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

Abstract

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).

Keywords: HFpEF; aortic stiffness; exercise; heart failure; hypertension.

Figure 1. Arterial load during exercise

With exercise, HFpEF subjects, compared to controls, demonstrated [A] increased Aortic Pulse Pressure (PP), mmHg [B] – higher Effective arterial elastance indexed (EaI), mmHg.m2/ml [C] – lower Total Arterial Compliance Index (TACI), ml/mmHg.m2 and [D] – lower Peripheral Pulse Pressure Amplification (PPA)

Figure 2. Correlation between arterial load and central hemodynamics

A higher exercise Pulmonary Capillary Wedge Pressure (PCWP), mmHg was associated with [A] lower Total Arterial Compliance Index (TACI), ml/mmHg.m2 and [B] higher Effective Arterial Elastance Index (EaI), mmHg.m2/ml. In addition, a lower Cardiac Output (CO) response was associated with lower exercise [C] arterial compliance and [D] elastance.

Figure 3. Correlation between wave reflection and central hemodynamics at peak exercise

Increased systolic pressure augmentation due to wave reflection (AIx) during peak exercise was correlated with [A] higher Effective Arterial Elastance Index (EaI), [B] lower total arterial compliance index (TACI), [C] higher Pulmonary Capillary Wedge Pressures (PCWP), and [D] depressed cardiac output (CO) reserve.

Figure 4. Effects of inorganic nitrite on resting and exercise arterial load

Percentage improvement with nitrite therapy in measures of [A] Resting reflective load: Backward Wave (Pb), Reflection Magnitude (RM), Peripheral Pulse Pressure Amplitude (PPPA) [B] Exercise arterial load: Effective Arterial Elastance Indexed (EaI), Total Arterial Compliance Index (TACI), Systemic Vascular Resistance Index (SVRI)

Central Illustration. Arterial load and wave reflections in HFpEF at rest and during exercise

At rest (upper panel), the aortic pressure waveform is shown as a composite of the forward wave (color) and reflected wave (color). Wave reflections, which develop at the points of impedance mismatch along the arterial tree, are reflected back to the aorta causing systolic pressure augmentation. Total arterial compliance, which reflects the ability of the arteries to store blood during systole without untoward elevation in pressure, is not significantly compromised, and pulmonary capillary wedge pressure (PCWP) is near-normal. During exercise (bottom panel), venous return and cardiac output increase. Stiffening of the aorta, along with a lack of small vessel vasodilation in the periphery (inadequate reduction in systemic vascular resistance), augments pressure wave reflections (color) and pressure augmentation of in the central aorta during mid to late systole. Total arterial compliance reserve becomes saturated, such that increases in stroke volume cause greater aortic pulse pressure increases, further augmenting left ventricular load. These changes are then correlated with pathologic increases in PCWP that dyspnea and impairment in forward cardiac output reserve limiting oxygen transfer to the body.