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Arterial Stiffening With Exercise inPatients With Heart Failure andPreserved 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

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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.

m the aDivision of Cardiovascular Diseases, Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota;

epartment of Cardiology, Aarhus University Hospital, Aarhus, Denmark; and the cIKEM (Institute for Clinical and Experimental

dicine), Department of Cardiology, Prague, Czech Republic. Dr. Borlaug is supported by RO1 HL128526 and U10 HL110262 from

National Institutes of Health; and research funding from Mast Pharmaceuticals. Dr. Reddy is supported by T32 HL007111 from

National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this

per to disclose. Drs. Reddy and Andersen contributed equally to this work.

nuscript received February 3, 2017; revised manuscript received May 5, 2017, accepted May 8, 2017.

AB BR E V I A T I O N S

AND ACRONYM S

AIx = Augmentation Index

A-VO2diff = arterial-venous O2

difference

BMI = body mass index

CO = cardiac output

EaI = effective arterial

elastance index

HF = heart failure

HFpEF = heart failure with

preserved ejection fraction

LV = left ventricle

J A C C V O L . 7 0 , N O . 2 , 2 0 1 7 Reddy et al.J U L Y 1 1 , 2 0 1 7 : 1 3 6 – 4 8 Aortic Stiffening in HFpEF

137

H uman senescence is characterized by anincrease in aortic stiffness (1). This causessystolic hypertension by reductions in arte-

rial compliance and increases in systolic wave reflec-tions (1,2). Aging, along with hypertension andobesity, are the strongest risk factors for the develop-ment of heart failure with preserved ejection fraction(HFpEF) (3). These comorbidities are believed to pro-mote the development of HFpEF by causing defi-ciency in nitric oxide-guanosine monophosphate(NO-cGMP) signaling, which may alter ventricularmechanical properties that result in hemodynamicfindings of HF (3–5).

SEE PAGE 149 NO = nitric oxide

NO-cGMP = nitric oxide-

guanosine monophosphate

PA = pulmonary artery

Pb = backward wave

PCWP = pulmonary capillary

wedge pressure

Pf = forward wave

PP = pulse pressure

PPA = pulse pressure

amplification

TACI = total arterial

compliance index

In addition to reporting ventricular abnormalities,prior studies have demonstrated that arterial stiffnessis increased in people with HFpEF above levels ex-pected from aging alone (6–11). This arterial stiffnesshas historically been ascribed to chronic systemichypertension, but recent data suggest it may be relatedin large part to comorbid conditions observed withHFpEF such as metabolic syndrome and obesity (3,4).Few studies have compared HFpEF subjects to a hy-pertensive control group (7,8), and no invasive dataare available that relate indices of arterial stiffness at

TABLE 1 Baseline Characteristics

Control(n ¼ 22)

HFpEF(n ¼ 98) p Value

Age, yrs 62 � 12 68 � 10 0.01

Females, % 45 56 0.48

Body mass index, kg/m2 26.9 � 4.1 34.1 � 7.9 <0.0001

Comorbidities, %

Coronary disease 27 35 0.50

Diabetes mellitus 23 31 0.46

Hypertension 100 98 1.00

Using medications shown, %

ACE Inhibitor or ARB 41 59 0.12

Beta-blocker 50 58 0.48

Calcium-channel blocker 32 23 0.41

Loop diuretic agent 13 43 0.01

Laboratory test results

Estimated GFR, ml/min 86 � 29 86 � 48 0.95

NT-proBNP, pg/ml 83 (42–295) 422 (122–1,022) 0.005

Echocardiography

Ejection fraction, % 62 � 9 63 � 8 0.59

E/e0 velocity, m/s 9 � 3 15 � 8 0.0003

RVSP, mm Hg 30 � 7 40 � 14 0.004

Values are mean � SD, %, or median (interquartile range).

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blockers; E/e0 ¼ ratio of early diastolic transmitral filling velocity (E) to early diastolic mitralannular tissue velocity (e0); GFR ¼ glomerular filtration rate; HFpEF ¼ heart failurewith preserved ejection fraction; NT-proBNP ¼ N-terminal pro–B-type natriureticpeptide; RVSP ¼ right ventricular systolic pressure.

RM = reflection magnitude

SVRI = systemic vascular

resistance index

VO2 = oxygen consumption

rest and during exercise to central hemody-namics in people with HFpEF.

We undertook the current study tocompare invasive measurements of arterialload in patients with invasively provenHFpEF with those in a matched hypertensivecontrol group at rest and during exercise. Wehypothesized that arterial stiffness would beincreased with exercise in HFpEF subjectscompared with that in hypertensive controlsubjects without HF, that this stiffeningwould be associated with abnormal cardiachemodynamics, and that acute treatmentwith inorganic sodium nitrite, a novel NO-cGMP agent (12–14), would partially reversearterial stiffening with exercise.

METHODS

STUDY SUBJECTS. The study populationincluded subjects participating in prospectivetrials conducted in our laboratory, all usingthe same uniform invasive supine exercise-testing protocol (13–18). Data from these co-horts have been published previously but notin total or as they relate to vascular indices inthe current analysis. In cohort 1, HFpEF andcontrol subjects underwent exercise testingin the evaluation of exertional dyspnea withsimultaneous echocardiographic imaging(15–18). In cohorts 2 and 3, HFpEF subjects

underwent exercise testing prior to and followingacute administration of either intravenous or inhaledsodium nitrite in a 1:1 randomized, double-blind,placebo-controlled fashion (13,14).

For the initial analysis comparing arterial load inHFpEF and control subjects, hemodynamic dataacquired prior to receiving study drug was includedfor cohorts 2 and 3 and was analyzed with cohort 1at matched workloads during cycle ergometry. Forthe next part of our analysis, we assessed the ef-fects of sodium nitrite, a novel NO donor, on arte-rial load in HFpEF. All studies were approved bythe Mayo Clinic Institutional Review Board andwere registered (NCT01418248, NCT01932606, andNCT02262078).

CASE DEFINITIONS. HFpEF and hypertensive controlsubjects were defined as previously specified (13–18).HFpEF was defined as symptoms of HF (fatigueand/or dyspnea) and preserved left ventricular ejec-tion fraction $50% with elevated pulmonary capil-lary wedge pressure (PCWP) at rest (>15 mm Hg)and/or with exercise ($25 mm Hg). Control subjects

TABLE 2 Resting Arterial Properties and Central Hemodynamics

PropertyControl(n ¼ 22)

HFpEF(n ¼ 98) p Value

Adjustedp Value*

Radial pressure, mm Hg

Radial systolic BP 163 � 22 160 � 25 0.63 0.17

Radial diastolic BP 73 � 6 71 � 10 0.34 0.44

Radial mean BP 104 � 11 103 � 14 0.60 0.46

Radial PP 90 � 18 89 � 21 0.89 0.18

Aortic pressure, mm Hg

Aortic systolic BP 145 � 23 145 � 24 0.99 0.39

Aortic diastolic BP 75 � 6 72 � 10 0.30 0.48

Aortic mean BP 104 � 11 103 � 14 0.60 0.46

Aortic PP 71 � 20 73 � 20 0.61 0.48

Arterial afterload

Ea indexed, mm Hg ∙ m2/ml 3.26 � 0.92 3.43 � 1.02 0.47 0.75†

SVRI, dyne-s ∙ m2/cm5 3,318 � 1,039 3,059 � 809 0.20 0.02†

TAC index, ml/mm Hg ∙ m2 0.61 � 0.24 0.55 � 0.19 0.19 0.80†

Pf, mm Hg 47 � 9 51 � 14 0.20 0.73

Pb, mm Hg 35 � 12 36 � 12 0.68 0.57

RM, % 74 (61–86) 68 (58–91) 0.78 0.98

Aortic AIx, % 28 � 16 31 � 15 0.32 0.70

Peripheral PPA 1.31 � 0.21 1.26 � 0.17 0.21 0.0001

Central hemodynamics

Heart rate, beats/min 69 � 15 69 � 11 0.93 0.53

RAP, mm Hg 4 � 2 11 � 5 <0.0001 <0.0001

PCWP, mm Hg 8 � 3 18 � 6 <0.0001 <0.0001

PA systolic pressure, mm Hg 27 � 6 44 � 15 <0.0001 0.008

PA mean pressure, mm Hg 16 � 4 28 � 9 <0.0001 0.0003

Stroke volume index, ml/m2 40 � 10 37 � 10 0.27 0.65†

Cardiac index, l/min ∙ m2 2.7 � 0.8 2.5 � 0.6 0.24 0.77†

Values are mean � SD or median (interquartile range). *p Value adjusted for age and body mass index. †Data thatwas already indexed to body weight was only adjusted for age. p Values are not adjusted for multiple hypothesistesting.

Aix ¼ augmentation index; BP ¼ blood pressure; Ea ¼ effective arterial elastance; HFpEF ¼ heart failure withpreserved ejection fraction; HR ¼ heart rate; PA ¼ pulmonary artery; Pb ¼ backward wave; PCWP ¼ pulmonarycapillary 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 totalarterial compliance.

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138

had systemic hypertension but no evidence of HF,with normal rest and exercise pulmonary artery (PA)pressures (<25 mm Hg at rest; <40 mm Hg duringexercise) and normal PCWP (<15 mm Hg atrest; <25 mm Hg during exercise). Exclusion criteriaincluded significant valvular heart disease (greaterthan mild stenosis or moderate regurgitation), sig-nificant pulmonary disease, congenital heart disease,left-to-right shunt, unstable coronary artery disease,myocardial infarction within 60 days, hypertrophic orrestrictive cardiomyopathy, high-output heart fail-ure, or constrictive pericarditis.

CATHETERIZATION PROTOCOL. Subjects were studied inthe postabsorptive state while taking chronic medi-cation, in the supine position, at rest, and duringsupine cycle ergometry as previously described (13–18).

The radial artery was cannulated using a 5- or 6-Fsheath for continuous recording of arterial pressurewaveforms and blood sampling. Right-heart catheteriza-tion was performed using a 9-F sheath inserted in the in-ternal jugular vein. Right atrial, PCWP, and PA pressureswere measured at end-expiration, using 2-F high-fidelitymicromanometer-tipped catheters (Millar Instruments,Houston, Texas) advanced through the lumen of a 7-Ffluid-filled balloon catheter (Arrow International Inc.,Reading, Pennsylvania).

Oxygen consumption (VO2) was measured usingbreath-by-breath expired gas analysis (MedGraphics,St. Paul, Minnesota). Because exercise was per-formed by using supine ergometry, peak VO2 valuesachieved are 40% to 50% lower than that observedwith upright treadmill exercise. Arterial-venous O2

difference (A-VO2diff) was measured directly as thedifference between systemic and PA O2 contents (O2

saturation ∙ hemoglobin ∙ 1.34). Cardiac index wascalculated using the direct Fick method (cardiacindex ¼ VO2/A-VO2diff ∙ body surface area). Strokevolume index was calculated as cardiac index/heartrate.

ARTERIAL WAVEFORM ANALYSIS. Radial artery pres-sure tracings were digitized (240 Hz) and stored foroffline analysis. Central aortic pressure waveformswere determined from radial artery pressure tracingsat rest and during exercise by mathematical transferfunction using customized software (SphygmoCor,AtCor, New South Wales, Australia) as previouslydescribed and validated at rest, during exercise, andwith drug therapy (19–21). Arterial waveform analysiswas performed in a blinded fashion without knowl-edge of the subject group, hemodynamics, or clinicaldata.

Steady, nonpulsatile arterial load was quantifiedby systemic vascular resistance index (SVRI ¼ 80 ∙[mean central blood pressure � right atrial bloodpressure] ∙ body surface area/cardiac output [CO]).Pulsatile arterial load was assessed by pulse pressure(PP), effective arterial elastance index (EaI) and totalarterial compliance index (TACI). EaI, a lumpedmeasure of the total “stiffness” of the arterial system,was assessed by end-systolic central blood pressure/stroke volume index (22). TACI, which is a linearapproximation of the pressure-volume relationshipfor the lumped arterial system, was calculated asstroke volume index/central PP (23–25). Peripheral PPamplification (PPA) was calculated as the peripheral-to-central PP ratio. An increase in pulsatile load isevidenced by increases in Ea and PP and decreases inTACI and PPA.

TABLE 3 Submaximal (20-W) Exercise Arterial and Ventricular Function

FunctionControl(n ¼ 22)

HFpEF(n ¼ 98) p Value

Adjustedp Value*

Radial pressure, mm Hg

Radial systolic BP 178 � 18 182 � 30 0.46 0.66

Radial diastolic BP 76 � 5 76 � 12 0.98 0.94

Radial mean BP 112 � 11 114 � 19 0.59 0.91

Radial PP 102 � 16 107 � 24 0.36 0.54

Aortic Pressure, mm Hg

Aortic systolic BP 151 � 19 160 � 27 0.12 0.52

Aortic diastolic BP 80 � 6 78 � 12 0.44 0.66

Aortic mean BP 112 � 11 114 � 19 0.59 0.91

Aortic PP 71 � 16 83 � 22 0.02 0.28

Arterial afterload

Ea indexed, mm Hg ∙ m2/ml 2.64 � 0.71 3.26 � 0.92 0.004 0.04†

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†

Pf, mm Hg 55 (51–60) 62 (51–70) 0.01 0.61

Pb, mm Hg 32 � 9 36 � 12 0.15 0.27

RM, % 58 � 14 59 � 19 0.76 0.35

Aortic AIx, % 20 � 11 21 � 18 0.86 0.40

Peripheral PPA 1.46 � 0.17 1.35 � 0.19 0.02 0.02

Central hemodynamics

Heart rate, beats/min 91 � 15 88 � 15 0.32 0.59

RAP, mm Hg 9 � 3 21 � 8 <0.0001 <0.0001

PCWP, mm Hg 14 � 5 32 � 7 <0.0001 <0.0001

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

Stroke volume index, ml/m2 47 � 10 39 � 10 0.0006 0.005†

Cardiac index, l/min ∙ m2 4.2 � 0.8 3.4 � 0.9 0.0005 0.004†

Values are mean � SD or median (interquartile range). *p Value adjusted for age and body mass index. †Data thatwere already indexed to body weight were only adjusted for age. p Values were not adjusted for multiplehypothesis testing.

Abbreviations as in Table 2.

J A C C V O L . 7 0 , N O . 2 , 2 0 1 7 Reddy et al.J U L Y 1 1 , 2 0 1 7 : 1 3 6 – 4 8 Aortic Stiffening in HFpEF

139

The contribution of wave reflections to arterialload was also assessed. Forward wave (Pf) and back-ward wave (Pb) pressures were isolated from thecomposite central aortic waveform as previouslydescribed (26). Wave reflections were quantified bythe reflection magnitude [RM ¼ Pb/Pf] and aorticaugmentation index (AIx) (21,26).

STATISTICAL ANALYSIS. Results are reported asmean � SD, median (interquartile range [IQR]), orpercentage. Differences between HFpEF subjectsand control subjects at rest and during exercisewere tested using chi-square, Student t test, orWilcoxon rank sum test as appropriate. All com-parisons were also adjusted for baseline differencesin age and body mass index (BMI), using multivar-iate linear regression. Pearson correlation and linearregression analyses were performed to detect thecorrelation between variables of interest. All testswere two-sided, and a p value of <0.05 wasconsidered significant. Analyses were performedusing JMP version 10.0.0 software (SAS Institute,Cary, North Carolina).

RESULTS

Compared to control subjects (n ¼ 22), subjects withHFpEF (n ¼ 98) were older and heavier (Table 1).Comorbidities including hypertension, diabetes, andcoronary disease were common and similarly prev-alent, with no group differences. As expected,HFpEF subjects had higher N-terminal pro–B-typenatriuretic peptide levels, increased E/e0 ratio, andhigher right ventricular systolic pressure on echo-cardiography, consistent with increased fillingpressures.

Because age and adiposity are well known to affectarterial properties and were different in HFpEF andcontrol subjects, all subsequent comparisons betweenHFpEF and control subjects were adjusted for thesecovariates.

BASELINE VENTRICULAR AND VASCULAR FUNCTION.

At rest, both HFpEF and control subjects displayedperipheral and central arterial hypertension, withno group differences (Table 2). There were also nodifferences in resting measurements of arterialafterload including systemic arterial resistance, ela-stance, compliance, or wave reflections. As expected,biventricular filling pressures and PA pressure werehigher at rest in the HFpEF group.

ARTERIAL RESERVE WITH SUBMAXIMAL EXERCISE.

During submaximal exercise (20 W), radial and aorticpressures in HFpEF were similar to those in control

subjects, although aortic pulse pressure tended toincrease more in HFpEF subjects (Table 3, Figure 1). Incontrast, direct measurements of arterial afterloadfailed to decrease as much in HFpEF subjects as theydid in control subjects during 20-W exercise, manifestby higher arterial elastance, lower total arterialcompliance, and decreased PPA (Table 3, Figure 1).Each of these differences persisted after adjusting forage and BMI.

As expected, HFpEF subjects developed typicalcardiac abnormalities with exercise including pul-monary venous and arterial hypertension andreduced CO reserve (Table 3). Lower total arterialcompliance and higher arterial elastance with exer-cise were correlated with higher PCWP and lower COduring exertion (Figure 2). These relationshipsremained significant after adjusting for age and BMI(both p < 0.001).

ARTERIAL RESERVE WITH PEAK EXERCISE. All ofthe control subjects (n ¼ 22) and 42 of the HFpEF

FIGURE 1 Arterial Load During Exercise

90

80

70

6020 W

Aort

ic P

P, m

m H

g

Rest

Group*Exercise p = 0.008

Controls HFpEF

A4.0

3.5

3.0

2.5

2.020 W

Eal,

mm

Hg.

m2 /m

l

Rest

Group*Exercise p = 0.02

B

0.8

0.7

0.5

0.6

0.420 W

TACI

. ml/m

m H

g.m

2

Rest

Group*Exercise p < 0.0001

C1.6

1.5

1.4

1.3

1.2

1.120 W

Perip

hera

l PPA

Rest

Group*Exercise p = 0.05

D

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.

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140

subjects (43%) exercised past the submaximal 20-Wworkload to volitional exhaustion. Peak exercise ca-pacity was roughly 40% lower in HFpEF subjects thanin control subjects (peak VO2 was 8.6 � 2.3 ml/min/kgvs. 14.8 � 3.8 ml/min/kg, respectively; p < 0.0001). Aswith 20-W exercise, systemic pressures were similarbut measurements of arterial afterload decreasedless at peak exercise in HFpEF subjects than in controlsubjects, with higher arterial elastance and systemicvascular resistance and lower total arterial compliance(Table 4). Unlike submaximal exercise, there was alsoevidence for increased wave reflection-associatedpressure load at peak exercise in HFpEF subjectscompared to that in control subjects. This was shownby higher AIx, RM, and lower PPA results. Among themeasurements of reflected pressurewaves, AIx at peakexercise was correlated with reduced total arterialcompliance, higher PCWP, EaI, and lower peak CO(Figure 3).

EFFECT OF NITRITE ON ARTERIAL PROPERTIES. Wenext evaluated the effects of sodium nitrite, a novelNO-providing agent, on the abnormalities observed incentral and peripheral arterial loading at rest andwith exercise in HFpEF subjects. Nitrite or matchingplacebo was administered in a randomized, blindedfashion intravenously in cohort 2 subjects (n ¼ 28)and by nebulized inhalation in cohort 3 subjects(n ¼ 26). Because plasma NO2 levels and hemody-namic effects were similar for intravenous andinhaled nitrite administration (Online Table 1), wecombined both nitrite and placebo groups to analyzethe 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, nitritedecreased aortic wave reflections at rest (lower Pb,RM, and AIx) but had no effect on arterial elastance orcompliance compared with placebo. In contrast, with

FIGURE 2 Correlation Between Arterial Load and Central Hemodynamics

60

40

r = –0.42p = < 0.0001

20

0

20 W

PCW

P (m

m H

g)

20 W TACI, ml/mm Hg.m20.0 0.5 1.0 1.5

Controls HFpEF

A60

40

r = 0.30p = 0.002

r = –0.66p < 0.0001

20

0

20 W

PCW

P (m

m H

g)20 W Eal, mm Hg.m2/ml

0 2 4 6 8

B

15

10

r = 0.56p < 0.0001

5

0

20 W

CO

(L/m

in)

20 W TACI, ml/mm Hg.m20.0 0.5 1.0 1.5

C15

10

5

0

20 W

CO

(L/m

in)

20 W Eal, mm Hg.m2/ml0 2 4 6 8

D

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.

J A C C V O L . 7 0 , N O . 2 , 2 0 1 7 Reddy et al.J U L Y 1 1 , 2 0 1 7 : 1 3 6 – 4 8 Aortic Stiffening in HFpEF

141

(20-W) exercise, nitrite reduced central aortic pres-sures, decreased arterial elastance, reduced systemicvascular resistance and AIx, and increased totalarterial compliance compared with placebo (Figure 4).These favorable arterial effects of nitrite werecoupled with salutary reductions in biventricularfilling pressures and PA pressures at rest and to agreater extent with exercise, along with an improve-ment in cardiac output (Table 5).

DISCUSSION

We comprehensively examined arterial propertiesinvasively in patients with proven HFpEF andcompared them to hypertensive control subjects atrest and during exercise by using gold standard inva-sive hemodynamic assessments while assessing theeffects of a novel NO-cGMP-providing agent that we

show partially reverses arterial stiffening. We showthat, compared to hypertensive control subjects, sub-jects with HFpEF displayed similar indices of arterialafterload when measured at rest. In contrast, exerciseunmasked significant limitations in arterial compli-ance and vasodilatory reserve that were correlatedwith classic hemodynamic abnormalities observed inHFpEF, including elevated ventricular filling pres-sures and inadequate CO (Central Illustration). Arterialstiffening was present despite similar arterial pres-sures measured centrally and peripherally. Arterialstiffening at rest and with exercise was partiallyreversed with inorganic sodium nitrite, a novel NO-providing therapy, and this was coupled with favor-able improvements in central hemodynamics. Thesedata emphasize the fact that arterial stiffening andimpaired arterial vasodilator reserve with exerciseplay an important role in the pathophysiology of

TABLE 4 Peak Exercise Arterial and Ventricular Function

FunctionControl(n ¼ 22)

HFpEF(n ¼ 42) p Value

Adjustedp Value*

Radial pressure, mm Hg

Radial systolic BP 188 � 19 192 � 25 0.53 0.37

Radial diastolic BP 76 � 6 75 � 10 0.88 0.33

Radial mean BP 113 � 10 114 � 17 0.79 0.57

Radial PP 112 � 17 116 � 21 0.25 0.54

Aortic pressures, mm Hg

Aortic systolic BP 149 � 15 158 � 24 0.11 0.59

Aortic diastolic BP 81 � 6 79 � 11 0.44 0.27

Aortic mean BP 113 � 10 114 � 17 0.79 0.57

Aortic PP 68 � 13 79 � 20 0.02 0.20

Arterial afterload

Ea indexed, mm Hg ∙ m2/ml 2.45 � 0.71 3.16 � 0.92 0.003 0.02†

SVRI, dyne-s ∙ m2/cm5 1,473 � 440 1,923 � 494 0.0007 0.007†

TAC index, ml/mm Hg ∙ m2 0.77 � 0.24 0.55 � 0.21 0.0006 0.006†

Pf, mm Hg 62 � 19 66 � 14 0.40 0.67

Pb, mm Hg 27 � 11 35 � 13 0.04 0.05

RM, % 41 (34–54) 50 (43–63) 0.08 0.05

Aortic AIx, % 8 � 11 17 � 13 0.007 0.009

Peripheral PPA 1.66 � 0.17 1.51 � 0.22 0.007 0.006

Central hemodynamics

Heart rate, beats/min 121 � 16 99 � 16 <0.0001 <0.0001

RAP, mm Hg 8 � 4 22 � 6 <0.0001 <0.0001

PCWP, mm Hg 14 � 5 34 � 7 <0.0001 <0.0001

PA systolic pressure, mm Hg 42 � 9 70 � 13 <0.0001 <0.0001

PA mean pressure, mm Hg 28 � 7 49 � 8 <0.0001 <0.0001

Stroke volume index, ml/m2 99 � 29 85 � 28 0.06 0.02†

Cardiac index, l/min ∙ m2 12.0 � 4.0 8.4 � 2.9 <0.0001 <0.0001†

Peak VO2, ml/kg/min 14.8 � 3.8 8.6 � 2.3 <0.0001 <0.0001†

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 formultiple hypothesis testing.

TAC ¼ total arterial compliance; other abbreviations as in Table 2.

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HFpEF that is independent of hypertension andmean blood pressure alone. These data also under-score the importance of central aortic stiffening inHFpEF as a viable therapeutic target that meritsfurther prospective study in this cohort of patients forwhom few treatment options exist.

CENTRAL ARTERIAL LOAD AND BLOOD PRESSURE.

Aging causes changes in the mechanical properties ofthe aorta and conduit arteries (1,2). One of the keysequelae of this change is a decrease in total arterialcompliance, which can be conceptualized as theability of the arteries to store blood during systolewithout excessive increases in pressure. The aortacontributes most of the compliance in the systemicarterial bed, unlike the lungs, where compliance isdistributed more evenly throughout the vasculature.Decreases in aortic distensibility heighten left ven-tricular (LV) afterload directly by augmenting the

amplitude of outgoing (incident) pressure waves andindirectly by increasing wave velocity, which en-hances early return of reflected pressure waves thatsum with incident waves to increase systolic pressureload (1,2). Acutely, these arterial changes adverselyaffect LV ejection performance and diastolic relaxa-tion (27,28). Chronically, these arterial changes maycontribute to concentric chamber remodeling,fibrosis, and changes in the mechanical properties ofthe LV (28).

As shown in the current study, arterial stiffening isoften not apparent in the peripheral arteries and re-quires careful assessment of central aortic pressureand flow characteristics (2). In the young and healthyarterial system, there is augmentation of systolicpressure in the peripheral arteries due to the effectsof wave reflection. With aortic stiffening, these re-flected pressure waves travel more rapidly, arriving inthe central aorta during systole rather than diastole,to increase aortic pressure load. This results in adecrease in PPA as vascular stiffness increases alongwith other characteristic changes in the central aorticwaveform.

VASCULAR STIFFENING IN HFpEF. Systemic hyper-tension is highly prevalent in HFpEF and has beenextensively implicated in its pathogenesis (3). Anumber of studies using noninvasive measuringtechniques have reported that arterial stiffness isincreased in HFpEF compared with that in healthycontrol subjects, and some studies have correlatedthis stiffening with decreased exercise capacity (6,9–11). However, elevation in blood pressure is associ-ated with reduced arterial distensibility in and of it-self, because the arterial pressure-volumerelationship is not linear and varies with ambientpressure. Thus, arterial stiffening may not be specificto HFpEF but common to all or most hypertensivepatients. In this regard, 2 studies comparing HFpEFsubjects with carefully matched hypertensive controlsubjects have reported little to no differences in mostmeasurements of arterial stiffness between groups(7,8).

The current data are consistent with those studies,showing that, compared with a hypertensive controlgroup, there was no discernable difference in restingarterial afterload in subjects with HFpEF. However,with increases in arterial pressure and blood flowassociated with exercise, abnormalities becameapparent, revealing vascular stiffening that was notclearly identifiable at rest. Older age and obesity are 2of the strongest risk factors for HFpEF and arebelieved to play major roles in its pathogenesis (3).Importantly, the differences in arterial stiffness

FIGURE 3 Correlation Between Wave Reflection and Central Hemodynamics at Peak Exercise

6

4

r = 0.34, p = 0.007

2

0

Peak

Eal

, mm

Hg.

m2 /m

l

Peak Alx, %–20 0 20 40 60

A1.5

1.0

r = –0.52, p < 0.0001

0.5

0.0

Peak

TAC

I (m

l/mm

Hg.

m2 )

Peak Alx, %–20 0 20 40 60

B

80

40

60

r = 0.29, p = 0.02

20

0

Peak

PCW

P (m

m H

g)

Peak Alx, %–20 0 20 40 60

C25

20

10

15

r = –0.54, p < 0.0001

5

0

Peak

CO

(l/m

in)

Peak Alx, %–20 0 20 40 60

D

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.

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observed in the present study during exercise per-sisted even after we adjusted for age and BMI, whichare known to directly affect arterial properties(29,30), and these differences were not related todifferences in arterial blood pressure. This importantobservation demonstrates that arterial stiffening andreduced arterial reserve are specific to the HFpEFphenotype, and are thus potentially important ther-apeutic targets.

This study is also unique due to the invasivedetermination of arterial and reflected load with ex-ercise, which allowed for direct correlation withsimultaneous filling pressures and CO during exer-cise. One previous noninvasive study measuredand demonstrated increased proximal aortic imped-ance and decreased arterial compliance withexercise but did not measure simultaneous reflectedload or filling pressures (9). Although causalitycannot be proven from this study design, the fact that

abnormalities in arterial compliance, elastance, andwave reflection were present in HFpEF, associatedwith abnormal hemodynamics and partly reversedby using nitrite in tandem with improved hemody-namics, strongly supports the notion that arterialstiffening plays an important role in the pathophysi-ology of HFpEF, especially during exercise.

THERAPEUTIC IMPLICATIONS. The finding of greaterarterial afterload with exercise in HFpEF suggests arole for drugs that enhance arterial compliance andreduce wave reflection. Different antihypertensiveagents have varying effects on wave reflection andaortic compliance properties. For example, betablockers increase wave reflection and central bloodpressure compared to vasodilators. This has beensuggested as a mechanism for the inferior outcomesseen with beta-blocker therapy for hypertension in theASCOT (Anglo Scandinavian Cardiac Outcomes Trial)

TABLE 5 Effect of Nitrite on Arterial Properties at Rest and Exercise

Arterial Property

Rest 20-W Exercise

Placebo-Corrected Nitrite Effect(n ¼ 52) p Value

Placebo-Corrected Nitrite Effect(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.

FIGURE 4 Effects of Inorganic Nitrite on Resting and Exercise Arterial Load

20

10

0

–10

–20

% C

hang

e

RestA Bp = 0.0002 p = 0.0002

p = 0.0002

Pb RM PPA

Placebo Nitrite

20

10

0

–10

–20

Exercise

p < 0.0001

p = 0.0002

p = 0.004

Eal TACI SVRI

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.

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CENTRAL ILLUSTRATION 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.

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compared to an amlodipine vasodilator regimen (31).Although this effect has been ascribed to negativechronotropic effects, this may not apply to all heartrate-lowering drugs. Ivabradine, which selectivelylowers the sinus rate, improves aortic compliance inpatients with HFrEF (32). Alternative vasodilators mayhave similar effects on lowering arterial stiffness andimproving central hemodynamics, but comparativedata for their hemodynamic effects in HFpEF arelacking, and we cannot assume that the current ob-servations will apply to all vasodilators. Future studiesevaluating both cardiac and arterial hemodynamiceffects of vasoactive medicines in HFpEF would bevaluable to address this important question.

Deficiency of NO and its downstream secondmessenger, cGMP, have been repeatedly implicated inthe pathogenesis of HFpEF and are being targeted in avariety of ongoing trials (3,4). Neprilysin inhibitorsincrease intracellular cGMP by decreasing the break-down of endogenous natriuretic peptides, and treat-ment with the neprilysin inhibitor omapatrilat hasbeen shown to improve central aortic distensibilityand reduce systolic wave reflections and characteristicimpedance in hypertensives (33). It remains unknownwhether similar vascular effects will be seen with thenewer neprilysin antagonist sacubitril, which iscurrently being tested in the PARAGON-HF (Prospec-tive comparison of ARni with Arb Global Outcomes inheart failure with preserved ejectioN fraction) trial inpatients with chronic HFpEF (NCT01920711).

The inorganic nitrate/nitrite/NO pathway repre-sents an alternative method to improve NO-cGMPavailability in HFpEF. Acute administration of inor-ganic nitrite (or its precursor nitrate) decreasesconduit vessel stiffness in healthy volunteers (12,34),enhances exercise capacity and vasodilation inHFpEF patients (13,14,35,36), and improves rest andexercise hemodynamics in HFpEF patients (13,14,37).Zamani et al. (35) recently found that inorganic ni-trate decreased AIx in HFpEF patients, whenmeasured at rest, while improving peak exercisecapacity. The current data importantly extend theseprevious findings, confirming salutary effects ofnitrite on wave reflection while demonstrating forthe first time direct improvements in arterialcompliance, elastance, and wave reflection at restand during exercise, when hemodynamic perturba-tions contribute to symptoms of dyspnea. Effectsof nitrite in hypertensive control subjects were notexamined 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, andBlood Institute are currently under way to evaluate

the effects of longer-term nitrite therapy in HFpEF(NCT02742129 and NCT02713126), and further studyis warranted using other novel therapies targetingarterial stiffness.

STUDY LIMITATIONS. Central aortic pressures werenot directly measured but were derived mathemati-cally from the directly measured radial artery trac-ings. However, this method has been previouslyvalidated compared with directly measured centralaortic pressures (19), and the use of directly measuredpressures from an arterial cannula is a uniquestrength, compared with prior studies that relied onnoninvasive applanation tonometry to measure radialwaveforms. Although imputation of central pressuresfrom radial waveforms has been validated followingnitroglycerin therapy (19), there are fewer validationdata available using other drug therapies. Correctionfor multiple hypothesis testing was not performed.Arterial stiffening may be related to structuralremodeling and changes in the material properties ofthe vasculature or to endothelial dysfunction andvasoconstriction, or both. We cannot identify whichcomponents explained the greater stiffening duringexercise in HFpEF. Future studies evaluating effectsof nitrite on individual components, such as aorticpulse wave velocity and endothelium-dependentvasodilation, would be important to help sort outthe mechanisms by which nitrite improves arterialstiffening. Subjects with HFpEF were older and hadhigher BMI than control subjects, which may influ-ence arterial properties independent of HFpEF status,but all key differences remained highly significantafter 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. Theseabnormalities are directly correlated with greaterhemodynamic severity of HF and worse functionalcapacity, even after controlling for the presence ofhypertension. Sodium nitrite mitigates these vascularperturbations in tandem with salutary effects on thehemodynamic abnormalities that contribute to effortintolerance. Further study is warranted to investigatewhether therapies targeting central aortic stiffnesscan improve clinical outcomes in HFpEF.

ADDRESS FOR CORRESPONDENCE: Dr. Barry A.Borlaug, Department of Cardiovascular Diseases, MayoClinic and Foundation, 200 First Street SW, Rochester,Minnesota 55905. E-mail: borlaug.barry@mayo.edu.

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.

TRANSLATIONAL OUTLOOK: Prospective studies are

needed to quantify the potential benefit of therapies that

target nitric oxide deficiency and ameliorate central

arterial stiffening and wave reflections in patients with

HFpEF.

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KEY WORDS aortic stiffness, exercise,heart failure, HFpEF, hypertension

APPENDIX For a supplemental table, pleasesee the online version of this article.