Calcitonin Gene-Related Peptide Receptor Agonism
A Double-Edged Sword?
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Article, see p 367
Patients with heart failure experience high rates of hospitalization and death, combined with a poor quality of life. Current treatment is aimed at increasing cardiac contractility, enhancing vasodilation, and preventing maladaptive cardiac remodeling. Nevertheless, as heart failure associates with higher age, its prevalence is increasing in our aging population, urging the need for new treatments. Recent developments include the inhibition of neprilysin with sacubitril (to increase the levels of natriuretic peptides) and drugs that stimulate the nitric oxide-cyclic guanosine monophosphate pathway.1 The latter may be achieved by enhancing soluble guanylate cyclase nitric oxide sensitivity (with vericiguat), directly activating soluble guanylate cyclase (with cinaciguat), or inhibiting the enzyme that breaks down cyclic guanosine monophosphate, phosphodiesterase-5, with sildenafil.
Sacubitril, when combined with angiotensin II type 1 receptor blockade, turned out to be highly successful in heart failure. However, given that neprilysin degrades multiple substrates in addition to natriuretic peptides, including amyloid β and endothelin-1, concerns exist about a link between neprilysin inhibition and Alzheimer’s disease1 and the detrimental consequences of endothelin-1 upregulation.2 Enhancing the nitric oxide-cyclic guanosine monophosphate pathway resulted in high rates of hypotension (cinaciguat), and heart failure trials investigating drugs interfering with this pathway were either inconclusive (vericiguat) or still need to be done on a sufficiently large scale (sildenafil).1
Calcitonin gene-related peptide (CGRP), a member of the calcitonin family, is a peptide that so far has received little attention in heart failure.3 It exists in 2 isoforms: αCGRP and βCGRP. αCGRP, a 37 amino-acid peptide, is formed by alternative splicing of the calcitonin gene, in particular in the central and peripheral nervous system, and acts as a potent vasodilator and modulator of cerebrovascular nociception. βCGRP is encoded by a second CGRP gene, predominantly expressed in the enteric sensory system.4 …