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

Abstract

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.

Disorders of Blood Pressure Regulation—Role of Catecholamine Biosynthesis, Release, and Metabolism

“…Catestatin resulted in lowering of resting heart rate and improvement in heart rate variability, highlighting its potential benefits in attenuating adverse cardiac affects of catecholaminergic drive [32]. These results appear to corroborate earlier clinical findings of the modification of human autonomic activity by catestatin.…”

Catestatin (Chromogranin A352–372) and Novel Effects on Mobilization of Fat from Adipose Tissue through Regulation of Adrenergic and Leptin Signaling

“…Initially identified as a physiological brake in catecholamine secretion (7), CST has been established as a pleiotropic hormone having effects on promoting angiogenesis (10), lowering of blood pressure (8,11,12), and cardiac contractility (13)(14)(15), as well as enhancing baroreflex sensitivity (16,17) and heart rate variability (18).…”

Catestatin Exerts Direct Protective Effects on Rat Cardiomyocytes Undergoing Ischemia/Reperfusion by Stimulating PI3K-Akt-GSK3β Pathway and Preserving Mitochondrial Membrane Potential

“…Cst exerts a vasodilator effect [8] and participates to blood pressure regulation: low Cst plasma levels have been measured not only in patients affected by essential hypertension, but also in their still normotensive offspring [12, 13]. Consistent with human findings [8, 12, 13], the severe hypertension, the dampened baroreflex sensitivity and the heart rate variability developed in knock-out mice for the CHGA gene can be rescued by the replacement with this peptide [14, 15]. Cardiac secretory granules containing CgA, CgB and Secretogranin 2 are present in murine heart.…”