Aop: 261

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

L-type calcium channel blockade leading to heart failure via decrease in cardiac contractility

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
L-type calcium channel blockade leading to heart failure via contractility decrease

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
W1siziisijiwmtgvmtavmtcvn2prbnbvzxbnm19bt1bfmjyxx0fpufdpa2kuanbnil0swyjwiiwidgh1bwiilci1mdb4ntawil1d?sha=ca91782be3f4ebed

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Luigi Margiotta-Casaluci, Brunel University London, UK (luigi.margiotta-casaluci@brunel.ac.uk)

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Luigi Margiotta-Casaluci
  • Arthur Author

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.45 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Blockade, L-Type Calcium Channels November 01, 2018 12:25
Decrease, Calcium currents June 19, 2018 14:19
Decrease, Calcium binding to Troponin C June 19, 2018 13:58
Decrease, Cardiac contractility June 19, 2018 14:02
Decrease, Cardiac ejection fraction June 19, 2018 14:03
Heart failure June 19, 2018 14:04
Disruption, Intracellular calcium mobilization June 21, 2018 04:46
Disruption, Sarcomere assembly June 21, 2018 04:46
Blockade, L-Type Calcium Channels leads to Decrease, Calcium currents June 19, 2018 13:54
Decrease, Calcium currents leads to Decrease, Calcium binding to Troponin C June 19, 2018 14:04
Decrease, Calcium binding to Troponin C leads to Decrease, Cardiac contractility June 19, 2018 14:04
Decrease, Cardiac contractility leads to Decrease, Cardiac ejection fraction June 19, 2018 14:05
Decrease, Cardiac ejection fraction leads to Heart failure June 19, 2018 14:08
Decrease, Calcium currents leads to Disruption, Intracellular calcium mobilization June 21, 2018 04:48
Disruption, Intracellular calcium mobilization leads to Disruption, Sarcomere assembly June 21, 2018 04:48
Disruption, Sarcomere assembly leads to Decrease, Cardiac contractility June 21, 2018 04:48
Calcium channel blockers June 21, 2018 04:57
Nifedipine November 02, 2018 07:40
Amlodipine November 02, 2018 07:41
Felodipine November 02, 2018 07:41
Nisoldipine November 02, 2018 07:42
Nimodipine November 02, 2018 07:42
Nitrendipine November 02, 2018 07:43
Diltiazem November 02, 2018 07:43
Verapamil November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Calcium ions play a vital role in cellular and organism physiology. These ions are a central component of a complex system of intracellular messenger that mediates a wide range of biological processes. In the heart, calcium dynamics and signaling are essential for cardiac muscle contraction, thus the perturbation of these processes may impair organ function and health. Different types of calcium channels contribute to the timely regulation of calcium currents at the cellular level. Among them, the L-type calcium channels (LTCCs) are responsible for the excitation-contraction coupling of skeletal, smooth, and cardiac muscle. The pharmacological modulation of this target is an important tool for the treatment of cardiac pathologies, and several drugs that block LTCCs have been developed in the last few decades. However, pharmaceuticals (or any other chemical) that unintentionally block this channel in cardiac cells may lead to adverse cardiovascular effects.

This AOP describes the mechanistic linkage between LTCCs blockade and heart failure mediated by the decrease in cardiac contractility and reduction of ejection fraction. This AOP should be considered part of a network, together with AOP 262. The AOP development was based on over 1,100 in vitro, ex vivo and in vivo data points extracted from approximately 150 publications that investigated a) the effects of calcium channel blockers on different components of the cardiovascular system, and b) the effects of genetic manipulations of the drug target. For each Key Event (KE), a quantitative analysis was performed to determine effect direction and degree of responsiveness. A database-specific confidence index was assigned to each KE according to the degree of reproducibility of the effect. Many KEs of this AOP can be experimentally quantified using different specific endpoints. Therefore, the responsiveness analysis of each endpoint was performed to quantify the sensitivity of each measurement to the blockade of LTCCs. This knowledge has both biological and methodological significance. In the latter case, it can effectively inform the development of suitable testing strategies aimed at maximizing the probability to detect changes in a given KE. Several in silico methods are currently available to determine the quantitative relationship between various KEs in the two proposed AOPs in humans. Future development efforts will be aimed at combining those different methods to develop a fully quantitative AOP network. This AOP is intended to support the interpretation of the cardiovascular risk associated with drug-induced blockade of LTCCs.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development. Drug-induced cardiovascular toxicity was identified as an area of potential interest for AOP development by a network of experts convened by the UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) and the European Union Reference Laboratory for alternatives to animal testing (EURL-ECVAM) in 2015. The blockade of L-type calcium channels (LTCCs) was proposed as one of the priority molecular initiating events (MIE) that may benefit from the AOP vision.

From a toxicological perspective, the key importance of ion currents for drug safety came to light with the discovery that hERG potassium channel inhibition is the most common mechanism of drug-induced long QT syndrome and torsades de pointes arrhythmia [PMID:16322774]. However, a growing body of research has demonstrated that drugs can affect more cardiac currents than previously expected (e.g. calcium current). Thus, the integrated assessment of drug inhibitory activity for multiple ion currents may provide a more accurate prediction of the toxicological risk [PMID:16322774]. Considering the newly recognized complexity of the phenomenon, several authors called for dedicated inter-disciplinary efforts aimed at improving our understanding of the mechanistic basis of cardiovascular liabilities, beyond hERG current blockade [PMID: 21306581]. This AOP is intended to support those efforts by providing a detailed map of the multi-scale effects mediated by LTCCs-blockade.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1529 Blockade, L-Type Calcium Channels Blockade, L-Type Calcium Channels
KE 1530 Decrease, Calcium currents Decrease, Calcium currents
KE 1531 Decrease, Calcium binding to Troponin C Decrease, Calcium binding to Troponin C
KE 1532 Decrease, Cardiac contractility Decrease, Cardiac contractility
KE 1533 Decrease, Cardiac ejection fraction Decrease, Cardiac ejection fraction
KE 1536 Disruption, Intracellular calcium mobilization Disruption, Intracellular calcium mobilization
KE 1537 Disruption, Sarcomere assembly Disruption, Sarcomere assembly
AO 1535 Heart failure Heart failure

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Vertebrates Vertebrates High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Male High
Female High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help