In their recent paper ‘Analysis of pacemaker activity in the human stomach’, Sanders, Ward and colleagues challenge several fundamental concepts of human gastric slow wave activity Rhee et al. 2011. The authors make the following claims, based on intracellular recordings from isolated gastric tissue strips: (1) The normal human gastric slow wave frequency ranges from approximately 5–8 cycles per minute (cpm), instead of the established 3 cpm; (2) There is no intrinsic interstitial cells of Cajal (ICC) frequency gradient in the human stomach; (3) Slow wave activity occurs in the gastric fundus; (4) The established clinical diagnostic norms for tachygastria and bradygastria are inaccurate; and (5) All past human gastric extracellular recordings are invalidated by movement artifacts.
If true, these claims would be highly remarkable. However, the authors appear to have been misled by artifactual changes known to occur in isolated tissues, and have also disregarded a substantial body of competing literature.
In a previous feline study, it was established that when gastric tissues are isolated and studied in the manner used by Rhee et al., that: (1) there is a rapid artifactual elevation in the intrinsic slow wave frequencies, (2) the intrinsic frequency gradient is artificially lost and (3) slow wave activity appears in normally quiescent proximal gastric tissues (e.g. fundus) (Xue et al. 1995). Similar effects probably explain the irregular results reported by Rhee et al. (2011) in humans. Xue et al. further reported that these in vitro effects could be prevented or reversed by indomethacin, when used in a different manner to that used by Rhee et al. (e.g. immediately after tissue dissection) (Xue et al. 1995).
The normal in vivo human gastric frequency of 3 cpm has been verified in many studies over a century (Alvarez, 1922; Hinder & Kelly, 1977; O'Grady et al. 2010). Notably, the normal contractile frequency of the human stomach is also well established to be 3 cpm (Alvarez, 1922; Pal et al. 2004; Marciani, 2011), and is not >5 cpm, as suggested by Rhee et al. from isolated muscle strip observations. Indeed, the overall pattern of in vivo human gastric contractions revealed by MRI shows very close concordance with extracellular mapping data, including the 3 cpm frequency and the pattern and velocity of waves (Pal et al. 2004; Gregory O'Grady et al. 2010).
The intrinsic frequency gradient that exists in the stomach has also been extensively demonstrated in in vivo recordings many times, including in humans (Weber & Kohatsu, 1970; Hinder & Kelly, 1977). This frequency gradient is a fundamental component of the current integrated understanding of whole-organ motility (Du et al. 2010), and cannot be disregarded without a suitable alternative explanation for entrainment.
The claim by Rhee et al. that all gastrointestinal extracellular studies are invalid, because the potentials ‘are largely movement artifacts’ (Rhee et al. 2011), deserves especially critical scrutiny. No human or other large animal extracellular data exist to support such speculation. This claim relates to a single in vitro murine study (Bayguinov et al. 2011), which, as previously noted, applied methods that were unlikely to be suitable for in vitro murine extracellular recordings, and which does not reflect a comparable experimental context to human in vivo recordings (O'Grady, 2012). The configuration of extracellular slow wave potentials has been extensively validated across varying pressure profiles and accords with the biophysics of slow wave membrane potentials, and not movement artifacts (e.g. Bortoff, 1967). Moreover, extracellular slow wave recordings are well known to precede contractions, meaning they cannot be explained as artifacts (reviewed in O'Grady, 2012). Furthermore, gastric pacing frequencies are delivered according to extracellularly recorded intrinsic frequencies (typically ∼3.3 cpm in humans; McCallum et al. 1998); pacing would not work if extracellular slow wave frequencies were misrepresenting the ‘true’ frequency.
Artifactual changes occurring in isolated tissues best explain the findings observed by Sanders, Ward and colleagues (Rhee et al. 2011), and their far-reaching claims cannot be supported. However, their study is nevertheless important, because it clearly demonstrates that in vitro studies of human gastric pacemaker activity may not accurately reflect in vivo pacemaker activity. Extracellular electrode recordings, performed in the manner of Xue et al. (1995), would seem a useful control for further investigating this significant matter in future.
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