricular AP
Methods
• Ten Tusscher human ventricular model (Am J Physiol Heart Circ Physiol 2004)
• [Ca2+]o ranging from 1 to 3 mM was analysed
Metodi
Metodi
fCa inf 


 fca 
 fca   fca   fca  N fCa
D fCa
1
[Ca2 ] 8
i
1 

 a

 fCa 
0.1
 fca 
([Ca 2 ]i b fCa )
1 e

g fCa
 fca 
1 e

0.0001
([Ca 2 ]i 0.00075)
0.0008
Metodi
Metodi
Metodi
LINZ & MEYER
TEN TUSSCHER
GRANDI & SEVERI
1.5
1
1
0.5
0.5
0
3.7
3.75
3.8
3.85
3.9
3.95
0
3.65
3.7
3.75
3.8
3.85
3.9
Figure 10. Influence of [Ca2+]i homeostasis on L-type Ca2+ current, charge transfer and L-type channel inactivation (fAP) during an action potential
with an overshoot of 50 mV
The panels show from top to bottom: command voltage, matching averaged 100 µM Cd2+-sensitive currents, averaged charge transfers, and averaged fAP
values plotted as function of time. A, effect of buffering [Ca2+]i with 10 mM EGTA ( , n = 9) or 10 mM BAPTA ( , n = 14). Recordings were obtained from
different cells. B, effect of inhibition of the SR by 1 µM ryanodine and 1 µM thapsigargin ( , n = 19), and of blocking Na+-Ca2+ exchange by rapidly substituting
Li+ for Na+ in the external solution ( , n = 8). Recordings were made on different cells. The data recorded under control conditions ( , n = 24) are redrawn
from Figs 3 and 5 to allow comparison of the results. Significance of difference from control values was tested using Student's t test (* P < 0·05; ** P < 0·01).
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we have shown (Fig. 6) that the AP prolongs as the store is depleted and shortens as the SR is refilled with
Ca2+ in about 20 beats. A similar time course has been shown experimentally [47]: after removal of caffeine
(which empties the SR, suppresses the Ca2+ transient and prolongs the AP), the APD is gradually
shortened to basal length in parallel with the restoration of the magnitude of the Ca2+ transient during the
refilling of the SR [49] as the rat cardiomyocytes are stimulated.
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Ringraziamenti