The Mechanism of Action
WHO Group 2 : Pulmonary Hypertension with Left Heart Disease
Patients with PH-HFpEF suffer from chronic elevation and backward transmission of left-sided filling pressures that lead to increases in pulmonary venous pressure and ultimately increased pulmonary artery pressure. Currently treatments have focused on targeting the reduced compliance of the left ventricle as the underlying mechanism of this disease. However, every attempt to treat that condition with heart failure medications has failed. Very recent research has now revealed that a critical component of PH-HFpEF is overfilling of the left ventricle from abnormally high venous blood flow, a maladaptive condition of chronic heart failure. This knowledge has shifted the focus of HFpEF to strategies to reduce venous blood flow by targeting the splanchnic (abdominal) venous circulation which regulates venous return.
Levosimendan acts through a unique first in class mechanism that is mediated through potassium channel (K-ATP) activation. These K+ channels control the vascular tone (state of constriction and dilation) of the arteries and veins in the body. Studies have shown that levosimendan specifically dilates the veins of the splanchnic circulation, and via that mechanism has the potential to lower the elevated PCWP that underlies PH-HFpEF. K-ATP channels also control the pulmonary arteries and veins, representing another pathway that levosimendan may be beneficial in PH-HFpEF.