Because these changes each alter βAR function in different ways, it would be naive to assume that they are all beneficial. in β-myosin heavy chain expression, whereas the most favorable response for atrial natriuretic factor and α-skeletal actin was with the βARKct-crossed mice. Given that the βARKct mice also show no evidence of myocardial hypertrophy, as assessed by heart-to-body weight ratios, it appears that expression of this peptide had the most favorable chronic effects of the crosses, within the context of the HCM phenotype. A consistent finding in these types of crossbreeding experiments with the βARKct animal is that beneficial effects are only found when βARK levels or activities are increased. Thus, in the muscle-specific LIMknockout (19), the HCM mouse, and the calsequestrin overexpression (20) models, βARK is increased, and in each case, transgenic overexpression of the inhibitor peptide substantially improves function. In contrast, the Gαq overexpressing model of cardiomyopathy, which also displays βAR desensitization, hypertrophy, and marked ventricular dysfunction (21), does not have elevated βARK levels, and in these cases, ventricular function and βAR responsiveness are not rescued with the βARK inhibitor (22, 23). Instead, restoration of other dysfunctional components of βAR signaling improves function in vitro or in vivo (23–25).

The βARKct peptide acts by binding the βγ subunits that are released from G-protein heterotrimers. βγ is required for βARK translocation and thus its ability to phosphorylate βARs. Since its beneficial effects are seen only in systems that feature elevated kinase activity, it appears that the inhibitory βARKct peptide acts specifically on this aspect of the pathogenesis. However, other physiologic and biochemical indices of hypertrophy are also improved by βARKct, and it is intriguing to consider whether blocking βγ may have effects other than inhibiting βARK. Indeed, βγ stimulates tyrosine kinase signaling and phospholipase C activation, which could accelerate hypertrophy. Another consideration is that as cardiac function improves when βγ signaling is attenuated, βAR function returns as a secondary response. This appears to be the case during βblocker treatment, as βAR function has