Abstract
Aim: The cardiac electrophysiology of mice and rats has been analyzed extensively, often in the context of pathological manipulations. However, the effects of beating rate on the basic electrical properties of the rodent heart remain unclear. Due to technical challenges, reported electrophysiological studies in rodents are mainly from ex vivo preparations or under deep anesthesia, conditions that might be quite far from the normal physiological state. The aim of the current study was to characterize the ventricular rate-adaptation properties of unanesthetized rats and mice.Methods: An implanted device was chronically implanted in rodents for atrial or ventricular pacing studies. Following recovery from surgery, QT interval was evaluated in rodents exposed to atrial pacing at various frequencies. In addition, the frequency dependence of ventricular refractoriness was tested by conventional ventricular programmed stimulation protocols.Results: Our findings indicate total absence of conventional rate-adaptation properties for both QT interval and ventricular refractoriness. Using monophasic action potential recordings in isolated mice hearts we could confirm the previously reported shortening of the action potential duration at fast pacing rates. However, we found that this mild shortening did not result in similar decrease of ventricular refractory period.Conclusion: Our findings indicate that unanesthetized rodents exhibit flat QT interval and ventricular refractory period rate-dependence. This data argue against empirical use of QT interval correction methods in rodent studies. Our new methodology allowing atrial and ventricular pacing of unanesthetized freely moving rodents may facilitate more appropriate utility of these important animal models in the context of cardiac electrophysiology studies.
Highlights
Mice and rats are used extensively in cardiac research to study pathophysiological mechanisms of human diseases (Gill et al, 1989; Lin et al, 1995; London, 2001; Jacob and Kwitek, 2002; Tarnavski et al, 2004; Bhindi et al, 2006)
We found that excessive rapid pacing of the ventricle, which was require to determine the ventricular effective refractory period (VERP), usually induced long-term shortening of the action potential duration (APD) or instability of the monophasic action potential (MAP) recordings
Drive trains with different basic cycle length (BCL) were applied starting from near normal BCL and reducing the BCL in 10 ms steps until there was a loss of 1:1 capture in the ventricular myocardium
Summary
Mice and rats are used extensively in cardiac research to study pathophysiological mechanisms of human diseases (Gill et al, 1989; Lin et al, 1995; London, 2001; Jacob and Kwitek, 2002; Tarnavski et al, 2004; Bhindi et al, 2006). Clinical manifestations include a tendency to develop syncope or cardiac arrest due to spontaneous polymorphic ventricular arrhythmias (Postema and Wilde, 2014) It is well-known that QT intervals in humans are dependent on the heart rate (HR) and need to be corrected for HR to improve risk stratification or to standardize QT intervals in experimental subjects (De Bruyne et al, 1999; Rautaharju et al, 2009; Holzgrefe et al, 2014). While drugs with multiple effects (e.g., isoproterenol) suggested dependence of the QT on the beating rate, the QT interval remained unaltered following the application of ivabradine, which selectively affect the HR alone
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