Natriuretic Peptide Therapeutics for Cardiomyopathy

Mechanism of Action and Therapeutic Rationale

• The European Society of Cardiology recommends that natriuretic peptides exert anti-proliferative and cytoprotective effects on myocardial and vascular structure and function, providing inhibition of cardiac and vascular remodeling, which is particularly relevant for cardiomyopathy treatment 1
• Natriuretic peptides promote vascular smooth muscle relaxation and vasodilation, reducing cardiac afterload, and cause pulmonary smooth muscle relaxation, which can benefit patients with pulmonary congestion 1
• The peptides have lusitropic effects (improved diastolic relaxation), and the European Heart Society notes that they work by activating natriuretic peptide receptor-A (NPR-A), generating cyclic guanosine monophosphate to mediate natriuresis, vasodilation, and inhibition of the renin-angiotensin-aldosterone system, although the exact mechanism is not fully understood 1

Clinical Context and Limitations

• The American Heart Association notes that heart failure is characterized by altered natriuretic peptide processing with secretion of less biologically active forms, which may explain why administered BNP shows beneficial effects despite high concentrations of endogenous immunoreactive natriuretic peptides 3
• ProBNP is the major immunoreactive form in heart failure patients, rather than the fully active BNP 1-32, according to the European Heart Journal 3
• The European Society of Cardiology recommends that BNP and NT-proBNP are excellent biomarkers for diagnosing and prognosticating heart failure, although the exogenous administration of these peptides as therapeutics has not achieved the same level of clinical success 1, 4

Novel Peptide Approaches

• Neutral endopeptidase inhibitors like candoxatrilat have been developed to prevent the breakdown of endogenous natriuretic peptides, thereby enhancing their therapeutic effects, as noted by the American College of Cardiology 2