Optimal Design of Challenge Response Experiments in Cardiac Electrophysiology (OCRE; NIH/NHLBI 1R01HL118392)

Table of Contents

Project Summary

Meetings are held monthly every second Monday at 11am.

Project History

9/1/2013	Project start date
9/9/2013	Kick-off teleconference
10/1/2013	Government (NIH/FDA) Shutdown Begin
10/14/2013	OCRE Monthly teleconference
10/15/2013	Minchun Zhou ENAR Abstract Submission
10/17/2013	Government (NIH/FDA) Shutdown End
11/18/2013	OCRE Monthly teleconference
12/16/2013	OCRE Monthly teleconference
01/13/2014	OCRE Monthly teleconference
02/10/2014	OCRE Monthly teleconference
04/14/2014	OCRE Monthly teleconference
09/13/2014	Sunil Kandel to present at the Applied Mathematics Conference at Oakland U. Poster_ISCRM_Conference.pdf

Literature

Statistical

Biological

Luo & Rudy (1991)	This paper introduces a mathematical model (now known as the LR model) of the membrane action potential of the mammalian ventricular cell. The model depends on the currents induced by the flow of K and Na ions through Guinea pig ventricular cell ion channels during an action potential. Some of the key findings are as follows: 1) The LR model is able to reproduce cardiac conditions, such as Wenckenbach periodicity and alternans. 2) The LR model accounts for changes in extracellular K (elevated in ischemia) that have been found to "exert a strong effect on the time course of repolarization." In particular, decreasing extracellular K concentration elongates action potentials, and increases the resting membrane potential, which affects the maximum rate of change in membrane potential (dV/dt). These data suggest that experimental recordings of resting V, dV/dt, and APD may be useful to investigate models of ischemia/anoxia that depend on changing extra potassium concentration. Extracellular K concentration also affects membrane (supranormal) excitability (which is investigated using strength-interval curve experiments). In particular, supranormal excitability is only observed below a threshold extracelluar K concentration. The 1991 LR model is considered "passive", since intra- and extracellular ion concentrations are not allowed to fluctuate. The later LRd ('d' for dynamic; described below) model incorporates fluctuating ion concentrations for Na, K, and Ca. Indeed Ca had not been considered at all in the (phase-1) LR model.
Luo & Rudy (1994)	This paper expands on the LR model (membrane ionic channel currents only) by introducing components that account for the currents associated with Ca and the Na-K pump. This "dynamic" version of the LR model is denoted "LRd". LRd Code
Shaw & Rudy (1997)	Shaw and Rudy use the LRd model to evaluate the three physiological conditions associated with cardiac ischemia, elevated extracellular potassium concentration, acidosis, and anoxia. These conditions were modeled successfully, and used to simulate ischemic action potentials that mimic experimental data.
Rodriguez, Ferrero, and Trenor (2002)	Rodriguez, Ferrero, and Trenor extend use the LRd model to investigate yet another mechanism of cardiac ischemia. Their approach focuses on the ATP-dependent K current, an ischemic inward Na current, and inhibition of Na-K pump activity in the absence of coronary flow. The authors claim that only the combined effects of these replicate the biphasic (sharp increase followed by plateau) time course of extracellular K concentration observed during the first 10-15 minutes of acute ischemia. The rate of K+ accumulation is affected by heart rate and other experimental conditions. Unlike Shaw & Rudy (1997), these authors model the full timecourse of ischemia, whereas others have modeled a single ischemic state.
Terkildsen, Crampin, and Smith (2007)	Terkildsen, Crampin, and Smith use the LRd model to investigate yet another mechanism of cardiac ischemia.
Gaur, Rudy, and Hool (2009)	Gaur, Rudy, and Hool extend the LRd model to account for the effects of acute hypoxia (not energy limiting) and found (among other resuts) that, combined with β-adrenergic receptor (a target of catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline); isoprenaline in this study) stimulation, the acute hypoxic action potential was elongated. Hypoxic effects on APD and dV/dt were minor without β-adrenergic stimulation. Early afterdepolarizations (EADs) and spontaneous tachycardia were induced.
Zhang, Zhang, Yang, Jin, and Huang

Bibliography (BibTeX)

@article{LuoRudy1991,
    author = {Luo, C H and Rudy, Y}, 
    title = {A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction.},
    volume = {68}, 
    number = {6}, 
    pages = {1501-26}, 
    year = {1991}, 
    doi = {10.1161/01.RES.68.6.1501}, 
    URL = {http://circres.ahajournals.org/content/68/6/1501.abstract}, 
    eprint = {http://circres.ahajournals.org/content/68/6/1501.full.pdf+html}, 
    journal = {Circulation Research} 
}

@article{LuoRudy1994,
    author = {Luo, C H and Rudy, Y}, 
    title = {A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes.},
    volume = {74}, 
    number = {6}, 
    pages = {1071-96}, 
    year = {1994}, 
    doi = {10.1161/01.RES.74.6.1071}, 
    URL = {http://circres.ahajournals.org/content/74/6/1071.abstract}, 
    eprint = {http://circres.ahajournals.org/content/74/6/1071.full.pdf+html}, 
    journal = {Circulation Research} 
}

@article{ShawRudy1997,
    author = {Shaw, Robin M. and Rudy, Yoram}, 
    title = {Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration},
    volume = {35}, 
    number = {2}, 
    pages = {256-272}, 
    year = {1997}, 
    doi = {10.1016/S0008-6363(97)00093-X}, 
    URL = {http://cardiovascres.oxfordjournals.org/content/35/2/256.abstract}, 
    eprint = {http://cardiovascres.oxfordjournals.org/content/35/2/256.full.pdf+html}, 
    journal = {Cardiovascular Research} 
}

@article {RodriguezFerreroTrenor2002,
    author = {B. Rodr{\i}́guez and J. M. Ferrero, Jr. and B. Tr{\'e}nor},
    title = {Mechanistic investigation of extracellular K+accumulation during acute myocardial ischemia: a simulation study},
    volume = {283},
    number = {2},
    pages = {H490--H500},
    year = {2002},
    doi = {10.1152/ajpheart.00625.2001},
    URL = {http://ajpheart.physiology.org/content/283/2/H490},
    eprint = {http://ajpheart.physiology.org/content/283/2/H490.full.pdf},
    journal = {American Journal of Physiology - Heart and Circulatory Physiology}
}

@article {TerkildsenCrampinSmith2007,
    author = {Jonna R. Terkildsen and Edmund J. Crampin and Nicolas P. Smith},
    title = {The balance between inactivation and activation of the Na+-K+ pump underlies the triphasic accumulation of extracellular K+ during myocardial ischemia},
    volume = {293},
    number = {5},
    pages = {H3036--H3045},
    year = {2007},
    doi = {10.1152/ajpheart.00771.2007},
    URL = {http://ajpheart.physiology.org/content/293/5/H3036},
    eprint = {http://ajpheart.physiology.org/content/293/5/H3036.full.pdf},
    journal = {American Journal of Physiology - Heart and Circulatory Physiology}
}

Other Resources

• NIH Grants Policy Statements: https://grants.nih.gov/grants/policy/policy.htm#gps
• NIH Pending Financial/Progress Report Search
  • IPF# 8721001
  • http://era.nih.gov/commons/quick_queries/index.cfm#progress

10/14/2013 OCRE Monthly Teleconference Agenda/Notes

1. IACUC restriction / Gov. shutdown: We are still waiting on removal of the IACUC restriction. The Govt. shutown must end before this will happen.
2. Updates/ideas:
   • Brad/Sunil: Brad and Sunil have submitted a paper comparing the Zhang et al. and LRd models with respect to the strength-interval curve.
   • John/Venya: Venya has completed two additional control anoxia experiments with rabbit hearts.
   • Matt/Vincent: Minchun Zhou has submitted an abstract related to challenge-response optimal design to ENAR 2014.
3. Shaw & Rudy vs. Rodriguez et al. vs. Terkildsen et al. models of ischemia (LRd extensions)
   • Do these models already accommodate an experimental design (dynamic alterations to K+, etc.)?
4. Actions
   • We will do two sets of ischemia/anoxia experiments, measuring dV/dt_max and APD_50/70/90 to distinguish the selected models. Both sets of experiments will have the option to "design" the pacing frequency, and to implement one or more ischemic/anoxic and recovery periods with specified durations (within reasonable limits). The first set of experiments will be designed by conventional means (i.e., by consensus of our model/experiment experts; best possible experiment using only the methods at hand). The second set of experiments will be designed in an optimal manner (i.e., by selecting the design that yields the most different predictions between the two competing models, accounting for sampling uncertainty that was observed in previous experiments).
   • The two competing models should take, as input, the entire sequence of an experiment (e.g., 90hz pacing, 5 minutes baseline, 6 minutes ischemia, 15 minutes recovery, ...), and output an estimate of the membrane voltage at a fine sampling frequency. This output will then be used to compute dV/dt_max and APD.

11/18/2013 OCRE Monthly Teleconference Agenda/Notes

1. IACUC restriction: IACUC restriction removed.
2. Updates/ideas:
   • Rick: Literature review.
   • Brad/Sunil: 20131118-Roth-APDvsTime-ChallengeResponse.pdf: Roth simulations related to Rodriguez et al (2002).
   • John/Venya: Discussion of I-wire potential and potential for contractility models.
   • Matt/Vincent: 20131118-Shotwell-APD90-GaurEtAlHypoxia.pdf: APD vs. Time - On/Off beta-adrenergic stimulation - Gaur et al (2009).
3. Shaw & Rudy vs. Rodriguez et al. vs. Terkildsen et al. models of ischemia (LRd extensions)
   • Do these models already accommodate an experimental design (dynamic alterations to K+, etc.): No
4. Guar et al. (2009): hypoxia + beta-adrenergic stimulation
   • C++ code available
5. Additional notes: There was some discussion of the feasibility of isoprenaline beta-adrenergic stimulation in isolated rabbit hearts, since this is part of the sympathetic response to hypoxia. We had considered some experiments to identify if this is a plausible mechanism in isolated rabbit hearts. http://www.ncbi.nlm.nih.gov/pubmed/2825040

12/16/2013 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick:
   • Brad/Sunil:
     • 20131216-KandelRoth.pdf
     • http://www.sciencedirect.com/science/article/pii/S0006349501759656
   • John/Venya:
   • Matt/Vincent:
2. Possible alternative mechanisms of ischemia
   • Shaw & Rudy
     1. Shaw and Rudy's model of ischemia is an ancestor of the models below, but not a serious contender. While the two models below are 'dynamic' in the sense that they model the timecourse of ischemia, the Shaw & Rudy model is static in this regard.
   • Rodriguez et al. (KATP channel is primary actor in extracellular K accumulation)
     1. Interruption of coronary flow ('...steeply increasing [the time constant for diffusion of ions from the interstitial clefts to the bulk extracellular medium] τdiff from its normoxic value (1,000 ms) to infinity...')
     2. Alteration of ATP-dependent potassium current ('...[the proportion of activated ATP-sensitive potassium channels] fATP was linearly increased during 14 min from zero to a different final maximum...')
     3. Na-K pump inhibition; the maximum current was decreased linearly during ischemia
     4. New inward Na current, '...which progressively increases with time of ischemia, beginning 2 min after onset...'
     5. Shrinkage of extracellular space ('...[the interstitial cleft volume] Vcleft was linearly decreased by 21% in 14 min of interrupted coronary flow.')
     6. Acidosis ('...linearly decreasing the conductances of INa and ICa.L until 75% of their nomoxic value during 14 min of simulated ischemia.')
   • Terkildsen et al. (Na-K pump is primary actor; they argue (with evidence from another paper) that KATP cannot account for the biggest proportion of K accumulation)
     1. Na-K pump alteration; uses Simth-Crampin Na-K pump model which is sensitive to intra- and extracellular Na and K concentration, and intracellular ATP and H+;
     2. KATP channel alteration; uses Michailova et al description of channel, depends on ATP, ADP, and extracellular K.
     3. Shrinkage of extracellular space (cellular osmolarity linearly increased over 15 minutes of ischemia)
     4. Ischemia alters the metabolite timecourses of intracellular ATP concentration, P, PCr, and pH, thereby affecting the KATP channel and Na-K pump

01/13/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick: Rick and Matt to discuss some statistical issues related to patch clamp experiments.
   • Brad/Sunil: Brad and Sunil are close to completing a Fortran implementation of the Rodriguez et al. model. Once this is completed, we must further modify the implementation as follows:
     1. parameterize the length of simulation, pacing frequency, start and stop of multiple ischemic events
     2. the program should be able to read parameters from an initialization file
     3. we will postulate and implement two or more mechanisms for transitioning from an ischemic to normal state (this was not considered by Rodriguez)

• • John/Venya: Venya is working to wind up preliminary rabbit anoxia/ischemia experiments
  • Matt/Vincent: Matt to help implement the code changes above

02/10/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick: Third model from Kyoto researchers.
   • Brad/Sunil: Brad and Sunil have completed the preliminary implementation of the Rodriguez et al. model, and are now working on the Terkidlsen model. Paper accepted in "Circulation Journal". Sunil ICERM presented paper. Sunil to attend Biophysical Society meeting in Feb.
   • John/Venya:
   • Matt/Vincent: Matt is working on revisions of the Rodriguez code in preparation for optimal design simulations. Matt gave talk at University of Louisville regarding optimal design of challenge response experiments in the context of pharmacokinetic analysis; work with B. Fissell and M. Zhou. Minchun Zhou will give a poster presentation at ENAR in March on the same topic.
2. We have started a Github repository for our code here: https://github.com/biostatmatt/ocre
3. Questions for Brad/Sunil regarding the Rodriguez implementation:
   1. ischemia begins at 30 seconds and lasts for 14 minutes
   2. cleft changes happen immediately
   3. after two minutes of ischemia Na channel is affected
   4. at the end of ischemia, there is no recovery
4. Follow-up with Rick

04/14/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick:
   • Brad/Sunil: Implemented Terkildsen model: Implementation-Terkildsen-2007-model.docx
   • John/Venya:
   • Matt/Vincent: Implemented some alternative ischemia 'recovery' mechanisms using the Rodriguez model: 20140414-rodriguez4-notes.pdf
2. Plans for optimal design:
   • The Rodriguez model for ischemia may not be well supported by the rabbit heart ischemia data; consider 'fitting' the 'fully exponential' model
   • Shotwell-2013-Biometrics-63-3-Preprint.pdf: Shotwell-2013-Biometrics-63-3-Preprint.pdf
   • Consider optimal designs to distinguish 'instantaneous' versus 'exponential' recovery; other suggestions welcome
3. Additional work
   • Modify Terkildsen model for recovery from ischemia

05/12/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick sent several papers to review.
   • John/Venya: John has put us in contact with Jeff Ardell, who has studied intrinsic neuronal mechanisms in cardiac tissue, which is perhaps responsible for the elongation of APD observed just after onset of anoxia.
   • Matt: Four distinct candidate mechanisms of recovery have been implemented and "fitted" to the anoxia data using an "overmodeling" or "model wrapping" technique. This method needs additional work, but is the basis for optimal design simulations, and evidence quantification.
2. Progress report: Due 6/15/2014

06/16/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick: Literature review.
   • Brad/Sunil: Literature search: Ito responsible 4-AP blocks transient outward current
   • John/Venya: Preparations for optimal experiments and Ito and beta-adrenergic antagonism experiments
   • Matt: optimal designs for recovery from ischemia
2. Progress report: Due 6/15/2015
3. Discuss papers and possibility of intrinsic neuronal mechanism
4. Discuss beta-adrenergic stimulation model and implementation

07/14/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick: paper/model review; paper modifies LR model for rabbit and implements a graphical interface;
   • Brad/Sunil: ImplementatioPuglisi pn of mechanisms for transient APD lengthening just after ischemia/anoxia.
   • John/Venya: Planned experiments.
   • Matt: Draft of PK/dialysis challenge response paper: https://data.vanderbilt.edu/collab/shotwems/20140714-optimal-design-pk-dialysis.pdf

08/11/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick:
   • Brad/Sunil: Ito results: Role of Ito Current in APD
   • John/Venya: Update on Langendorf experiments/iWire
   • Matt:
     • Need to accelerate Langendorf experiments (those associated with optimal design and otherwise)
     • Grant entering second award year

09/08/2014 OCRE Monthly Teleconference Agenda/Notes

1. Updates/ideas:
   • Rick: progress on modeling & Pras' paper; how to incorporate this work?
     • Markov models
   • Brad/Sunil: progress on Ito model (elongation of APD); Guar, Rudy, Hool?
   • John/Venya: rabbit experiments update; iWire update?
     • 3 additional experiments
       • 4-aminopyridine
   • Matt/Vincent: PK/Dialysis challenge response paper 'revise and resubmit'

10/20/2014 OCRE Monthly Teleconference Agenda/Notes

11/17/2014 OCRE Monthly Teleconference Agenda/Notes

12/15/2014 OCRE Monthly Teleconference Agenda/Notes

• details of voltage trace ("trace_8590.dat")
  • conditions (normoxic/anoxic)
  • units (normalized potential; how to get absolute potential)
• details of additional anoxia experiments (APD90? Yes)
  • transient elongation of APD during first event; no elongation at second event
• TODO: compare anoxia results with predictions about anoxia recovery
• need more replicates of 'optimal' anoxia experiments?
• updates on LR model modifications (Saucerman, Beard)
• next steps: strength-interval curve (recovery of excitability) experiments (pg. 14 of resubmission document)
  • "Make" is when the stimulus begins; "Break" is when the stimulus ends, right?
  • "Adjacent regions of depolarization (positive transmembrane potential) are created along the fiber direction." "One source is the depolarization caused directly by the S2 stimulus (the virtual cathode), but another source is the surrounding depolarization arising from the previous S1 action potential." I don't get the first part, but the dip is due to the interaction of these two sources of depolarization? Was this the gist of Brad's paper?
  • Two models: bidomain (M1) versus Na-Ca exchange current (M2)
  • what are our optimal design "knobs"? "diffusion coefficient"
  • what experimental framework will we use (optical whole heart)?
• Hill model (electromechanical)

01/12/2015 OCRE Monthly Teleconference Agenda/Notes

• Set new time for teleconference.
• View and discuss additional data from Venya.
  • APD90 traces
  • membrane potential traces in anoxia/control
• Updates from Venya. (additional thoughts on APD elongation after onset of anoxia?)
• Updates from Brad.
• TODO
  • Evaluate evidence in new APD data against alternative models of recovery from ischemia/anoxia.

02/09/2015 OCRE Monthly Teleconference Agenda/Notes

• View and discuss additional data from Venya.
  • APD90 traces
  • verify measurement times (seven minutes of anoxia?)
  • membrane potential traces in anoxia/control (to what extent can we learn about AP shape from these traces?)
• Updates from Venya. (additional thoughts on APD elongation after onset of anoxia?)
• Updates from Brad.
• Discuss next steps (mechanical / electro-mechanical models?)
• TODO
  • Evaluate evidence in new APD data against alternative models of recovery from ischemia/anoxia.
  • Simulate from modified LR model corresponding to Venya's experiments under each of four recovery parameterizations.

04/13/2015 OCRE Monthly Teleconference Agenda/Notes

• What to do with APD prolongation after anoxia data?
  • Neither beta- or Ito-blocker (propranolol and 4-AP, respectively) inhibits transient APD prolongation following acute anoxia.
  • Just one heart? Any degree of inhibition? Dose sufficient to inhibit? Drug infused?
• status of project 1.
  • experiment-matching simulations complete
  • TODO: prototype regression: adjust for location, scale, and secular trends; upweight region of interest
  • TODO: quantify information/effort; criterion based; curvature of likelihood component; likelihood ratio
  • TODO: report writing
• status/plan of project 2.
  • use Rick's model in bidomain
  • where does model fail (against experimental data; or other model predictions); APD restitution curve
  • compare simplified model to LR-1 (may not be gold-standard) with regard to the strength-interval curve.
  • compare linear versus nonlinear potassium kinetics in the strength-interval curve; design stimulus waveform
  • adjust S2 shape to get better recovery of excitability curve;
• mechanical model (i-wire)

06/08/2015 OCRE Monthly Teleconference Agenda/Notes

• progress report due June 15th.
• status of project 1.
  • experiment-matching simulations complete
  • prototype regression: adjust for location, scale, and secular trends; upweight region of interest
  • TODO: quantify information/effort; criterion based; curvature of likelihood component; likelihood ratio
  • TODO: report writing
• status/plan of project 2.
  • use Rick's model in bidomain
  • where does model fail (against experimental data; or other model predictions); APD restitution curve
  • compare simplified model to LR-1 (may not be gold-standard) with regard to the strength-interval curve.
  • compare linear versus nonlinear potassium kinetics in the strength-interval curve; design stimulus waveform
  • adjust S2 shape to get better recovery of excitability curve;
• mechanical model (i-wire)
  • gentle introduction: http://www.shadmehrlab.org/book/musclemodel.pdf
  • have a lot of data already
  • have candidate modifications to the model
  • can design and implement optimized experiments to further model development

07/27/2015 OCRE Monthly Teleconference Agenda/Notes

• good news:
  • progress report submitted.
  • Galappaththige and Roth paper published in PLoS One
  • Pathmanathan, Shotwell, Gavaghan, Cordeiro, and Gray paper published in Prog. Biophys. Mol. Biol.
  • Shotwell, Zhou, & Fissell paper accepted in J. Biopharm. Stat.
  • Shotwell & Gray paper submitted to J. Comp. Stat. Data Anal.
  • 2 additional papers from Roth et al.
• status of project 1.
  • experiment-matching simulations complete
  • prototype regression: adjust for location, scale, and secular trends; upweight region of interest
  • TODO: quantify information/effort; criterion based; curvature of likelihood component; likelihood ratio
  • TODO: report writing
• status/plan of project 2.
  • use Rick's model in bidomain: discuss results from Brad
  • adjust S2 shape? Currently a square wave stimulus (cathode and anode)?
  • investigate repolarization current characteristics on SI curve?
• mechanical model (I-wire)
  • Venya's contraction force restitution experiments
  • Minchun working to reproduce Alison's analysis; may try to simulate contraction force restitution experiments

09/21/2015 OCRE Monthly Teleconference Agenda/Notes

• good news:
  • Drake et al paper published in Physiological Reports
  • NoGA received
• status of project 1.
  • TODO: quantify information/effort; criterion based; curvature of likelihood component; likelihood ratio
  • TODO: report writing
• status/plan of project 2.
  • use Rick's model in bidomain; code from Brad
  • adjust S2 shape? Currently a square wave stimulus (cathode and anode)?
  • investigate repolarization current characteristics on SI curve?
• mechanical model (I-wire)
  • Minchun still working on model implementation; may try to simulate contraction force restitution experiments
• direct fit to VC data
  • need more VC protocols

12/17/2015 OCRE Monthly Teleconference Agenda/Notes

• News:
  • Rick and Matt paper "Estimability Analysis and Optimal Design in Dynamic Multi-scale Models of Cardiac Electrophysiology" reviewed very well; will resubmit shortly.
  • Matt present poster at Rock Mountain Bioinformatics conference "Estimating parameters of the Hodgkin-Huxley cardiac cell model by integrating raw data from multiple types of voltage-clamp experiments"; manuscript forthcoming.
• Status of project 1.
  • Get GMail addresses for John, Venya, and Vincent, in order to share draft: view only link
  • Discuss draft of "Extending LRd to model recovery from ischemia using an optimal design technique"
• Rick to lead discussion.
• Mechanical model (I-wire)
  • Minchun still working on model implementation; may try to simulate contraction force restitution experiments
• Direct fit to VC data
  • need more VC protocols

01/11/2016 OCRE Monthly Teleconference Agenda/Notes

• News:
  • Rick and Matt paper "Estimability Analysis and Optimal Design in Dynamic Multi-scale Models of Cardiac Electrophysiology" accepted
  • Other news?
• Status of project 1.
  • Waiting on comments/revisions to "Extending LRd to model recovery from ischemia using an optimal design technique"
• Mechanical model (I-wire)
  • Minchun still working on model implementation; may try to simulate contraction force restitution experiments
  • What is the Hill model?
    • Differential equation in time with two variables: muscle force and length
    • Based on mechanical model (system of springs and dampeners)
    • Need to input "active" force function of time (looks like AP)
    • Tension and length are related in the I-wire construct, introducing a second equation
    • Can solve system for tension (or length) as function of time
  • What can we do with this (in the context of optimal design)?
    • Does model fit well with Venya's data?
    • Consider alternative models fit better (stimuli that better distinguish models).
    • Does model predict high frequency stimulation data (Venya have HF stim data?)?
    • Apply mechanical twitch.

02/08/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique"
  • Need Sunil PhD thesis citation
  • Need Sidorov et al. 2007,2008 citations
  • Working on final touches.
• Mechanical model (I-wire)
  • see webpage: http://data.vanderbilt.edu/collab/shotwems/Schroer-I-wire/
  • TODO: characterize variability in I-wire mechanical properties across preps...
  • what are the design 'knobs'?
• Integrate work with Rick.
  • Suran's initial results of the cardiac SI curves using Rick's minimal model (and movies).
  • Simultaneously combine multiple types of VC data to estimate model parameters
  • VC protocol design

03/21/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique"
  • Working on final touches and reformatting (LaTeX).
• Updates on Brad/Suran's work.
  • Continuing to work on strength-interval curve; biphasic and bipolar (few mm apart) stimuli.
  • Learn whether we can see stimulus effects with smaller stimulus strengths (e.g., break excitation with smaller stimulus strength).
• Mechanical model (I-wire)
  • see webpage: https://data.vanderbilt.edu/collab/shotwems/con-iso-Iwire-data/
  • what other types of experiment can we try (simulate)?
  • can we set up these experiments?

04/18/2016 OCRE Monthly Teleconference Agenda/Notes

• Progress report due mid June; need information
• Review strategy.
• "Extending LRd to model recovery from ischemia using an optimal design technique"
  • Need final approval.
• Updates on Brad/Suran's work.
• Mechanical model (I-wire)
  • status of papers.
  • see webpage: https://data.vanderbilt.edu/collab/shotwems/con-iso-Iwire-data/
  • examine stiffness of probe and twitch characteristics (how fast is necessary)
  • compare calcium signal with inferred active force function

05/09/2016 OCRE Monthly Teleconference Agenda/Notes

• Progress report due mid June; need information
• Review strategy
  • I-wire: identify experiments to isolate muscle mechanics and active force function
  • I-wire: consider model with mass term, and experiments to validate mass term model
  • electrophysiological modeling; maybe meet with Rick and John C regarding ideas for this component; VC
• Updates on Brad/Suran's work.
  • knobs: electrode position; stimulus characteristics; population variability
• "Extending LRd to model recovery from ischemia using an optimal design technique"
  • uploaded and ready to submit pending FDA approval
• Mechanical model (I-wire)
  • https://data.vanderbilt.edu/collab/shotwems/Iwire-optim-simul/
    • consider probe stiffness
    • consider simultaneous dynamic stretch and electrical stimulation
  • status of papers other papers

06/13/2016 OCRE Monthly Teleconference Agenda/Notes

• Progress report submitted
• "Extending LRd to model recovery from ischemia using an optimal design technique" resubmitted to "Communications in Statistics: Case Studies, Data Analysis and Applications"
• I-wire I and II resubmitted
• Integrating Brad/Suran's work.
  • Brad and Suran are using Rick's model in combination with bi-domain model to simulate behaviors of (2D) cardiac tissue
  • Are there any particular phenomena that we might examine with this model? Data to back it up? We can ask whether model parameters estimable using existing data.
• Revisit work for poster at Rocky:
  • "Estimating parameters of the Hodgkin-Huxley cardiac cell model by integrating raw data from multiple types of voltage clamp experiments"
• Mechanical model (I-wire)
  • consider probe stiffness
  • consider simultaneous dynamic stretch and electrical stimulation
• Direction: Examine the (parameters) INa model; design VC experiments; AP alternans; John Cordiero (Masonic Research Lab; Utica, NY).
  • This may be a longer term project (perhaps as part of renewal or new grant).
• Direction: Examine the two IK1 parameters (b1, b2) of Rick's model; two knobs: anode-cathode distance and resting potential; strength-interval curve
  • Brad and Suran are going to do additional work to ensure SI-curve code working well then pass to Matt for simulation and optimal design.

07/11/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique" under review with "Communications in Statistics: Case Studies, Data Analysis and Applications"
• I-wire I and II resubmitted?
• Brad/Suran's update.
  • Examine the two IK1 parameters (b1, b2) of Rick's model; two knobs: anode-cathode distance and resting potential; strength-interval curve
  • Brad and Suran are going to do additional work to ensure SI-curve code working well then pass to Matt for simulation and optimal design
  • Venya has evaluated bipolar stimulation 1.5mm; 2ms and 20ms stimuli; strength-interval curve
• Revisit work for poster at Rocky:
  • "Estimating parameters of the Hodgkin-Huxley cardiac cell model by integrating raw data from multiple types of voltage clamp experiments"
• Mechanical model (I-wire)
  • consider probe stiffness
  • consider simultaneous dynamic stretch and electrical stimulation
• Direction: Examine the (parameters) INa model; design VC experiments; AP alternans; John Cordiero (Masonic Research Lab; Utica, NY).
  • This may be a longer term project (perhaps as part of renewal or new grant).

08/08/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique" under review with "Communications in Statistics: Case Studies, Data Analysis and Applications"
• I-wire II reviewed; resubmission status?
• Brad/Suran's updates
  • bipolar stimulation SI simulation results/videos
  • TODO: Shotwell to consider optimal anode-cathode distance, orientation of electrodes, resting potential (using Brad/Suran code) for the purpose of estimating minimal model parameters
  • TODO: Brad to send paper that decribes simulation videos
• John/Venya updates
  • bipolar stimulation SI data/figures
• Mechanical model (I-wire) updates
  • probe stiffness & simultaneous stretch and electrical stimulation results
  • TODO: Shotwell to consider optimal weighting of experiments
• Direction: Examine the (parameters) INa model; design VC experiments; AP alternans; John Cordiero (Masonic Research Lab; Utica, NY).
  • This may be a longer term project (perhaps as part of renewal or new grant).
  • We will meet in DC later in August.
• Vincent

09/19/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique" in revision
• I-wire II reviewed; need co-author comments before resubmission!
• Brad/Suran's updates
  • SI curve mimial ionic model
• John/Venya updates
  • Ca change during pacing and spontaneous ECTC activity
• Mechanical model (I-wire) updates
  • probe stiffness & simultaneous stretch and electrical stimulation results
  • TODO: Shotwell to consider optimal weighting of experiments
• Vincent

10/17/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique" in revision
• I-wire II reviewed and resubmitted (I-wire I too?)
• Brad/Suran's updates
  • description and movies
• John/Venya updates
  • Ca change during pacing and spontaneous ECTC activity
• Mechanical model (I-wire) updates
  • probe stiffness & simultaneous stretch and electrical stimulation results
  • TODO: Shotwell to consider optimal weighting of experiments
• Shotwell/Gray abstract to Rocky 2016 accepted: "Automated Optimal Design of Voltage Clamp Protocols to Study Sodium Channel Kinetics Using a Minimal Cardiac Ion Channel Model."

11/21/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique" in revision
• I-wire II accepted: "I-Wire Heart-on-a-Chip II: Biomechanical analysis of contractile, three-dimensional cardiomyocyte tissue constructs" Acta Biomaterialia
• Brad/Suran's updates
  • resubmitted unipolar paper
  • working on bipolar paper
  • Shotwell to check if received bipolar code from Brad/Suran
• John/Venya updates
  • Venya has calcium and contractile force data; simultaneous
  • What is state of the art in modeling calcium-force curve?
    • Rick sent Shotwell auxotonic calcium-length data; simultaneously
    • Plug in Venya's calcium data to hill model
    • Tissue chips proposal; paragraph about advanced analysis using Hill model with calcium data (Hill model and future), etc.; Organ on chips for disease models
• Mechanical model (I-wire) updates
  • TODO: Shotwell to consider optimal weighting of experiments
  • Consider alternative model extensions to account for calcium data
  • Twisting (shearing force during development); mechanotransduction during muscle development
• Shotwell/Gray abstract to Rocky 2016 accepted: "Automated Optimal Design of Voltage Clamp Protocols to Study Sodium Channel Kinetics Using a Minimal Cardiac Ion Channel Model."
• Prepping for no-cost extension in order to complete research dissemination

12/19/2016 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique" in revision
• Brad/Suran's updates
  • Discussion of I-wire
• John/Venya updates
  • Simultaneous contractile and calcium data
• Shotwell/Gray poster presented at Rocky 2016: "Automated Optimal Design of Voltage Clamp Protocols to Study Sodium Channel Kinetics Using a Minimal Cardiac Ion Channel Model."
• Prepping for no-cost extension in order to complete research dissemination

01/23/2017 OCRE Monthly Teleconference Agenda/Notes

• "Extending LRd to model recovery from ischemia using an optimal design technique" in revision
• Both I-wire papers accepted
• Brad/Suran's updates
  • unipolar paper accepted
  • working on bipolar paper
  • Shotwell to use examine bipolar code for potential optimal design applications
• John/Venya updates
  • Venya plan to resume calcium experiments in Feb.
• Mechanical model (I-wire) updates
  • Shotwell to use simultaneous calcium/force data with Hill model.
  • Consider alternative model extensions to account for calcium data
  • Consider idea of ET-optimality for comparing Hill model extensions * Prepping for no-cost extension in order to complete research dissemination

02/20/2017 OCRE Monthly Teleconference Agenda/Notes

• "Applying optimal experimental design to a `black box' cardiac cell model" to be submitted to PLoS One
• Brad/Suran's updates
  • Updates on bipolar simulation paper
• John/Venya updates
  • Updates on I-wire experiments
• Mechanical model (I-wire) updates
  • Updates on I-wire modeling with modified Hill equations
• Prepping for no-cost extension in order to complete research dissemination

03/31/2017 OCRE Monthly Teleconference Agenda/Notes

• "Applying optimal experimental design to consider alternative extensions of a complex cardiac cell model"; working on submission to PLoS One
• Brad/Suran's updates
  • Suran Ph.D. dissertation defended
  • Bipolar simulation paper submitted to Chaos
  • PLoS One unipolar paper published
• John/Venya updates
• Mechanical model (I-wire) updates
  • Updates on I-wire modeling with modified Hill equations
• Prepping for no-cost extension
• Ideas for the future

05/15/2017 OCRE Monthly Teleconference Agenda/Notes

• "Applying optimal experimental design to consider alternative extensions of a complex cardiac cell model"; working on submission to PLoS One
• Brad/Suran's updates
• John/Venya updates
• Mechanical model (I-wire) updates
  • Updates on I-wire modeling with modified Hill equations
• Notes on no-cost extension
• Competing renewal deadline: July 5th
  • Ideas: quantifying pharmacological effects on cardiac electromechanophysiology using I-wire
  • Ideas: translational applications? STEMI? tPA? preventative? development?
  • Ideas: should we consult with cardiologist/developmental/preventative clinician?
  • John's ideas w.r.t I-wire:
    • GSK/I-wire
    • Charles Hong (VUMC) (characterize/develop models for differentiation of ISPC-derived cardiomyocytes)
    • Venya and John Curci; Mechanisms by which AAA occurs (contractility or elasticity of smooth muscle); Use I-wire as a mechanical model of AAA; use mathematical model to quantify/characterize changes in I-wire mechanics over time or in response to perturbation/therapy. Mechanical bidomain model.