Early detection of acute allograft rejection by linear and nonlinear analysis of heart rate variability

Abstract

Objective: The first months after orthotopic heart transplantation are associated with the highest risk of acute allograft rejection. This study explores the utility and reliability of linear and novel nonlinear metrics of heart rate variability as predictors of graft rejection. The underlying hypothesis is that the transplanted heart, in response to inflammatory mediators, alters the dynamic properties of its rhythm-generating system. Methods: In a cross-sectional study of 45 patients who had undergone heart transplantation, spanning a period of 4 months after the operation, heart rate variability was examined by time- and frequency-domain analysis. The nonlinear features of heart rate variability were studied by computing a point-wise correlation dimension of R-R interval time series. The results of heart rate variability analysis were compared with those of endomyocardial surveillance biopsy studies using the International Society for Heart and Lung Transplantation scoring system. Results: Duration of heart transplantation itself exhibited a significant (P < .05) association with the onset of rejection. Specific predictors of acute rejection based on heart rate variability were identified, including shortening of the R-R interval (from 700 ± 68 to 648 ± 72 ms), an increase in the ratio of low-frequency (0.04-0.15 Hz) to high-frequency (0.15-0.40 Hz) spectral power (from 0.3 ± 0.2 to 0.6 ± 0.4), and a decrease in pointwise correlation dimension values (from 1.7 ± 0.7 to 0.9 ± 0.3 units). Multivariable logistic regression analysis (R2 = 0.4) revealed that the only significant independent risk predictors were pointwise correlation dimension (odds ratio, 2.2 per 0.1 unit) and duration of heart transplantation (odds ratio, 1.7 per week). Conclusion: Nonlinear measures of heart rate variability provide noninvasive means for identifying patients undergoing cardiac transplantation with acute rejection, thereby enabling the assessment of the time-dependent adaptive response of the donor heart to its host.