<p>Predicting drug-induced cardiac toxicity is critical for drug safety assays, especially when evaluating risks of inducing Torsade de Pointes (TdP). This study proposes an integrated electromechanical model of myocytes for TdP risk assessment, extending the CiPA framework. Human electrophysiological models of CiPAORdv1.0, ORD, and ToR were integrated with a Land mechanical ventricle model. Twenty-seven parameters were observed, including the net current (<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(qNet\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi mathvariant="italic">qNet</mi> </mrow> </math></EquationSource> </InlineEquation>), inward current (<InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(qInward\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi mathvariant="italic">qInward</mi> </mrow> </math></EquationSource> </InlineEquation>), action potential profile, intracellular calcium profile, and tension profile. We used ordinal logistic regression with 12 drugs as training dataset and validated using unseen data from the remaining 16 drugs following the protocol from the FDA. We observed that the electromechanical model improved the TdP risk classification in most of the parameters derived from the action potential, Calcium Transient (<InlineEquation ID="IEq3"> <EquationSource Format="TEX">\({Ca}_{i}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">Ca</mi> </mrow> <mi>i</mi> </msub> </math></EquationSource> </InlineEquation>)<i>,</i> and tension profile. The CiPAORdv1.0 + Land not only preserved <InlineEquation ID="IEq4"> <EquationSource Format="TEX">\(qNet\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi mathvariant="italic">qNet</mi> </mrow> </math></EquationSource> </InlineEquation> performance but improved the classification performance using <InlineEquation ID="IEq5"> <EquationSource Format="TEX">\({APD}_{50}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">APD</mi> </mrow> <mn>50</mn> </msub> </math></EquationSource> </InlineEquation>, <InlineEquation ID="IEq6"> <EquationSource Format="TEX">\({APD}_{90}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">APD</mi> </mrow> <mn>90</mn> </msub> </math></EquationSource> </InlineEquation><i>, </i><InlineEquation ID="IEq7"> <EquationSource Format="TEX">\({CaD}_{90}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">CaD</mi> </mrow> <mn>90</mn> </msub> </math></EquationSource> </InlineEquation><i>, </i><InlineEquation ID="IEq8"> <EquationSource Format="TEX">\({Ca}_{tri}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">Ca</mi> </mrow> <mrow> <mi mathvariant="italic">tri</mi> </mrow> </msub> </math></EquationSource> </InlineEquation><i>,</i> <InlineEquation ID="IEq9"> <EquationSource Format="TEX">\({ti}_{tri}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">ti</mi> </mrow> <mrow> <mi mathvariant="italic">tri</mi> </mrow> </msub> </math></EquationSource> </InlineEquation>, and <InlineEquation ID="IEq10"> <EquationSource Format="TEX">\(EMW\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi mathvariant="italic">EMW</mi> </mrow> </math></EquationSource> </InlineEquation>. On the other hand, ToR + Land model improved the parameter of <InlineEquation ID="IEq11"> <EquationSource Format="TEX">\({CaTD}_{50}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">CaTD</mi> </mrow> <mn>50</mn> </msub> </math></EquationSource> </InlineEquation> and <InlineEquation ID="IEq12"> <EquationSource Format="TEX">\({CaD}_{50,tp}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">CaD</mi> </mrow> <mrow> <mn>50</mn> <mo>,</mo> <mi>t</mi> <mi>p</mi> </mrow> </msub> </math></EquationSource> </InlineEquation>. The ORD + Land model showed some improvement in <InlineEquation ID="IEq13"> <EquationSource Format="TEX">\({V}_{max}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>V</mi> <mrow> <mi mathvariant="italic">max</mi> </mrow> </msub> </math></EquationSource> </InlineEquation>, and some well for other parameters including <InlineEquation ID="IEq14"> <EquationSource Format="TEX">\({CaTD}_{90}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">CaTD</mi> </mrow> <mn>90</mn> </msub> </math></EquationSource> </InlineEquation><i>, </i><InlineEquation ID="IEq15"> <EquationSource Format="TEX">\({CaD}_{90,tp}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">CaD</mi> </mrow> <mrow> <mn>90</mn> <mo>,</mo> <mi>t</mi> <mi>p</mi> </mrow> </msub> </math></EquationSource> </InlineEquation><i>,</i> <InlineEquation ID="IEq16"> <EquationSource Format="TEX">\({Ca}_{tri}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">Ca</mi> </mrow> <mrow> <mi mathvariant="italic">tri</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> and <InlineEquation ID="IEq17"> <EquationSource Format="TEX">\({ti}_{tri}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="italic">ti</mi> </mrow> <mrow> <mi mathvariant="italic">tri</mi> </mrow> </msub> </math></EquationSource> </InlineEquation>. This work highlights the advantage of an electromechanical ventricular model for assessing drug-induced TdP risk compared to an electrophysiological model. Overall, the coupled models improved the TdP classification performance based on APD and calcium as well as tension profile. Further optimization of the models and inclusion of more drugs in training the models can improve interpretability and predictive accuracy for TdP risk assessment.</p>

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Drug induced TdP risks classification assay using electro-mechanical models of human ventricle based on CiPA framework

  • Aulia Khamas Heikhmakhtiar,
  • Ali Ikhsanul Qauli,
  • Yunendah Nur Fu’adah,
  • Muhammad Adnan Pramudito,
  • Iga Narendra Pramawijaya,
  • Aroli Marcellinus,
  • Kim Yoo Seok,
  • Frederique Jos Vanheusden,
  • Ki Moo Lim

摘要

Predicting drug-induced cardiac toxicity is critical for drug safety assays, especially when evaluating risks of inducing Torsade de Pointes (TdP). This study proposes an integrated electromechanical model of myocytes for TdP risk assessment, extending the CiPA framework. Human electrophysiological models of CiPAORdv1.0, ORD, and ToR were integrated with a Land mechanical ventricle model. Twenty-seven parameters were observed, including the net current ( \(qNet\) qNet ), inward current ( \(qInward\) qInward ), action potential profile, intracellular calcium profile, and tension profile. We used ordinal logistic regression with 12 drugs as training dataset and validated using unseen data from the remaining 16 drugs following the protocol from the FDA. We observed that the electromechanical model improved the TdP risk classification in most of the parameters derived from the action potential, Calcium Transient ( \({Ca}_{i}\) Ca i ), and tension profile. The CiPAORdv1.0 + Land not only preserved \(qNet\) qNet performance but improved the classification performance using \({APD}_{50}\) APD 50 , \({APD}_{90}\) APD 90 , \({CaD}_{90}\) CaD 90 , \({Ca}_{tri}\) Ca tri , \({ti}_{tri}\) ti tri , and \(EMW\) EMW . On the other hand, ToR + Land model improved the parameter of \({CaTD}_{50}\) CaTD 50 and \({CaD}_{50,tp}\) CaD 50 , t p . The ORD + Land model showed some improvement in \({V}_{max}\) V max , and some well for other parameters including \({CaTD}_{90}\) CaTD 90 , \({CaD}_{90,tp}\) CaD 90 , t p , \({Ca}_{tri}\) Ca tri and \({ti}_{tri}\) ti tri . This work highlights the advantage of an electromechanical ventricular model for assessing drug-induced TdP risk compared to an electrophysiological model. Overall, the coupled models improved the TdP classification performance based on APD and calcium as well as tension profile. Further optimization of the models and inclusion of more drugs in training the models can improve interpretability and predictive accuracy for TdP risk assessment.