Repurposing Cyclic Guanosine Monophosphate Pathway Medications, from Vasodilation toward Changing the Face of Heart Failure

Abstract

Advanced heart failure (HF) is characterized by repeated hospital admissions due to recurring need for intravenous inotropes. Among the most commonly used medications used in this context, is milrinone, which increases the myocardial relaxation velocity, what is known as lusitropy. This effect is mediated by increasing cyclic adenosine monophosphate, which in turn switches on phospholamban (PLB) activity, an enzyme promoting calcium reuptake by the sarcoplasmic reticulum. The aim of this review is to shed light on oral medications that can play a similar role by alternative pathways. PLB can be as well stimulated by cyclic guanosine monophosphate (cGMP), the latter is known to be increased by medications which inhibit phosphodiesterase 5. Two well-established drugs can perform this action and are currently exclusively used as vasodilators, namely sildenafil and tadalafil. Another emerging hope is vericiguat; a medication that can directly stimulate guanylyl cyclase, leading to increase in cGMP. We speculate that the possible introduction of these oral medications is thought to replace the need for repeated hospital and intensive care admissions. This also might mean delaying the necessity for mechanical support or transplantations, which can change the face of advanced or end-stage HF.

Keywords: Cyclic guanosine monophosphate-dependent kinases; lusitropy; milrinone; vericiguat.

Figure 1

Alternative pathways to lusitropy. Ca: Calcium, cAMP: Cyclic adenine monophosphate, cGMP: Cyclic guanine monophosphate, PD: Phosphodiesterase, PKG: Protein kinase G, PLB: Phospholamban, SR: Sarcoplasmic reticulum