Arterial Stiffening With Exercise in Patients With Heart Failure and Preserved Ejection Fraction

BACKGROUND Aortic stiffening and reduced nitric oxide (NO) availability may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). OBJECTIVES We assessed indices of arterial stiffness at rest and during exercise in subjects with HFpEF and hypertensive controls, to examine their relationship to cardiac hemodynamics and determine whether exertional arterial stiffening can be mitigated by inorganic nitrite. METHODS Twenty-two hypertensive controls and 98 HFpEF subjects underwent hemodynamic exercise testing with simultaneous expired gas analysis. Invasively measured radial artery pressure waveforms were converted to central aortic waveforms by transfer function to assess integrated measures of pulsatile aortic load, including arterial compliance, resistance, elastance, and wave reflection. RESULTS Arterial load and wave reflections were similar in HFpEF and controls at rest. During submaximal exercise, HFpEF subjects displayed reduced total arterial compliance and higher effective arterial elastance despite similar mean arterial pressures to controls. This was directly correlated with higher ventricular filling pressures and depressed cardiac output reserve (both p <0.0001). With peak exercise, increased wave reflections impaired compliance, resistance and elastance were observed. A subset of HFpEF subjects (n = 52) received sodium nitrite or placebo in a 1:1 double blind, randomized fashion. Compared to placebo, nitrite decreased aortic wave reflections at rest and improved arterial compliance, elastance, and improved central hemodynamics during exercise. CONCLUSION Abnormal pulsatile aortic loading during exercise occurs in HFpEF independent of hypertension, and is correlated with classical hemodynamic derangements that develop with stress. Inorganic nitrite mitigates arterial stiffening with exercise and improves hemodynamics, indicating that arterial stiffening with exercise is at least partially reversible. Further study is required to test effects of agents that target the NO pathway in reducing arterial stiffness in HFpEF.