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Minimal force-frequency modulation of inotropy and relaxation of in situ murine heart
1Division of Cardiology, Department of Medicine and Department of Biomedical Engineering, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Insights
Mice have limited heart rate (HR) reserve for cardiac contraction and relaxation compared to humans. This study reveals minimal force-frequency dependence in mice within physiological HR ranges, impacting genetic model interpretation.
Area of Science:
- Cardiovascular Physiology
- Mammalian Physiology
Background:
- The influence of heart rate (HR) on cardiac contraction and relaxation in mice is not well understood, hindering the interpretation of genetically engineered models.
- Previous in vivo studies showing positive effects only at subphysiological HRs may be confounded by experimental conditions.
Purpose of the Study:
- To investigate the force-frequency relationship in mice across a physiological range of heart rates.
- To determine cardiac-specific contractile and relaxation indexes independent of vascular load.
Main Methods:
- Open-chest mice (n=16) were instrumented with a pressure-volume catheter for left ventricular (LV) volume calibration.
- Heart rate was manipulated using ultra-low frequency stimulation (ULFS-49) and atrial/ventricular pacing.
- Pressure-volume data provided load-insensitive contractile and relaxation indexes.
Main Results:
- At a resting HR of 600 beats/min, peak pressure-rise rate (dP/dt(max)) and relaxation time constant were comparable to conscious animals.
- Load-insensitive indexes varied minimally between 500-850 beats/min, with dP/dt(max) peaking at 600 beats/min.
- Contraction and relaxation were modestly enhanced (13-15%) at HRs of 400-500 beats/min, with minimal force-frequency dependence due to rapid calcium cycling.
Conclusions:
- Mice exhibit a very limited force-frequency reserve at physiological HRs, contrasting with larger mammals and humans.
- This finding is crucial for interpreting genetic models affecting calcium handling and sarcoplasmic reticulum function.
- Understanding mouse cardiac physiology is vital for disease modeling and survival studies.
Abstract:
1. The normal influence of heart rate (HR) on cardiac contraction and relaxation in the mouse remains uncertain despite its importance in interpreting many genetically engineered models. Prior in vivo data have repeatedly shown positive effects only at subphysiological heart rates, yet depressed basal conditions and use of load-dependent parameters probably have an impact on these results. 2. Open-chest mice of various strains (n = 16, etomidate/urethane anaesthesia) were instrumented with a miniaturized pressure-volume catheter employing absolute left ventricular (LV) volume calibration. HR was slowed (< 400 beats min(-1)) using ULFS-49, and atrial or ventricular pacing was achieved via an intra-oesophageal catheter. Pressure-volume data yielded cardiac-specific contractile indexes minimally altered by vascular load. 3. At a resting HR of 600 beats min(-1), peak pressure-rise rate (dP/dt(max)) was 16 871 +/- 2941 mmHg s(-1) (mean +/- S.D.) and the relaxation time constant was 3.9 +/- 0.8 ms, similar to values in conscious animals. Within the broad physiological range (500-850 beats min(-1)), load-insensitive contractile indexes and relaxation rate varied minimally, whereas dP/dt(max) peaked at 600 +/- 25 beats min(-1) and decreased at higher rates due to preload sensitivity. Contraction and relaxation were enhanced modestly (13-15 %) at HRs of between 400 and 500 beats min(-1). 4. The minimal force-frequency dependence was explained by rapid calcium cycling kinetics, with a mechanical restitution time constant of 9 +/- 2.7 ms, and by dominant sarcoplasmic reticular buffering (recirculation fraction of 93 +/- 1 %). 5. The mouse normally has a very limited force-frequency reserve at physiological HRs, unlike larger mammals and man. This is important to consider when studying disease evolution and survival of genetic models that alter calcium homeostasis and SR function.