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2, 2017
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 mea-
sures 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 sub-
maximal 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 ¼ 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) (J Am Coll Cardiol 2017;70:136–48)
© 2017 by the American College of Cardiology Foundation.
Manuscript received February 3, 2017; revised manuscript received May 5, 2017, accepted May 8, 2017.
JACC VOL. 70, NO. 2, 2017 Reddy et al. 137
JULY 11, 2017:136–48 Aortic Stiffening in HFpEF
H uman senescence is characterized by an rest and during exercise to central hemody- ABBREVIATIONS
increase in aortic stiffness (1). This causes namics in people with HFpEF. AND ACRONYMS
in age and body mass index (BMI), using multivar- SVRI, dyne-s ∙ m2/cm5 2,052 389 2,239 569 0.15 0.45†
TAC index, ml/mm Hg ∙ m2 0.70 0.22 0.50 0.18 <0.0001 0.0009†
iate linear regression. Pearson correlation and linear
Pf, mm Hg 55 (51–60) 62 (51–70) 0.01 0.61
regression analyses were performed to detect the
Pb, mm Hg 32 9 36 12 0.15 0.27
correlation between variables of interest. All tests
RM, % 58 14 59 19 0.76 0.35
were two-sided, and a p value of <0.05 was Aortic AIx, % 20 11 21 18 0.86 0.40
considered significant. Analyses were performed Peripheral PPA 1.46 0.17 1.35 0.19 0.02 0.02
using JMP version 10.0.0 software (SAS Institute, Central hemodynamics
Cary, North Carolina). Heart rate, beats/min 91 15 88 15 0.32 0.59
RAP, mm Hg 93 21 8 <0.0001 <0.0001
PCWP, mm Hg 14 5 32 7 <0.0001 <0.0001
RESULTS
PA systolic pressure, mm Hg 38 11 67 17 <0.0001 <0.0001
PA mean pressure, mm Hg 25 6 43 11 <0.0001 <0.0001
Compared to control subjects (n ¼ 22), subjects with Stroke volume index, ml/m2 47 10 39 10 0.0006 0.005†
HFpEF (n ¼ 98) were older and heavier (Table 1). Cardiac index, l/min ∙ m2 4.2 0.8 3.4 0.9 0.0005 0.004†
Comorbidities including hypertension, diabetes, and
coronary disease were common and similarly prev- Values are mean SD or median (interquartile range). *p Value adjusted for age and body mass index. †Data that
were already indexed to body weight were only adjusted for age. p Values were not adjusted for multiple
alent, with no group differences. As expected, hypothesis testing.
A B
90 4.0
Group*Exercise p = 0.008 Group*Exercise p = 0.02
3.5
Eal, mm Hg.m2/ml
Aortic PP, mm Hg
80
3.0
70
2.5
60 2.0
Rest 20 W Rest 20 W
C D
0.8 1.6
Group*Exercise p < 0.0001 Group*Exercise p = 0.05
1.5
TACI. ml/mm Hg.m2
0.7
Peripheral PPA 1.4
0.6
1.3
0.5
1.2
0.4 1.1
Rest 20 W Rest 20 W
Controls HFpEF
With exercise, HFpEF subjects demonstrated (A) increased aortic PP (mm Hg) (B) higher EaI (mm Hg ∙ m2/ml) (C), lower TACI (ml/mm Hg ∙ m2)
and (D) lower PPA. EaI ¼ effective arterial elastance indexed; PP ¼ pulse pressure; PPA ¼ pulse pressure amplification; TACI ¼ total arterial
compliance index.
subjects (43%) exercised past the submaximal 20-W EFFECT OF NITRITE ON ARTERIAL PROPERTIES. We
workload to volitional exhaustion. Peak exercise ca- next evaluated the effects of sodium nitrite, a novel
pacity was roughly 40% lower in HFpEF subjects than NO-providing agent, on the abnormalities observed in
in control subjects (peak V O2 was 8.6 2.3 ml/min/kg central and peripheral arterial loading at rest and
vs. 14.8 3.8 ml/min/kg, respectively; p < 0.0001). As with exercise in HFpEF subjects. Nitrite or matching
with 20-W exercise, systemic pressures were similar placebo was administered in a randomized, blinded
but measurements of arterial afterload decreased fashion intravenously in cohort 2 subjects (n ¼ 28)
less at peak exercise in HFpEF subjects than in control and by nebulized inhalation in cohort 3 subjects
subjects, with higher arterial elastance and systemic (n ¼ 26). Because plasma N O 2 levels and hemody-
vascular resistance and lower total arterial compliance namic effects were similar for intravenous and
(Table 4). Unlike submaximal exercise, there was also inhaled nitrite administration (Online Table 1), we
evidence for increased wave reflection-associated combined both nitrite and placebo groups to analyze
pressure load at peak exercise in HFpEF subjects the effects on arterial load.
compared to that in control subjects. This was shown At rest, nitrite modestly reduced arterial pressures,
by higher AIx, RM, and lower PPA results. Among the with greater effects noted on central pressure wave-
measurements of reflected pressure waves, AIx at peak forms (Table 5). Compared with placebo, nitrite
exercise was correlated with reduced total arterial decreased aortic wave reflections at rest (lower Pb,
compliance, higher PCWP, EaI, and lower peak CO RM, and AIx) but had no effect on arterial elastance or
(Figure 3). compliance compared with placebo. In contrast, with
JACC VOL. 70, NO. 2, 2017 Reddy et al. 141
JULY 11, 2017:136–48 Aortic Stiffening in HFpEF
A B
60 60
r = –0.42 r = 0.30
p = < 0.0001 p = 0.002
20 W PCWP (mm Hg)
20 20
0 0
0.0 0.5 1.0 1.5 0 2 4 6 8
20 W TACI, ml/mm Hg.m2 20 W Eal, mm Hg.m2/ml
C D
15 15
20 W CO (L/min)
20 W CO (L/min)
10 10
r = –0.66
p < 0.0001
5 5
r = 0.56
p < 0.0001
0 0
0.0 0.5 1.0 1.5 0 2 4 6 8
20 W TACI, ml/mm Hg.m2 20 W Eal, mm Hg.m2/ml
Controls HFpEF
A higher exercise PCWP (mm Hg) was associated with (A) lower TACI (ml/mm Hg ∙ m2) and (B) higher EaI (mm Hg ∙ m2/ml). In addition, a
lower CO response was associated with lower exercise, (C) arterial compliance, and (D) elastance. CO ¼ cardiac output; other abbreviations as
in Figure 1.
(20-W) exercise, nitrite reduced central aortic pres- show partially reverses arterial stiffening. We show
sures, decreased arterial elastance, reduced systemic that, compared to hypertensive control subjects, sub-
vascular resistance and AIx, and increased total jects with HFpEF displayed similar indices of arterial
arterial compliance compared with placebo (Figure 4). afterload when measured at rest. In contrast, exercise
These favorable arterial effects of nitrite were unmasked significant limitations in arterial compli-
coupled with salutary reductions in biventricular ance and vasodilatory reserve that were correlated
filling pressures and PA pressures at rest and to a with classic hemodynamic abnormalities observed in
greater extent with exercise, along with an improve- HFpEF, including elevated ventricular filling pres-
ment in cardiac output (Table 5). sures and inadequate CO (Central Illustration). Arterial
stiffening was present despite similar arterial pres-
DISCUSSION sures measured centrally and peripherally. Arterial
stiffening at rest and with exercise was partially
We comprehensively examined arterial properties reversed with inorganic sodium nitrite, a novel NO-
invasively in patients with proven HFpEF and providing therapy, and this was coupled with favor-
compared them to hypertensive control subjects at able improvements in central hemodynamics. These
rest and during exercise by using gold standard inva- data emphasize the fact that arterial stiffening and
sive hemodynamic assessments while assessing the impaired arterial vasodilator reserve with exercise
effects of a novel NO-cGMP-providing agent that we play an important role in the pathophysiology of
142 Reddy et al. JACC VOL. 70, NO. 2, 2017
A B
6 r = 0.34, p = 0.007 1.5 r = –0.52, p < 0.0001
4 1.0
2 0.5
0 0.0
–20 0 20 40 60 –20 0 20 40 60
Peak Alx, % Peak Alx, %
C D
80 r = 0.29, p = 0.02 25 r = –0.54, p < 0.0001
20
Peak PCWP (mm Hg)
60
Peak CO (l/min)
15
40
10
20
5
0 0
–20 0 20 40 60 –20 0 20 40 60
Peak Alx, % Peak Alx, %
Controls HFpEF
Increased systolic pressure augmentation due to AIx during peak exercise was correlated with (A) higher EaI, (B) lower TACI, (C) higher PCWP,
and (D) depressed CO reserve. AIx ¼ wave reflection; other abbreviations as in Figures 1 and 2.
observed in the present study during exercise per- abnormalities in arterial compliance, elastance, and
sisted even after we adjusted for age and BMI, which wave reflection were present in HFpEF, associated
are known to directly affect arterial properties with abnormal hemodynamics and partly reversed
(29,30), and these differences were not related to by using nitrite in tandem with improved hemody-
differences in arterial blood pressure. This important namics, strongly supports the notion that arterial
observation demonstrates that arterial stiffening and stiffening plays an important role in the pathophysi-
reduced arterial reserve are specific to the HFpEF ology of HFpEF, especially during exercise.
phenotype, and are thus potentially important ther-
apeutic targets. THERAPEUTIC IMPLICATIONS. The finding of greater
This study is also unique due to the invasive arterial afterload with exercise in HFpEF suggests a
determination of arterial and reflected load with ex- role for drugs that enhance arterial compliance and
ercise, which allowed for direct correlation with reduce wave reflection. Different antihypertensive
simultaneous filling pressures and CO during exer- agents have varying effects on wave reflection and
cise. One previous noninvasive study measured aortic compliance properties. For example, beta
and demonstrated increased proximal aortic imped- blockers increase wave reflection and central blood
ance and decreased arterial compliance with pressure compared to vasodilators. This has been
exercise but did not measure simultaneous reflected suggested as a mechanism for the inferior outcomes
load or filling pressures (9). Although causality seen with beta-blocker therapy for hypertension in the
cannot be proven from this study design, the fact that ASCOT (Anglo Scandinavian Cardiac Outcomes Trial)
144 Reddy et al. JACC VOL. 70, NO. 2, 2017
Radial pressures, mm Hg
Radial systolic BP 4 5 0.46 2 3 0.59
Radial diastolic BP 3 2 0.09 4 1 0.01
Radial mean BP 6 3 0.04 6 2 0.02
Radial PP 1 4 0.81 þ2 3 0.55
Aortic pressures and flow, mm Hg
Aortic systolic BP 10 5 0.05 9 3 0.01
Aortic diastolic BP 3 2 0.07 4 1 0.02
Aortic mean BP 6 3 0.04 6 2 0.02
Aortic PP 8 4 0.04 5 2 0.03
Arterial afterload
Ea indexed, mm Hg ∙ m2/ml 0.13 0.20 0.50 0.38 0.14 0.008
SVRI, dyne-s ∙ m2/cm5 90 173 0.61 204 75 0.009
TAC index, ml/mm Hg ∙ m2 þ0.06 0.04 0.14 þ0.10 0.02 0.0005
Pf, mm Hg þ2 3 0.53 0 2 0.83
Pb, mm Hg 7 3 0.009 3 2 0.06
RM, % 19 5 0.0003 5 4 0.14
Aortic AIx, % 8 5 0.002* 8 2 <0.0001*
Peripheral PPA þ0.12 0.03 0.0001 þ0.12 0.03 <0.0001
Central hemodynamics
Heart rate, beats/min þ3 2 0.13 þ3 2 0.12
RAP, mm Hg 1 1 0.01 4 1 <0.0001
PCWP, mm Hg 3 1 0.001 8 1 <0.0001
Cardiac output, l/min 0.01 0.3 0.99 þ0.8 0.3 0.01
Values are mean SD. *According to Wilcoxon rank sum test result. Table shows placebo-corrected values (change with study drug minus change with placebo).
Abbreviations as in Table 2.
A Rest B Exercise
20 p = 0.0002 p = 0.0002 20 p = 0.0002
p = 0.0002 p = 0.004
10 10
p < 0.0001
% Change
0 0
–10 –10
–20 –20
Placebo Nitrite
Percentage of improvement with nitrite therapy in measurements of (A) resting reflective load: Pb, RM, and PPA; and (B) exercise arterial load: EaI,
TACI, and SVRI. Pb ¼ backward wave; RM ¼ reflection magnitude; SVRI ¼ systemic vascular resistance index; other abbreviations as in Figure 1.
JACC VOL. 70, NO. 2, 2017 Reddy et al. 145
JULY 11, 2017:136–48 Aortic Stiffening in HFpEF
C ENTR AL I LL U STRA T I O N Arterial Load and Wave Reflections in HFpEF at Rest and During Exercise
At rest (left panel), the aortic pressure waveform, Pa (orange) is shown as a composite of the forward wave, Pf (blue) and reflected wave, Pb (green). Wave
reflections, which develop at the points of impedance mismatch along the arterial tree, are reflected back to the aorta causing systolic pressure augmen-
tation. 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 PCWP is near normal. During exercise (right 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, Pb
(green) and pressure augmentation of the central aorta during mid to late systole. Total arterial compliance reserve becomes saturated, such that increases in
stroke volume cause greater elevation in aortic pulse pressure, further augmenting left ventricular load. These changes are then correlated with pathologic
increases in PCWP that promote symptoms of dyspnea, and impairment in forward cardiac output reserve, limiting oxygen transfer to the body.
Ppcw ¼ pulmonary capillary wedge pressure.
146 Reddy et al. JACC VOL. 70, NO. 2, 2017
compared to an amlodipine vasodilator regimen (31). the effects of longer-term nitrite therapy in HFpEF
Although this effect has been ascribed to negative (NCT02742129 and NCT02713126), and further study
chronotropic effects, this may not apply to all heart is warranted using other novel therapies targeting
rate-lowering drugs. Ivabradine, which selectively arterial stiffness.
lowers the sinus rate, improves aortic compliance in STUDY LIMITATIONS. Central aortic pressures were
patients with HFrEF (32). Alternative vasodilators may not directly measured but were derived mathemati-
have similar effects on lowering arterial stiffness and cally from the directly measured radial artery trac-
improving central hemodynamics, but comparative ings. However, this method has been previously
data for their hemodynamic effects in HFpEF are validated compared with directly measured central
lacking, and we cannot assume that the current ob- aortic pressures (19), and the use of directly measured
servations will apply to all vasodilators. Future studies pressures from an arterial cannula is a unique
evaluating both cardiac and arterial hemodynamic strength, compared with prior studies that relied on
effects of vasoactive medicines in HFpEF would be noninvasive applanation tonometry to measure radial
valuable to address this important question. waveforms. Although imputation of central pressures
Deficiency of NO and its downstream second from radial waveforms has been validated following
messenger, cGMP, have been repeatedly implicated in nitroglycerin therapy (19), there are fewer validation
the pathogenesis of HFpEF and are being targeted in a data available using other drug therapies. Correction
variety of ongoing trials (3,4). Neprilysin inhibitors for multiple hypothesis testing was not performed.
increase intracellular cGMP by decreasing the break- Arterial stiffening may be related to structural
down of endogenous natriuretic peptides, and treat- remodeling and changes in the material properties of
ment with the neprilysin inhibitor omapatrilat has the vasculature or to endothelial dysfunction and
been shown to improve central aortic distensibility vasoconstriction, or both. We cannot identify which
and reduce systolic wave reflections and characteristic components explained the greater stiffening during
impedance in hypertensives (33). It remains unknown exercise in HFpEF. Future studies evaluating effects
whether similar vascular effects will be seen with the of nitrite on individual components, such as aortic
newer neprilysin antagonist sacubitril, which is pulse wave velocity and endothelium-dependent
currently being tested in the PARAGON-HF (Prospec- vasodilation, would be important to help sort out
tive comparison of ARni with Arb Global Outcomes in the mechanisms by which nitrite improves arterial
heart failure with preserved ejectioN fraction) trial in stiffening. Subjects with HFpEF were older and had
patients with chronic HFpEF (NCT01920711). higher BMI than control subjects, which may influ-
The inorganic nitrate/nitrite/NO pathway repre- ence arterial properties independent of HFpEF status,
sents an alternative method to improve NO-cGMP but all key differences remained highly significant
availability in HFpEF. Acute administration of inor- after adjusting for these baseline differences.
ganic nitrite (or its precursor nitrate) decreases
conduit vessel stiffness in healthy volunteers (12,34), CONCLUSIONS
enhances exercise capacity and vasodilation in
HFpEF patients (13,14,35,36), and improves rest and People with HFpEF display impaired arterial compli-
exercise hemodynamics in HFpEF patients (13,14,37). ance, resistance, and elastance reserve that are pro-
Zamani et al. (35) recently found that inorganic ni- voked by the physiologic stress of exercise. These
trate decreased AIx in HFpEF patients, when abnormalities are directly correlated with greater
measured at rest, while improving peak exercise hemodynamic severity of HF and worse functional
capacity. The current data importantly extend these capacity, even after controlling for the presence of
previous findings, confirming salutary effects of hypertension. Sodium nitrite mitigates these vascular
nitrite on wave reflection while demonstrating for perturbations in tandem with salutary effects on the
the first time direct improvements in arterial hemodynamic abnormalities that contribute to effort
compliance, elastance, and wave reflection at rest intolerance. Further study is warranted to investigate
and during exercise, when hemodynamic perturba- whether therapies targeting central aortic stiffness
tions contribute to symptoms of dyspnea. Effects can improve clinical outcomes in HFpEF.
of nitrite in hypertensive control subjects were not
examined in this study but may also produce favor- ADDRESS FOR CORRESPONDENCE: Dr. Barry A.
able effects on exercise tolerance. Larger clinical tri- Borlaug, Department of Cardiovascular Diseases, Mayo
als sponsored by the U.S. National Heart, Lung, and Clinic and Foundation, 200 First Street SW, Rochester,
Blood Institute are currently under way to evaluate Minnesota 55905. E-mail: borlaug.barry@mayo.edu.
JACC VOL. 70, NO. 2, 2017 Reddy et al. 147
JULY 11, 2017:136–48 Aortic Stiffening in HFpEF
PERSPECTIVES
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