Isolated Heart (Langendorff)

The Isolated Heart (Langendorff) Assay

Request a Study Outline from IPST

Highlights:

  • Isolated heart perfused with increasing concentrations of test article
  • Spontaneously-beating or stimulated hearts
  • RR, PR, QRS, QT, QTc intervals
  • Left-ventricle contraction
  • Rat, guinea-pig, rabbit, dog hearts
Isolated rabbit heart mounted into a perfusion chamber, with ECG and stimulation leads
Isolated rabbit heart mounted into a perfusion chamber, with ECG and stimulation leads
Representative left ventricular pressure ,ECG and MAP measurements obtained from an isolated rabbit heart.
Representative left ventricular pressure ,ECG and MAP measurements obtained from an isolated rabbit heart.

Retrograde heart perfusion (Langendorff) with monitoring of ECGs, left ventricular pressure and Monophasic Action Potential (MAP)

Pre-IND (GLP-compliant) or exploratory designs (screen = non-GLP)

The potential to prolong the QT interval has a major impact on drug development programs. The isolated heart preparation by Langendorff provides rapid, inexpensive, reproducible and sensitive predictions of QT-prolonging potential. Moreover, the Langendorff preparation allows the assessment of the effects of a drug on electrophysiological (ECG, MAP) and mechanical (left ventricular tension, coronary pressure and flow rate) parameters, yielding a variety of safety or toxicity indicators in a single study. Common disease phenotypes are easily reproduced using this complex ex vivo model.

Study Outline:

  • Number of hearts exposed to the test article: 5 hearts  (Screens: 3)
  • Number of concentrations of test article tested: 4 or more  (Screens: 3)
  • The model can be surgically altered to reproduce disease characteristics of interest
  • Stimulation : variable frequencies of stimulation or spontaneously beating hearts
  • A study includes positive, negative, and vehicle controls

Study Outcome:

  • A simultaneous assessment of cardiac electrophysiological and mechanical parameters
  • Dissection and compilation of RR, PR, QRS, QT, QTc, intervals and LVP, dLVP/dt
  • Continuous monophasic action potential (MAP), coronary pressure and flow monitoring
  • Clinical cardiology interpretation of the ECG signal, describing events and tendencies
  • FDA-ready hard copy and e-report for electronic IND submission
  • Holistic interpretation of a positive signal, considering all other data generated

Graphs:

1- RR versus test article concentration (experimental conditions)
2- PR versus test article concentration
3- QRS versus test article concentration
4- QT and QTc versus test article concentration
5- Coronary pressure versus test article concentration
6- LVP versus test article concentration
7- Rate of contraction (dLVP/dt) versus test article concentration
8- APD90 versus test article concentration

Study timeline:

One week to finalize the protocol/formulation
Three (3) days per test article for data acquisition and three (3) days for analysis

Reporting:

Non-audited summary of results two (2) weeks following the last measurement. Audited draft of the final report two (2) weeks following the release of the summary of results.

Options:

  • Additional frequencies of pacing
  • Reverse rate dependence (1.5Hz, 3Hz, 4Hz)
  • Perfusate collection (for signs of inflammation)

Recommended reading:

  1. Skrzypiec-Spring M. Grotthus B. Szelag A. Schulz R., Isolated heart perfusion according to Langendorff– Still viable in the new millenium., J of Pharm. And Tox. Methods., 2007; 55:113-126.
  2. Valentin J-P. Hoffman P. Clerck FD. Hammond TG. Hondeghem L., Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs., J of Pharm. & Tox. Methods., 2004; 49:171-181