Chromogranin A in heart failure.

Since the initial demonstration of increased circulating norepinephrine in patients with chronic heart failure, a large number of investigations on neuroendocrine activation in heart failure have followed. It is now clear that persistent activation of neuroendocrine systems, notably the adrenergic system and the renin–angiotensin system is maladaptive in heart failure (reviewed in). In this issue, Ceconi et al. report that serum levels of chromogranin A, the major secretory granule matrix protein in neuroendocrine cells, are elevated in patients with heart failure. The increases in chromogranin A serum levels are related to decreasing functional status and provide independent prognostic information, i.e. within a given NYHA class, patients with chromogranin A levels above the median have a worse prognosis than patients with chromogranin A levels below the median. As with many novel observations, the work by Ceconi et al. raises many questions and leaves room for imagination. Therefore, let us take a closer look at chromogranin A from a cardiologist’s standpoint. Chromogranin A, a protein initially described in catecholamine storage vesicles of the adrenal medulla, has a widespread distribution in secretory vesicles throughout the endocrine, neuroendocrine and nervous system, where it is co-localized and co-secreted with the respective peptide or amine hormone. Chromogranin A plays a pivotal role in the process of hormone packaging and secretory granule formation. Importantly, chromogranin A also functions as a multipurpose prohormone. The primary structure of chromogranin A contains several pairs of basic amino acids that represent proteolytic cleavage sites for the generation of a number of biologically active peptides. Proteolysis of chromogranin A takes place in a tissue-specific manner both within secretory granules and after secretion into the extracellular space. An emerging functional pattern is that such chromogranin A-derived peptides inhibit further hormone release from the (neuro)endocrine cell of origin. For example, in catecholaminergic cells, proteolytic processing of chromogranin A liberates catestatin, a peptide with catecholamine secretion–inhibitory and vasodilating activities. Among the many chrom-