Chromogranin A and the Autonomic System: Decomposition of Heart Rate Variability and Rescue by Its Catestatin Fragment

Chromogranin A (CHGA/Chga) has been implicated in the genesis of systemic hypertension and consequent cardiac abnormalities. Catestatin (CST) (human CHGA(352-372)) replacement reduces blood pressure elevation and increases baroreflex sensitivity in Chga knockout (KO) mice. Because of the dampened baroreflex sensitivity, we reasoned that KO mice would display altered heart rate variability (HRV). Thus, we evaluated beat-to-beat measurements in HRV in wild-type (WT) and KO mice, before and after CST replacement. HR dynamics were evaluated by bipolar Einthoven electrocardiogram, with deconvolution into time and frequency domains, as well as Lorenz nonlinear return analyses. At baseline, HR was higher [444 +/- 24 beats per minute (bpm)] in KO compared with WT (330 +/- 18 bpm) mice. The total power in the HRV spectra was substantially diminished in KO animals. CST increased total power but only in KO mice. Each time-domain parameter was substantially lower in KO compared with WT mice, and the CST in the KO group could reverse the differences. Lorenz analysis revealed reductions in S1 (short axis perpendicular to the line of identity in the ellipse) and S2 (long axis along the line of identity in the ellipse) in KO animals, indicating that regulation of HRV is diminished in the parasympathetic and sympathetic domains. CST replacement caused restoration of both S1 and S2, in the KO group. These data suggest that Chga has a profound effect on autonomic tone to the heart and that its CST fragment is responsible for such actions. The results suggest future strategies for intervention in cardiovascular disorders accompanied by adverse HRV profiles. (Endocrinology 151: 2760-2768, 2010)