Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction (PH-HFpEF)

Definition

Pulmonary hypertension (PH) is a well-recognized complication of left ventricular dysfunction. Chronic elevation of left sided filling pressures in patients with left ventricular dysfunction lead to increases in pulmonary venous pressure and increased pulmonary vascular resistance (PVR), and ultimately increased pulmonary artery pressure.  The World Health Organization (WHO) classification of PH lists PH resulting from left-side heart failure (HF) under Group II (pulmonary venous hypertension). WHO Group II is defined as an increase in mean pulmonary artery pressure (PAP) >25 mm Hg at rest secondary to an elevation in pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg.  Pulmonary hypertension is prevalent in heart failure patients who have preserved ejection fraction (HFpEF). It is estimated that as many as 50% of the HFpEF patients in the US develop pulmonary hypertension, which is referred to as PH-HFpEF (1,2,3)

Unmet Medical

While the actual prevalence of PH-HFpEF is uncertain, several reports have estimated that the US population exceeds 1.5 million patients (2,3) In many patients PH-HFpEF leads to right heart failure. Coexisting right heart failure in PH-HFpEF patients is associated with poor outcomes, including increased mortality. (4)

No therapies are approved to treat PH-HFpEF.  Several of the currently approved therapies for Group I PAH patients have been investigated for the treatment of PH-HFpEF, but none have proven to be effective. Given the high prevalence, poor associated outcomes, and complete lack of effective therapies to treat this condition, PH-HFpEF represents a condition of high unmet medical need.

Scientific Rationale for Levosimendan in PH-HFpEF

We believe that levosimendan may provide several benefits to PH-HFpEF patients, including:

  • Many PH-HF patients suffer with right heart failure and the  inotropic properties of levosimendan may provide important benefits to these patients. To date, no inotropic drug has ever been developed for right heart failure.
  • PH-HFpEF patients also need a drug that will lower elevated pulmonary wedge pressures. The very large clinical experience with levosimendan in left heart failure provides evidence that levosimendan consistently lowers the pulmonary wedge pressure in patients with  elevated pulmonary wedge pressures.
  • It is important for levosimendan to have favorable effects in patients with pulmonary hypertension (e.g. tends to lower the PVR). The existing preliminary clinical studies suggest that this is the case.

 

 

  1. Thenappan, Thenappan, et al. “Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction.” Circulation: Heart Failure(2011): CIRCHEARTFAILURE-110
  2. Guazzi, Marco, et al. “Pulmonary hypertension in heart failure with preserved ejection fraction.” Circulation(2011): CIRCULATIONAHA-110.
  3. Dixon, Debra D., Amar Trivedi, and Sanjiv J. Shah. “Combined post-and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction.” Heart failure reviews3 (2016): 285-297
  4. Mohammed SF, Roger VL, Abou Ezzeddine OF, Redfield MM. Right ventricular systolic function in subjects with hfpef: A community based study.Circulation. 2011;124:A17407