Atrial remodeling in hypertrophic cardiomyopathy: insights from mouse models carrying different

mutations in cTnT.

Background: We recently showed that in hypertrophic cardiomyopathy (HCM), genotype is not predictive
of onset or severity of atrial myopathy, which rather appears to be rather driven by hemodynamic
determinants, such as diastolic dysfunction and outflow obstruction (Bongini et al. Am J Cardiol 2016). In
human and murine HCM ventricular myocardium, primary changes in myofilament function, related to the
presence of disease-causing mutations in sarcomeric proteins, are often associated with secondary
abnormalities due to adverse remodeling of cardiomyocyte EC-coupling (Coppini et al. Circulation 2013,
Coppini et al. ABS Biophysical Journal 2015). Methods and results: Here we characterize the changes in Commented [RC1]: Non citerei labstract
sarcomere function and EC-coupling that occur in the atria of two HCM mouse models carrying different
mutations in cTnT, R92Q and E163R. Echocardiography showed LV hypertrophy, diastolic dysfunction and
enlarged left atria in both HCM models; atrial dilatation was more pronounced in the R92Q mice. Left atrial
trabeculae were dissected and mounted isometrically to record twitch tension. We studied the steady-state
force-frequency relationship and the response to positive inotropic stimuli such as Isoproterenol 10 -7 mM
(ISO) and 8 mM extracellular [Ca2+]. Compared to WT, R92Q atrial trabeculae showed: (i) slower kinetics of
both force development and relaxation, (ii) impaired twitch amplitude at high pacing rates, (iii) depressed
rested-state contractions and (iv) blunted increase of twitch tension in ISO and high [Ca 2+]. None of these
changes were observed in intact E163R atrial trabeculae. LastLast, we studied the mechanical properties of
E163R myofibrils and found that in spite of a significant increase in the rate of the initial isometric slow
phase of relaxation, overall relaxation from maximal activation was impaired and prolonged vs WT. The
2+
kinetics of force development and maximal tension at saturating Ca2+ were instead similar in E163R and
WT. Preliminary isometric force and ATPase measurements performed on skinned E163R trabeculae are in
line with the results obtained from single myofibrils. Conclusions: Atrial remodeling in R92Q is more
pronounced compared to E163R, and related to E-C coupling alterations. In E163 mice, the mild atrial
dilatation detected in vivo is associated with impaired myofilament function. These findings suggest that
atrial myopathy in HCM can be produced via different pathophysiological mechanisms, according
todepending on the underlying mutation involved.