Humans cardiomyocites
Human cardiomyocytes

Human cardiomyocytes derived from iPS cells for preclinical drug studies

Healthy human heart cells are very rare and only available in very small quantities for obvious reasons of accessibility. Human cardiomyocytes derived from induced pluripotent stem cells (hiPSC-CM) allow to access human ventricular-like myocytes more easily. Due to their origin, these cells present the same functional and electrophysiological characteristics as human cardiomyocytes and offer a good alternative to ex vivo and in vivo models for drug development.

Human cardiomyocytes & cardiac safety studies

Human cardiomyocytes derived from iPS cells provide a good solution to study the repercussion of ion channels effects on cardiac electrical activity during preclinical studies. This human in vitro model can be used to evaluate the cardiac safety of newly developed drugs and is currently validated by the CiPA initiative for cardiac preclinical safety assessment.

What is shown?

To measure the effects of newly developed drugs on cardiac safety, we study their action potential, i.e. we measure ion movements through the different transmembrane ionic channels. The modification of the shape of the action potential gives information about ion channel effects.

MEA impedance

Impedance measurements

Healthy human heart cells are very rare and only available in very small quantities for obvious reasons of accessibility. Human cardiomyocytes derived from induced pluripotent stem cells (hiPSC-CM) allow to access human ventricular-​like myocytes more easily. Due to their origin, these cells present the same functional and electrophysiological characteristics as human cardiomyocytes and offer a good alternative to ex vivo and in vivo models for drug development.

Microelectrode array

MicroElectrode Array (MEA) recordings are a non-invasive way to measure integrated ion channel activity. The MEA system provides ECG-like results and detects modifications in beat rate, pro-arrhythmic events and other adverse effects.

Technique

  • xCELLigence RTCA Cardio ECR platform

Study model

  • Human IPSc derived cardiomyocytes
  • 48 wells plate format
  • Simultaneous recording of MEA and impedance signals on the entire plate

Protocol

  • 1 negative control (DMSO 0.1%)
  • 2 or 3 positive controls (1 concentration)
  • Compounds: several options from 1 compound (6 concentrations, n=6) up to 9 compounds (1 concentration, n=4)
  • Short-term and long-term exposure (up to 48 to 72h)

Measured parameters

  • Cell viability: Cell Index
  • Electrophysiology (MEA)
    • Firing rate
    • FPD
    • FPDc (Fredericia)
    • Spike amplitude
  • Contraction (Impedance)
    • Amplitude of contraction
    • Beat rate
    • Beating period
    • Individual beat duration (IBD10, 50, 90)
    • Proarrhythmic events (BRI)
Mea-impedance

Reference compounds

  • Nifedipine
  • E-4031
  • Pentamidine

Results

  • Stability of recorded parameters in control conditions and reproductibility between plates

Typical effects of DMSO 0.1% on Beat rate.

Nifedipine (Low TdP risk)

Nifedipine

Typical effects of Nifedipine on the amplitude of contraction.

Pentamidine (long-term exposure)

Pentamidine

Typical effects of Pentamidine on impedance signal and FPDc.

Action potential recordings

Technique

  • Manual Patch Clamp (current clamp configuration)
  • Non-cumulative concentrations

Study model

  • Pluricyte® from Ncardia
  • 3 or 6 treated cells

Measured parameters

  • Resting Potential (mV)
  • Amplitude (mV)
  • Action Potential Duration at 20% and 90% repolarisation : ADP20  - ADP90(ms)

Pluricyte® cardiomyocytes

Pluricyte® cardiomyocytes

Typical effects of nifedipine and bepridil on human cardiomyocytes derived from iPS (action potential recordings) on Pluricyte® cardiomyocytes.

Main cardiac ion channel recordings

The voltage-clamp technique allows to record the three specific currents (Ik, INa, ICa) that are involved in the action potential on individual human cardiomyocytes.

Technique

  • Manual Patch Clamp (current clamp configuration)
  • Non-cumulative concentrations

Study model

  • Human cardiomyocytes
  • 3 or 6 treated cells

Calcium current recordings

Calcium current recordings

Sodium current recordings

Sodium current recordings

Potassium current recordings

Potassium current recordings

Additional tests according to PhysioStim scientist’s expertise

PhysioStim Isolated Perfused Heart

Isolated perfused heart

hERG assays

PhysioStim Sodium Channel assays

Sodium channel assays

Calcium channel

Calcium channel assays

PhysioStim Potassium Channel assays

Other Potassium channel assays

Need help with your preclinical safety studies?

contact us