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Ann Thorac Surg 2007;83:1128
© 2007 The Society of Thoracic Surgeons
Physiology and Membrane Biology, University of California Davis, One Shields Ave, 4147A Tupper Hall, Davis, CA 95616-8644
(Email: seanderson{at}ucdavis.edu).
The study by Wang and colleagues [1] demonstrates that when the Na/H exchange inhibitor cariporide and the ß-blocker metoprolol are given together prior to ischemia, infarct size is limited more than by cariporide alone. This result could become very important in improving treatments to limit ischemia/reperfusion (I/R) injury. However, because the model exposes the heart to exceedingly high left ventricular end-diastolic pressure (EDP), there may be problems extrapolating to clinical situations.
To reiterate, the model used by Wang and colleagues [1] and many others includes a water-filled left ventricular balloon that is filled to give a baseline EDP of 0 to 5 mm Hg, and the volume is held constant thereafter. This results in an EDP of 40 to 75 mm Hg during I/R (see Fig 2) with pressures much higher than clinical. The authors stated, "All treatments showed improved recovery compared to control, mainly due to decreased EDP (Fig 2)." If this is true, one must ask whether there would be any effect clinically.
Furthermore, increases in EDP trigger responses that limit ventricular function. For example, Downing and colleagues [2] showed that under continuously perfused conditions intraventricular pressures of 40 mm Hg diminished contractile function.
High EDP protocols may have major effects different from those observed clinically in at least three ways. First, exceedingly high EDP during reperfusion is likely to limit re-flow [3]. Second, very high EDP indicates a left ventricular volume relatively greater than that occurring clinically, and thus must "stretch" some muscle fibers. Finally, to the extent protective effects of cariporide plus metoprolol are "mainly due to decreased EDP," they may have limited clinical effect.
One could argue all of the measured effects of cariporide plus metoprolol are the result of limiting cytosolic Ca accumulation which normally limits mitochondrial Ca loading [4]. Thus it is pertinent that cell stretch increases Ca entry via stretch activated channels or as a result of stretch activated increases in intracellular Na which promote Na/Ca exchange-mediated Ca entry [5].
Specifically, in perfused rat hearts, an EDP of 10 mm Hg causes a stretch-activated channel-dependent activation of heat-shock factor to increase HSP72 [6]. Similarly, EDP of 25 mm Hg caused stretch-induced activation of ERK 1/2 and p38MAP kinase which could be diminished by the PKC inhibitor chelerythrine [7]. PKC [8], ERK 1/2 (via p90RSK) [9], and p38MAPK [10] all stimulate the Na/H exchanger isoform 1 (NHE1), the target of cariporide. Similarly, stretching papillary muscles caused an NHE1-dependent, chelerythrine inhibitable increase in intracellular pH [11] and in rat cardiac myocytes cariporide inhibition of stretch-stimulated NHE1 limits increases in [Ca]i [12].
Thus until the treatment tested by Wang and colleagues [1] is tested clinically or under clinical EDP levels, we must question how much we can extrapolate from this model. Indeed protocols that include exceedingly high EDP must be interpreted with caution and perhaps should no longer be used to model clinical myocardial I/R conditions. Instead it may be more useful to assess end-diastolic stiffness by measuring changes in left ventricular volume while EDP is maintained at pressures less than 10 mm Hg.
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