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Hemodynamic Response toNitroprusside in Patients WithLow-Gradient Severe Aortic Stenosisand Preserved Ejection Fraction
James W. Lloyd, MD, Rick A. Nishimura, MD, Barry A. Borlaug, MD, Mackram F. Eleid, MDABSTRACT
Fro
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BACKGROUND Low-gradient severe aortic stenosis (LGSAS) with preserved ejection fraction (EF) is incompletely
understood. The influence of arterial afterload and diastolic dysfunction on the hemodynamic presentation of LGSAS
remains unknown.
OBJECTIVES The authors sought to determine the acute hemodynamic response to sodium nitroprusside in LGSAS with
preserved EF.
METHODS Symptomatic patients with LGSAS and preserved EF underwent cardiac catheterization with comparison of
hemodynamic measurements before and after nitroprusside.
RESULTS Forty-one subjects (25 with low flow [LF], stroke volume index [SVI] #35 ml/m2, 16 with normal flow
[NF]) were included. At baseline, LF patients had lower total arterial compliance (0.36 � 0.12 ml/m2/mm Hg vs.
0.48 � 0.16 ml/m2/mm Hg; p ¼ 0.01) and greater effective arterial elastance (2.77 � 0.84 mm Hg $ m2/ml vs.
1.89 � 0.82 mm Hg $ m2/ml; p ¼ 0.002). In all patients, nitroprusside reduced elastance, left ventricular filling
pressures, and pulmonary artery pressures and improved compliance (p < 0.05). Aortic valve area increased to $1.0 cm2
in 6 LF (24%) and 4 NF (25%) subjects. Change in SVI with nitroprusside varied inversely to baseline SVI and
demonstrated improvement in LF only (3 � 6 ml/m2; p ¼ 0.02).
CONCLUSIONS Nitroprusside reduces afterload and left ventricular filling pressures in patients with LGSAS and
preserved EF, enabling reclassification to moderate stenosis in 25% of patients. An inverse relationship between baseline
SVI and change in SVI with afterload reduction was observed, suggesting that heightened sensitivity to afterload is a
significant contributor to LF-LGSAS pathophysiology. These data highlight the utility of afterload reduction in the
diagnostic assessment of LGSAS. (J Am Coll Cardiol 2017;70:1339–48) © 2017 by the American College of Cardiology
Foundation.
T he classification of aortic stenosis (AS)severity is based on measures of aortic valvearea (AVA), aortic mean (transvalvular)
gradient, and peak aortic jet velocity (1). In patientswith low-gradient severe aortic stenosis (LGSAS) adiscrepancy is encountered between measured AVA(<1.0 cm2 and thus severe by definition) and trans-valvular gradient (<40 mm Hg and therefore consis-tent with less-than-severe disease). This apparent
m the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, M
relationships relevant to the contents of this paper to disclose.
nuscript received May 11, 2017; revised manuscript received June 26, 201
paradox frequently confounds decision making ontreatment.
Clinically distinct subgroups of LGSAS includethose with preserved ejection fraction (EF) and thosewith reduced EF (2). Patients with LGSAS and pre-served EF can also be dichotomized into those withlow-flow (LF) LGSAS and those with normal-flow (NF)LGSAS states. Patients with LF-LGSAS demonstrateincreased mortality (2–6), greater left ventricular
innesota. The authors have reported that they have
7, accepted July 10, 2017.
ABBR EV I A T I ON S
AND ACRONYMS
AS = aortic stenosis
AVA = aortic valve area
CI = confidence interval
EF = ejection fraction
LF = low-flow
LGSAS = low-gradient severe
aortic stenosis
MAP = mean aortic pressure
NF = normal-flow
SVI = stroke volume index
Lloyd et al. J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7
Nitroprusside in Low-Gradient Severe Aortic Stenosis S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8
1340
afterload, smaller left ventricular cavity size,more concentric remodeling, and more leftventricular systolic and diastolic dysfunctionrelative to patients with NF-LGSAS, who havea prognosis similar to moderate AS (7–9).Despite such differences, distinguishing trulysevere AS in the setting of LGSAS with pre-served EF has been difficult in practice due toa multitude of potential factors that maycontribute to discordant AS criteria. Theseinclude measurement error, body size,concomitant valvular lesions, systemic hy-pertension, and a lack of a validated stress
protocol (10–12). Although dobutamine challenge canbe useful for differentiating truly severe from“pseudosevere” AS in patients with left ventricularsystolic dysfunction and reduced EF (13), its utility toaugment stroke volume in patients with normal EF isunknown. By contrast, given the frequent coexis-tence of increased arterial afterload (14) and previousheart failure events (15) in patients with LGSAS, avasodilator such as sodium nitroprusside may betteraugment flow to enable differentiation of severe frompseudosevere AS and show the contribution ofincreased afterload to the pathophysiology in pa-tients with LGSAS and preserved EF. We have previ-ously demonstrated the utility of nitroprusside inhypertensive patients with LGSAS with preserved EF(15), though its utility in patients across the entireLGSAS population with a broad spectrum of bloodpressure and stroke volume values is unknown.Accordingly, we hypothesized that administration ofintravenous nitroprusside to symptomatic patientswith LGSAS and preserved EF would result in differ-ential responses in left ventricular afterload and for-ward stroke volume in patients depending onbaseline flow. We further hypothesized that suchimprovement in afterload and cardiac function (i.e.,stroke volume index [SVI]) would aid in differenti-ating AS severity and the underlying contributors tosymptoms.
SEE PAGE 1349
METHODS
PATIENTS. This study was approved by the MayoClinic (Rochester, Minnesota) Institutional ReviewBoard. Symptomatic patients with evidence of LGSASon transthoracic echocardiography were enrolledfrom January 1, 2007, to March 1, 2017. These patientswere referred for invasive evaluation of their valvulardisease. Accordingly, inclusion criteria consisted of
transthoracic echocardiography findings revealing forsevere aortic stenosis with either AVA <1.0 cm2 oraortic valve index <0.6 cm2/m2 and mean trans-valvular gradient <40 mm Hg with preserved EF($50%). Patients were excluded from this study ifthey were <18 years of age; had >moderate aorticregurgitation; or had identified complex congenitalheart disease.
INVASIVE HEMODYNAMIC EVALUATION. Each pa-tient underwent invasive hemodynamic left andright heart catheterization using conventional 6-Fand 7-F fluid-filled catheters within 30 days ofbaseline transthoracic echocardiography. Baselineinvasive hemodynamic measurements were obtainedbefore any medication administration, fluid infusion,or physical maneuvers. Left ventricular end-systolicpressure was measured by examining individualsimultaneous aortic and left ventricular pressuretracings, and identifying their intersection point asthe left ventricular end-systolic pressure. For aorticvalve assessment, simultaneous pressure measure-ments were taken from 2 separate sampling catheterspositioned in the central aorta and the left ventricle.Measurements obtained in this fashion were ac-quired digitally for offline storage and subsequentreview using proprietary software (CathCoding,Mayo Clinic). Cardiac output was determined byeither thermodilution technique or Fick method,indexed to body surface area, and used to calculateSVI. For the Fick method, oxygen consumption wasmeasured by expired gas analysis at the time ofcatheterization (Medical Graphics Corporation, St.Paul, Minnesota). AVA was calculated using theGorlin formula.
INVASIVE ASSESSMENT OF ARTERIAL AFTERLOAD.
Effective arterial elastance, a composite measure ofarterial afterload combining resistive (pressure) andpulsatile (flow) components, was calculated as the ra-tio of left ventricular end-systolic pressure (mm Hg) toSVI (ml/m2) (16). Total systemic arterial compliance, ameasure of vascular stiffness, was calculated as theratio of SVI to aortic pulse pressure (mm Hg). Systemicvascular resistance index (dynes $ s $ m2/cm5)was calculated as the difference between meanaortic pressure (MAP) (mm Hg) and mean right atrialpressure (mm Hg) relative to the correspondingcardiac output (l/min). Valvuloarterial impedance wascalculated as the ratio of the sum of aortic systolicpressure (mm Hg) and transvalvular gradient (mm Hg)to SVI (16).
NITROPRUSSIDE ADMINISTRATION. Nitroprussidewas administered to reduce afterload (15,17,18).
TABLE 1 Patient Demographics and Clinical History
Low Flow(n ¼ 25)
Normal Flow(n ¼ 16) p Value
Male 11 (44.0) 4 (25.0) 0.32
Age, yrs 76.8 � 11.5 77.1 � 8.9 0.93
Symptoms 25 (100.0) 16 (100.0) 1.00
Angina 8 (32.0) 5 (31.3) 1.00
Syncope 1 (4.0) 1 (6.3) 1.00
Heart failure (of any class) 25 (100.0) 16 (100.0) 1.00
History of radiation exposure 6 (24.0) 0 (0.0) 0.07
History of CHF-related hospitalization 12 (48.0) 1 (6.3) 0.006
Ejection fraction (via TTE), % 62.4 � 6.3 66.6 � 4.6 0.03
Comorbidities
Atrial fibrillation 12 (48.0) 5 (31.3) 0.34
CHF
NYHA functional class I 3 (12.0) 0 (0.0) 0.27
NYHA functional class II 2 (8.0) 3 (18.8) 0.36
NYHA functional class III 19 (76.0) 12 (66.7) 1.00
NYHA functional class IV 1 (4.0) 1 (6.3) 1.00
COPD 4 (16.0) 6 (37.5) 0.15
Coronary artery disease 22 (88.0) 10 (62.5) 0.12
Prior CABG 7 (28.0) 2 (12.5) 0.11
Prior PCI 5 (20.0) 3 (18.8) 1.00
Dementia 2 (8.0) 1 (6.3) 1.00
Hyperlipidemia 12 (48.0) 5 (31.3) 0.34
Interstitial lung disease 2 (8.0) 2 (12.5) 0.64
Stroke history 1 (4.0) 2 (12.5) 0.55
Systemic hypertension 21 (88.0) 16 (100.0) 0.14
Type 2 diabetes mellitus 7 (28.0) 3 (18.8) 0.71
Values are n (%) or mean � SD. p Values for categorical and numerical variables are reported for the Fisher exactand unpaired parametric 2-tailed Student t tests, respectively. Bold p values indicate significance (<0.05).
CABG ¼ coronary artery bypass grafting; CHF ¼ congestive heart failure; COPD ¼ chronic obstructive pul-monary disease; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention;TTE ¼ transthoracic echocardiogram.
J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7 Lloyd et al.S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8 Nitroprusside in Low-Gradient Severe Aortic Stenosis
1341
Exclusion criteria for nitroprusside administrationincluded: baseline systolic blood pressure<100 mm Hg; MAP <60 mm Hg; or history of allergicreaction to nitroprusside. Nitroprusside infusionwas begun at 0.5 mcg/min/kg and increased at 0.5 to1.0 mg/min/kg every 5 min until whichever 1 of severalpre-defined endpoints was reached first: a maximaldose of 10 mg/kg/min; aortic valve mean gradient>40 mm Hg; MAP <60 mm Hg; or the development ofintolerable patient side effects and/or symptoms.Hemodynamicmeasurements including cardiac index,aortic valve mean gradient, and AVA were conductedat peak nitroprusside infusion in the same fashion asat baseline. Patients with an improvement inmeasured SVI of 20% or more with vasodilator chal-lenge were classified during subsequent analysis ashaving “flow reserve.”
STATISTICAL ANALYSIS. Subjects were divided intoLF- and NF-LGSAS groups on the basis of SVI, with anSVI #35 ml/m2 corresponding to an LF state (5).Categorical variables were evaluated using eitherchi-square or Fisher exact test. Continuous variableswere compared using either paired or unpairedparametric Student t tests for intragroup and inter-group comparisons, respectively. Linear regressionanalysis was used to examine the relationship be-tween baseline SVI and change in SVI with nitro-prusside. Multivariable logistic regression analysiswas used to identify predictors of AVA increase to>1.0 cm2. Multivariable proportional hazard analysiswas performed to identify predictors of all-causemortality (variables analyzed included: age, sex,SVI, mean gradient, atrial fibrillation, coronary arterydisease, hypertension, and history of congestiveheart failure). Overall survival (either death or loss tofollow-up evaluation) after index catheterization ofLF- and NF-LGSAS patients was assessed via Kaplan-Meier analysis and log-rank testing. Further survivalanalysis among patients undergoing aortic valvereplacement and those not in LF and NF states wasperformed in a similar fashion. Significance wasdefined as a p value <0.05.
RESULTS
BASELINE CHARACTERISTICS. A total of 41 patientswere included in the study (excluded patientsincluded the following: 31 patients with meangradient $40 mm Hg; 42 patients with baseline aorticvalve area >1.0 cm2; 43 patients with EF <50%;1 patient with >moderate aortic regurgitation; and3 patients with complex congenital heart disease).Patients with LF-LGSAS (n ¼ 25) were more commonly
male and had similar symptoms compared with pa-tients with NF-LGSAS (n ¼ 16) (Table 1). LF-LGSASpatients were more likely to have a history of priorhospitalization for heart failure exacerbation. Therewas a trend toward greater prevalence of a history ofcoronary artery disease, prior coronary artery bypassgrafting, and radiation exposure in patients withLF-LGSAS, whereas chronic obstructive pulmonarydisease tended to be more common in patients withNF-LGSAS (Table 1).
BASELINE HEMODYNAMICS. As compared with sub-jects with NF-LGSAS, subjects with LF-LGSAS dis-played lower total systemic arterial compliance andhigher left ventricular afterload (valvuloarterialimpedance, effective arterial elastance, and aorticvalve resistance) at baseline (Table 2). As comparedwith NF, patients with LF tended to have greatersystemic vascular resistance, pulmonary vascularresistance, and pulmonary artery mean pressure.
TABLE 3 Hemodyna
Aortic Stenosis
Heart rate, beats/min
Pulmonary artery mean
Aortic systolic pressure
Aortic diastolic pressur
Aortic mean pressure,
Aortic pulse pressure, m
Left ventricular end-di
Left ventricular dP/dt,
Cardiac index, l/min/m
Stroke volume index, m
Aortic valve area, cm2
Aortic valve index, cm2
Aortic valve mean grad
Aortic valve resistance
Pulmonary vascular res
Valvuloarterial impedan
Effective arterial elasta
Total arterial complian
Systemic vascular resis
Values are mean � SD. p Vasignificance (<0.05).
TABLE 2 Comparison of Baseline Invasive Hemodynamic Measures
Low Flow(n ¼ 25)
Normal Flow(n ¼ 16) p Value
Heart rate, beats/min 77 � 11 62 � 9 <0.0001
Pulmonary artery mean pressure, mm Hg 39 � 11 34 � 12 0.16
Aortic systolic pressure, mm Hg 154 � 33 163 � 27 0.38
Aortic diastolic pressure, mm Hg 71 � 12 67 � 14 0.44
Aortic mean pressure, mm Hg 106 � 20 104 � 17 0.84
Aortic pulse pressure, mm Hg 84 � 25 96 � 27 0.17
Left ventricular end-diastolic pressure, mm Hg 17 � 7 18 � 4 0.56
Left ventricular dP/dt, mm Hg/s 2,001 � 634 2,075 � 429 0.66
Cardiac index, l/min/m2 2.1 � 0.4 2.6 � 0.5 0.002
Stroke volume index, ml/m2 28 � 4 43 � 10 <0.0001
Aortic valve area, cm2 0.83 � 0.13 0.86 � 0.15 0.54
Aortic valve index, cm2/m2 0.44 � 0.07 0.47 � 0.08 0.21
Aortic valve mean gradient, mm Hg 24 � 6 27 � 6 0.19
Aortic valve resistance, dynes $ s/cm5 621 � 139 474 � 129 0.002
Pulmonary vascular resistance, dynes $ s/cm5 402 � 282 286 � 120 0.09
Valvuloarterial impedance, mm Hg/ml/m2 6.62 � 1.42 4.55 � 1.02 <0.0001
Effective arterial elastance, mm Hg $ m2/ml 2.77 � 0.84 1.89 � 0.82 0.002
Total arterial compliance, ml/m2/mm Hg 0.36 � 0.12 0.48 � 0.16 0.01
Systemic vascular resistance, dynes $ s/cm5 1,942 � 603 1,673 � 429 0.10
Values are mean � SD. p Values are reported for unpaired parametric 2-tailed Student t tests. Bold p valuesindicate significance (<0.05).
Lloyd et al. J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7
Nitroprusside in Low-Gradient Severe Aortic Stenosis S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8
1342
Both groups, however, demonstrated a similar dis-tribution of AVA and transvalvular gradient at base-line. Systemic hypertension (aortic systolic pressure>140 mm Hg) was highly prevalent in both groups
mic Response to Nitroprusside in Low-Flow Low-Gradient Severe
Baseline(n ¼ 25)
Nitroprusside(n ¼ 25) p Value
77 � 11 80 � 12 0.04
pressure, mm Hg 39 � 11 27 � 10 <0.0001
, mm Hg 154 � 33 110 � 28 <0.0001
e, mm Hg 71 � 12 54 � 12 <0.0001
mm Hg 106 � 20 77 � 18 <0.0001
m Hg 84 � 25 55 � 20 <0.0001
astolic pressure, mm Hg 17 � 7 11 � 6 <0.0001
mm Hg/s 2,001 � 634 1,930 � 719 0.362 2.1 � 0.4 2.4 � 0.5 0.002
l/m2 28 � 4 30 � 5 0.02
0.83 � 0.13 0.92 � 0.14 0.003
/m2 0.44 � 0.07 0.49 � 0.08 0.003
ient, mm Hg 24 � 6 27 � 7 0.0002
, dynes $ s/cm5 621 � 139 636 � 163 0.64
istance, dynes $ s/cm5 402 � 282 278 � 234 0.01
ce, mm Hg/ml/m2 6.62 � 1.42 4.55 � 1.01 <0.0001
nce, mm Hg $ m2/ml 2.77 � 0.84 1.74 � 0.63 <0.0001
ce, ml/m2/mm Hg 0.36 � 0.12 0.63 � 0.22 <0.0001
tance, dynes $ s/cm5 1,942 � 603 1,209 � 471 <0.0001
lues are reported for paired parametric 2-tailed Student t tests. Bold p values indicate
(n ¼ 21 [88.0%] in LF vs. 16 [100.0%] in NF; p ¼ 0.14)(Table 2).
HEMODYNAMIC EFFECTS OF NITROPRUSSIDE. Withnitroprusside, both groups experienced significantimprovement in measures of left ventricularafterload (Tables 3 to 5, Central Illustration, Figure 1,Online Figure 1), including reductions in aortic sys-tolic, diastolic, mean, and pulse pressures; an in-crease in Gorlin AVA; a reduction in systemic andpulmonary vascular resistance; reductions in leftventricular end-diastolic and pulmonary artery meanpressures; and improvement in total arterial compli-ance. Both groups displayed improvements in val-vuloarterial impedance and effective arterialelastance, but these improvements were greater inpatients with LF-LGSAS (Table 5, Central Illustration,Figure 1, Online Figure 1). SVI improved with nitro-prusside more in those with LF compared with NF(p ¼ 0.006). Overall, the change in SVI with nitro-prusside varied inversely with baseline SVI, rangingfrom the most pronounced improvement in LF pa-tients to the least improvement (and often decre-ment) in NF patients (R2 ¼ 0.42; p < 0.0001)(Figure 2). In LF-LGSAS, 7 patients (28.0%) exhibitedflow reserve with nitroprusside (20% or greater in-crease in SVI), whereas no subjects in the NF groupexhibited this response (p ¼ 0.03).
EFFECT OF NITROPRUSSIDE ON MEASURES OF AS
SEVERITY. Nitroprusside administration led to a sig-nificant increase in AVA in both LF and NF groups(Table 5). The mean change in AVA in each group wasnot significantly different on comparison (CentralIllustration, Online Figure 1). Those with LF-LGSASalso demonstrated a significant increase in trans-valvular gradient, whereas a similar, though insig-nificant, trend was identified in patients withNF-LGSAS. With nitroprusside therapy, 6 of 25LF-LGSAS patients (24%) were reclassified as havingmoderate AS (AVA $1.0). Similarly, in the NF-LGSASgroup, 4 patients (25%) were reclassified as havingmoderate AS. Multivariable analysis did not identifyany significant predictors of AVA increase to>1.0 cm2. A subgroup analysis of patients excludingadditional valvular disease showed similar results(Online Appendix).
VALVULOARTERIAL IMPEDANCE AND PROGNOSIS.
LF and NF patients were stratified by impedance levelinto low-, medium-, and high-risk survival groups onthe basis of published criteria (19) before and aftertreatment with nitroprusside (Figure 3). Twenty-fourof 25 LF-LGSAS patients (96.0%) had baselineimpedance consistent with high risk. By contrast, 9 of
CENTRAL ILLUSTRATION Effect of Nitroprusside Therapy on Hemodynamic Variables and Aortic Valve Area inLow-Gradient Severe Aortic Stenosis
20
10
0 p = 0.006
–10
–20
–30Low-Flow Normal-Flow
Chan
ge in
Str
oke
Volu
me
Inde
x(m
L/m
2 )
4
2
0 p = 0.03
–2
–4
–6Low-Flow Normal-Flow
Chan
ge in
Val
vulo
arte
rial
Impe
danc
e (m
m H
g/m
L/m
2 )
0.8
0.6
0.4
p = 0.33
0.2
0.0
–0.2
Low-Flow Normal-FlowChan
ge in
Aor
tic V
alve
Are
a (c
m2 ) 20
10
p = 0.950
–10Low-Flow Normal-Flow
Chan
ge in
Aor
ticVa
lve
Mea
n Gr
adie
nt (m
m H
g)
Lloyd, J.W. et al. J Am Coll Cardiol. 2017;70(11):1339–48.
Scatterplots of change in hemodynamic variables and aortic valve area with nitroprusside.
J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7 Lloyd et al.S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8 Nitroprusside in Low-Gradient Severe Aortic Stenosis
1343
16 NF-LGSAS patients (56.3%) were high risk atbaseline (Figure 3). With nitroprusside therapy, thenumber of patients with high-risk impedance levelsin the LF group improved to 13 of 25 (down 41.0% to55.0%). This improvement was chiefly from high- tomedium-risk levels. Meanwhile, patients withNF-LGSAS demonstrated improvement as well, withonly 2 of 12 patients (17.0% and thus reduced 39.3%)having high-risk valvuloarterial impedance withnitroprusside therapy. In this group, however, theimprovement was commonly to the level of low-riskvalvuloarterial impedance (Table 6).
CLINICAL OUTCOMES FOLLOWING CATHETERIZATION.
In 25 LF-LGSAS patients, the median follow-upduration was 496 days. Mean time to deathfollowing index evaluation was 23.6 � 19.7 months(range 0.8 to 66.3 months). Nine (36.0%) of the 25
LF-LGSAS patients underwent aortic valve replace-ment (at an average of 9.3 � 11.0 months followingindex evaluation). After valve replacement, patientsdemonstrated a median survival time of 46.7months. Of the remaining LF-LGSAS patients whodid not undergo valve replacement (n ¼ 16 [64.0%]),a median overall survival of 18.1 months wasobserved. Accordingly, improved overall survivalwas observed in those undergoing valve replace-ment, compared with patients managed conserva-tively (p ¼ 0.02).
Of the 16 NF-LGSAS patients, median follow-upduration was 865 days. Mean time to deathfollowing index evaluation was 41.4 � 38.9 months(range 4.0 to 90.2 months). Eight (50.0%) of the 16NF-LGSAS patients underwent aortic valve replace-ment (at an average of 9.1 � 10.4 months followingindex evaluation). Median survival of these patients
FIGURE 1 Change in Hemodynamic Variables in Response to Nitroprusside in Low-Flow and Normal-Flow Low-Gradient Severe Aortic Stenosis Patients
Low-Flow, p = 0.003Normal-Flow, p = 0.007
1.8A
1.5
1.2
0.9
0.6
0.3
0.0
Aort
ic V
alve
Are
a (c
m2 )
Low-Flow, p = 0.0002Normal-Flow, p = 0.10
50B
40
30
20
10
0Aort
ic V
alve
Mea
n Gr
adie
nt (m
m H
g)
Low-Flow, p = 0.64Normal-Flow, p = 0.02
1250C
1000
750
500
250
0Aort
ic V
alve
Res
istan
ce (d
ynes
*s/c
m5 )
Low-Flow, p = 0.02Normal-Flow, p = 0.07
80D
60
40
20
0
Stro
ke V
olum
e In
dex
(mL/
m2 )
Low-Flow, p < 0.0001Normal-Flow, p = 0.0003
10E
8
6
4
2
0
Valv
uloa
rter
ial I
mpe
danc
e(m
m H
g/m
L/m
2 )
Low-Flow, p < 0.0001Normal-Flow, p < 0.0001
6F
4
2
0
Effec
tive
Arte
rial E
last
ance
(mm
Hg*
m2 /
mL)
Low-Flow, p < 0.0001Normal-Flow, p < 0.0001
40
G
30
20
10
0
Left
Ven
tric
ular
End
-Dia
stol
icPr
essu
re (m
m H
g)
Low-Flow, p < 0.0001Normal-Flow, p < 0.0001
60
H
40
20
0
Pulm
onar
y Ar
tery
Mea
nPr
essu
re (m
m H
g)
Low-Flow, p < 0.0001Normal-Flow, p < 0.0001
4000
I
3000
1000
2000
0
Syst
emic
Vas
cula
r Res
istan
ce (d
ynes
*s/c
m5 )
The following variables are accompanied by mean � SD: (A) aortic valve area; (B) aortic valve mean gradient; (C) aortic valve resistance; (D) stroke volume index;
(E) valvuloarterial impedance; (F) effective arterial elastance; (G) left ventricular end-diastolic pressure; (H) pulmonary artery mean pressure; and (I), systemic
vascular resistance.
Lloyd et al. J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7
Nitroprusside in Low-Gradient Severe Aortic Stenosis S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8
1344
following valve replacement was 86.5 months. Of theremaining NF-LGSAS patients, 8 (50.0%) did notundergo valve replacement and had a median overallsurvival of 43.8 months. Difference in median
overall survival between NF patients who underwentvalve replacement and those who did not was48 months, and subsequent survival analysisdemonstrated a significant difference between these
TABLE 4 Hemodynamic Response to Nitroprusside in Normal-Flow Low-Gradient Severe
Aortic Stenosis
Baseline(n ¼ 16)
Nitroprusside(n ¼ 16) p Value
Heart rate, beats/min 62 � 9 70 � 11 0.0006
Pulmonary artery mean pressure, mm Hg 34 � 12 22 � 9 <0.0001
Aortic systolic pressure, mm Hg 163 � 27 104 � 16 <0.0001
Aortic diastolic pressure, mm Hg 67 � 14 48 � 10 <0.0001
Aortic mean pressure, mm Hg 104 � 17 69 � 10 <0.0001
Aortic pulse pressure, mm Hg 96 � 27 56 � 17 <0.0001
Left ventricular end-diastolic pressure, mm Hg 18 � 4 11 � 5 <0.0001
Left ventricular dP/dt, mm Hg/s 2,075 � 429 2,183 � 604 0.24
Cardiac index, l/min/m2 2.6 � 0.5 2.8 � 0.5 0.27
Stroke volume index, ml/m2 43 � 10 40 � 8 0.07
Aortic valve area, cm2 0.86 � 0.15 1.01 � 0.21 0.007
Aortic valve index, cm2/m2 0.47 � 0.08 0.56 � 0.11 0.005
Aortic valve mean gradient, mm Hg 27 � 6 30 � 5 0.10
Aortic valve resistance, dynes $ s/cm5 474 � 129 566 � 124 0.02
Pulmonary vascular resistance, dynes $ s/cm5 286 � 120 152 � 99 0.0002
Valvuloarterial impedance, mm Hg/ml/m2 4.55 � 1.02 3.43 � 0.79 0.0003
Effective arterial elastance, mm Hg $ m2/ml 3.48 � 0.91 2.38 � 0.58 <0.0001
Total arterial compliance, ml/m2/mm Hg 0.48 � 0.16 0.81 � 0.37 0.0003
Systemic vascular resistance, dynes $ s/cm5 1,673 � 429 1,023 � 279 <0.0001
Values are mean � SD. p Values are reported for paired parametric 2-tailed Student t tests. Bold p values indicatesignificance (<0.05).
FIGURE 2 Change in SVI as a Function of Baseline SVI
0 20 40 60
R2 = 0.42p < 0.0001
80
Baseline SVI (mL/m2)
20
Chan
ge in
SVI
(mL/
m2 )
10
0
–10
–30
–20
Low-Flow Normal-Flow
An inverse linear relationship was observed between change in SVI and baseline SVI.
SVI ¼ stroke volume index.
J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7 Lloyd et al.S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8 Nitroprusside in Low-Gradient Severe Aortic Stenosis
1345
2 groups (p ¼ 0.01). One-year overall survival in NFand LF patients, however, was similar betweengroups (82% [95% confidence interval (CI): 65% to98%] vs. 77% [95% CI: 66% to 105%]; p ¼ 0.79,respectively), though LF was associated withincreased mortality beyond 1 year (Figure 4). Onmultivariate analysis, the only significant indepen-dent predictor of mortality included female sex(hazard ratio 2.99; 95% CI: 1.06 to 10.61; p ¼ 0.04).
DISCUSSION
In this invasive hemodynamic study of symptomaticpatients with LGSAS and preserved EF, we observedthat: 1) with nitroprusside, LGSAS patients demon-strated significant reductions in valvuloarterialimpedance, systemic and pulmonary resistance, andleft ventricular filling pressures; 2) AVA increased to>1 cm2 in 25% of patients regardless of baseline strokevolume and systemic aortic pressure, allowingreclassification from severe to moderate AS; and3) greater improvement in forward stroke volumewith nitroprusside occurred in patients with lowerbaseline SVI, suggesting the low-output state inLF-LGSAS with preserved EF responds more favor-ably to vasodilator therapy.
LGSAS with preserved EF commonly coexists withincreased vascular afterload and can be considered tohave 2 simultaneous obstructions to left ventricularoutflow: both AS and the sequential, more distalcontribution of heightened arterial resistance andreduced arterial compliance. This study demonstratesthat the more distal, vascular contribution to total leftventricular afterload influences hemodynamicmeasures of AS, complicates its evaluation, and mayinfluence treatment strategy. With nitroprussidetherapy, this vascular contribution is effectivelyminimized, resulting in significant and similarreductions in measures of arterial afterload andleft ventricular filling pressures in both LF- andNF-LGSAS patients. These reductions lead simulta-neously to meaningful and clinically relevant changesin both measures of hemodynamic function andaortic valve area.
With nitroprusside therapy, an inverse relation-ship was observed between baseline SVI and itschange with vasodilation, highlighting the specificinfluence of afterload reduction on stroke volume inLF-LGSAS relative to its NF counterpart; of the25 patients with LF-LGSAS, 7 (28.0%) exhibited flowreserve (as defined by an increase in SVI of 20% ormore), whereas none of the NF subjects displayedsuch reserve. The greater improvement in SVI in the
LF-LGSAS population may reflect the baselinegreater effective arterial elastance in this group andsuggests that SVI in patients with LF-LGSAS is moreheavily influenced by arterial afterload than in
FIGURE 3 Valvuloarterial Impedance in Low-Flow and Normal-Flow Low-GradientSevere Aortic Stenosis
100
Patie
nts (
%)
80
60
40
0
20
High Medium Low
Low-Fl
ow - Base
line
Low-Fl
ow - Nitr
oprusside
Normal-
Flow - B
aselin
e
Normal-
Flow - N
itroprussi
de
Distribution of valvuloarterial impedance (according to prognostic groups of low,
medium, and high) in patients with low-flow and normal-flow low-gradient severe aortic
stenosis at baseline and in response to nitroprusside.
TABLE 5 Comparison of Hemodynamic Change With Nitroprusside in Low-Flow and
Normal-Flow Low-Gradient Severe Aortic Stenosis
Low Flow(n ¼ 25)
Normal Flow(n ¼ 16) p Value
Heart rate, beats/min 3 � 7 8 � 8 0.02
Pulmonary artery mean pressure, mm Hg �12 � 9 �12 � 8 0.89
Aortic systolic pressure, mm Hg �45 � 32 �59 � 24 0.12
Aortic diastolic pressure, mm Hg �16 � 13 �20 � 9 0.37
Aortic mean pressure, mm Hg �30 � 21 �35 � 17 0.30
Aortic pulse pressure, mm Hg �29 � 21 �39 � 19 0.09
Left ventricular end-diastolic pressure, mm Hg �6 � 5 �8 � 4 0.40
Left ventricular dP/dt, mm Hg/s �71 � 381 108 � 350 0.13
Cardiac index, l/min/m2 0.3 � 0.4 0.1 � 0.4 0.18
Stroke volume index, ml/m2 3 � 6 �3 � 7 0.006
Aortic valve area, cm2 0.09 � 0.14 0.15 � 0.19 0.33
Aortic valve index, cm2/m2 0.05 � 0.07 0.08 � 0.10 0.26
Aortic valve mean gradient, mm Hg 3 � 3 3 � 6 0.95
Aortic valve resistance, dynes $ s/cm5 15 � 160 92 � 139 0.11
Pulmonary vascular resistance, dynes $ s/cm5 �124 � 222 �134 � 98 0.85
Valvuloarterial impedance, mm Hg/ml/m2 �2.07 � 1.74 �1.12 � 0.95 0.03
Effective arterial elastance, mm Hg $ m2/ml �1.03 � 0.78 �0.62 � 0.52 0.04
Total arterial compliance, ml/m2/mm Hg 0.27 � 0.25 0.32 � 0.28 0.52
Systemic vascular resistance, dynes $ s/cm5 �734 � 554 �650 � 388 0.57
Values are mean � SD. p Values are reported for unpaired parametric 2-tailed Student t tests. Bold p valuesindicate significance (<0.05).
Lloyd et al. J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7
Nitroprusside in Low-Gradient Severe Aortic Stenosis S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8
1346
patients with NF-LGSAS. The improvement in SVIwith vasodilator therapy in LF-LGSAS despite stilllower average cardiac index relative to NF-LGSASalso suggests the presence of baseline myocardialdysfunction in LF-LGSAS and is consistent with priorstudies and supported by the greater prevalence ofprior heart failure exacerbations identified in thissame group (3,7). Collectively, these findingsdemonstrate that afterload reduction in LF-LGSASuniquely lessens the effect of apparent myocardialdysfunction on effective SVI and may in turn helpidentify patients more likely to benefit from moresustained afterload reduction and escalation invasodilator therapies.
In addition to changes in SVI with nitroprusside,key changes in aortic valve properties were alsoidentified. Chief among these changes was a signif-icant increase in AVA in both the LF- and NF-LGSASgroups, whereby a trend toward greater AVAenlargement was evident in the latter. With thesechanges, 6 of 25 LF-LGSAS patients (24%) werereclassified from having severe AS to having mod-erate AS. Similarly, in NF-LGSAS, 4 of the original16 patients (25%) in this group were reclassified ashaving moderate AS. Such reclassification highlightsthe utility of nitroprusside in assessing patientswith LGSAS by neutralizing the effects of arterialafterload on myocardial function and allowingfor a more targeted assessment of aortic valvedisease.
Apart from assessing the influence of afterloadreduction on AVA in LGSAS, this study further ex-pands on the previous investigation of hypertensivepatients with LGSAS (15) by including patients withboth normal and elevated systemic aortic pressureand analyzing the effect of baseline SVI on responseto nitroprusside. A key finding of this study is thatnitroprusside has utility in all patients with LGSAS,not only those with systemic hypertension. Theapplication of nitroprusside in the assessment ofLGSAS highlights the potential advantage of treatingelevated afterload in those with low-flow states inwhom greater baseline valvuloarterial impedance ispresent and in whom symptoms may stem morefrom underlying myocardial dysfunction andincreased sensitivity to afterload than AS per se. Forinstance, forward stroke volume improved only inthe LF patients, suggesting that they are morepoised to benefit from vasodilation (similar to pa-tients with heart failure and reduced EF) (17).Conversely, nitroprusside, despite clear reductionsin afterload, did not improve forward flow in the NFpatients. This finding may be related to reductionsin left ventricular preload from venodilation,
FIGURE 4 Overall Survival in Low-Flow and Normal-Flow Low-Gradient Severe
Aortic Stenosis
1.0
Surv
ivin
g
0.8
0.6
0.4
0.00 1 2 3
No. at risk
P = 0.01
25 17 8 516 12 10 7
0.2
Years
Low flow
Normal flow
Kaplan-Meier analysis of overall survival demonstrates reduced survival in patients with
low-flow compared with normal-flow low-gradient severe aortic stenosis.
TABLE 6 Comparison of Invasive Hemodynamic Variables on Nitroprusside in Low-Flow
and Normal-Flow Low-Gradient Severe Aortic Stenosis
Low Flow(n ¼ 25)
Normal Flow(n ¼ 16) p Value
Heart rate, beats/min 80 � 12 70 � 11 0.008
Pulmonary artery mean pressure, mm Hg 27 � 10 22 � 9 0.12
Aortic systolic pressure mm Hg 110 � 28 104 � 16 0.41
Aortic diastolic pressure, mm Hg 54 � 12 48 � 10 0.07
Aortic mean pressure, mm Hg 77 � 18 69 � 10 0.09
Aortic pulse pressure, mm Hg 55 � 20 56 � 17 0.90
Left ventricular end-diastolic pressure, mm Hg 11 � 6 11 � 5 0.86
Left ventricular dP/dt, mm Hg/s 1,930 � 719 2,183 � 604 0.23
Cardiac index, l/min/m2 2.4 � 0.5 2.8 � 0.5 0.06
Stroke volume index, ml/m2 30 � 5 40 � 8 <0.0003
Aortic valve area, cm2 0.92 � 0.14 1.01 � 0.21 0.18
Aortic valve index, cm2/m2 0.49 � 0.08 0.56 � 0.11 0.04
Aortic valve mean gradient, mm Hg 27 � 7 30 � 5 0.21
Aortic valve resistance, dynes $ s/cm5 636 � 163 566 � 124 0.13
Pulmonary vascular resistance, dynes $ s/cm5 278 � 234 152 � 99 0.03
Valvuloarterial impedance, mm Hg/ml/m2 4.55 � 1.01 3.43 � 0.79 0.0003
Effective arterial elastance, mm Hg $ m2/ml 1.74 � 0.63 2.38 � 0.58 0.008
Total arterial compliance, ml/m2/mm Hg 0.63 � 0.22 0.81 � 0.37 0.09
Systemic vascular resistance, dynes $ s/cm5 1,209 � 471 1,023 � 279 0.12
Values are mean � SD. p Values are reported for unpaired parametric 2-tailed Student t tests. Bold p valuesindicate significance (<0.05).
J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7 Lloyd et al.S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8 Nitroprusside in Low-Gradient Severe Aortic Stenosis
1347
which might offset any salutary effects on afterload,and is consistent with the inverse relationshipbetween baseline SVI and change in SVI with nitro-prusside observed in this study. In this fashion,characterization of stroke volume in LGSAS may helpidentify patients more likely to benefit from escala-tion in vasodilator therapies.
Collectively, the findings of this study reveal thediagnostic value of afterload reduction in the inva-sive hemodynamic assessment of patients withLGSAS and preserved EF. By allowing for thereclassification of AS severity in nearly 25% of pre-senting LGSAS patients with preserved EF andidentifying patients with elevated afterload, nitro-prusside challenge can help identify patients whomay benefit from more aggressive medical therapyand in whom aortic valve replacement can be de-ferred. Accordingly, we recommend that symptom-atic patients with LGSAS and preserved EF undergofurther diagnostic testing to determine the trueseverity of AS. An invasive hemodynamic study withthe use of nitroprusside can help determine theresponse of both systolic and diastolic performanceto lower afterload, which has clinical implications.Patients with uncontrolled systemic hypertensionshould undergo more aggressive medical therapyfollowed by a repeat assessment of hemodynamicsand symptoms before consideration of aortic valvereplacement. Normotensive patients who are foundto have an increase in AVA to >1 cm2 with nitro-prusside should have further investigation into po-tential causes of symptoms other than AS and maybenefit from initial treatment with vasodilator ther-apy. By contrast, LGSAS patients who continue tohave an AVA <1 cm2 despite nitroprusside therapyshould be considered for aortic valve replacement,and further data are needed to confirm thisrecommendation.
STUDY LIMITATIONS. This study was overall limitedby the number of enrolled subjects, the reliance onphysician referrals for recruitment, and, though notsignificantly different between groups, the potentialconfounding influence of concomitant comorbidities,including coronary artery disease and congestiveheart failure (Table 1). Such limitations influence theability to make further distinctions between LF-LGSAS patients and those with NF-LGSAS, includinglonger-term survival, and invite potential selectionbias. Future comparative studies evaluating afterloadreduction and its influence on time to valve replace-ment, clinical symptomatology, morbidity, and mor-tality are needed to determine whether suchreduction is of true clinical benefit.
CONCLUSIONS
Nitroprusside results in a decrease in arterial after-load and left ventricular filling pressures in patientswith LGSAS with preserved EF, resulting in an
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: The
response to administration of intravenous nitroprus-
side during cardiac catheterization can help clarify the
severity of aortic valve stenosis in patients with a low
gradient and normal left ventricular ejection fraction.
TRANSITIONAL OUTLOOK: Longer-term studies
are needed to assess of the effect of arterial
vasodilator therapy on clinical outcomes in patients
with low-flow, low-gradient severe aortic stenosis.
Lloyd et al. J A C C V O L . 7 0 , N O . 1 1 , 2 0 1 7
Nitroprusside in Low-Gradient Severe Aortic Stenosis S E P T E M B E R 1 2 , 2 0 1 7 : 1 3 3 9 – 4 8
1348
increase in SVI proportionate to lower baseline SVI.These findings confirm that heightened sensitivity toafterload is an important contributor to pathophysi-ology in LF-LGSAS. Reclassification from severe tomoderate aortic stenosis occurred in 25% of patientswith LGSAS. Collectively, these observations high-light the diagnostic utility of afterload reduction withnitroprusside in the invasive hemodynamic evalua-tion of LGSAS and preserved EF.
ADDRESS FOR CORRESPONDENCE: Dr. MackramF. Eleid, Department of Cardiovascular Diseases,Mayo Clinic, 200 1st Street SW, Rochester,Minnesota 55905. E-mail: eleid.mackram@mayo.edu.
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KEY WORDS aortic stenosis,catheterization, low gradient, nitroprusside,pathophysiology
APPENDIX For a subgroup analysis, pleasesee the online version of this article.