Download Hemodynamic and clinical significance of the pulmonary

635
JACC Vol. 6, No.3
September 1985:635-45
REPORTS ON THERAPY
Hemodynamic and Clinical Significance of the Pulmonary Vascular
Response to Long-Term Captopril Therapy in Patients With Severe
Chronic Heart Failure
MILTON PACKER, MD, FACC, WAI HUNG LEE, MD, NORMA MEDINA, RN,
MADELINE YUSHAK, RN
New York, New York
Exercise capacity in patients with left heart failure is
closely related to the performance of the right ventricle
and the pulmonary circulation. To determine the significance of changes in pulmonary resistance during longterm vasodilator therapy, hemodynamic studies were
performed before and after 1 to 3 months of treatment
with captopril in 75 patients with severe chronic left
heart failure.
Patients were grouped according to the relative
changes in pulmonary and systemic resistances during
long-term therapy: patients in Group I (n = 24) showed
greater decreases in pulmonary arteriolar resistance (PAR)
than in systemic vascular resistance (SVR) (% .:1 PAR/%
.:1 SVR > 1.0), whereas patients in Group II showed
predominant systemic vasodilation (% .:1 PAR/% .:1 SVR
< 1.0). Despite similar changes in systemic resistance,
patients in Group I showed greater increases in cardiac
index, stroke volume index and left ventricular stroke
work index (p < 0.01 to 0.001) but less dramatic decreases in mean systemic arterial pressure (p < 0.02)
than did patients in Group II. Despite similar changes
Inhibition of the angiotensin-converting enzyme with captopril is an established approach to the treatment of patients
with severe chronic heart failure (1), Randomized placebocontrolled trials (2,3) have shown that long-term therapy
with captopril produces hemodynamic and symptomatic
benefits that are accompanied by significant increases in
exercise tolerance. Captopril also preferentially increases
From the Division of Cardiology, Department of Medicine, Mount
Sinai School of Medicine of The City University of New York, New York,
New York. Dr. Packer is the recipient of Research Career Development
Award K04-HL-01229 from the National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, Maryland. Manuscript received
February 6, 1985; revised manuscript received April I, 1985, accepted
April 22, 1985.
Address for reprints: Milton Packer, MD, Division of Cardiology,
Mount Sinai Medical Center, One Gustave Levy Place, New York, New
York 10029.
© 1985 by the American College of Cardiology
in left ventricular filling pressure, patients in Group I
showed greater decreases in mean pulmonary artery and
mean right atrial pressures (p < 0.02 to 0.01) than did
patients in Group II. Pretreatment variables in Groups
I and II were similar, except that plasma renin activity
was higher (8.7 ± 2.1 versus 3.0 ± 0.6 ng/ml per h)
and serum sodium concentration was lower (133.1 ±
0.9 versus 137.1 ± 0.6 mEq/liter) in Group II than in
Group I (both p < 0.05). Both groups improved clinically
after 1 to 3 months, but symptomatic hypotension occurred more frequently in Group II than in Group I (3~
versus 8%) (p < 0.005).
These findings indicate that changes in the pulmonary
circulation modulate alterations in both right and left
ventricular performance during the treatment of patients with left heart failure. Hyponatremic patients are
likely to experience symptomatic hypotension with captopril because they are limited in their ability to increase
cardiac output as a result of an inadequate pulmonary
vasodilator response to the drug.
(J Am Coll CardioI1985;6:635-45)
renal and cerebral blood flow and favorably modifies salt
and water homeostasis (4-9), and these actions may contribute significantly to the therapeutic effects of the drug.
Because excessive systemic resistance has been regarded
as the principal hemodynamic abnormality in patients with
heart failure, previous studies of captopril have focused
largely on its effects on the systemic vasculature and left
ventricle, and little attention has been given to its actions
on the pulmonary circulation. Recent evidence (10, II) indicates, however, that exercise capacity in patients with left
heart failure is more closely related to the performance of
the right ventricle than that of the left ventricle, because the
pulmonary circulation fails to dilate significantly in these
patients during exertion and may thereby limit any increase
in cardiac output that might be expected to follow a decrease
in resistance to left ventricular ejection. Therefore, treat0735-1097/85/$3.30
636
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
ment with systemic vasodilator drugs may not increase forward flow and exercise capacity if the decrease in pulmonary
resistance fails to match the decrease in systemic resistance
(12), but fortunately, most vasodilating agents dilate the
systemic and pulmonary circulations to a similar degree
(13-15). Such a balanced effect may not occur during converting enzyme inhibition, however, because angiotensin
exerts little direct constrictor effect on the pUlmonary circuit
in doses that markedly affect systemic vessels (16-20).
Therefore, short-term treatment with captopril in patients
with heart failure produces decreases in pulmonary resistance that are less marked than the concomitant decreases
in systemic resistance (21,22). Whether this hemodynamic
discordance persists during long-term therapy with the drug,
however, remains unknown. In the present study we evaluated the long-term changes in pulmonary arteriolar resistance in patients with severe left ventricular failure treated
with captopril to determine their hemodynamic and clinical
significance and to postulate potential mechanisms that may
underlie the occurrence of these changes.
Methods
Study patients. The study group consisted of 75 consecutive patients with severe chronic heart failure treated
with captopril who underwent invasive hemodynamic studies during short- and long-term treatment with the drug. All
patients had dyspnea and fatigue at rest or on minimal exertion despite optimal therapy with digitalis and diuretic
drugs; all had a left ventricular ejection fraction less than
30% by radionuclide angiography. There were 55 men and
20 women, aged 28 to 83 years (mean 64). The cause of
heart failure was ischemic heart disease in 46 patients, primary dilated cardiomyopathy in 23 patients and primary
mitral or aortic valve regurgitation, or both, in 6 patients,
3 of whom had undergone valve replacement surgery. No
patient had had an acute myocardial infarction within 4
weeks or an acute exacerbation of symptoms of heart failure
within 2 weeks.
Hem9dynamic assessmt!nt. Each patient received captopril under controlled study conditions for 1 to 3 months,
during which time the hemodynamic effects of the drug
were assessed by right heart catheterization performed before initiation of therapy and at the end of the treatment
period. At the beginning of the trial, for at least 5 days
before administration of captopril, doses of digoxin and
diuretic drugs remained constant, all previous vasodilator
drugs were discontinued and patients maintained stable weight
while consuming a 2 g sodium diet. After completion of
this initial stabilization period, right heart catheterization
and arterial cannulation were performed for measurement
of intracardiac and systemic pressures, respectively (9,15,21).
Left ventricular filling pressure was estimated from the mean
pulmonary capillary wedge pressure (71 patients) or from
JACC Vol. 6, No.3
September 1985 :635-45
the pulmonary artery diastolic pressure after its identity with
wedge pressure was established (4 patients). Thermodilution
cardiac outputs were determined in triplicate by a bedside
cardiac output computer using iced injectate.
Drug administration. The following hemodynamic
variables were measured repeatedly for at least 2 hours (with
a variation of less than 10%) to ensure stability of the pretreatment hemodynamic state before drug administration:
mean arterial pressure, heart rate, left ventricular filling
pressure, mean right atrial pressure and cardiac output. Each
patient then received an initial dose of 25 mg of captopril
orally followed by long-term therapy with the drug. Because
the response to converting enzyme inhibition is not dose
dependent (23,24), the doses of captopril prescribed for
long-term treatment were based on each patient's renal function: patients with a serum creatinine concentration less than
2.0 mg/dl generally received 150 to 300 mg orally daily,
whereas patients with higher concentrations received 75 to
150 mg orally daily. For the next 1 to 3 months, doses of
digitalis, diuretic agents and captopril remained unaltered,
and a 2 g sodium diet was maintained. At the end of the
treatment period, patients were again hospitalized for a 5
day stabilization period, after which right heart catheterization and arterial cannulation were again performed to assess
the long-term response to treatment. The protocol for the
second evaluation was identical in all respects to that of the
first study.
During the first hemodynamic study, all hemodynamic
variables determined during the baseline period were reassessed every 30 minutes for 3 hours after administration of
the first 25 mg dose of captopril; during the second hemodynamic study, these variables were measured at identical
intervals after administration of the same dose of captopril
each patient had been receiving during the previous 1 to 3
months.
Additional pharmacologic testing was performed in selected patients during the second hemodynamic study after
the long-term effects of captopril had been assessed. In nine
patients in whom captopril produced minimal changes in
pulmonary arteriolar resistance, nitroglycerin (0.4 mg sublingually) was administered 30 to 60 minutes after the peak
effect of captopril was observed, and aU hemodynamic variables were reassessed every 2 to 5 minutes for 20 to 30
minutes.
Biochemical and clinical determinations. Blood samples were collected just before initiation of captopril therapy
for determination of blood urea nitrogen and serum creatinine concentration in all patients and for measurement of
plasma renin activity in 71 of the 75 patients; these variables
were reassessed during the second hemodynamic study 90
minutes after captopril administration. All samples were
drawn at the same time of day, while patients were consuming a 2 g sodium diet, and after at least 4 hours in the
supine position.
lACC Vol. 6. No.3
September 1985:635-45
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
Changes in the clinical status of each patient after 1 to
3 months of treatment with captopril were assessed in relation to symptoms of dyspnea and fatigue at rest and exercise tolerance. Because all patients had symptoms at rest
or on minimal exertion, formal exercise testing was not
performed.
Data analysis. Mean systemic and pulmonary artery
pressures were determined by electronic filtration. Derived
hemodynamic variables were calculated as follows: cardiac
index (CI) = CO/body surface area (liters/min per m2);
stroke volume index (SVI) = CIIHR (beats/min); LV stroke
work index = (MAP - LVFP) x SVI x 0.0136 (g.mlm2);
RV stroke work index = (MPAP - MRAP) x SVI x
0.0136 (g.mlm 2); systemic vascular resistance (SVR) =
80 x (MAP - MRAP)/CO (dynes.s-cm- 5 ); pulmonary arteriolar resistance (PAR) = 80 x (MPAP - LVFP)/CO
(dynes.s.cm - 5), where CO = cardiac output, HR = heart
rate, LV = left ventricular, R V = right ventricular, MAP
= mean systemic arterial pressure, L VFP = left ventricular
filling pressure, MPAP = mean pulmonary artery pressure
and MRAP = mean right atrial pressure.
The hemodynamic effects of captopril during the first
and second hemodynamic studies were assessed at its peak
effect on left ventricular filling pressure and mean systemic
arterial pressure (60 ± 30 minutes after drug administration). The hemodynamic responses seen during short- and
long-term therapy in our 75 patients were compared with
the pre-captopril hemodynamic state (Table 1) by a repeated
measures analysis of variance procedure, in which Duncan's
multiple range test was used to differentiate among significant responses.
Patients were then classified into three groups according
to the hemodynamic responses observed during long-term
treatment: Patients in Group I showed predominant pulmonary vasodilation, as evidenced by a percent decrease in
pulmonary arteriolar resistance (PAR) that was greater than
the percent decrease in systemic vascular resistance (SVR)
(% ~ PAR/% ~ SVR > 1.0) with both variables decreasing
by at least 20%; this definition is similar to those we and
other investigators utilized to identify an active pulmonary
vasodilator response in previous studies (25-27). Patients
in Group II showed predominant systemic vasodilation, as
evidenced by a % ~ PAR/% ~ SVR less than 1.0, with
both variables decreasing by at least 20%. Patients in whom
neither systemic vascular resistance nor pulmonary arteriolar
resistance decreased at least 20% during long-term treatment
were identified as Group III.
Statistics. The control hemodynamic, biochemical and
hormonal variables before captopril administration in the
three groups were compared by one-way analysis of variance
followed by the t test for independent variables to differentiate among significant responses. Qualitative differences
Table 1. Short- and Long-Term Hemodynamic Effects of Captopril in 75 Patients With Severe
Chronic Heart Failure
Cardiac index
(liters/min per m2 )
Stroke volume index
(ml/beat per m2)
Heart rate
(beats/min)
Left ventricular filling
pressure (mm Hg)
Mean systemic arterial
pressure (mm Hg)
Mean pulmonary artery
pressure (mm Hg)
Mean right atrial
pressure (mm Hg)
Systemic vascular
resistance (dynes·s·cm 5)
Pulmonary arteriolar
resistance (dynes's'cm- s)
Right ventricular stroke
work index (g'mim2)
Left ventricular stroke
work index (g'm/m2)
637
C
01
LT
P Value
1.78
±0.05
21.8
±0.8
85.4
± 1.8
26.8
±0.6
83.9
± 1.6
40.8
±0.8
11.5
±0.7
2,003
±75
393
±21
8.6
±0.4
16.7
±0.9
2.07*
±0.06
27.7*
± 1.0
78.0*
± 1.8
17.9*
±0.7
67.1 *
± 1.8
31.6*
±0.8
8.3*
±0.6
1,442*
±79
333*
±17
8.5
±0.4
18.3t
±0.8
2.03*
±0.05
27.8*
±0.9
75.9*
± 1.8
16.0*
±0.9
67.8*
± 1.8
28.8*
± 1.0
6.6*
±0.7
1,465*
±58
310*
± 15
8.3
±0.4
19.8*
± 1.0
NS
NS
NS
< 0.05
NS
< 0.01
< 0.01
NS
NS
NS
< 0.05
Symbols indicate significance of difference from pre-captopril values: *p < 0.01, tp < 0.05. Values for
p indicate significance of 01 versus LT, where C = control (pre-captopril); 01 = first captopril dose; LT =
long-term captopril therapy (I to 3 months).
638
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
JACC Vol. 6. No.3
September 1985:635-45
among the three groups were assessed by the chi-square
statistic. The long-term biochemical and hormonal effects
of captopril were compared with pretreatment values within
each group by the t test for paired data and among the three
groups by analysis of variance. The hypotheses that two
variables were related were tested by least squares linear
regression analysis. The responses to nitroglycerin in nine
patients were assessed and compared with the effects of
captopril in these patients by a repeated measures analysis
of variance procedure similar to tha~ utilized for Table 1.
All group data are expressed as mean ± SEM.
Results
Overall short- and long-term hemodynamic responses
(Table 1). In our 75 patients with severe chronic heart
failure, captopril produced significant increases in cardiac
index, stroke volume index and left ventricular stroke work
index and significant decreases in left ventricular filling
pressure, mean pulmonary and systemic arterial pressures,
mean right atrial pressure and systemic and pulmonary resistances during short- and long-term therapy (p < 0.01)
without significant changes in right ventricular stroke work
index. During the course of treatment, we noted a progressive increase in left ventricular stroke work index and a
progressive decrease in left ventricular filling pressure, mean
pulmonary artery pressure and mean right atrial pressure
(p < 0.05 to 0.01), whereas other hemodynamic variables
generally remained at levels similar to those seen after the
first dose of the drug.
After the first doses of captopril, the magnitude of the
decrease in pulmonary arteriolar resistance was substantially
less than the magnitude of the qecrease in systemic vascular
resistance (15 versus 28%, p < 0.001), and this discordance
persisted during long-term treatment with the drug. There
was a significant relation between the magnitude of the
decrease in pulmonary arteriolar resistance after the first
dose of captopril and the decrease in this variable after 1
to 3 months of therapy in individual patients (r == 0.57,
P < 0.001).
. Intergroup differences in the hemodynamic response
to captopril (Table 2). Patients in Groups I, II and III were
similar with respect to all pretreatment hemodynamic variables, except that patients in Group III had a significantly
lower mean pulmonary artery pressure and pulmonary arteriolar resistance than did patients in Groups I and II (whose
pretreatment hemodynamic state was similar with respect
to all measured variables). The hemodynamic responses to
long-term captopril therapy in patients in Groups I and II
are shown and compared in Figures 1 to 3. In patients in
Table 2. Pretreatment Hemodynamic and Clinical Variables in Patient Subsets
Age (yr)
Sex (M/F)
CHF etiology
Weight (kg)
BUN (mg/dl)
Serum Cr (mg/dl)
PRA (ng/ml per h)
Serum Na (mEq/liter)
CI (liters/min per m 2)
SVI (ml/beat per m 2)
HR (beats/min)
MAP (mm Hg)
LVFP (mm Hg)
MPAP (mm Hg)
MRAP (mm Hg)
SVR (dynes·s·cm- 5 )
PAR (dynes.s'cm- 5)
RVSWI (g'mlm 2 )
LVSWI (g'mlm2)
Group I
(n = 24)
Group II
(n = 28)
Group III
(n = 23)
p Value
65.5 :!: 1.9
2113
ICM(l6), POC(6), VR(2)
69.1 :!: 2.5
33.2 :!: 3.4
1.5 :!: 0.1
3.0 :!: 0.6
137.1 :!: 0.6
1.74 :!: 0.09
20.6:!: 1.3
87.2 :!: 2.8
86.7 :!: 2.8
27.1 :!: 0.9
43.6 :!: 1.2
12.0 :!: 1.2
2,002 :!: 126
459 :!: 48
8.8 :!: 0.7
16.8 :!: 1.5
61.9 :!: 2.6
19/9
ICM(l9), POC(6), VR(3)
62.1 :!: 2.9
47.8 :!: 6.8
1.7 :!: 0.1
8.7 :!: 2.1
133.1 :!: 0.9
1.70 :!: 0.06
20.5 :!: 1.2
88.0 :!: 3.2
81.3 :!: 1.7
26.8 :!: 1.1
40.5 :!: 1.4
11.0 :!: 1.2
2,075 :!: 110
407 :!: 27
8.2 :!: 0.6
15.2 :!: 1.1
63.7 :!: 2.8
15/8
ICM(lI), POC(I)), VR(I)
64.7 :!: 2.3
45.7 :!: 7.5
2.0 :!: 0.4
2.5 :!: 0.7
136.0 :!: 0.6
1.92 :!: 0.11
24.6:!: 1.6
79.9 :!: 2.9
84.3 :!: 3.8
26.5 :!: 1.3
38.3 :!: 1.5
11.5 :!: 1.3
1,926 :!: 164
308 :!: 27
8.8 :!: 0.6
18.4 :!: 1.9
NS
NS
NS
NS
NS
NS
< 0.01
< 0.01
NS
NS
NS
NS
NS
< 0.05
NS
NS
< 0.02
NS
NS
Group I = patients with predominant pulmonary vasodilation; Group II = patients with predominant systemic vasodilation; Group III = patients
with neither systemic nor pUlmonary vasodilation. Values for p indicate significance among the three groups by analysis of variance. The significance
of plasma renin ;lctivity (PRA) and serum sodium (Na) results from differences between Group II and the other two groups; the significance of mean
pUlmonary artery pressure (MPAP) and pulmonary arteriolar resistance (PAR) results from differences between Group III and the other two groups.
BUN = blood urea nitrogen; CHF = congestive heart failure; q = cardiac index; Cr = creatinine; F = female; HR = heart rate; ICM = ischemic
cardiomyopathy; L VFP = left ventricular filling pressure; LVSWI = left ventricular stroke work index; M = male; MAP = mean systemic arterial
pressure; MRAP = mean right atrial pressure; POC = primary dilated cardiomyopathy; RVSWI = right ventricular stroke work index; SVI = stroke
volume index; SVR = systemic vascular resistance; VR = valvular regurgitation.
lACC Vol. 6, No.3
September 1985 :635-45
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~-conlro/
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Groups I and II, captopril produced similar decreases in
systemic vascular resistance (- 34 versus - 35%, respectively), whereas, by definition, Group I showed significantly
greater decreases in pulmonary arteriolar resistance than did
Group II (-45 versus -18%, p < 0.001). Consequently,
cardiac index increased (+0,54 versus + 0.23 liter/min
per m 2 , p < 0.001) and mean pulmonary artery pressure
decreased (-18.1 versus -12.7 mm Hg, p < 0.02) to a
greater degree in Group I than in Group II.
The difference noted between Groups I and II with respect to cardiac index was not due to different effects of
captopril on heart rate in the two groups; heart rate decreased
significantly (p < 0.001) and similarly in both cohorts
(87.2 ± 2.8 to 76.3 ± 2.8 beats/min in Group I and 88.0
± 3.2 to 76.2 ± 3.1 beats/min in Group II). Therefore,
Figure 2. Changes in mean pulmonary artery pressure, mean right
atrial pressure and pulmonary arteriolar resistance during longterm captopril therapy in patients in Groups I and II. Format and
symbols as in Figure 1.
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Drug
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Figure 1. Changes in cardiac index, mean systemic arterial pressure and systemic vascular resistance during long-term captopril
therapy in patients in Group I (predominant pulmonary vasodilation) and Group II (predominant systemic vasodilation). Asterisks
indicate significance of captopril effect from pretreatment values
within each group (*p < 0.001); P values at the top of each panel
indicate significance of differences in the long-term responses between the two groups. Group data expressed as mean ± SEM.
(111-
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639
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
0 L...J........~L.JII"-IT
Figure 3. Changes in stroke volume index, left ventricular (LV)
stroke work index and left ventricular filling pressure during longterm captopril therapy in patients in Groups I and II. Format and
symbols as in Figure I.
stroke volume index ( + 10.0 versus + 6.1 mllbeat per m 2 ,
p < 0.01) and left ventricular stroke work index (+6,7
versus + 1.2 g.mlm2 , p < 0.001) increased more in Group
I than in Group II. The small increase in left ventricular
stroke work index seen in patients in Group II was not
significant. Because the decrease in systemic vasc~lar resistance in the two groups was similar and the increase in
cardiac index in patients in Group I was greater than in
Group II, mean systemic arterial pressure decreased less in
patients with predominant pulmonary vasodilation than in
those with predominant systemic vasodilation (Group I versus Group II, -16.4 versus -21.7 mm Hg, respectively;
p < 0.02).
Left ventricular filling pressures decreased similarly in
both groups, but because pulmonary arteriolar resistance
decreased more in Group I than in Group II, patients in
Group I showed a greater decrease in mean right atrial
pressure than did those in Group II ( - 8.0 versus - 4.1 mm
Hg, P < 0.0 I). Although right ventricular stroke work index
increased slightly in Group I and decreased slightly in Group
II, these changes did not reach statistical significance.
Patients in Group III showed small but significant (p <
0.05) increases in stroke volume index and decreases in left
ventricular filling pressure, mean pulmonary artery pressure,
mean right atrial pressure and systemic vascular resistance
without changes in cardiac index, right or left ventricular
stroke work index or pulmonary arteriolar resistance (data
not shown). The magnitude of these changes (where significant) was less than the changes seen in Groups I and II
for all hemodynamic variables (p < 0.05 to 0.01).
Intergroup differences in the hormonal and clinical
response to captopril (Tables 2 and 3). Patients in Groups
I, II and III were similar with respect to age, sex, cause of
heart failure, pretreatment body weight and pretreatment
renal function. Pretreatment values for plasma renin activity, however, were significantly higher in patients in Group
II (8.7 ± 2.1 ng/ml per h) than in Groups I and III
640
JACC Vol. 6, No.3
September 1985:635-45
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
Table 3. Changes in Biochemical and Hormonal Variables During Long-Term Captopril Therapy in Specific Patient Subsets
Group I
Body weight (kg)
Blood urea
nitrogen (mg/dl)
Serum creatinine
concentration (mg/dl)
Plasma renin
activity (ng/ml per h)
Group II
Group III
C
CPT
C
CPT
C
CPT
P Value
69.1
±2.5
33.2
±3.4
1.5
±O.I
3.0
±0.6
67.2*
±2.3
44.0
±6.4
1.6
±0.2
21.7*
±4.9
62.1
±2.9
47.8
±6.8
1.7
±O.I
8.7
±2.1
62.6
±2.9
56.1
±7.1
1.8
±O.I
17.0*
±2.3
64.7
±2.3
45.7
±7.5
2.0
±0.4
2.5
±0.7
63.7
±2.2
51.0
±7.6
2.1
±0.3
10.7*
± 1.8
< 0.05
NS
NS
< 0.05
*Significance of change (p < 0.01) during long-term captopril therapy within each group. Values for p in the last column signify significance of
differences among the three groups (by analysis of variance) in the magnitude of captopril-induced changes; with respect to weight and plasma renin
activity, the observed significance is the result of changes in Group I that were greater in magnitude than those seen in Groups II and III. C = control;
CPT = I to 3 months of captopril therapy.
(3,0 ± 0,6 and 2.5 ± 0.7 ng/ml per h, respectively, both
p < 0.05 versus Group II). Accordingly, values for serum
sodium concentration were lower in patients in Group II
(133.1 ± 0.9 mEg/liter) than in Groups I and III (137.1
± 0.6 and 136.0 ± 0.6 mEg/liter, respectively; p < 0.01
and 0.05 versus Group II, respectively). Considering only
patients in Groups I and II (in whom systemic vascular and
pulmonary arteriolar resistance both decreased), we noted
a linear but inverse relation between the pretreatment plasma
renin activity (PRA) and the ratio of the change in pulmonary to the change in systemic resistance during longterm captopril therapy (PRA versus % d PAR/% d SVR;
r = 0.53; P < 0.001) (Fig. 4).
Changes in biochemical and hormonal variables in the
three groups ofpatients before and after captopril are shown
in Table 3. Plasma renin activity increased significantly
(p < 0.01) in all three groups of patients; the magnitude of
reactive hyperreninemia in patients in Group I ( + 18.7 ±
4.9 ng/ml per h), however, was significantly greater than
Figure 4. Relation between the ratio of the change in pulmonary
arteriolar resistance to the change in systemic vascular resistance
(% .:l PAR/% .:l SVR) during long-term captopril therapy to pretreatment values for plasma renin activity in individual patients in
Groups I and II who showed a decrease in both pulmonary and
systemic resistance.
3.0.-------------,
y' -0.22 log. x + 1.29
2.5
r
'-0.53 P<.OOI
0::
i;; 2.0
<I
~
'1.5
0::
~
<I
~
o
o
1.0
o
...., -,...
.......
.
o
o
1.0
2.0
Discussion
00
O.L-~~-L-~~~~~~~~
0.2 0.5
Body weight decreased during the course of captopril therapy only in patients in Group I (69.1 ± 2.5 to 67.2 ± 2.3
kg, P < 0.01), whereas there was no significant change in
weight in the other two groups. Blood urea nitrogen and
serum creatinine concentration failed to change significantly
in any of the three groups.
With respect to clinical response during the course of
long-term captopril therapy, 19 (79%) of 24 patients in
Group 1,20 (71 %) of 28 patients in Group II and 11 (48%)
of 23 patients in Group III improved clinically by at least
one New York Heart Association functional class (Group
III versus the other two groups, p < 0.05). Therapy was
complicated by symptomatic hypotension, however, in 10
(36%) of 28 patients in Group II, but in only 2 (8%) of 24
patients in Group I and only I (4%) of 23 patients in Group
III (Group II versus Groups I and III, p < 0.005).
Hemodynamic effects of nitroglycerin in Group II
(Table 4). Nine patients in Group II received nitroglycerin
0.4 mg sub lingually 30 to 60 minutes after the assessment
of the responses to long-term captopril therapy. Compared
with the immediate pretreatment hemodynamic state (30 to
60 minutes after peak captopril effect), nitroglycerin significantly decreased (within 10 minutes) right and left ventricular filling pressures, mean systemic and pulmonary artery pressures and pulmonary and systemic vascular resistances
(p < 0.05 to p < 0.01). Compared with the hemodynamic
state observed at peak captopril effect, however, only the
decrease in mean pulmonary artery pressure (p < 0.05) and
pulmonary arteriolar resistance (p < 0.01) was significant,
and this pulmonary vascular response occurred without
changes in other hemodynamic variables.
0
.5
in Group II (+ 8.3 ± 2.7 ng/ml per h) and in Group III
(+ 8.2 ± 1.7 ng/ml per h, both p < 0.05 versus Group I).
5.0 10.0 25.0 50.0
PLASMA RENIN ACTIVITY (ng/ml/hrl
The findings of the present study indicate that changes
in pulmonary arteriolar resistance play an important role in
determining the long-term hemodynamic and clinical re-
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
JACC Vol. 6, NO.3
September 1985:635-45
641
Table 4. Hemodynamic Responses to Nitroglycerin in Patients in Group II (n = 9)
CI
(liters/min per m2 )
MAP
(mmHg)
LVFP
(mmHg)
MPAP
(mmHg)
MRAP
(mmHg)
HR
(beats/min)
SVR
(dynes's'cm -5)
PAR
(dynes's'cm- 5 )
Pre-C
C-DI
C-LT
Pre-N
Post-N
Pre-Versus Post-N
C-LT Versus
Post-N
1.72
±0.18
84.2
±5.4
24.8
±J.3
36.8
±J.3
10.8
± 1.1
84.9
±3.7
2,152
±202
368
±45
1.91
±O.IS
67.0*
±4.5
15.7*
±2.3
28.1*
±2.6
8.0t
±0.9
80.7
±3.0
1,554*
± ISS
340
±35
1.96
±O.IS
61.6*
±4.S
11.3*
±3.3
23.0*
±2.7
6.0*
±J.7
74.2*
±3.6
1,437*
± 164
333
±43
I.S1
±0.16
69.3*
±5.1
15.1 *
±2.8
27.6*
±2.9
7.3*
± 1.8
76.1 *
±3.S
1,709*
± 169
353
±46
2.05
±0.14
59.4*
±4.1
9.0*
±2.7
19.0*
±3.S
4.6*
±1.4
73.8*
±2.S
1,316*
± 119
247*
±40
NS
NS
P < 0.01
NS
P < 0.05
NS
P < 0.01
P < 0.05
P < 0.05
NS
NS
NS
P < 0.01
NS
P < 0.01
P < 0.01
Symbols indicate significance from pre-captopril values: *p < 0.01, tp < 0.05. The last two columns indicate significance between columns by
analysis of variance. Pre-C = pre-captopril; C-DI = first dose of captopril; C-LT = long-term captopril therapy; Pre-N = before nitroglycerin (30 to
60 minutes after C-LT); Post-N = after nitroglycerin; other abbreviations as in Table 2.
sponses to captopril therapy in patients with severe chronic
left ventricular failure. Despite similar decreases in left ventricular filling pressure and systemic vascular resistance,
patients who showed substantial pulmonary vasodilation
(Group I) experienced greater increases in cardiac index,
stroke volume index and left ventricular stroke work index
than did patients who demonstrated predominant systemic
vasodilation (Group II); similarly, right ventricular stroke
work index was preserved at a lower right ventricular filling
pressure in patients in Group I than in those in Group II.
Although both groups improved clinically, patients in whom
pulmonary arteriolar resistance decreased during converting
enzyme inhibition had less dramatic decreases in systemic
blood pressure (and thus experienced less symptomatic hypotension) and had a greater decrease in body weight during
treatment (presumably due to a drug-induced natriuresis)
than did patients who showed primarily systemic vasodilator
effects and in whom sodium excretion may have been limited by the hypotensive effects of the drug (28,29); this
natriuresis may have contributed significantly to the substantial decrease in central venous pressures seen in patients
in Group I. These data strongly support the concept that the
pulmonary circulation modulates changes in both right and
left ventricular performance during vasodilator therapy in
patients with left heart failure.
Role of the pulmonary circulation in left ventricular
failure. Clinicians have long believed that excessive elevation of systemic vascular resistance is the principal hemodynamic abnormality of patients with congestive heart failure and is responsible for their depressed left ventricular
function and the severity of their symptoms. Recent studies
(10,11) have shown, however, that right ventricular ejection
fraction and pulmonary arteriolar resistance are important
determinants of the functional status of patients with left
heart failure and correlate better with exercise capacity than
do measures of left ventricular performance. In such patients, the ability to increase cardiac output during exertion
is the primary determinant of exercise duration; if this ability
is limited by heightened pulmonary arteriolar resistance or
by right ventricular dysfunction, cardiac output may not
increase sufficiently to meet the metabolic requirements of
the body, even if systemic vascular resistance decreases
dramatically (10). Furthermore, systemic vasodilation in the
absence of pulmonary vasodilation may result in severe
hypotension. Such hypotensive episodes are well known in
patients with pulmonary hypertension secondary to obliterative pulmonary vascular disease whose pulmonary vessels
are unable to respond to systemic vasodilator therapy (25,26);
our data indicate that similar hemodynamic events may explain the hypotensive symptoms of patients with left ventricular failure treated with vasodilator drugs. If, on the other
hand, pulmonary vasodilation does occur during long-term
therapy, right ventricular performance may improve dramatically and result in an increase in cardiac output and
exercise capacity (I 2).
Limited pulmonary vasodilator effects of angiotensin
suppression. A desired goal of vasodilator therapy for patients with left ventricular failure, therefore, is balanced
systemic and pulmonary vasodilation. Direct-acting vasodilator drugs (such as nitroprusside and nitrates) decrease
systemic and pulmonary resistances to a similar degree
(13-15), but converting enzyme inhibition generally produces
dilation in the pulmonary circulation far less dramatically
than it does in the systemic circuit (21,22). These observations are consistent with the fact that angiotensin is a
potent systemic vasoconstrictor that exerts little direct action
642
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
on the pulmonary vessels in physiologic concentrations
(16,20); thus, neutralization of its effects during captopril
therapy produces minimal pulmonary vasodilation. Previous
studies have established the limited pulmonary vascular effects of captopril during short-term therapy (21,22); the
present findings extend these observations to long-term
treatment. These observations may explain why right ventricular stroke work failed to increase during converting
enzyme inhibition in our 75 patients, even though left ventricular stroke work increased significantly as resistance to
left ventricular systolic ejection decreased. These discordant
responses probably account for the greater frequency of
symptomatic hypotension with captopril compared with other
vasodilator drugs (l ,21). Furthermore, the limited ability
of captopril to improve right ventricular function may restrict the potential of some patients to benefit from converting enzyme inhibition. Patients with poor right ventricular function do not respond well to captopril therapy (30,31),
and pretreatment right ventricular function appears to be the
principal determinant of long-term survival in patients with
left heart failure treated with converting enzyme inhibitors
(31,32).
Mechanisms of pulmonary vasodilation during captopril therapy. The mechanisms just outlined logically explain why our patients with the highest pretreatment plasma
renin activity and the lowest serum sodium concentration
showed the least pulmonary vasodilation during long-term
therapy with captopril. These patients have the greatest activation of the renin-angiotensin system and appear to be
highly dependent on angiotensin II to support circulatory
homeostasis (33); interference with angiotensin II formation, therefore, can be expected to result in dramatic systemic (but not pulmonary) vasodilation and symptomatic
hypotension (34), the severity of which is likely to be potentiated by the limited pulmonary vascular responses seen
in this group (25). Such mechanisms, however, fail to account for the marked and balanced pulmonary and systemic
vasodilation during long-term therapy with captopril in our
patients in Group I, who generally had a low plasma renin
activity. Why should captopril have resulted in dramatic
hemodynamic and clinical benefits in these patients? Converting enzyme inhibition may produce hemodynamic improvement in some patients with low renin heart failure by
further reducing the low (but potentially still physiologically
important) levels of circulating angiotensin II (35). If withdrawal of the actions of angiotensin were the only mechanism of action in these patients, however, we would have
expected their pulmonary and systemic vasodilator responses to captopril to be similar to those seen in our high
renin patients; because the reverse was true, we must postulate other mechanisms to explain our observations. The
angiotensin-converting enzyme is also the same enzyme
responsible for the degradation of endogenous kinins (36),
which exert potent vasodilating effects by their ability to
stimulate the production of prostaglandins by the kidney
lACC Vol. 6, NO.3
September 1985:635-45
(37,38). Hence, by inhibiting the converting enzyme, captopril may retard kinin metabolism and thereby enhance
prostaglandin synthesis, which may contribute substantially
to the circulatory effects of the drug. That these concepts
have therapeutic significance is supported by clinical data
showing I) a marked increase in the level of prostaglandin
E metabolites in the urine of patients with hypertension and
heart failure treated with captopril (39-41), and 2) attenuation of the effects of captopril in hypertensive patients
by agents that inhibit prostaglandin synthesis (40). Studies
by two independent groups of investigators (42,43) have
concluded that prostaglandins play the major role in mediating the therapeutic effects of converting enzyme inhibition in patients with a low plasma renin activity; in contrast, arachidonic acid metabolites appear to have little
significance in patients with marked activation of the reninangiotensin system.
Our findings provide circumstantial support for the hypothesis that prostaglandins may mediate some of the hemodynamic effects of captopril in patients with low renin heart
failure. In our patients in Group I (predominant pulmonary
vasodilation) whose average plasma renin activity was only
3.0 ± 0.6 ng/ml per h, captopril produced marked decreases
in both pulmonary and systemic vascular resistance, a response that is more consistent with the known hemodynamic
effects of prostaglandin E than the events expected to follow
interference with the renin-angiotensin system; unlike angiotensin II, prostaglandin E (particularly E 1) has direct
actions on the pulmonary circulation (44,45) and produces
balanced systemic and pulmonary vasodilator effects in patients with congestive heart failure (46). Furthermore, production of prostaglandins by the kidney may contribute significantly to the increase in plasma renin activity that follows
converting enzyme inhibition (43,47), which may explain
why reactive hyperreninemia was most marked in patients
with the greatest pulmonary vasodilator responses. The enhanced synthesis of renal prostaglandins may serve to potentiate the effects of furosemide (8,43), which may also
be mediated by prostaglandin E intermediates (48-50); this
hormonal interaction may account for the diuresis seen in
patients in Group I. Further research is needed to validate
these concepts; such studies should include both measurement of prostaglandin metabolites and hemodynamic assessment of the effects of inhibitors of prostaglandin synthesis during treatment with captopril to determine whether
these hormonal and hemodynamic events correlate with the
magnitude of pulmonary vasodilation. It is also possible that
other hormonal events (for example, the reduction in circulating levels of catecholamines and vasopressin that accompanies long-term converting enzyme inhibition [51-53])
may contribute significantly to the hemodynamic responses
we observed.
Limitations of the study. Our findings need to be interpreted in the context of certain precautions and limitations. We attempted to measure changes in vessel tone and
lACC Vol. 6. No.3
September 1985:635-45
caliber in the pulmonary circulation by calculating pulmonary arteriolar resistance, but conventional approaches to
the measurement of this variable may not be accurate, because the relation between blood flow and resistance in the
pulmonary circulation may not be linear (54,55). Furthermore, df4g-induced changes in left atrial pressure may induce secondary alterations in pulmonary arteriolar resistance
in the absence of any direct pulmonary vasodilating action
(56,57); this observation is unlikely to have explained the
different pulmonary vascular responses seen in patients in
Groups I and II, however, because the groups demonstrated
similar decreases in left ventricular filling pressure. An increase in pulmonary blood flow (secondary to an increase
in cardiac output) can itself lower pulmonary resistance by
the passive recruitment of unused vascular channels rather
than by a direct active pulmonary vasodilating effect of a
drug (58). All of these passive components of the pulmonary
vascular response may interact with active pulmonary vasodilation to determine the hemodynamic effects of therapy.
Despite these complexities, we believe that selective pulmonary vasodilation can be assumed to have occurred if the
decrease in resistance in the pulmonary circulation exceeds
that seen in the systemic circulation; this generally occurs
when pulmonary arteriolar resistance decreases simultaneously with an increase in cardiac output and a decrease
in mean pulmonary artery pressure (27). Because the changes
in all three variables were greater in patients in Group I
(predominant pulmonary vasodilation) than in Group II (predominant systemic vasodilation), we believe that the greater
decrease in pulmonary arteriolar resistance in patients in
Group I was the result of active pulmonary vasodilation, a
response that is difficult to explain on the basis of angiotensin II suppression alone.
We considered the possibility that our patients in Group
II (predominant systemic vasodilation) did not show an active pulmonary vasodilator response during treatment with
captopril because they had fixed structural disease of the
pulmonary vasculature. Such pulmonary vascular obliteration may occur in patients who have long-standing increases
in pulmonary venous pressure (with secondary fibrosis and
hemosiderosis), particularly in those with severe mitral stenosis. The degrees of elevation of pulmonary arteriolar resistance in Groups I and II, were similar, however; we would
have anticipated higher levels of pulmonary resistance for
similar levels of left ventricular filling pressure if additional
structural changes in the pulmonary vessels had developed
in patients in Group II. Most important, the selective decrease in pulmonary arteriolar resistance after nitroglycerin
administration in our patients in Group II strongly supports
our hypothesis that the increased pulmonary resistance in
these patients was the result of active pulmonary vasoconstriction that was still responsive to vasodilator therapy (Table 4).
Finally, it is possible that patients in Group II did not
show substantial pulmonary vasodilation because treatment
PACKER ET AL.
PULMONARY VASODILATION IN HEART FAILURE
643
with captopril activated endogenous vasoconstrictor forces
that selectively antagonized the pulmonary vasodilation that
might have been expected to accompany any drug-induced
decrease in left ventricular filling pressures. The activation
of such forces has been shown to limit the systemic effect
of other vasodilator drugs in patients with severe chronic
heart failure (59,60). There is little evidence, however, that
such forces are activated during long-term treatment with
captopril. Circulating levels of both catecholamines and vasopressin decrease during long-term captopril therapy (51-53);
these additional hormonal changes may contribute significantly to the hemodynamic improvement as well as to the
decreases in heart rate and the correction of hyponatremia
that follow the converting enzyme inhibition in these patients (8,9). Furthermore, neither norepinephrine nor vasopressin is known to selectively constrict the pulmonary
vasculature. Consequently, selective reflex vasoconstriction
is an unlikely explanation for our findings.
Conclusions. The present study indicates that the pulmonary circulation plays an important role in modifying the
hemodynamic responses seen during long-term angiotensinconverting enzyme inhibition in patients with severe chronic
heart failure. Patients with hyponatremia and a high plasma
renin activity generally show little long-term pulmonary
vasodilator response to captopril; therefore, because the patients' ability to increase cardiac output is limited, clinical
and hemodynamic benefits are achieved at the cost of frequent episodes of symptomatic hypotension. On the other
hand, some patients with low renin heart failure show marked
pulmonary vasodilator effects during treatment that dramatically el1hance the improvement in left ventricular performance that might be expected to accompany any druginduced decrease in systemic vascular resistance without
additional hypotensive risk; such pulmonary vasodilator effects are difficult, however, to explain on the basis of angiotensin suppression alone. These observations suggest that
some patients with severe chronic heart failure may benefit
from long-term captopril therapy through mechanisms independent of interference with the renin-angiotensin system.
We are indebted to the nurses of the Ames and Rose Cardiac Care Units
of the Mount Sinai Hospital for the excellent care they provided for the
patients in this study.
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