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Multifactorial Impact of Channel Beta‐Subunit Gene Mutation on Automaticity

To the Editor: We are pleased that Dr. Lakatta and colleague no longer argue, as they did a decade ago, that Ca homeostasis is the sole basis of automaticity independent of membrane depolarization.1 More recently they have refined their arguments around the concept of a “coupling” or integration of Ca handling (and its impact on Na/Ca exchanger and L-type currents) with membrane events (notably the pacemaker current, If). In their Letter to the Editor2 commenting on the paper of Nawathe et al.,3 they expound on this concept to suggest that inhibition of If initiates a series of events beginning with a direct rate decrease, which then results in reduced Ca influx per unit time and thus disruption of Ca homeostasis, thereby leading to a positive feedback loop to further reduce rate. We do not disagree with this general principle (though certainly on the details), and in fact first provided evidence of the interdependence of Ca homeostasis and If in 20034 and more recently demonstrated5 that the mechanism could be provided by the Ca-stimulated adenylyl cyclase isoforms, known to be present in the sinoatrial node.6 As intellectually stimulating and at times entertaining as these debates on the molecular basis of automaticity can be (see Ref. 7), they are rather beside the point in terms of the results and conclusions of Nawathe et al.3 In advancing their argument for the role of Ca in sinoatrial node automaticity they have misinterpreted our conclusion. Their opening paragraph claims we argue that the bradycardic effects associated with the MiRP1 mutation we are studying “are attributable solely to direct If inhibition.” Nothing could be further from the truth. Where Yaniv and Lakatta go astray is in repeatedly talking of HCN4 mutations, whereas our study addressed a mutation in the MiRP1 beta-subunit, and this is a fundamental distinction. But before discussing that, let us consider their argument regarding our results. By attempting to interpret our data solely on the basis of inhibition of If (again, something we did not do), they must argue that the above positive feedback loop is quite powerful, in that the modest inhibition of If we measure in heterologous studies with mutated MiRP1 must lead to profound disruption of Ca homeostasis in order to account for the marked bradycardia of our patient. But such logic is inconsistent with what they themselves have referred to as “only minor to moderate effects”7 of If blockade on rate. Certainly, if the measured effect of our MiRP1 mutation on HCN4 were sufficient to cause, via changes in Ca handling, the marked bradycardia in our patient then ivabradine should similarly lead to profound bradycardia, and it does not.8 Further, if a significant fraction of ivabradine’s rate slowing effect was due to effects on Ca handling, one would expect alteration