Pharmacological cardiotoxicity

Illustration of a bottle of drugs inside a road sign

Pharmacological cardiotoxicity is a cardiac damage under the action of drugs and it can occur both affecting the performances of the cardiac muscle and by altering the Ion channels/currents of the functional cardiac cells, named the cardiomyocytes.

Two distinct case in which can occur are related both with anti-cancer drugs and with antiarrhythmic drugs. From early observations, some of the first ones which go under the name of anthracycline, it has emerged that such drugs cause a progressive form of heart failure leading to cardiac death. The mechanism of cell injury is thought to account for iron-dependent generation of reactive oxygen species with a spreading of oxidative damage to the cardiomyocytes. On the other hand, related to the antiarrhythmic drugs, the cardiotoxicity is associated to the risk of induce a potential fatal arrhythmias due to an unbalance in the amount of ion currents that flows in/out the cell membrane of the cardiomyocytes.

Pharmacological action

The pharmacological action represents a mechanism by means of a specific effect can be obtained. Depending on the class and type of the drug, the pharmacological action may be different.

In case of electrophysiology, the drug directly acts at the level of the Cells, affecting the mechanism of opening/closure of the ionic channels, as it happens with the anti-arrhythmic drugs. Due to the ionic permeability properties of the cardiac cells' membrane, during the action potential, the opening of the ion channels generates ion currents that flow in/out of the lipophilic cell membrane.

The anti-arrhythmic drugs' action is that of modifying such ion currents, acting on the structure of the ion channel and trying to restore the physiologicalopening/closure mechanism of the ion channels. It may be that, instead of provide a benefit to the heart, such as the aforementioned desired effect, a new drug can negatively affect the ion currents, ending up to excessively modifying the amount of ion currents flowing throughout the cell membrane, increasing the risk of inducing a potential fatal arrhythmias. .

Examples of pharmacological cardiotoxicity

Anti-arrhythmic drugs cardiotoxicity

Representation of the ion channel opening/closure.

The anti-arrhythmic drugs are a class of pharmacological compounds whose action is that of restore the normal sinus rhythm when a patient is affected by an arrhythmia, so their action is that of performing a pharmacological cardioversion.

The pharmacological cardiotoxicity of anti-arrhythmic compounds is related, indeed, to the action of these drugs to induce potential fatal arrhythmias such as torsade de pointes or ventricular fibrillation. The anti-arrhythmic drugs directly act on the opening/closure of ion channels, modifying as a consequence the ion currents.

In treating arrhythmias, the pharmacological therapeutic action is related to the generation of a new combination of the blockage/opening of ion channels. Neverthelesse, This new pharmacologically induced configuration may lead to an unbalanace in ionic currents and as a consquence causing a modificatio in the action potential morphology which increases the risk of inducing an arrhythmia.

It has been in fact studied over the years how the change of the action potential shape, i.e. prolungation of the repolarization phase or early after depolarizations, is bonded to the likely of inducing fatal arrhythmias such as torsade de pointes. So, the risk of inducing a fatal arrhythmias has to be prevented assessing the pharmacological cardiotoxicity at the early stages of the manufacturing of a new drug.

Clinical cardiotoxicity assessment

During the study of a new pharmacological compound, a clinical trials is one of the phases before the market release

At this level, following the directions of the clinical trial protocol, the new drug is administrated to the patient as a therapy and the patient’s clinical status is monitored aiming to evaluate possible side effects.

Old paradigm

To assess pharmacological cardiotoxicity, it was common practice to measure QT interval in vivo and the blockage of Potassium channel . Nevertheless, since 2013 a new paradigm has been developed to overcome the limits of the previous one. It has been in fact demonstrated that the old paradigm was too stringent, labelling as pro-arrhythmic some pharmacological compounds which actually were not.

New paradigm: CiPA

So the Comprehensive in vitro pro-arrhythmia assay was born, accounting for both experimental data and detailed computational models which take into account multiple ionic currents instead of measuring just QT interval and Potassium channel blockage. This new paradigm aims to interlink the clinical evidence with in silico modeling to reconstruct the atrial and ventricular action potential and evaluate the likely for early afterdepolarization to occur.

In Silico cardiotoxicity assessment

Background

In the last years, In Silico Medicine turned out to be promising, aiding scientists and clinicians to prevent and adequately cure several diseases . Computational modeling aid in understanding complex phenomena, allowing scientists to vary parameters aiming to measure variables that otherwise could have not been investigated.

In the field of electrophysiology, the pharmacological cardiotoxicity assessment can be carried out leveraging specific computational models. According to the type and paramaters to be investigated in the research, it is possible to analyze the pharmacological effect on the atria and ventricles separately.

Since the two cardiac chambers are very different each other and play a key role both on a functional and anatomical basis, suitable computational models have to be accounted for to describe their different behaviour. During the years several models have been developed: Courtemanche model for atria or O'Hara model for ventricles, in such way to best characterize and replicate the cellular action potential behaviour of the most relevant anatomical region of the heart.

Creation of a population of cellular action potentials

Ventricular Action Potential

In this way, It has been possible to create a virtual cellular population of cardiomyocytes and vary their conductances that are related to the main ionic currents which contribute to the action potential morphology, reflective of a specifical anatomical region of the heart .

In order to create a stable population of cellular action potentials, the biomarkers have to been accounted for. During the years several biomarkers have been developed to best characterize the instability of cellular action potentials. Few are reported as follows:

• APD90: it represents the action potential duration when the phase of the repolarization is at 90%, so it possible to associate to this value a time and it can be expressed as:

$APD_{90}=t_{90}-t_{0}$

• APD90: it represents the action potential duration when the phase of the repolarization is at 50%, so it possible to associate to this value a time and it can be expressed as:

$APD_{50}=t_{50}-t_{0}$

• APD20: it represents the action potential duration when the phase of the repolarization is at 20%, so it possible to associate to this value a time and it can be expressed as:

$APD_{20}=t_{20}-t_{0}$

• Triangulation: it is a measure of how triangular is an action potential, expressed as:

$Triangulation=APD_{90}-APD_{50}$

• APA: it represents the action potential amplitude, expressed as:

$APA=V_{Max}-V_{0}$

Many other can be used according to the needs of the research .

Regional clusterization

Once the cellular population is stable, all the action potential are compared to physiological data related to the most relevant anatomical regions, in such way to appropriately filter the action potential aiming to consider just the physiologically relevant ones At the atrial level, the clusterization occurs with data associated to:

• Right atrium
• Right atrial appendage
• Left atrium
• Left atrial appendage
• Atrioventricular rings
• Crista terminalis
• Right Bachmann's bundle
• Left Bachmann's bundle
• Pectinate muscles

Simulation of the pharmacological action

Early afterdepolarization

According to pharmacokinetic and pharmacodynamic data of the drugs, the pharmacological action is integrated in the model and by means of specific electrical stimuli protocols , the pharmacological effect of a new drug can be investigated in a completely safe and controlled computational enviroment, providing preliminary important considerations concerning the cardiotoxicity of new pharmacological compounds.

According to the outcome of the simulations, several aspects can be investigated in order to identify the pro-arrhythmiciy of a new pharmacological compound. The typical changes, called repolarization abnormalities, in the action potential morphology that are considered pro-arrhytmhmic may be:

• Early afterdepolarization
• Electrical alternans
• Repolarization failures

Torsade de point risk score

Simulation can be carried out at different effective plasmatic therapuetic level of the drugs to identify the level at which cardiotoxicity can not be neglected. The data collected could be finally managed to create a score system aimed to define the torsadogenisk risk, namely the risk of inducing torsade de pointes, of the new drugs .

A possible Torsade de Point risk score to asess cardiotoxicity could be:

$TdPRS={\frac {\sum _{c}(W_{c}\cdot nRA_{c})}{N\cdot \sum _{c}W_{c})}}$

where $\sum _{c}$ is the sum of all concentrations, [C] is the concentration taken into account, $W_{c}={\frac {EFTPC}{[C]}}$ , $N$ is the total n umber of models in the population and $nRA_{c}$ represents the number of models showing repolarization abnormalities.

Tissue simulations

More detailed computation simulations can be carried out accounting for not cellular models, but taking into consideration the functional syncytium and enabling the cells to mutually interact, the so called electrotonic coupling.

In case of tissue simulation or in wider cases, such as in whole organ simulations, all the cellular models are note appliable anymore and several corrections have to be made. Firstly the governing equations can not be just ordinary differential equation but a system of partial differential equation has to be accounted for. A suitable choice may be the monodomain model:

$\triangledown \cdot (D\nabla V)=(C_{m}{\frac {\partial V}{\partial t}}+I_{ion}(V,u))$ $in$ $\Omega$

$n\cdot (D\nabla V)=0$ $in$ $\partial \Omega$

where $D$ is the effective conductivity tensor, $C_{m}$is the capacitance of the cellular membrane, $I_{ion}$ the transmembrane ionic current, $\Omega$ and $\partial \Omega$ are the domain of interest and its boundary respectively, with $n$ the outward boundary of $\partial \Omega$.

See also

• Arrhythmias
• Cardiology
• Electrophysiology
• Pharmacology

External links

• American Heart Association
• Food and Drug Administration
• European-Heart-Rhythm-Association