• change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  

• change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  
• changes in hemodynamics assessed by echocardiography after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  
• time to clinical worsening after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  
• levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  
• Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  
• Adverse event count after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  

Heart Failure with preserved ejection fraction is with more than 50% of cases the most common form of heart failure. Typically patients are elderly women with arterial hypertension. Mortality, hospitalization rates due to heart failure and in-hospital complications do not differ significantly from patients with systolic heart failure. However there are some subgroups of HFPEF-patients with a worse prognosis, for example up to 30% of patients develop secondary pulmonary hypertension and thus right ventricle dysfunction. Increased right-ventricle systolic pressure is associated with increased mortality in patients with all forms of heart failure.

There is a lack of evidence about HFPEF. Drugs for treating systolic heart failure showed no improvement in mortality and prognosis. Diuretics are just able to relieve symptoms. There are no clinical trials concerning HFPEF with secondary pulmonary hypertension.

The endothelin system is not only activated in PAH, but also in pulmonary venous hypertension and congestive heart failure, where ET-1 levels rise with the severity of secondary pulmonary hypertension. Pulmonary congestion leads to endothelial dysfunction that results in increased levels of Endothelin-1 (ET-1).

ET-1 is a potent vasoconstrictor. In pulmonary arterial vessels the ETA receptor is the predominant receptor (ratio of ETA to ET B = 9:1), which is responsible for vasoconstriction and remodeling of the pulmonal vasculature. In heart failure the ETA receptor is upregulated. Elevated plasma ET-1 levels correlate with pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and inversely with peak exercise capacity.

Recent clinical and laboratory findings indicate comparable pathophysiological mechanisms in pulmonary hypertension secondary to left ventricular dysfunction and pulmonary arterial hypertension. Yet, despite an expanding application in pulmonary artery hypertension, according to current opinion, the oral dual endothelin (ETA/ETB) antagonist bosentan is not indicated for PVH caused by left ventricle / left atrial pressure overload and preserved systolic function. However, there are several studies which show some effects of pulmonary vessel dilating drugs in PAH and left ventricle dysfunction.