AOP-Wiki

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<html lang="en">
<div id="title">
<h2>AOP ID and Title:</h2>
<div class="title">AOP 433: hERG channel blockade leading to sudden cardiac death</div>
<strong>Short Title: From hERG blockade to death</strong>
</div>
<h2>Graphical Representation</h2>
~~<img src="https://aopwiki.org/system/dragonfly/production/2023/01/30/9263c8cvqd_Capture.PNG" height="500" width="700" alt=""/>~~
<img src="https://www.aopwiki.org/system/dragonfly/production/2023/01/30/9263c8cvqd_Capture.PNG" height="500" width="700" alt=""/>
<div id="authors">
<h2>Authors</h2>
<p>Egemen Bilgin</p>
<p> </p>
</div>
<div id="status">
<h2>Status</h2>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Author status</th>
<th scope="col">OECD status</th>
<th scope="col">OECD project</th>
<th scope="col">SAAOP status</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Open for comment. Do not cite</td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="abstract">
<h2>Abstract</h2>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Segoe UI",sans-serif"><span style="color:#212529">Adverse Outcome Pathways aim to give a precise mechanistic description of relevant toxicological effects. In the current study, an AOP framework is used for increased mortality triggered by drug-mediated blockade of human ether-a-gogo-related gene (hERG) channel. An extensive review of the related scientific literature was conducted for this purpose in order to figure out key events (KEs). The KEs include the inhibition of rapid delayed rectifying potassium current, prolongation of action potential duration, prolongation of QT interval  and Torsades de Pointes. Overall, all these steps clearly indicate that there has been a distruption in cardiac electrophysiology, leading to sudden cardiac death on individual level.</span></span></span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="font-size:11.0pt"><span style="background-color:white"><span style="font-family:"Segoe UI",sans-serif"><span style="color:#212529">AOP development was performed in parallel with OECD guideline. The postulated AOP is expected to serve as the basis for the development of novel drugs with less risk of sudden cardiac death mainly triggered by hERG channel blockade.</span></span></span></span></span></span></p>
</div>
<div id="background">
</div>
<div id="aop_summary">
<h2>Summary of the AOP</h2>
<h3>Events</h3>
<h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sequence</th>
<th scope="col">Type</th>
<th scope="col">Event ID</th>
<th scope="col">Title</th>
<th scope="col">Short name</th>
</tr>
</thead>
<tbody>
<tr>
<td></td>
<td>MIE</td>
<td>2099</td>
<td><a href="/events/2099">hERG channel blockade</a></td>
<td>hERG channel blockade</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td></td>
<td>KE</td>
<td>2100</td>
<td><a href="/events/2100">Inhibition of rapid delayed rectifying potassium current </a></td>
<td>Inhibition of rapid delayed rectifying potassium current </td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1961</td>
<td><a href="/events/1961">Prolongation of Action Potential Duration</a></td>
<td>Prolongation of Action Potential</td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1962</td>
<td><a href="/events/1962">Prolongation of QT interval</a></td>
<td>Prolongation of QT interval</td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1963</td>
<td><a href="/events/1963">Torsades de Pointes</a></td>
<td>Torsades de Pointes</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td></td>
<td>AO</td>
<td>1964</td>
<td><a href="/events/1964">Sudden cardiac death</a></td>
<td>Sudden cardiac death</td>
</tr>
</tbody>
</table>
</div>
<h3>Key Event Relationships</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Upstream Event</th>
<th scope="col">Relationship Type</th>
<th scope="col">Downstream Event</th>
<th scope="col">Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/relationships/2850">hERG channel blockade</a></td>
<td>adjacent</td>
<td>Inhibition of rapid delayed rectifying potassium current </td>
<td>High</td>
<td></td>
</tr>
<tr>
<td><a href="/relationships/2851">Inhibition of rapid delayed rectifying potassium current </a></td>
<td>adjacent</td>
<td>Prolongation of Action Potential Duration</td>
<td>High</td>
<td></td>
</tr>
<tr>
<td><a href="/relationships/2540">Prolongation of Action Potential Duration</a></td>
<td>adjacent</td>
<td>Prolongation of QT interval</td>
<td>High</td>
<td></td>
</tr>
<tr>
<td><a href="/relationships/2541">Prolongation of QT interval</a></td>
<td>adjacent</td>
<td>Torsades de Pointes</td>
<td>Low</td>
<td></td>
</tr>
<tr>
<td><a href="/relationships/2542">Torsades de Pointes</a></td>
<td>adjacent</td>
<td>Sudden cardiac death</td>
<td>Low</td>
<td></td>
</tr>
<tr>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="overall_assessment">
<h2>Overall Assessment of the AOP</h2>
<h3>Domain of Applicability</h3>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>Not Specified</td>
</tr>
</tbody>
</table>
</div>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<p><em>Homo sapiens</em></p>
</div>
<div id="considerations_for_potential_applicaitons">
<h2>Considerations for Potential Applications of the AOP (optional)</h2>
<p>The AOP may be useful in the risk assessment on several types molecules including drugs, as well as other types of chemicals, biocides, or pesticides. This AOP elucidating the pathway from hERG blockade to sudden cardiac death may provide important insights into the potential toxicity of direct and/or indirect hERG inhibitors.</p>
</div>
<div id="references">
<h2>References</h2>
<p>1. Choi K-E, Balupuri A, Kang NS. The Study on the hERG Blocker Prediction Using Chemical Fingerprint Analysis. <em>Molecules (Basel, Switzerland)</em>. 25(11). doi:10.3390/molecules25112615</p>
<p>2. Robert M. Lester & Joy Olbertz (2016) Early drug development: assessment of proarrhythmic risk and cardiovascular safety, Expert Review of Clinical Pharmacology, 9:12, 1611-1618, DOI: <a href="https://doi.org/10.1080/17512433.2016.1245142">10.1080/17512433.2016.1245142</a></p>
<p>3.Hancox JC, McPate MJ, El Harchi A, Zhang Y hong. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. <em>Pharmacology and Therapeutics</em>. 2008;119(2):118-132. doi:10.1016/j.pharmthera.2008.05.009</p>
<p>4.Chen WH, Wang WY, Zhang J, Yang D, Wang YP. State-dependent blockade of human ether-a-go-go-related gene (hERG) K(+) channels by changrolin in stably transfected HEK293 cells. Acta Pharmacol Sin. 2010 Aug;31(8):915-22. doi: 10.1038/aps.2010.84. PMID: 20686516; PMCID: PMC4007811.</p>
<p>5.Yao X, Anderson DL, Ross SA, et al. Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model. <em>Br J Pharmacol</em>. 2008;154(7):1446-1456. doi:10.1038/bjp.2008.267</p>
<p>6.Aronov AM. Predictive in silico modeling for hERG channel blockers. <em>Drug Discovery Today</em>. 2005;10(2):149-155. doi:10.1016/S1359-6446(04)03278-7.</p>
<p>7.Yang, P.-C. ( 1 ) <em>et al.</em> (no date) ‘A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm’, <em>Circulation Research</em>, pp. 947–964. doi: 10.1161/CIRCRESAHA.119.316404.</p>
<p>8.Braga RC, Alves VM, Silva MF, Muratov E, Fourches D, Tropsha A, Andrade CH. Tuning HERG out: antitarget QSAR models for drug development. Curr Top Med Chem. 2014;14(11):1399-415. doi: 10.2174/1568026614666140506124442. PMID: 24805060; PMCID: PMC4593700.</p>
<p>9.Mamoshina P, Rodriguez B, Bueno-Orovio A. Toward a broader view of mechanisms of drug cardiotoxicity. <em>Cell Reports Medicine</em>. 2021;2(3). doi:10.1016/j.xcrm.2021.100216</p>
<p>10.Dennis A, Wang L, Wan X, Ficker E. hERG channel trafficking: novel targets in drug-induced long QT syndrome. Biochem Soc Trans. 2007 Nov;35(Pt 5):1060-3. doi: 10.1042/BST0351060. PMID: 17956279.</p>
<p>11.Calderone V, Testai L, Martinotti E, Del Tacca M, Breschi M. Drug-induced block of cardiac HERG potassium channels and development of torsade de pointes arrhythmias: the case of antipsychotics. <em>JOURNAL OF PHARMACY AND PHARMACOLOGY</em>. 2005;57(2):151-161. doi:10.1211/0022357055272</p>
<p>12.Yu Z, IJzerman AP, Heitman LH. Kv 11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv 11.1 (hERG) inhibitors. Br J Pharmacol. 2015 Feb;172(3):940-55. doi: 10.1111/bph.12967. Epub 2014 Dec 15. PMID: 25296617; PMCID: PMC4301700.</p>
<p>13.Mladěnka P, Applová L, Patočka J, Costa VM, Remiao F, Pourová J, Mladěnka A, Karlíčková J, Jahodář L, Vopr&scaron;alová M, Varner KJ, &Scaron;těrba M; TOX-OER and CARDIOTOX Hradec Králové Researchers and Collaborators. Comprehensive review of cardiovascular toxicity of drugs and related agents. Med Res Rev. 2018 Jul;38(4):1332-1403. doi: 10.1002/med.21476. Epub 2018 Jan 5. PMID: 29315692; PMCID: PMC6033155.</p>
<p>14.Jing Y, Easter A, Peters D, Kim N, Enyedy IJ. In silico prediction of hERG inhibition. Future Med Chem. 2015;7(5):571-86. doi: 10.4155/fmc.15.18. PMID: 25921399.</p>
<p>15.Tsujimae K, Suzuki S, Murakami S, Kurachi Y. Frequency-dependent effects of various IKr blockers on cardiac action potential duration in a human atrial model. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H660-9. doi: 10.1152/ajpheart.01083.2006. Epub 2007 Jan 12. PMID: 17220183.</p>
<p>16.Aronov AM. Common pharmacophores for uncharged human ether-a-go-go-related gene (hERG) blockers. J Med Chem. 2006 Nov 16;49(23):6917-21. doi: 10.1021/jm060500o. PMID: 17154521.</p>
<p>17.Yu HB, Zou BY, Wang XL, Li M. Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay. Acta Pharmacol Sin. 2016 Jan;37(1):111-23. doi: 10.1038/aps.2015.143. PMID: 26725739; PMCID: PMC4722980.</p>
<p>18.Di Veroli GY, Davies MR, Zhang H, Abi-Gerges N, Boyett MR. High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment. Am J Physiol Heart Circ Physiol. 2013 Jan 1;304(1):H104-17. doi: 10.1152/ajpheart.00511.2012. Epub 2012 Oct 26. PMID: 23103500.</p>
<p>19.Thomas D, Kiehn J, Katus HA, Karle CA. Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res. 2003 Nov 1;60(2):235-41. doi: 10.1016/j.cardiores.2003.08.002. PMID: 14613852.</p>
<p>20.Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006 Mar 23;440(7083):463-9. doi: 10.1038/nature04710. PMID: 16554806.</p>
<p>21.Hoffmann P, Warner B. Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends. J Pharmacol Toxicol Methods. 2006 Mar-Apr;53(2):87-105. doi: 10.1016/j.vascn.2005.07.003. Epub 2005 Nov 11. PMID: 16289936.</p>
<p>22.Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M, Suter W. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol. 2004 Jan 19;484(1):41-8. doi: 10.1016/j.ejphar.2003.11.003. PMID: 14729380.</p>
<p>23.Tse G, Chan YW, Keung W, Yan BP. Electrophysiological mechanisms of long and short QT syndromes. Int J Cardiol Heart Vasc. 2016 Nov 26;14:8-13. doi: 10.1016/j.ijcha.2016.11.006. PMID: 28382321; PMCID: PMC5368285.</p>
<p>24.Foo B, Williamson B, Young JC, Lukacs G, Shrier A. hERG quality control and the long QT syndrome. J Physiol. 2016 May 1;594(9):2469-81. doi: 10.1113/JP270531. Epub 2016 Feb 9. PMID: 26718903; PMCID: PMC4850197.</p>
<p>25.Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol. 2016 Apr 5;67(13):1639-1650. doi: 10.1016/j.jacc.2015.12.063. PMID: 27150690.</p>
<p>26.Cohagan B, Brandis D. Torsade de Pointes. 2021 Aug 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 29083738.</p>
<p>27.Konstantinos P. LETSAS . 2010 . İlaca Bağlı Qt İnterval Uzaması ve Torsade de Pointes: Risk Faktörlerinin Saptanması . Balkan Medical Journal</p>
</div>
<div id="appendicies">
<h2>Appendix 1</h2>
<h3>List of MIEs in this AOP</h3>
<h4><a href="/events/2099">Event: 2099: hERG channel blockade</a></h4>
<h5>Short Name: hERG channel blockade</h5>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">Aop:433 - hERG channel blockade leading to sudden cardiac death</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Molecular</td></tr>
</tbody>
</table>
</div>
<h3>List of Key Events in the AOP</h3>
<h4><a href="/events/2100">Event: 2100: Inhibition of rapid delayed rectifying potassium current </a></h4>
<h5>Short Name: Inhibition of rapid delayed rectifying potassium current </h5>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">Aop:433 - hERG channel blockade leading to sudden cardiac death</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4><a href="/events/1961">Event: 1961: Prolongation of Action Potential Duration</a></h4>
<h5>Short Name: Prolongation of Action Potential</h5>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">Aop:433 - hERG channel blockade leading to sudden cardiac death</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/519">Aop:519 - Cardiac ion channels blockade leading to increased incidence of cardiovascular morbidity and mortality </a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/555">Aop:555 - Inhibition, Ether-a-go-go (ERG) Voltage-Gated Potassium Channel leading to heart failure</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Organ</td></tr>
</tbody>
</table>
</div>
<h4><a href="/events/1962">Event: 1962: Prolongation of QT interval</a></h4>
<h5>Short Name: Prolongation of QT interval</h5>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">Aop:433 - hERG channel blockade leading to sudden cardiac death</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/552">Aop:552 - Inhibiton of L-Type Calcium Channels leading to heart failure via QT interval prolongation and Torsades de Pointes (TdP)</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/555">Aop:555 - Inhibition, Ether-a-go-go (ERG) Voltage-Gated Potassium Channel leading to heart failure</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Organ</td></tr>
</tbody>
</table>
</div>
<h4><a href="/events/1963">Event: 1963: Torsades de Pointes</a></h4>
<h5>Short Name: Torsades de Pointes</h5>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">Aop:433 - hERG channel blockade leading to sudden cardiac death</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/552">Aop:552 - Inhibiton of L-Type Calcium Channels leading to heart failure via QT interval prolongation and Torsades de Pointes (TdP)</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Organ</td></tr>
</tbody>
</table>
</div>
<h3>List of Adverse Outcomes in this AOP</h3>
<h4><a href="/events/1964">Event: 1964: Sudden cardiac death</a></h4>
<h5>Short Name: Sudden cardiac death</h5>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">Aop:433 - hERG channel blockade leading to sudden cardiac death</a></td>
<td>AdverseOutcome</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Individual</td></tr>
</tbody>
</table>
</div>
<h2>Appendix 2</h2>
<h2>List of Key Event Relationships in the AOP</h2>
<div id="evidence_supporting_links">
<h3>List of Adjacent Key Event Relationships</h3>
<div>
<h4><a href="/relationships/2850">Relationship: 2850: hERG channel blockade leads to Inhibition of rapid delayed rectifying potassium current </a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">hERG channel blockade leading to sudden cardiac death</a></td>
<td>adjacent</td>
<td>High</td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<h4><a href="/relationships/2851">Relationship: 2851: Inhibition of rapid delayed rectifying potassium current leads to Prolongation of Action Potential</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">hERG channel blockade leading to sudden cardiac death</a></td>
<td>adjacent</td>
<td>High</td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<h4><a href="/relationships/2540">Relationship: 2540: Prolongation of Action Potential leads to Prolongation of QT interval</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">hERG channel blockade leading to sudden cardiac death</a></td>
<td>adjacent</td>
<td>High</td>
<td></td>
</tr>
<tr>
<td><a href="/aops/555">Inhibition, Ether-a-go-go (ERG) Voltage-Gated Potassium Channel leading to heart failure</a></td>
<td>adjacent</td>
<td>High</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<h4><a href="/relationships/2541">Relationship: 2541: Prolongation of QT interval leads to Torsades de Pointes</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">hERG channel blockade leading to sudden cardiac death</a></td>
<td>adjacent</td>
<td>Low</td>
<td></td>
</tr>
<tr>
<td><a href="/aops/552">Inhibiton of L-Type Calcium Channels leading to heart failure via QT interval prolongation and Torsades de Pointes (TdP)</a></td>
<td>adjacent</td>
<td>High</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<h4><a href="/relationships/2542">Relationship: 2542: Torsades de Pointes leads to Sudden cardiac death</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/433">hERG channel blockade leading to sudden cardiac death</a></td>
<td>adjacent</td>
<td>Low</td>
<td></td>
</tr>
</tbody>
</table>
</div>
</div>
</div>
</div>
</div>
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