Prognostic Significance and Determinants of the 6-minute Walk Test in Patients with Pulmonary Hypertension Associated with Heart Failure and Preserved Ejection Fraction

Introduction: Symptoms of exertional fatigue and dyspnea, as well as a reduced exercise tolerance are cardinal features of pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF). The aim of the present study was to define the prognostic significance and clinical determinants of the six-minute walking distance (6-MWD) in affected patients.

Methods: Consecutive patients with a definite diagnosis of PH-HFpEF, as confirmed by right heart catheter, were enrolled in our prospective registry. Hospitalization for HF and/or death for cardiac reason were defined as the primary study endpoint. To establish determinants of the 6-MWD, 4 separate multiple regression models were constructed for TTE, hemodynamic, laboratory and pulmonary parameters. For quantification of left ventricular (LV) extracellular matrix (ECM) using the TissueFAXS software, myocardial biopsies were taken from 18 patients.

Results: Between December 2010 and July 2013, 142 PH-HFpEF patients (99 f/43 m, mean age 71 ± 9 years) were included to the study. After a mean follow-up of 14.0 ± 10.0 months (range 0.5 – 34.0 months), 43 patients (30.3%) reached the combined endpoint. Patients in the adverse outcome group had a significantly shorter 6-MWD (246.8 ± 115.6 m vs. 345 ± 110.2 m, P< 0.001) and a higher Borg dyspnea score (5 ± 2 vs. 3 ± 2, P< 0.001). The 6-MWD (HR: 0.992; 95% CI: 0.990; 0.995; P= 0.013) was found to be an independent predictor of outcome. The following parameters were found to be independent determinants of the 6-MWD: systolic and mean pulmonary artery pressures, transpulmonary gradient, pulmonary arterial compliance, hemoglobin, urea, partial pressure of carbon dioxide in arterial blood and vital capacity. There was a significant inverse correlation between the 6-MWD and the amount of ECM (R =-0.50, P= 0.034) in the heart tissue samples.

Discussion: The limited exercise capacity in PH-HFpEF patients can be explained by a variety of cardiac and non-cardiac factors that contribute to increased ECM deposition in the LV and consecutive hemodynamic alterations. We hypothesize that PH-HFpEF is a multifactorial systemic disease with end-organ damage of the heart.