Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction.
`E Loh, J S Stamler, J M Hare, J Loscalzo and W S Colucci
`
`Circulation
`
`1994;90:2780-2785
`Circulation. 
`doi: 10.1161/01.CIR.90.6.2780
`is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
`Copyright © 1994 American Heart Association, Inc. All rights reserved.
`Print ISSN: 0009-7322. Online ISSN: 1524-4539
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`2779
`
`

`

`2780
`
`Cardiovascular Effects of Inhaled Nitric Oxide
`in Patients With Left Ventricular Dysfunction
`
`Evan Loh, MD; Jonathon S. Stamler, MD; Joshua M. Hare, MD;
`Joseph Loscalzo, MD, PhD; Wilson S. Colucci, MD
`
`pulmonary artery wedge pressure and despite a 4±2%
`(P<.05) decrease in cardiac index. The magnitude of the
`decrease in PVR with inhaled NO was inversely related
`(r= -.713; P<.001) to the baseline PVR. Inhaled NO had no
`effect on heart rate, systemic arterial pressure, systemic vas-
`cular resistance, or LV peak +dP/dt or -dP/dt.
`In patients with heart failure due to LV dys-
`Conclusions
`function, inhalation of NO causes a decrease in the PVR
`associated with an increase in LV filling pressure. These
`findings predict that inhaled NO, if used alone at this dose (80
`ppm), may have adverse effects in patients with LV failure.
`(Circulation. 1994;90:2780-2785.)
`nitric oxide
`Key words
`*
`*
`endothelium-derived factors
`
`lung
`
`*
`
`heart failure
`
`.
`
`Background Pulmonary vascular resistance (PVR) is fre-
`quently elevated in patients with advanced heart failure. Nitric
`oxide (NO), which contributes to the activity of endothelium-
`derived relaxing factor, causes relaxation of pulmonary arter-
`ies and veins in vitro. Inhalation of NO gas causes pulmonary
`vasodilation in patients with primary and secondary forms of
`pulmonary hypertension.
`Methods and Results To test the hypothesis that inhalation
`of NO gas lowers PVR in patients with heart failure, we
`studied the hemodynamic effects of a 10-minute inhalation of
`NO (80 ppm) in 19 patients with New York Heart Association
`class III (n=5) and class IV (n=14) heart failure due to left
`ventricular (LV) dysfunction. Although inhalation of NO had
`no effect on pulmonary artery pressures, the PVR decreased
`by 31±7% (P<.001) due to a 23±+7% increase (P<.001) in
`
`T he endothelium plays an essential role in the
`dynamic regulation of vascular tone by synthe-
`sizing and releasing a variety of substances, one
`of which, endothelium-derived relaxing factor (EDRF),
`has the physicochemical properties of nitric oxide (NO)
`or a closely related substance.12 Endogenous NO pro-
`duced by endothelial cells diffuses into neighboring
`vascular smooth muscle cells, where it binds to the heme
`component of guanylyl cyclase, thereby activating the
`enzyme, resulting in increased cyclic GMP production
`and relaxation.34 Arterial and venous endothelial cells
`in the pulmonary vasculature produce NO constitutively
`and in response to a variety of stimuli.5-8 NO appears to
`be involved both in the regulation of basal pulmonary
`vascular resistance (PVR)9,10 and in counterregulating
`the effects of vasoconstrictor substances.1"-"
`PVR is frequently increased in patients with ad-
`vanced heart failure. The underlying mechanism for
`increased PVR in heart failure is not known, but it
`almost certainly involves activation of vasoconstrictor
`pathways by the sympathetic nervous system, the renin-
`angiotensin system, and/or endothelin.'6'17 Although
`there is evidence that endothelium-dependent vasodila-
`tion is impaired in the systemic vasculature of both
`animal models18 and patients with heart failure,19-22 it is
`
`Received June 20, 1994; revision accepted August 7, 1994.
`From the Cardiovascular (E.L., J.M.H., J.L., W.S.C.) and Res-
`piratory (J.S.S.) Divisions, Departments of Medicine, Brigham
`and Women's Hospital and Harvard Medical School, Boston,
`Mass.
`Correspondence to Wilson S. Colucci, MD, Cardiovascular
`Division, Brigham and Women's Hospital, 75 Francis St, Boston,
`MA 02115.
`© 1994 American Heart Association, Inc.
`
`not known whether this mechanism contributes to in-
`creased PVR.
`Inhalation of NO gas causes pulmonary vasodilation
`in patients with primary pulmonary hypertension23 and
`pulmonary hypertension secondary to congenital heart
`disease24 and to adult respiratory distress syndrome.25
`These observations suggest that inhaled NO might
`ameliorate pulmonary vasoconstriction, and they led to
`our hypothesis that inhalation of NO would lower PVR
`in patients with heart failure. To test this hypothesis, we
`studied the hemodynamic effects of a 10-minute inha-
`lation of NO (80 ppm) in 19 patients with moderate to
`severe heart failure secondary to LV dysfunction from
`idiopathic or ischemic dilated cardiomyopathy.
`Methods
`
`Study Population
`Nineteen patients with New York Heart Association func-
`tional class III (n=5) or IV (n= 14) heart failure were studied.
`All patients were receiving digitalis, diuretics, and angiotensin-
`converting enzyme inhibitors. There were 15 men and 4
`women, with a mean age of 52±3 years. The cause of heart
`failure was ischemic cardiomyopathy in 10 patients and idio-
`pathic dilated cardiomyopathy in 9. The peak VO2 averaged
`9.9 + 1.6 mL * kg-' min- . The study protocol was approved by
`the Committee for the Protection of Human Subjects from
`Research Risks at the Brigham and Women's Hospital, and
`written informed consent was obtained in all cases.
`Hemodynamic Measurements
`Vasodilators, converting enzyme inhibitors, digitalis, and
`diuretics were withheld on the morning of the catheterization.
`A 7F Swan-Ganz catheter (Arrow International, Inc) was
`placed in the pulmonary artery. Femoral artery pressure was
`monitored via an 8F side-arm sheath (Cordis Laboratories). In
`10 patients, a 7F micromanometer-tipped pigtail catheter
`
`
`
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`2780
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`

`Loh et al
`
`Cardiovascular Effects of NO
`
`2781
`
`60 -
`
`55 -
`
`50 -
`
`0O
`
`I
`
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`
`0
`
`* 0
`*
`0
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`u
`
`Nitric Oxide
`Room Air
`Graph showing pulmonary artery wedge pressure before
`FIG 2.
`and after a 10-minute inhalation of room air or NO. *P<.001 vs
`room air.
`
`(LVEDP), and LV +dP/dt and -dP/dt were calculated by
`averaging at least 50 consecutive beats under each experimen-
`tal condition.
`
`Inhalation of Nitric Oxide
`NO gas (800 ppm) and N2 (Airco) were mixed by use of a
`standard low-flow blender (Low Flow MicroBlender, Bird
`Products Corp) before introduction into the inspiratory limb
`of a closed breathing circuit attached to a face mask. The
`inhaled concentrations of NO and oxygen were regulated
`separately. The inhaled 02 concentration was measured
`directly with an on-line oximeter (Ohmeda Oximeter). The
`inhaled concentrations of NO, nitrogen dioxide (NO2), and
`the higher oxides of nitrogen (NOx) were measured contin-
`uously by a chemiluminescence technique (Chemilumines-
`cent NOx-NO2 Analyzer, Thermo Environmental Instru-
`ments, Inc). The exhaled gases were scavenged by a vacuum
`system.
`To establish baseline conditions, patients inhaled room air
`(Fio2, 21%; N2, 79%) via the closed face mask system for 10
`minutes before the baseline hemodynamic measurements.
`Patients then inhaled NO at 80 ppm (FIO2, 21%; N2, 79%) via
`
`650 -
`
`600 -
`
`550 -
`
`500 -
`
`450 -
`E400-
`C)
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`
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`
`0-
`
`o
`
`Nitric Oxide
`Room Air
`Graph showing effect of NO inhalation on pulmonary
`FIG 3.
`vascular resistance (PVR). *P<.001 vs room air.
`
`TABLE 1. Hemodynamic Effects of Inhaled NO in
`Patients With Congestive Heart Failure (n=19)
`P
`Room Air
`NO
`HR, bpm
`90+3
`93+3
`NS
`79±3
`MAP, mm Hg
`81+3
`NS
`SVR, dyne* s *cm`
`1041 ±97
`1102+104
`NS
`35±4
`37±4
`PA, mm Hg
`NS
`25±3
`PAWP, mm Hg
`31+4
`<.001
`LVEDP, mm Hg; n=10
`28±4
`34±5
`.02
`PVR,dyne*s.cm-5
`226±30
`119±13
`<.001
`PA-PAWP, mm Hg
`11±1
`6±0.5
`<.001
`SVI, mL/m2
`26±2
`24±2
`.03
`Cl, L- min-1 m-2
`2.3±0.2
`2.1±0.2
`.03
`HR indicates heart rate; bpm, beats per minute; MAP, mean
`arterial pressure; SVR, systemic vascular resistance; PA, mean
`pulmonary artery measure; PAWP, pulmonary artery wedge
`pressure; LVEDP, left ventricular end-diastolic pressure; PVR,
`pulmonary vascular resistance; SVI, stroke volume index; and
`Cl, cardiac index.
`
`(Millar Industries) was placed in the left ventricle (LV),
`allowing for simultaneous dP/dt and right heart pressure
`measurements. The ECG, femoral artery pressure, pulmonary
`artery pressure, and LV pressure were recorded on a strip
`chart recorder (Electronics for Medicine, PPG Biomedical
`Systems Division). Cardiac output was determined by the Fick
`method, based on the measured oxygen uptake (model MRM
`2B, Waters Instruments, Inc) and oxygen content in the
`pulmonary and femoral arteries.26 Oxygen content was calcu-
`lated from the blood hemoglobin and oxygen saturation by
`standard methods.26 Blood oxygen saturation was determined
`in duplicate samples on a Ciba-Corning model 270 Co-oxime-
`ter. LV peak +dP/dt (+dP/dt) and peak -dP/dt (-dP/dt)
`were computed on-line by an Electronics for Medicine ampli-
`fier (model 220A). Values for heart rate, arterial pressure,
`pulmonary arterial pressure, pulmonary artery wedge pres-
`sure, LV systolic pressure, LV end-diastolic pressure
`
`TT
`
`_ Room Air
`M 80 ppm NO|
`
`T
`
`T
`
`T
`
`T
`
`60
`
`55
`
`50
`
`45
`
`0) 40
`E 35
`
`1-1
`(D 30
`
`) 25
`Cl)
`0)
`L_ 20-
`
`m 15
`
`10
`
`5
`
`...buik
`
`_.ti ...,
`
`Wedae
`oyo.,9.st_,._;
`Bar graph showing effect of inhalation of NO gas (80
`FIG 1.
`ppm, 10 minutes) on pulmonary artery (PA) pressures in 19
`patients with heart failure secondary to left ventricular dysfunc-
`tion. Measurements were made after the patients inhaled room
`air (shaded bars) or NO (solid bars) from a face mask for 10
`minutes. *P<.001 vs room air.
`
`
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`2782
`
`Circulation
`
`Vol 90, No 6 December 1994
`
`face mask for 10 minutes, and hemodynamic measurements
`were repeated.
`Statistical Methods
`All data are presented as the mean±SEM. Differences
`between two observations for one variable within the same
`group were determined by two-tailed paired t test. Differ-
`ences between groups were determined by two-tailed un-
`test. Differences were considered significant if
`paired t
`the null hypothesis could be rejected at the .05 probability
`level.
`
`Results
`Hemodynamic Effect of Inhaled NO
`Baseline measurements during inhalation of room air
`revealed moderate LV failure with elevation of the
`LVEDP and mean pulmonary artery wedge pressure,
`and reduced stroke volume and cardiac indexes (Table
`1). There was moderate reactive pulmonary hyperten-
`sion, with an average PVR of 226±30 dyne sec cm
`Inhalation of NO caused no change in heart rate,
`mean systemic arterial pressure, systemic vascular resis-
`tance, or pulmonary artery pressure (systolic, diastolic,
`or mean) but caused a 23 ± 7% increase in the mean
`pulmonary artery wedge pressure (Table 1, Figs 1 and
`2) associated with 4±2% and 7±2% decreases in car-
`diac index and stroke volume index, respectively (Table
`1). The mean transpulmonary pressure gradient de-
`creased by 35 ±7% (Table 1), and the PVR decreased by
`31±7% (Table 1 and Fig 3).
`The decrease in PVR was due to the increase in
`pulmonary artery wedge pressure, as shown by the corre-
`lation (r= -.848, P=.0001) between the changes in PVR
`and pulmonary artery wedge pressure (Fig 4A) and lack
`of correlation with changes in pulmonary artery pressure
`(Fig 4B; r=.13) or cardiac index (Fig 4C; r=.04). The
`increase in mean pulmonary artery wedge pressure was
`due to an increase in LV filling pressure, as shown by the
`correlation (r=.939, P<.0001) between the changes in LV
`end-diastolic pressure and pulmonary artery wedge pres-
`sure with inhaled NO (Fig 5).
`
`TABLE 2. Hemodynamic Characteristics of Patients
`With a Change in Pulmonary Artery Wedge Pressure
`Above or Below the Median With Inhalation of NO
`% PAWP
`% PAWP
`<0.26
`>0.26
`(n=g)
`(n=10)
`p
`HR, bpm
`87±4
`94+3
`NS
`MAP, mm Hg
`75±3
`84+3
`.02
`SVR, dyne * s* cm`
`987+153
`1218±148
`NS
`PA, mm Hg
`29+5
`42±5
`.02
`PAWP, mm Hg
`21±4
`28±4
`.02
`SVI, mL/m2
`21±2
`30+2
`.004
`Cl, L. min-1 * m-2
`2.6+0.2
`1.9+0.2
`.01
`PVR, dyne. s* cm`
`295±40
`138+23
`.002
`LVEDD, cm
`6.2+0.4
`7.1 +0.3
`.04
`V02
`11 .7±0.8
`9.6+0.1
`NS
`LVEDD indicates left ventricular end-diastolic dimension; VO2,
`peak oxygen consumption. Other abbreviations as in Table 1.
`n=19 for all parameters except EDD (n=16) and VO2 (n= 17).
`
`Hemodynamic Determinants of an Increase in
`Pulmonary Artery Wedge Pressure With
`Inhaled NO
`The most prominent hemodynamic effect of NO
`inhalation was the increase in pulmonary artery wedge
`pressure (median increase, 26%). In the 10 patients
`with an increase in pulmonary artery wedge pressure of
`.26% (mean increase, 33+7%), the baseline pulmo-
`nary artery pressure, pulmonary vascular resistance,
`and LV end-diastolic dimension (by M-mode echocar-
`diography; n= 16) were higher and the cardiac index and
`stroke volume index were lower than in the 9 patients
`with an increase of <26% (Table 2). Thus, more severe
`LV dysfunction (as evidenced by higher left heart filling
`pressures, lower stroke volume, and larger LV cavity
`size) was present in the patients who had the largest
`increases in pulmonary artery wedge pressure with
`inhaled NO.
`
`R = 0.04
`P=0.87
`
`0
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`0 0
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`0
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`0
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`P = 0.61
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`
`-20
`
`20
`
`40
`
`0
`PAWP (% change)
`Scatterplots of regression analyses depicting the relation between the change in pulmonary vascular resistance (PVR) with NO
`FIG 4.
`(vs room air) and the change in pulmonary artery wedge pressure (PAWP) (left), mean PA pressure (middle), or cardiac index (right) in
`19 patients.
`
`.
`0
`
`.
`
`20
`-20
`Mean PA Pressure (% Change)
`
`40
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`-10
`20
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`Cardiac Index (% Change)
`
`0
`
`
`
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`2782
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`

`

`Loh et al
`
`Cardiovascular Effects of NO
`
`2783
`
`30
`
`20 -
`
`10
`
`o 0
`
`-10 -
`
`-20
`
`0
`
`0
`
`0
`
`R=0.948
`Op/0.0001
`
`.I
`
`-30
`
`-20
`
`-10
`0
`20
`10
`PAWP (% change)
`Scatterplot showing relation between the percent
`FIG 5.
`changes in pulmonary artery wedge pressure (PAWP) and left
`ventricular end-diastolic pressure (LVEDP) with inhaled NO in 10
`patients.
`
`30
`
`40
`
`The baseline PVR was more than twofold higher in
`the group that had the largest increases in pulmonary
`artery wedge pressure with inhaled NO (Table 2),
`suggesting that resting PVR might be a determinant or
`predictor of the response to inhaled NO. Consistent
`with this view, there was a strong correlation (r= -.713,
`P<.001) between the baseline PVR and the decrease in
`PVR with inhaled NO (Fig 6).
`As an alternative approach to this issue, we identi-
`fied a subgroup of 5 patients who had "compensated"
`LV failure, as defined by a pulmonary artery wedge
`pressure .18 mm Hg (mean, 12±2 mm Hg) and a
`cardiac index .2.5 L min- m2 (mean, 2.8+±0.3
`L - min-1 * m-2). In these patients, inhalation of NO
`has no effect on pulmonary artery wedge pressure
`(+7+3%) or PVR (+5±13%). In the remaining 14
`patients with "decompensated" LV failure (mean
`pulmonary artery wedge pressure, 30+2 mm Hg;
`mean cardiac index, 1.9±0.1 L. min-l m-2), inhala-
`tion of NO increased the pulmonary artery wedge
`pressure by 27±3% (P<.001) and decreased the PVR
`by 43±7% (P<.001).
`Effects of Inhaled NO on LV Function
`Since it has been suggested that NO can depress the
`contractile function of isolated cardiac myocytes,27 we
`considered the possibility that inhaled NO exerted a
`negative inotropic effect on the LV. A negative inotro-
`pic effect of inhaled NO was suggested by a decrease in
`stroke volume index despite an increase in pulmonary
`artery wedge pressure (Fig 7A). However, in the 10
`patients in whom it was measured, inhaled NO had no
`effect on LV peak +dP/dt, despite increasing LVEDP
`by 8±1 mm Hg (Fig 7B). LV peak -dP/dt, which
`reflects isovolumic relaxation in the absence of changes
`in loading conditions or heart rate,2829 was also not
`affected by inhaled NO (baseline, 807+140 mm Hg/s;
`NO, 800±139 mm Hg/s; P=NS; n=10).
`Discussion
`The major finding of this study is that in patients with
`reactive pulmonary arterial hypertension secondary to
`LV failure, inhalation of NO causes reciprocal changes
`in the PVR (decrease) and LV filling pressure (in-
`crease). In patients with primary pulmonary hyperten-
`sion, inhalation of NO causes a decrease in pulmonary
`artery pressure.23 In contrast, in patients with LV
`failure, we found that inhalation of NO is associated not
`with a decrease in pulmonary artery pressure, but
`rather, with an increase in LV filling pressure that
`accounts for the decrease in PVR. Preliminary reports
`from two other groups30,31 also indicate a similar effect
`of inhaled NO on LV filling pressure in patients with
`LV failure.
`The observed decrease in transpulmonary artery
`pressure gradient, particularly in the setting of no
`change or a small decrease in cardiac output, indicates
`that inhaled NO caused pulmonary vasodilation. NO
`diffuses readily through tissues, and therefore inhala-
`tion of NO may increase the concentration of NO in the
`vicinity of vascular smooth muscle cells in pulmonary
`resistance vessels, thereby exerting a direct vasodilator
`effect.
`We believe that the NO-induced increase in LV filling
`pressure is due to a small increase in LV volume that
`
`occurred secondary to an increase in pulmonary venous
`return to the LV. For a given pulmonary artery pres-
`sure, a decrease in PVR will result in an increase in the
`net driving force for LV filling. Although an increase in
`LV volume would result in increases in ejection fraction
`and stroke volume in a normal LV, in our patients LV
`function was severely depressed and may have been on
`the flat portion of the Starling relation. In addition, an
`NO-induced increase in LV volume may have increased
`the magnitude of functional mitral regurgitation that is
`present in the majority of such hearts.3233 Thus, an
`NO-induced redistribution of blood from the right
`ventricle to the LV may occur with no increase, or even
`a small decrease, in stroke volume. Since the failing LV
`often operates on the steep portion of the diastolic
`pressure/volume relation, a substantial increase in LV
`filling pressure might reflect only a small NO-induced
`increase in LV volume.
`
`40 -
`20
`
`20 -
`
`0-
`
`0
`0
`
`0
`
`r- -20
`(0
`
`0~
`
`a-40
`
`-60
`
`-80-
`
`n 1
`o
`m= -U.001
`P < 0.001
`
`0 0
`
`0
`
`0
`
`500
`400
`200
`300
`100
`Baseline PVR (dyne-sec-cm-5)
`Scatterplot showing relation between the baseline pul-
`FIG 6.
`monary vascular resistance (PVR) and the percent change in
`PVR after inhalation of NO in 19 patients.
`
`600
`
`
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`2783
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`

`2784
`
`Circulation
`
`Vol 90, No 6 December 1994
`
`110 -
`
`105 -
`
`100 -
`
`95-
`
`90-
`
`85-
`
`80-
`
`7 -
`
`X
`(U
`
`2-
`m
`Je
`(0
`X.
`-
`C:
`
`m 70-
`(U
`o 65-
`
`60 -
`
`55 -
`
`p = 0.03
`
`] p = NS
`
`p <0.05
`
`30 r
`
`28 h
`
`CN 26
`
`E 0n E -
`
`>
`
`=0.02
`
`p p
`
`24
`
`22 F
`
`20 L
`20
`
`35
`
`so
`
`30
`
`30
`25
`PAWP (mmHg)
`PAWP (mmHg)
`FIG 7.
`Graphs showing (left) effect of inhaled NO on the relation between stroke volume index (SVI) and mean pulmonary artery wedge
`pressure (PAWP) and (right) effect of inhaled NO on the relation between left ventricular (LV) peak +dP/dt and PAWP.
`
`32
`
`34
`
`36
`
`38
`
`40
`
`The NO-induced changes in LV filling pressure and
`PVR correlated with both the baseline PVR (see Fig 6)
`and the severity of hemodynamic compromise (see
`Table 2). It was previously observed that inhaled NO
`has no hemodynamic effects in control subjects who
`have a normal PVR.34 Since the degree of reactive
`pulmonary hypertension is generally related to the
`severity of hemodynamic compromise in patients with
`LV failure, it might be anticipated that patients with
`more severe heart failure will have a more marked
`hemodynamic response to inhaled NO. To examine this
`prediction further, we compared the effects of inhaled
`NO in a subset of 5 patients with relatively compensated
`hemodynamics ("compensated group," defined by a
`pulmonary artery wedge pressure
`18 mm Hg and a
`cardiac index >2.5 L. m` m-2) and those of the re-
`maining 14 patients ("decompensated group," defined
`by a pulmonary artery wedge pressure >18 mm Hg
`and/or a cardiac index <2.5 L. m` m-2). Although the
`LV ejection fractions were comparable in the two
`groups, the baseline PVR was higher in the decompen-
`sated group (Table 2). As predicted by our hypothesis,
`the NO-induced fall in PVR (43% versus 7%) and
`increase in LV filling pressure (27% versus 0%) were
`larger in the decompensated group. Taken together,
`these observations suggest that the greater effect of
`inhaled NO in patients with decompensated LV failure
`is due to the greater degree of reactive pulmonary
`hypertension present in such patients.
`A second potential explanation for the decrease in
`transpulmonary gradient is that inhaled NO exerts a
`direct negative inotropic effect on the LV, resulting in a
`primary increase in LV filling pressure. In this scenario,
`passive pulmonary vasodilation might occur because of
`recruitment of precapillary vessels, an effect that has
`been demonstrated in animals.35 However, we feel that
`a direct negative inotropic effect of inhaled NO is less
`likely, for several reasons. First, NO is rapidly inacti-
`vated by hemoglobini and might not be expected to
`reach the coronary circulation under these conditions.
`
`Second, we observed no decrease in LV +dP/dt, a
`highly sensitive measure of changes in contractile state.
`Third, it has been shown that in humans, the intracor-
`onary infusion of nitroprusside, to donate NO to the
`myocardium, has no effect on +dP/dt and, contrary to
`our findings with inhaled NO, caused a decrease in LV
`filling pressure apparently due to an increase in ventric-
`ular distensibility.36
`An interesting corollary of these observations is that
`selective pulmonary vasodilation, in the absence of
`systemic vasodilation, may not be desirable in patients
`with severe LV failure. Clearly, inhaled NO, adminis-
`tered alone at the dose used in this study (80 ppm), may
`have adverse effects in such patients. Nevertheless, the
`ability of inhaled NO to reduce PVR selectively (ie,
`without causing systemic vasodilation), resulted in a
`unique physiological situation and thus provided the
`basis for these novel observations. Finally, on the basis
`of these observations, it is intriguing to speculate that
`an elevation in PVR may play an important adaptive
`role in patients with LV failure by limiting LV filling and
`thereby "protecting" the LV from excessive dilation,
`albeit at the expense of increased right ventricular work.
`Acknowledgments
`This study was supported in part by grants MOI-RR0088,
`HL-42539, HL-43344, and HL-48763 from the National In-
`stitutes of Health (NIH). Dr Loh is the recipient of Physician-
`Scientist Award KL-HL-02514 from the National Heart,
`Lung, and Blood Institute. Dr Colucci was a Sandoz Estab-
`lished Investigator of the American Heart Association. Dr
`Loscalzo is the recipient of a Research Career Development
`Award (HL-02273) from the NIH. We would like to thank Dr
`Eugene Braunwald for his insightful comments, Erin Graydon
`for technical assistance with NO gas administration, Dr Jeffrey
`Drazen for his generous support, the staff of the Cardiac
`Catheterization Laboratory for their help and patience, and
`Paula McColgan for expert typing.
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