1. Computational modelling approaches to QT interval changes in paediatric severe malaria.
George W Kagugube*, Alan P Benson, Arun V Holden
*Busitema University, P.O BOX 1460, Mbale, Uganda
Malaria fever is associated with tachycardia, hypertension and severe cardiac haemodynamic changes which may be lethal. In adults, malarial fever is associated with ST elevation in leads I, II and aVL along with QT prolongation in the ECG recordings.
In children malarial fever is associated with QT shortening and its treatment by quinine by QT prolongation. Death following treatment with antimalarial drugs is widely reported The mechanisms of these changes is unknown. Changes in cell and tissue electrophysiology of propagating activity in the cardiac conducting system and myocardium may be involved. Computational modelling may provide insights into the mechanisms underlying these ECG changes during severe malaria in adults, and its treatment in children
1D model for adult normal sinus rhythm (NSR)
A 1D computational model for propagating activity during human normal sinus rhythm, constricted from sinoatrial, atrial, atrioventricular, Purkinje fibre and ventricular cell models, can reproduce clinical ECG intervals how they change with heart rate, at different rates [1]. The cell models are derived from the Courtemarche-Ramirez –Natel atrial and the O’Hara-Rudy ventricular cell models, with parameters for the sinoatrial node cell model (a modified CRN model) adjusted to give appropriate rates for observed RR intervals, diffusion coefficients to give ventricular conduction velocities of m/s, and lengths of strand components adjusted to reproduce PR and QT intervals of the ECG (Fig. 1).
Fig.1. Colour coded space time plot of cell membrane potential (red depolarised, blue repolarised) for 3 s of normal sinus rhythm in normal adult, with parameters selected to reproduce the intervals of superimposed single channel ECG recording (RR= 0.815, PR=0.168, QT=0.274 s).
atrial
ventricular-endo
vent. - epi
Fig. 2 The computed RR interval is from the upswing of the nth ventricular AP to the upswing of the (n+1)th AP in the same node . The computed PR interval is from the upswing of the nth atrial AP in the first atrial node to the upswing of the nth AP in the first ventricular node. The computed QT interval was from the upswing of the nth ventricular AP in the first node to the latest mid-repolarisation of the nth AP (in the M cell region)
1D model for NSR in child (< 2 years old)
Neonatal and paediatric resting heart rates are higher than in adults, so the SAN parameters (gf and gK1) are modified to reproduce RR interval data, and the number of nodes (not diffusion coefficient) to produce the PR and QT intervals.
Fig.3. Colour coded space time plot of neonatal NSR, with computed RR= 557 , PR= 123 , QT = ms.
NSR in child (<2 years old) with malaria.
Fig. 4. Space time plot for NSR in model of child with malaria, illustrating the development of an intermittent conduction block. The parameters (gf and gK1) are modified to reproduce RR interval data, and the number of nodes (not diffusion coefficient) to produce the PR and QT intervals, with ventricular cell properties (ionic concentrat- ions, pH effects) modified as for adult malaria in Fig 3.
As in severe malarial fever in the adult, bradycardia and occasional dysrhythmia are observed.
Quinine effects in young children with malaria
Anti malarial drugs are associated with unwanted cardiovascular effects. Intravenous quinine and quinidine have been reported to cause death in clinical treatment of severe malaria especially in young children [4]. Changes in the serum electrolytes and ion current conductances that have been reported in the intravenous administration of quinine are studied here. To simulate the effects of quinine in young children with malaria, fast sodium currents (INa) and repolarising potassium currrents (IKr) were reduced in our malaria model of children. 50% reduction in the gNa and gKr was ran to simulate the 50% reduction in these currents, corresponding to plasma 60μmol/L of quinine [5].
Fig.5 . Space time plot for NSR in model of child with
malaria (as in Fig 4), with further changes to reproduce the effects of quinidine. The NSR rate is reduced, the QT interval prolonged, while the intermittent conduction block seen with these parameters remains.
The data from the models both adult and children is consistent with published clinical data of ECG interval changes widely reported during malaria infection. The shortening of the QT interval due to the infection, a prolongation of this interval with quinine is seen.
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Time (s)
Malarial model: adult
The mechanisms of severe Malaria associated cardiovascular dysfunction which are often manifested in hemodynamic largely remain unknown. Metabolic acidosis reported in malaria, serum electrolytes and intracellular sodium concentration are reported to change during the infection. To study these mechanisms, acidotic changes often reported in excitable cells intracellular [Na+] concentration is adjusted to 15 nM [3] and RYR3 sensitivity to calcium was reduced by 0.25 equating to a pH change of 0.3 units. Similarly, extracellular [Na+], [K+], [Cl-] and [Ca++] were adjusted to mimic malaria related changes [3].
Fig. 4. Space time plot for NSR in model of adult with
malaria. SAN parameters (gf and gK1) are modified to reproduce RR interval data, and the number of nodes (not diffusion coefficient) to produce the PR and QT intervals, with ventricular cell properties (ionic concentrations, pH effects) modified as in text.
Cardiac ECG resting NSR intervals
RR (s) PR (s) QT (s) Ref
Adult
Adult + M [2]
0 - 2 yrs [3]
0 -2yrs +M [3]
0-2yrs + M + Q [3]
*M = Malaria *Q = Quinine
Computed NSR intervals
RR (ms) PR (ms) QT (ms)
Adult
Adult + M
0 - 2 yrs
0 -2yrs +M
0-2yrs + M + Q
Summary
Using a 1D model, we have successfully reproduced the normal ECG intervals for adults and children (<2 years old), with malaria, and with treatment. The 1D model may be used to model paediatric ECG interval changes, to evaluate the relative roles of physical (temperature) biophysical (membrane conductance), electrochemical (ionic concentrations) and possible toxicological mechanisms during death during severe malarial fevers, and its potential therapies.
[1] Pervolaraki et al.Towards computational modelling of the human foetal ECG: normal sinus rhythm and congenital heart block. Europace DOI: /europace/eut
[2] Maude RJ(1) et al. Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria? Am J Trop Med Hyg Jan;80(1):126-32
[3] Roggelin L. Disease-associated QT-shortage versus quinine associated QT-prolongation: age dependent ECG-effects in Ghanaian children with severe malaria. Malar J Jun 5;13:219. doi: /
[4] Touze JE, et al., Effects of antimalarial drugs and cardiomyocytes. Pathogenic approach and new therapeutic recommendations. Bull Acad Natl Med eb;190(2):439-49; discussion Review. French. PubMed PMID:
[5] White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis Aug;7(8): Review.