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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, MD
ABSTRACT

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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.

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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)


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).



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

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Str

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2 )

4

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0 p = 0.03

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Chan

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Impe

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e (m

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0.8

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0.2

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–0.2

Low-Flow Normal-FlowChan

ge in

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tic V

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a (c

m2 ) 20

10

p = 0.950


Chan

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Mea

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m H

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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.


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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

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Low-Flow, p < 0.0001Normal-Flow, p = 0.0003

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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.



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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



Stroke volume index, ml/m2 43 � 10 40 � 8 0.07






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


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.


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)



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


Stroke volume index, ml/m2 3 � 6 �3 � 7 0.006





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


Systemic vascular resistance, dynes $ s/cm5 �734 � 554 �650 � 388 0.57




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)



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



Stroke volume index, ml/m2 30 � 5 40 � 8 <0.0003






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


Systemic vascular resistance, dynes $ s/cm5 1,209 � 471 1,023 � 279 0.12



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.



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: [email protected].

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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.

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