JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2, 2017
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VOL. 70, NO.
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.05.029
Arterial Stiffening With Exercise in
Patients With Heart Failure and
Preserved Ejection Fraction
Yogesh N.V. Reddy, MD,a Mads J. Andersen, MD, PHD,a,b Masaru Obokata, MD, PHD,a Katlyn E. Koepp,a
Garvan C. Kane, MD, PHD,a Vojtech Melenovsky, MD, PHD,a,c Thomas P. Olson, PHD,a Barry A. Borlaug, MDa
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.
From the a
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota;
b
Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; and the cIKEM (Institute for Clinical and Experimental
Medicine), Department of Cardiology, Prague, Czech Republic. 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.
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

systolic hypertension by reductions in arte- We undertook the current study to

AIx = Augmentation Index
rial compliance and increases in systolic wave reflec- compare invasive measurements of arterial
A-VO2diff = arterial-venous O2
tions (1,2). Aging, along with hypertension and load in patients with invasively proven
difference
obesity, are the strongest risk factors for the develop- HFpEF with those in a matched hypertensive
BMI = body mass index
ment of heart failure with preserved ejection fraction control group at rest and during exercise. We
CO = cardiac output
(HFpEF) (3). These comorbidities are believed to pro- hypothesized that arterial stiffness would be
EaI = effective arterial
mote the development of HFpEF by causing defi- increased with exercise in HFpEF subjects
elastance index
ciency in nitric oxide-guanosine monophosphate compared with that in hypertensive control
HF = heart failure
(NO-cGMP) signaling, which may alter ventricular subjects without HF, that this stiffening
HFpEF = heart failure with
mechanical properties that result in hemodynamic would be associated with abnormal cardiac preserved ejection fraction
findings of HF (3–5). hemodynamics, and that acute treatment
LV = left ventricle
with inorganic sodium nitrite, a novel NO-
SEE PAGE 149 NO = nitric oxide
cGMP agent (12–14), would partially reverse
NO-cGMP = nitric oxide-
In addition to reporting ventricular abnormalities, arterial stiffening with exercise. guanosine monophosphate
prior studies have demonstrated that arterial stiffness
METHODS PA = pulmonary artery
is increased in people with HFpEF above levels ex-
Pb = backward wave
pected from aging alone (6–11). This arterial stiffness
STUDY SUBJECTS. The study population PCWP = pulmonary capillary
has historically been ascribed to chronic systemic wedge pressure
included subjects participating in prospective
hypertension, but recent data suggest it may be related
trials conducted in our laboratory, all using Pf = forward wave
in large part to comorbid conditions observed with
the same uniform invasive supine exercise- PP = pulse pressure
HFpEF such as metabolic syndrome and obesity (3,4).
testing protocol (13–18). Data from these co- PPA = pulse pressure
Few studies have compared HFpEF subjects to a hy- amplification
horts have been published previously but not
pertensive control group (7,8), and no invasive data
in total or as they relate to vascular indices in TACI = total arterial
are available that relate indices of arterial stiffness at compliance index
the current analysis. In cohort 1, HFpEF and
RM = reflection magnitude
control subjects underwent exercise testing
T A B L E 1 Baseline Characteristics in the evaluation of exertional dyspnea with SVRI = systemic vascular
resistance index
Control HFpEF simultaneous echocardiographic imaging
(n ¼ 22) (n ¼ 98) p Value VO2 = oxygen consumption
(15–18). In cohorts 2 and 3, HFpEF subjects
Age, yrs 62  12 68  10 0.01 underwent exercise testing prior to and following
Females, % 45 56 0.48
acute administration of either intravenous or inhaled
Body mass index, kg/m2 26.9  4.1 34.1  7.9 <0.0001
sodium nitrite in a 1:1 randomized, double-blind,
Comorbidities, %
placebo-controlled fashion (13,14).
Coronary disease 27 35 0.50
Diabetes mellitus 23 31 0.46 For the initial analysis comparing arterial load in
Hypertension 100 98 1.00 HFpEF and control subjects, hemodynamic data
Using medications shown, % acquired prior to receiving study drug was included
ACE Inhibitor or ARB 41 59 0.12 for cohorts 2 and 3 and was analyzed with cohort 1
Beta-blocker 50 58 0.48 at matched workloads during cycle ergometry. For
Calcium-channel blocker 32 23 0.41
the next part of our analysis, we assessed the ef-
Loop diuretic agent 13 43 0.01
fects of sodium nitrite, a novel NO donor, on arte-
Laboratory test results
Estimated GFR, ml/min 86  29 86  48 0.95
rial load in HFpEF. All studies were approved by
NT-proBNP, pg/ml 83 (42–295) 422 (122–1,022) 0.005 the Mayo Clinic Institutional Review Board and
Echocardiography were registered (NCT01418248, NCT01932606, and
Ejection fraction, % 62  9 63  8 0.59 NCT02262078).
E/e0 velocity, m/s 93 15  8 0.0003
CASE DEFINITIONS. HFpEF and hypertensive control
RVSP, mm Hg 30  7 40  14 0.004
subjects were defined as previously specified (13–18).
Values are mean  SD, %, or median (interquartile range). HFpEF was defined as symptoms of HF (fatigue
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blockers; E/
0
e ¼ ratio of early diastolic transmitral filling velocity (E) to early diastolic mitral
and/or dyspnea) and preserved left ventricular ejec-
annular tissue velocity (e0 ); GFR ¼ glomerular filtration rate; HFpEF ¼ heart failure tion fraction $50% with elevated pulmonary capil-
with preserved ejection fraction; NT-proBNP ¼ N-terminal pro–B-type natriuretic
peptide; RVSP ¼ right ventricular systolic pressure. lary wedge pressure (PCWP) at rest (>15 mm Hg)
and/or with exercise ($25 mm Hg). Control subjects
138 Reddy et al. JACC VOL. 70, NO. 2, 2017

Aortic Stiffening in HFpEF JULY 11, 2017:136–48

The radial artery was cannulated using a 5- or 6-F

T A B L E 2 Resting Arterial Properties and Central Hemodynamics
sheath for continuous recording of arterial pressure
Control HFpEF Adjusted waveforms and blood sampling. Right-heart catheteriza-
Property (n ¼ 22) (n ¼ 98) p Value p Value*
tion was performed using a 9-F sheath inserted in the in-
Radial pressure, mm Hg
ternal jugular vein. Right atrial, PCWP, and PA pressures
Radial systolic BP 163  22 160  25 0.63 0.17
Radial diastolic BP 73  6 71  10 0.34 0.44 were measured at end-expiration, using 2-F high-fidelity
Radial mean BP 104  11 103  14 0.60 0.46 micromanometer-tipped catheters (Millar Instruments,
Radial PP 90  18 89  21 0.89 0.18 Houston, Texas) advanced through the lumen of a 7-F
Aortic pressure, mm Hg fluid-filled balloon catheter (Arrow International Inc.,
Aortic systolic BP 145  23 145  24 0.99 0.39 Reading, Pennsylvania).
Aortic diastolic BP 75  6 72  10 0.30 0.48
Oxygen consumption (V O 2) was measured using
Aortic mean BP 104  11 103  14 0.60 0.46
breath-by-breath expired gas analysis (MedGraphics,
Aortic PP 71  20 73  20 0.61 0.48
Arterial afterload
St. Paul, Minnesota). Because exercise was per-
Ea indexed, mm Hg ∙ m2/ml 3.26  0.92 3.43  1.02 0.47 0.75† formed by using supine ergometry, peak V O 2 values
SVRI, dyne-s ∙ m2/cm5 3,318  1,039 3,059  809 0.20 0.02† achieved are 40% to 50% lower than that observed
TAC index, ml/mm Hg ∙ m2 0.61  0.24 0.55  0.19 0.19 0.80† with upright treadmill exercise. Arterial-venous O2
Pf, mm Hg 47  9 51  14 0.20 0.73 difference (A-V O 2diff) was measured directly as the
Pb, mm Hg 35  12 36  12 0.68 0.57
difference between systemic and PA O2 contents (O 2
RM, % 74 (61–86) 68 (58–91) 0.78 0.98
saturation ∙ hemoglobin ∙ 1.34). Cardiac index was
Aortic AIx, % 28  16 31  15 0.32 0.70
calculated using the direct Fick method (cardiac
Peripheral PPA 1.31  0.21 1.26  0.17 0.21 0.0001
Central hemodynamics index ¼ VO 2/A-VO2diff ∙ body surface area). Stroke
Heart rate, beats/min 69  15 69  11 0.93 0.53 volume index was calculated as cardiac index/heart
RAP, mm Hg 42 11  5 <0.0001 <0.0001 rate.
PCWP, mm Hg 83 18  6 <0.0001 <0.0001
PA systolic pressure, mm Hg 27  6 44  15 <0.0001 0.008 ARTERIAL WAVEFORM ANALYSIS. Radial artery pres-
PA mean pressure, mm Hg 16  4 28  9 <0.0001 0.0003 sure tracings were digitized (240 Hz) and stored for
Stroke volume index, ml/m2 40  10 37  10 0.27 0.65† offline analysis. Central aortic pressure waveforms
Cardiac index, l/min ∙ m2 2.7  0.8 2.5  0.6 0.24 0.77†
were determined from radial artery pressure tracings
Values are mean  SD or median (interquartile range). *p Value adjusted for age and body mass index. †Data that at rest and during exercise by mathematical transfer
was already indexed to body weight was only adjusted for age. p Values are not adjusted for multiple hypothesis function using customized software (SphygmoCor,
testing.
Aix ¼ augmentation index; BP ¼ blood pressure; Ea ¼ effective arterial elastance; HFpEF ¼ heart failure with AtCor, New South Wales, Australia) as previously
preserved ejection fraction; HR ¼ heart rate; PA ¼ pulmonary artery; Pb ¼ backward wave; PCWP ¼ pulmonary described and validated at rest, during exercise, and
capillary wedge pressure; Pf ¼ forward wave; PP ¼ pulse pressure; PPA ¼ pulse pressure amplification;
RAP ¼ right atrial pressure; RM ¼ reflection magnitude; SVRI ¼ systemic vascular resistance index; TAC ¼ total with drug therapy (19–21). Arterial waveform analysis
arterial compliance.
was performed in a blinded fashion without knowl-
edge of the subject group, hemodynamics, or clinical
data.
had systemic hypertension but no evidence of HF, Steady, nonpulsatile arterial load was quantified
with normal rest and exercise pulmonary artery (PA) by systemic vascular resistance index (SVRI ¼ 80 ∙
pressures (<25 mm Hg at rest; <40 mm Hg during [mean central blood pressure  right atrial blood
exercise) and normal PCWP (<15 mm Hg at pressure] ∙ body surface area/cardiac output [CO]).
rest; <25 mm Hg during exercise). Exclusion criteria Pulsatile arterial load was assessed by pulse pressure
included significant valvular heart disease (greater (PP), effective arterial elastance index (EaI) and total
than mild stenosis or moderate regurgitation), sig- arterial compliance index (TACI). EaI, a lumped
nificant pulmonary disease, congenital heart disease, measure of the total “stiffness” of the arterial system,
left-to-right shunt, unstable coronary artery disease, was assessed by end-systolic central blood pressure/
myocardial infarction within 60 days, hypertrophic or stroke volume index (22). TACI, which is a linear
restrictive cardiomyopathy, high-output heart fail- approximation of the pressure-volume relationship
ure, or constrictive pericarditis. for the lumped arterial system, was calculated as
stroke volume index/central PP (23–25). Peripheral PP
CATHETERIZATION PROTOCOL. Subjects were studied in amplification (PPA) was calculated as the peripheral-
the postabsorptive state while taking chronic medi- to-central PP ratio. An increase in pulsatile load is
cation, in the supine position, at rest, and during evidenced by increases in Ea and PP and decreases in
supine cycle ergometry as previously described (13–18). TACI and PPA.
JACC VOL. 70, NO. 2, 2017 Reddy et al. 139
JULY 11, 2017:136–48 Aortic Stiffening in HFpEF

The contribution of wave reflections to arterial

T A B L E 3 Submaximal (20-W) Exercise Arterial and Ventricular Function
load was also assessed. Forward wave (Pf) and back-
ward wave (Pb) pressures were isolated from the Control HFpEF Adjusted
Function (n ¼ 22) (n ¼ 98) p Value p Value*
composite central aortic waveform as previously
Radial pressure, mm Hg
described (26). Wave reflections were quantified by
Radial systolic BP 178  18 182  30 0.46 0.66
the reflection magnitude [RM ¼ Pb/Pf] and aortic Radial diastolic BP 76  5 76  12 0.98 0.94
augmentation index (AIx) (21,26). Radial mean BP 112  11 114  19 0.59 0.91
Radial PP 102  16 107  24 0.36 0.54
STATISTICAL ANALYSIS. Results are reported as
Aortic Pressure, mm Hg
mean  SD, median (interquartile range [IQR]), or
Aortic systolic BP 151  19 160  27 0.12 0.52
percentage. Differences between HFpEF subjects
Aortic diastolic BP 80  6 78  12 0.44 0.66
and control subjects at rest and during exercise Aortic mean BP 112  11 114  19 0.59 0.91
were tested using chi-square, Student t test, or Aortic PP 71  16 83  22 0.02 0.28
Wilcoxon rank sum test as appropriate. All com- Arterial afterload
parisons were also adjusted for baseline differences Ea indexed, mm Hg ∙ m2/ml 2.64  0.71 3.26  0.92 0.004 0.04†

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.

HFpEF subjects had higher N-terminal pro–B-type Abbreviations as in Table 2.

natriuretic peptide levels, increased E/e 0 ratio, and

higher right ventricular systolic pressure on echo-
subjects, although aortic pulse pressure tended to
cardiography, consistent with increased filling
increase more in HFpEF subjects (Table 3, Figure 1). In
pressures.
contrast, direct measurements of arterial afterload
Because age and adiposity are well known to affect
failed to decrease as much in HFpEF subjects as they
arterial properties and were different in HFpEF and
did in control subjects during 20-W exercise, manifest
control subjects, all subsequent comparisons between
HFpEF and control subjects were adjusted for these by higher arterial elastance, lower total arterial

covariates. compliance, and decreased PPA (Table 3, Figure 1).

Each of these differences persisted after adjusting for
BASELINE VENTRICULAR AND VASCULAR FUNCTION. age and BMI.
At rest, both HFpEF and control subjects displayed As expected, HFpEF subjects developed typical
peripheral and central arterial hypertension, with cardiac abnormalities with exercise including pul-
no group differences (Table 2). There were also no monary venous and arterial hypertension and
differences in resting measurements of arterial reduced CO reserve (Table 3). Lower total arterial
afterload including systemic arterial resistance, ela- compliance and higher arterial elastance with exer-
stance, compliance, or wave reflections. As expected, cise were correlated with higher PCWP and lower CO
biventricular filling pressures and PA pressure were during exertion (Figure 2). These relationships
higher at rest in the HFpEF group. remained significant after adjusting for age and BMI
(both p < 0.001).
ARTERIAL RESERVE WITH SUBMAXIMAL EXERCISE.
During submaximal exercise (20 W), radial and aortic ARTERIAL RESERVE WITH PEAK EXERCISE. All of
pressures in HFpEF were similar to those in control the control subjects (n ¼ 22) and 42 of the HFpEF
140 Reddy et al. JACC VOL. 70, NO. 2, 2017

Aortic Stiffening in HFpEF JULY 11, 2017:136–48

F I G U R E 1 Arterial Load During Exercise

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
workload to volitional exhaustion. Peak exercise ca-
pacity was roughly 40% lower in HFpEF subjects than
in control subjects (peak V O2 was 8.6  2.3 ml/min/kg
vs. 14.8  3.8 ml/min/kg, respectively; p < 0.0001). As
with 20-W exercise, systemic pressures were similar
but measurements of arterial afterload decreased
less at peak exercise in HFpEF subjects than in control
subjects, with higher arterial elastance and systemic
vascular resistance and lower total arterial compliance
(Table 4). Unlike submaximal exercise, there was also
evidence for increased wave reflection-associated
pressure load at peak exercise in HFpEF subjects
compared to that in control subjects. This was shown
by higher AIx, RM, and lower PPA results. Among the
measurements of reflected pressure waves, AIx at peak
exercise was correlated with reduced total arterial
compliance, higher PCWP, EaI, and lower peak CO
(Figure 3).
EFFECT OF NITRITE ON ARTERIAL PROPERTIES. We
next evaluated the effects of sodium nitrite, a novel
NO-providing agent, on the abnormalities observed in
central and peripheral arterial loading at rest and
with exercise in HFpEF subjects. Nitrite or matching
placebo was administered in a randomized, blinded
fashion intravenously in cohort 2 subjects (n ¼ 28)
and by nebulized inhalation in cohort 3 subjects
(n ¼ 26). Because plasma N O 2 levels and hemody-
namic effects were similar for intravenous and
inhaled nitrite administration (Online Table 1), we
combined both nitrite and placebo groups to analyze
the effects on arterial load.
At rest, nitrite modestly reduced arterial pressures,
with greater effects noted on central pressure wave-
forms (Table 5). Compared with placebo, nitrite
decreased aortic wave reflections at rest (lower Pb,
RM, and AIx) but had no effect on arterial elastance or
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

F I G U R E 2 Correlation Between Arterial Load and Central Hemodynamics

A B
60 60
r = –0.42 r = 0.30
p = < 0.0001 p = 0.002
20 W PCWP (mm Hg)

20 W PCWP (mm Hg)

40 40

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-
sures, decreased arterial elastance, reduced systemic
vascular resistance and AIx, and increased total
arterial compliance compared with placebo (Figure 4).
These favorable arterial effects of nitrite were
coupled with salutary reductions in biventricular
filling pressures and PA pressures at rest and to a
greater extent with exercise, along with an improve-
ment in cardiac output (Table 5).
DISCUSSION
We comprehensively examined arterial properties
invasively in patients with proven HFpEF and
compared them to hypertensive control subjects at
rest and during exercise by using gold standard inva-
sive hemodynamic assessments while assessing the
effects of a novel NO-cGMP-providing agent that we
show partially reverses arterial stiffening. We show
that, compared to hypertensive control subjects, sub-
jects with HFpEF displayed similar indices of arterial
afterload when measured at rest. In contrast, exercise
unmasked significant limitations in arterial compli-
ance and vasodilatory reserve that were correlated
with classic hemodynamic abnormalities observed in
HFpEF, including elevated ventricular filling pres-
sures and inadequate CO (Central Illustration). Arterial
stiffening was present despite similar arterial pres-
sures measured centrally and peripherally. Arterial
stiffening at rest and with exercise was partially
reversed with inorganic sodium nitrite, a novel NO-
providing therapy, and this was coupled with favor-
able improvements in central hemodynamics. These
data emphasize the fact that arterial stiffening and
impaired arterial vasodilator reserve with exercise
play an important role in the pathophysiology of
142 Reddy et al. JACC VOL. 70, NO. 2, 2017

Aortic Stiffening in HFpEF JULY 11, 2017:136–48

amplitude of outgoing (incident) pressure waves and

T A B L E 4 Peak Exercise Arterial and Ventricular Function
indirectly by increasing wave velocity, which en-
Control HFpEF Adjusted hances early return of reflected pressure waves that
Function (n ¼ 22) (n ¼ 42) p Value p Value*
sum with incident waves to increase systolic pressure
Radial pressure, mm Hg
load (1,2). Acutely, these arterial changes adversely
Radial systolic BP 188  19 192  25 0.53 0.37
Radial diastolic BP 76  6 75  10 0.88 0.33 affect LV ejection performance and diastolic relaxa-
Radial mean BP 113  10 114  17 0.79 0.57 tion (27,28). Chronically, these arterial changes may
Radial PP 112  17 116  21 0.25 0.54 contribute to concentric chamber remodeling,
Aortic pressures, mm Hg fibrosis, and changes in the mechanical properties of
Aortic systolic BP 149  15 158  24 0.11 0.59 the LV (28).
Aortic diastolic BP 81  6 79  11 0.44 0.27
As shown in the current study, arterial stiffening is
Aortic mean BP 113  10 114  17 0.79 0.57
often not apparent in the peripheral arteries and re-
Aortic PP 68  13 79  20 0.02 0.20
Arterial afterload
quires careful assessment of central aortic pressure
Ea indexed, mm Hg ∙ m2/ml 2.45  0.71 3.16  0.92 0.003 0.02† and flow characteristics (2). In the young and healthy
SVRI, dyne-s ∙ m2/cm5 1,473  440 1,923  494 0.0007 0.007† arterial system, there is augmentation of systolic
TAC index, ml/mm Hg ∙ m2 0.77  0.24 0.55  0.21 0.0006 0.006† pressure in the peripheral arteries due to the effects
Pf, mm Hg 62  19 66  14 0.40 0.67 of wave reflection. With aortic stiffening, these re-
Pb, mm Hg 27  11 35  13 0.04 0.05
flected pressure waves travel more rapidly, arriving in
RM, % 41 (34–54) 50 (43–63) 0.08 0.05
the central aorta during systole rather than diastole,
Aortic AIx, % 8  11 17  13 0.007 0.009
to increase aortic pressure load. This results in a
Peripheral PPA 1.66  0.17 1.51  0.22 0.007 0.006
Central hemodynamics decrease in PPA as vascular stiffness increases along
Heart rate, beats/min 121  16 99  16 <0.0001 <0.0001 with other characteristic changes in the central aortic
RAP, mm Hg 84 22  6 <0.0001 <0.0001 waveform.
PCWP, mm Hg 14  5 34  7 <0.0001 <0.0001
VASCULAR STIFFENING IN HFpEF. Systemic hyper-
PA systolic pressure, mm Hg 42  9 70  13 <0.0001 <0.0001
tension is highly prevalent in HFpEF and has been
PA mean pressure, mm Hg 28  7 49  8 <0.0001 <0.0001
Stroke volume index, ml/m 2
99  29 85  28 0.06 0.02†
extensively implicated in its pathogenesis (3). A
Cardiac index, l/min ∙ m 2
12.0  4.0 8.4  2.9 <0.0001 <0.0001† number of studies using noninvasive measuring
Peak VO2, ml/kg/min 14.8  3.8 8.6  2.3 <0.0001 <0.0001† techniques have reported that arterial stiffness is
increased in HFpEF compared with that in healthy
Values are mean  SD or median (interquartile range). *p Values were 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
control subjects, and some studies have correlated
multiple hypothesis testing. this stiffening with decreased exercise capacity (6,9–
TAC ¼ total arterial compliance; other abbreviations as in Table 2.
11). However, elevation in blood pressure is associ-
ated with reduced arterial distensibility in and of it-
self, because the arterial pressure-volume
HFpEF that is independent of hypertension and relationship is not linear and varies with ambient
mean blood pressure alone. These data also under- pressure. Thus, arterial stiffening may not be specific
score the importance of central aortic stiffening in to HFpEF but common to all or most hypertensive
HFpEF as a viable therapeutic target that merits patients. In this regard, 2 studies comparing HFpEF
further prospective study in this cohort of patients for subjects with carefully matched hypertensive control
whom few treatment options exist. subjects have reported little to no differences in most
measurements of arterial stiffness between groups
CENTRAL ARTERIAL LOAD AND BLOOD PRESSURE. (7,8).
Aging causes changes in the mechanical properties of The current data are consistent with those studies,
the aorta and conduit arteries (1,2). One of the key showing that, compared with a hypertensive control
sequelae of this change is a decrease in total arterial group, there was no discernable difference in resting
compliance, which can be conceptualized as the arterial afterload in subjects with HFpEF. However,
ability of the arteries to store blood during systole with increases in arterial pressure and blood flow
without excessive increases in pressure. The aorta associated with exercise, abnormalities became
contributes most of the compliance in the systemic apparent, revealing vascular stiffening that was not
arterial bed, unlike the lungs, where compliance is clearly identifiable at rest. Older age and obesity are 2
distributed more evenly throughout the vasculature. of the strongest risk factors for HFpEF and are
Decreases in aortic distensibility heighten left ven- believed to play major roles in its pathogenesis (3).
tricular (LV) afterload directly by augmenting the Importantly, the differences in arterial stiffness
JACC VOL. 70, NO. 2, 2017 Reddy et al. 143
JULY 11, 2017:136–48 Aortic Stiffening in HFpEF

F I G U R E 3 Correlation Between Wave Reflection and Central Hemodynamics at Peak Exercise

A B
6 r = 0.34, p = 0.007 1.5 r = –0.52, p < 0.0001

Peak TACI (ml/mm Hg.m2)

Peak Eal, mm Hg.m2/ml

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-
sisted even after we adjusted for age and BMI, which
are known to directly affect arterial properties
(29,30), and these differences were not related to
differences in arterial blood pressure. This important
observation demonstrates that arterial stiffening and
reduced arterial reserve are specific to the HFpEF
phenotype, and are thus potentially important ther-
apeutic targets.
This study is also unique due to the invasive
determination of arterial and reflected load with ex-
ercise, which allowed for direct correlation with
simultaneous filling pressures and CO during exer-
cise. One previous noninvasive study measured
and demonstrated increased proximal aortic imped-
ance and decreased arterial
exercise but did not measure simultaneous reflected
load or filling pressures (9). Although causality
cannot be proven from this study design, the fact that
abnormalities in arterial compliance, elastance, and
wave reflection were present in HFpEF, associated
with abnormal hemodynamics and partly reversed
by using nitrite in tandem with improved hemody-
namics, strongly supports the notion that arterial
stiffening plays an important role in the pathophysi-
ology of HFpEF, especially during exercise.
THERAPEUTIC IMPLICATIONS. The finding of greater
arterial afterload with exercise in HFpEF suggests a
role for drugs that enhance arterial compliance and
reduce wave reflection. Different antihypertensive
agents have varying effects on wave reflection and
aortic compliance properties. For example, beta
blockers increase wave reflection and central blood
compliance with pressure compared to vasodilators. This has been
suggested as a mechanism for the inferior outcomes
seen with beta-blocker therapy for hypertension in the
ASCOT (Anglo Scandinavian Cardiac Outcomes Trial)
144 Reddy et al. JACC VOL. 70, NO. 2, 2017

Aortic Stiffening in HFpEF JULY 11, 2017:136–48

T A B L E 5 Effect of Nitrite on Arterial Properties at Rest and Exercise

Rest 20-W Exercise

Placebo-Corrected Nitrite Effect Placebo-Corrected Nitrite Effect

Arterial Property (n ¼ 52) p Value (n ¼ 52) p Value

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.

F I G U R E 4 Effects of Inorganic Nitrite on Resting and Exercise Arterial Load

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

Pb RM PPA Eal TACI SVRI

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

Reddy, Y.N.V. et al. J Am Coll Cardiol. 2017;70(2):136–48.

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.
Aortic Stiffening in HFpEF
compared to an amlodipine vasodilator regimen (31).
Although this effect has been ascribed to negative
chronotropic effects, this may not apply to all heart
rate-lowering drugs. Ivabradine, which selectively
lowers the sinus rate, improves aortic compliance in
patients with HFrEF (32). Alternative vasodilators may
have similar effects on lowering arterial stiffness and
improving central hemodynamics, but comparative
data for their hemodynamic effects in HFpEF are
lacking, and we cannot assume that the current ob-
servations will apply to all vasodilators. Future studies
evaluating both cardiac and arterial hemodynamic
effects of vasoactive medicines in HFpEF would be
valuable to address this important question.
Deficiency of NO and its downstream second
messenger, cGMP, have been repeatedly implicated in
the pathogenesis of HFpEF and are being targeted in a
variety of ongoing trials (3,4). Neprilysin inhibitors
increase intracellular cGMP by decreasing the break-
down of endogenous natriuretic peptides, and treat-
ment with the neprilysin inhibitor omapatrilat has
been shown to improve central aortic distensibility
and reduce systolic wave reflections and characteristic
impedance in hypertensives (33). It remains unknown
whether similar vascular effects will be seen with the
newer neprilysin antagonist sacubitril, which is
currently being tested in the PARAGON-HF (Prospec-
tive comparison of ARni with Arb Global Outcomes in
heart failure with preserved ejectioN fraction) trial in
patients with chronic HFpEF (NCT01920711).
The inorganic nitrate/nitrite/NO pathway repre-
sents an alternative method to improve NO-cGMP
availability in HFpEF. Acute administration of inor-
ganic nitrite (or its precursor nitrate) decreases
conduit vessel stiffness in healthy volunteers (12,34),
enhances exercise capacity and vasodilation in
HFpEF patients (13,14,35,36), and improves rest and
exercise hemodynamics in HFpEF patients (13,14,37).
Zamani et al. (35) recently found that inorganic ni-
trate decreased AIx in HFpEF patients, when
measured at rest, while improving peak exercise
capacity. The current data importantly extend these
previous findings, confirming salutary effects of
nitrite on wave reflection while demonstrating for
the first time direct improvements in arterial
compliance, elastance, and wave reflection at rest
and during exercise, when hemodynamic perturba-
tions contribute to symptoms of dyspnea. Effects
of nitrite in hypertensive control subjects were not
examined in this study but may also produce favor-
able effects on exercise tolerance. Larger clinical tri-
als sponsored by the U.S. National Heart, Lung, and
Blood Institute are currently under way to evaluate
JACC VOL. 70, NO. 2, 2017
JULY 11, 2017:136–48
the effects of longer-term nitrite therapy in HFpEF
(NCT02742129 and NCT02713126), and further study
is warranted using other novel therapies targeting
arterial stiffness.
STUDY LIMITATIONS. Central aortic pressures were
not directly measured but were derived mathemati-
cally from the directly measured radial artery trac-
ings. However, this method has been previously
validated compared with directly measured central
aortic pressures (19), and the use of directly measured
pressures from an arterial cannula is a unique
strength, compared with prior studies that relied on
noninvasive applanation tonometry to measure radial
waveforms. Although imputation of central pressures
from radial waveforms has been validated following
nitroglycerin therapy (19), there are fewer validation
data available using other drug therapies. Correction
for multiple hypothesis testing was not performed.
Arterial stiffening may be related to structural
remodeling and changes in the material properties of
the vasculature or to endothelial dysfunction and
vasoconstriction, or both. We cannot identify which
components explained the greater stiffening during
exercise in HFpEF. Future studies evaluating effects
of nitrite on individual components, such as aortic
pulse wave velocity and endothelium-dependent
vasodilation, would be important to help sort out
the mechanisms by which nitrite improves arterial
stiffening. Subjects with HFpEF were older and had
higher BMI than control subjects, which may influ-
ence arterial properties independent of HFpEF status,
but all key differences remained highly significant
after adjusting for these baseline differences.
CONCLUSIONS
People with HFpEF display impaired arterial compli-
ance, resistance, and elastance reserve that are pro-
voked by the physiologic stress of exercise. These
abnormalities are directly correlated with greater
hemodynamic severity of HF and worse functional
capacity, even after controlling for the presence of
hypertension. Sodium nitrite mitigates these vascular
perturbations in tandem with salutary effects on the
hemodynamic abnormalities that contribute to effort
intolerance. Further study is warranted to investigate
whether therapies targeting central aortic stiffness
can improve clinical outcomes in HFpEF.
ADDRESS FOR CORRESPONDENCE: Dr. Barry A.
Borlaug, Department of Cardiovascular Diseases, Mayo
Clinic and Foundation, 200 First Street SW, Rochester,
Minnesota 55905. E-mail: borlaug.barry@mayo.edu.
JACC VOL. 70, NO. 2, 2017
JULY 11, 2017:136–48
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: Arterial
stiffness and wave reflections increase during exercise in
patients with HFpEF. These abnormalities are associated
with higher cardiac filling pressures and lower cardiac
output but improve after administration of inorganic
nitrite medications.
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KEY WORDS aortic stiffness, exercise,
heart failure, HFpEF, hypertension
A PPE NDI X For a supplemental table, please
see the online version of this article.
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