Author + information
- Received February 3, 2017
- Revision received May 5, 2017
- Accepted May 8, 2017
- Published online July 3, 2017.
- Yogesh N.V. Reddy, MDa,
- Mads J. Andersen, MD, PhDa,b,
- Masaru Obokata, MD, PhDa,
- Katlyn E. Koeppa,
- Garvan C. Kane, MD, PhDa,
- Vojtech Melenovsky, MD, PhDa,c,
- Thomas P. Olson, PhDa and
- Barry A. Borlaug, MDa,∗ ()
- aDivision of Cardiovascular Diseases, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota
- bDepartment of Cardiology, Aarhus University Hospital, Aarhus, Denmark
- cIKEM (Institute for Clinical and Experimental Medicine), Department of Cardiology, Prague, Czech Republic
- ↵∗Address for correspondence:
Dr. Barry A. Borlaug, Department of Cardiovascular Diseases, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905.
Background Aortic stiffening and reduced nitric oxide (NO) availability may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF).
Objectives This study compared indices of arterial stiffness at rest and during exercise in subjects with HFpEF and hypertensive control subjects to examine their relationships to cardiac hemodynamics and determine whether exertional arterial stiffening can be mitigated by inorganic nitrite.
Methods A total of 22 hypertensive control subjects and 98 HFpEF subjects underwent hemodynamic exercise testing with simultaneous expired gas analysis to measure oxygen consumption. 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 in HFpEF were similar to those in control subjects at rest. During submaximal exercise, HFpEF subjects displayed reduced total arterial compliance and higher effective arterial elastance despite similar mean arterial pressures in control subjects. 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, and increased resistance and elastance were observed in subjects with HFpEF. A subset of HFpEF subjects (n = 52) received sodium nitrite or placebo therapy in a 1:1 double-blind, randomized fashion. Compared to placebo, nitrite decreased aortic wave reflections at rest and improved arterial compliance and elastance and central hemodynamics during exercise.
Conclusions 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. (Study of Exercise and Heart Function in Patients With Heart Failure and Pulmonary Vascular Disease [EXEC]; NCT01418248. Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction; NCT01932606. Inhaled Sodium Nitrite on Heart Failure With Preserved Ejection Fraction; NCT02262078)
Dr. Borlaug is supported by RO1 HL128526 and U10 HL110262 from the National Institutes of Health; and research funding from Mast Pharmaceuticals. Dr. Reddy is supported by T32 HL007111 from the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Drs. Reddy and Andersen contributed equally to this work.
- Received February 3, 2017.
- Revision received May 5, 2017.
- Accepted May 8, 2017.
- 2017 American College of Cardiology Foundation