Heart failure is a major medical and socioeconomic problem in western industrial countries, especially with aging populations. Heart failure with normal left ventricle systolic function (heart failure with preserved ejection fraction, HFPEF, heart failure with normal ejection fraction, HFNEF) are common causes of hospitalization mainly in the elderly population and are frequently associated with pulmonary hypertension. It is commonly seen, that patients with left heart disease and pulmonary hypertension with right ventricle dysfunction have a worse prognosis.

The investigators hypothesize, that an additional treatment with Bosentan in this patients will improve their exercise capacity, symptoms, hemodynamics and quality of life.

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.

Inclusion Criteria:

• Clinically signs or history of congestive heart failure NYHA II-III (Fatigue, dyspnea on exertion, lung crepitations, pulmonary edema, ankle and or lower leg swelling, jugular pressure enhancement, hepatomegaly)
• Echocardiographic signs of diastolic dysfunction (heart failure with normal ejection fraction)
• Right ventricle enlargement with pulmonary hypertension
• 6 minute walking distance > 150 m < 400 m
• Right Heart Catheterization: Mean PAP > 25 mmHg, PCWP > 15 mmHg

Echocardiographic requirements for definition of heart failure with normal ejection fraction

• E/E' > 15, or
• E/E' > 8 + NTpBNP > 220 pg/ml, or
• E/E' > 8 + E:A < 0.5 + DT > 280 ms or
• Ard-Ad > 30 ms or
• atrial enlargement or
• atrial fibrillation
• NTpBNP > 220 pg/ml + combination
• IVRT - IVRTm < 0 septal und lateral

Echocardiographic requirements for pulmonary hypertension and right ventricle dysfunction

• RVEDD > 30 mm short axis parasternal, and

• one of the following:

  • Tricuspid valve regurgitation velocity (TRV) > 3 m/s;
  • RV-annular systolic velocity < 10 cm/sec (TDI)
  • TAPSE < 18 mm

Exclusion Criteria:

• Patients who are not on guideline conform treatments for cardiovascular disease.

• Left ventricle systolic dysfunction (EF < 50 %), aortic stenosis with peak gradient (instantane) > 40 mm Hg,moderate and severe aortic insufficiency

• moderate and severe mitral regurgitation,

• acute coronary disease, stable coronary artery disease or peripheral vascular disease limiting exercise.

• Other causes of pulmonary - artery - hypertension:

  • relevant obstructive ventilatory disease > grade II (lung functions tests)
  • collagen disease (Tests: MSCT and ANA, ANCA),
  • chronic thrombo- embolic pulmonary arterial hypertension (MSCT),
  • sleep disorder.
  • HIV, HCV, HBV infection.
  • Drug related PAH.

• Orthopaedic disease, immobility, inability to perform 6MWT and cancer.

• Liver disease Child-Pugh B and C, three fold above normal elevated liver enzymes,

• anaemia Hb < 10 mg/dl,

• other specific treatment of pulmonary arterial hypertension including other endothelin receptor blockers, phosphodiesterase inhibitors, prostaglandins and L-arginin

• drug therapy with glibenclamide, rifampicin, tacrolimus, sirolimus, cyclosporine A

• known adverse reactions to bosentan and

• pregnancy and lactation