E-wave asymmetry elucidates diastolic ventricular stiffness-relaxation coupling: Model-based prediction with in vivo validation

Load, chamber stiffness, and relaxation are the three established determinants of global diastolic function (DF). Coupling of systolic stiffness and isovolumic relaxation has been hypothesized; however, diastolic stiffness-relaxation coupling (DSRC) remains unknown. The parametrized diastolic filling (PDF) formalism, a validated DF model incorporates DSRC. PDF model-predicted DSRC was validated by analysis of 159 Doppler E-waves from a published data set (22 healthy volunteers undergoing bicycle exercise). E-waves at varying (46-120 bpm) heart rates (HR) demonstrated variation in acceleration time (AT), deceleration time (DT), and E-wave peak velocity. AT, DT, and Epeak were converted into PDF parameters: Stiffness (k), relaxation (c), and load (xo) using published numerical methods. Univariate linear regression showed that over a twofold increase in HR, AT, and DT decrease (r =-0.44; P < 0.001 and r =-0.42; P < 0.001, respectively), while, DT/AT remains constant (r =-0.04; P = 0.67). Similarly, k increases with HR (r = 0.55; P < 0.001), while c has no significant correlation with HR (r = 0.08; P = 0.32). However, the dimensionless DSRC parameter w = c2/4k shows no significant correlation with HR (r =-0.03; P = 0.7). Furthermore, w is uniquely determined by DT/AT rather than AT or DT independently. Constancy of w in spite of a twofold increase in HR establishes that stiffness (k) and relaxation (c) are coupled and manifest via a HR-invariant parameter of E-wave asymmetry and should not be considered independent of each other. The manifestation of DSRC through E-wave asymmetry via w underscores the value of DT/AT as a physiological, mechanism-derived index of DF.