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Minute ventilation (VE) controlled rate adaptive pacemakers determine the paced rate increase during exercise by measuring changes in transthoracic impedance that have been shown to correlate well with VE. To determine the normal coupling of heart rate (HR) to VE this relationship was evaluated in 30 younger and 25 older, healthy subjects using peak cardiopulmonary exercise testing. After determining the anaerobic threshold (AT), the linear HR to VE slope was determined both below and above the AT. In addition, the entire curve of the HR to VE relationship was assessed by a "best fit" regression analysis method. The relationship of HR to VE was more often logarithmic in younger as compared to older subjects. The HR to VE slope below the AT was always steeper than above the AT in younger subjects. Females of both age subgroups demonstrated a significantly greater slope below and above the AT. For the appropriate programming of VE controlled, rate responsive pacemakers, one should take into consideration age- and sex-specific differences in the HR to VE relationship throughout exercise. Therefore, age- and sex-specific programmable features for rate responsive parameters should be incorporated into pacemakers using VE controlled rate adaptive algorithms.