Download Hemodynamic Response: Decrease in Cardiac Output vs Reduction

Hemodynamic Response: Decrease in Cardiac
Output vs Reduction in Vascular Resistance
PER LUND-JOHANSEN,
M.D.
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SUMMARY From a hemodynamic point of view, an adequate response to antihypertensive therapy
would be restoration of a normal circulatory system. In most patients with mild to moderate essential
hypertension considered to need drug therapy, the cardinal hemodynamic disturbance is an increased
total peripheral resistance (TPR) and a normal or reduced cardiac output (CO). During a 10- to 17year follow-up of untreated hypertensives, a gradual increase in TPR, increase in MAP, and a
decrease in CO and stroke volume (SV) were seen. Hemodynamic responses to chronic drug therapy
were studied at rest and during exercise in 250 men with mild to moderate essential hypertension in
WHO Stage I. A significant reduction in TPR was seen on thiazide diuretics, nifedipine and verapamil, but there was no increase of subnormal CO or SV. A greater normalization of central hemodynamics was achieved by prazosin, which induced a reduction in TPR and an increase in CO and SV,
particularly during exercise. In contrast, beta-blocker therapy was associated with a chronic reduction in CO and heart rate (HR) and usually no reduction in TPRI below pretreatment values. The
chronic CO reduction was associated with an increase in arteriovenous oxygen difference. In 14
patients with therapy-resistant hypertension, a marked increase in TPR was found. Captopril induced a reduction in TPR with rest and exercise, and also a reduction in cardiac output. Prolonged
therapy for 5 years with beta-blockers did maintain blood pressure control, but with no further
decrease in TPR. In contrast, 5 years of therapy with labetalol induced a gradualfall in TPR below
pretreatment levels, and a gradual increase in CO. (Hypertension 5 (supp til): 111-49—Hf-57, 1983)
KEY WORDS * hypertension • hemodynamics • diuretics • beta-blockers
• labetalol • vefapamil • nifedipine • captopril
F
ROM a hemodynamic point of view, an adequate response to antihypertensive therapy
could be defined as a restoration of a normal
circulatory system — at rest as well as during exercise.
An inadequate response would mean lack of this effect
even if the blood pressure is reduced.
The central hemodynamic disturbance in most hypertensive patients considered to need drug treatment
is an increased total peripheral resistance (TPR).1-3
Increased vascular resistance is generally found in
most vascular beds, such as in the kidneys, splanchnic
organs, and skin, and in advanced hypertension, also
in the skeletal muscles.2 4 The cardiac output (CO)
during rest is usually normal or reduced, and the stroke
volume (SV) is subnormal. During muscular exercise,
subnormal CO and SV are usually found even in mild
hypertension in young persons.1
* prazosin
When hypertension is left untreated, the spontaneously occurring changes are characterized by a gradual
fall in CO and SV and an increase in TPR - at rest as
well as during muscular exercise.1 The changes in
blood pressure (BP) may vary, but in most patients
with mild or moderate established hypertension (not
borderline hypertension), BP will increase over a 10to 17-year period. Ina 10-year follow-up of 29 patients
with mild hypertension, CO fell by 20% and TPR
increased by 30% during rest.1 Eight of these subjects
have had a third hemodynamic study after 17 years.
The changes seen at the 10-year follow-up had progressed, as shown in figure 1.
This review will first discuss how the most commonly used antihypertensive agents affect central
hemodynamics during chronic treatment in typical patients with mild to moderate essential hypertension. It
will also discuss whether inadequate blood pressure
reduction could be due to extreme degrees of hemodynamic disturbances and/or to improper drug selection.
The review will be limited to diuretics, alpha- and
beta-blockers (alone or in combination), calcium antagonists, and to the converting-enzyme inhibitor, captopril.
From the Cardiology Section, Medical Department, University
of Bergen, Bergen, Norway.
Address: Prof. P. Lund-Johansen, Cardiology Section, Medical
Department, 5016 Haukeland Hospital, Bergen, Norway.
111-49
111-50
RESPONSE TO HYPERTENSION THERAPY
SUPP
III HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983
TPRI
dyn s*c c m - ' m'c
MAP
mmHg
\
140
• ••"
130
4000 r
*
•••
•
I
>
no
R5
SOW
100W
150 W
°
. !•-
2000
I
R5
75
3000
/
120
1965(17-39yrs)
o
\"5
-82 (34-56yrs)
«•«
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100 W
150 W
RS
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100W
150 W
HR
b«ati mm- 1
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ml stroke ' m '
160
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70
140
60
120
50
100
40
80
RS
sow
100 W
150W
RS
50 W
100 W
150 W
FIGURE 1. Systemic hemodynamics in eight men with untreated essential hypertension first studied in 1965 (17-39 years of age),
then in 1975, and in 1982 (aged 34-56 years). RS = rest sitting.W = wat;Cl = cardiac index; MAP = mean arterial pressure; TPRI
= total peripheral resistance index; SI = stroke index; HR = heart rate. Stars show statistical significance of differences between the
first and last study. * = p < 0.05; • • = p < 0.01; *•* = p < 0.001.
Hemodynamic Changes Induced by 1-Year
Therapy
Over the years, we have studied the hemodynamic
responses to chronic drug therapy in 250 men with
mild to moderate essential hypertension (diastolic
pressure 100-120 mm Hg) in WHO Stage I. Before
treatment, practically all the subjects demonstrated an
increased TPRI* ( > 2800 d y n s e c c m " 5 -m2) at rest
and also increased values during exercise. CO was
normal or moderately decreased; SV was usually normal during rest and subnormal during exercise (reduced by about 20%). During exercise, the arteriovenous oxygen difference was generally increased by 10%
to 15%.'
Diuretics (Thiazide Diuretics and Tienilic Acid)
About 20 years ago it was shown by Conway and
Lauwers5 that BP reduction during the first days of
thiazide treatment was associated with fall in CO and
no change in TRP. However, prolonged use over sev-
*TPRI = MAP x 80 -H CI.
eral months caused a fall in TPR toward normal levels
and a gradual increase in CO. About 10 years later,
these results were confirmed in our laboratory and we
also showed that the BP control during exercise was
maintained by the same mechanisms — a fall in TRP
without reduction in CO. The heart rate (HR) response
to exercise was unaffected.6 A similar hemodynamic
response was later demonstrated with tienilic acid.7
Thus, the thiazide diuretics and tienilic acid might be
said to induce at least a partial correction of the hemodynamic disturbances: partial because the subnormal
SV and CO during exercise is not corrected.^
Beta-Blockers
There are well-documented differences among hemodynamic responses to the different types of betablockers during the rest situation, but the responses
during muscular exercise are largely the same, especially during chronic treatment.9'13 We have studied
seven different beta-blockers in 89 patients with mild
to moderate essential hypertension, all previously untreated.14 The typical response to chronic treatment
with beta-blockers without intrinsic sympathomimetic
activity (ISA) was a BP reduction of about 15% to
111-51
HEMODYNAMIC RESPONSE/Lund-Johansen
Cl
l/min/m2
1O
MAP mmHg
4000
150
TPRI dyn sec cm"5 m 2
3000
2OOO
100
90
300
1000
1000
500
1OO0
500
1000
VOj ml /mm / m 2
HR/beats / min
•10 HRxMAP b e a t s / m m mm Hg
26 r
150
9 ml /strc+e/m 2
20
70
60
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100
50
10
40
3O
50
500
1000
500
1000
500
. 1000
\O 2 ml /min/rry?
FIGURE 2. Hemodynamic changes induced by I-year therapy of atenolol in 13 men with essential hypertension. V02 = oxygen
consumption. Legends are as in figure 1;
= before therapy;
= on therapy. Note the increase in SI during exercise after
therapy, partly compensating the reduction in HR (see ref. 15).
20%, and a fall in HR and CO of about 20% to 25%
during rest. During exercise, there was some compensatory increase in SV and a somewhat less reduction in
CO (10% to 15%). TPR did usually not fall below
pretreatment levels. Figure 2 shows the results in a
group of hypertensives treated with atenolol for 1
year.15
Beta-blockers with strong ISA, such as pindolol,
usually maintained BP reduction during rest, with less
decrease in HR and CO than from beta-blockers without ISA. TPR stayed at pretreatment levels or was
slightly reduced. During exercise (when sympathetic
tone is increased), the reduction in HR was significant
but usually less than on beta-blockers without ISA. SV
increased (compared to pretreatment level) and TPR
during exercise fell slightly below pretreatment level.
Most investigators have agreed upon these hemodynamic changes,10"13 but some reports have differed and
patients responding to chronic beta-blocker therapy
with increase in CO and marked fall in TPR have been
described.16'17 In patients with mild to moderate essential hypertension, however, this reaction pattern is
rare. Figure 3 shows the individual changes in cardiac
index (CI) in our series. It is seen that CI fell in most
patients and the fall was greatest in those with the
highest CI values. However, also in patients with rather low CI substantial reductions in CI were seen. Figure 4 shows that in this type of patient relatively few
responded with reduction in TPRI. Table 1 shows that
the number of patients who demonstrated at least a
10% reduction in TPRI at rest and during two exercise
loads was relatively small.
Most studies have shown that chronic beta-blocker
treatment causes little change in oxygen consumption
(V0 2 ) at rest as well as during exercise.14 Since Cl is
reduced (usually 20% to 25%), this means that the
arteriovenous oxygen difference is increased accordingly. The significance of this is not known. However,
although many patients react to initiation of betablocker therapy with muscular fatigue and cold hands
and feet, these complaints often disappear during
chronic treatment, at least in patients with mild to
moderate hypertension. Cold extremities, however,
which are most likely due to reduced peripheral blood
flow, are an important problem in cold climate. However, from a hemodynamic point of view, patients on
chronic beta-blocker therapy have replaced their normokinetic hypertensive circulatory system by a nor-
111-52
RESPONSE TO HYPERTENSION THERAPY
FIGURE 3. Changes in cardiac index (Cl) related to pretreatment cardiac index sitting at
rest in 89 men with mild to moderate essential
hypertension treated with different betablockers (see ref. 14).
SUPP III HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983
g.55
Cl I mlrr'nr 2
0 • -/A- -#-oA •
-0.5
?<£ a
-1.0
a
oa
•
-1.5
• Atenolol
• Metoprolol
A Timolol
o Penbutolol
• Alprenolol
* Pindolol
+ Bunitrolol
-2.0-
-25
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ACI
I mirr1 rrr2
motensive but hypokinetic system. It is of course important that the blood pressure x heart rate product is
markedly reduced on beta-blocker therapy, especially
during muscular exercise when a 40% reduction or
more might be seen. This reaction is of course most
adequate in patients with a compromised coronary circulation.
A TPRI
dyn sec cm"5m2
Alpha-Blockers (Prazosin)
Studies of prazosin have generally agreed that acutely as well as chronically BP is reduced entirely through
reduction in TPR.18"20 HR as well as CO is unchanged
during rest. During exercise, CO is increased due to an
increase in SV and a slight, insignificant increase in
HR. Fall in TPR is a very consistent finding. The
2107
1
2000-
1000-
&a
O A
o-yy
*». •
•<
«•
•
+
o
+
-1000
TPRI dyn sec cm"5m2-1O3
5
A
•
o
A
o
•
*
•
Atenolol
Metoprolol
Timolol
Penbutolol
Alprenolol
Pindolol
Bunitrolol
FIGURE 4. Changes in total peripheral resistance index (TPRI) related to pretreatment TPRI during chronic
beta-blockade in 89 men (see ref. 14).
ffl-53
HEMODYNAMIC RESPONSEJLund-Johansen
TABLE 1.
sponses
Individual
Total Peripheral
Resistance
(TPR)
Re-
A TPR > - 10%
(Rest sitting — 2 workloads)
no.
Drug
1/13
1/12
0/16
4/13
1/10
0/11
3/14
10/89 (11%)
Atenolol
Metoprolol
Timolol
Penbutolol
Alprenolol
Bunitrolol
Pindolol
Total
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results from our 1-year study are shown in figure 5. In
conclusion, prazosin might be said to restore normal
circulation in the majority of patients with mild to
moderate essential hypertension. No reduction in renal
or peripheral blood flow is seen.20 However, in patients with compromised coronary circulation it should
be noted that the workload on the heart is reduced far
less than by the use of beta-blockers, since HR is not
decreased, only the BP.
Combination of Alpha- and Beta-Blockade
(Labetalol)
When alpha- and beta-blockade is properly balanced, a marked reduction in BP is often achieved, the
BP reduction being partly due to reduction in TPR and
partly due to fall in CO. 21 An increase in SV might be
expected, and the decrease in CO during exercise is
less than when beta-blockers are used alone.
Labetalol induced similar changes, as might be expected since this drug blocks alpha- as well as beta,and betaj-receptors.22"23 A substantial BP reduction
might then be achieved by one single drug. In our
series, the mean reduction was 23%. During exercise,
CO was reduced much less than on conventional betablockers.24
Calcium Antagonists (Verapamil and Nifedipine)
In recent years, the calcium antagonists have been
introduced for therapy of hypertension.26"30 These
drugs reduce BP through reduction in TPR. During
long-term therapy, nifedipine,30 given in long-acting
form, reduced BP 17% during rest without any significant changes in CO, SV, or HR (fig. 6). Verapamil
induced similar reduction in TPR, but also about 10%
CI l / m i n / m 2
10
TPRITdyn sec c m " 5
MAP mm Hg
4000 r
150
100
500
1000
500
1000
VO2 m l / m i n / m 2
500
1000
HR x MAP b«als / m i n mm Hg
HR
500
1000
28000
beats/min
150
20000
100
10000
70
4000
500
1000
5000
1000
VO2 m l / m i n / m 2
FIGURE 5. Hemodynamic changes induced by I-year therapy with prazosin in 10 men with essential hypertension. Note the
substantial fall in total peripheral resistance (TPRl). and the significant increase in cardiac index (CI) during exercise. Also note the
small reduction in HR X MAP. Abbreviations are as in figures I and 2 (see ref. 19).
m-54
RESPONSE TO HYPERTENSION THERAPY
SUPP 111 HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983
•
o
Cl I min"'m'2
before
afttr
TPRl dyn sec crrr'm2
40001
MAP mmHg
3000-
1505-
1000
500
500
1000
500
HRMAP beats min'1mmHg
28 103!
HR beats min'1
1000
150-
SI ml stroke"'m"2
701
20-
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60-
r^---9
50-
-?
10010-
40
50
10k
-rr'/r500
1000
500
1000
500
1000
VO2 ml min' l m" 2
FIOURE 6. Hemodynamic changes during chronic treatment with long-acting nifedipine in 14 men with essential hypertension. Note
the reduction in total peripheral resistance (TPRl), and no significant changes in cardiac index (Cl), stroke index (SI), and heart rate
(HR) (see ref. 30).
C
I min"
ni 1 m' 2
5O
?560
MAP
mm Hg
TPRl
dyn sec cm" 5 m~2
140
4000
4.0
120
3000
3.0
100
2000
2.0
B 1year
5years
B 1year
5years
B 1year
5 years
FIGURE 7. Individual changes in cardiac index (Cl), mean blood pressure (MAP), and total peripheral resistance (TPRl) in 10 men on chronic atenolol therapy studied before therapy, after 1 year, and after 5 years.
shows mean values (see ref. 31).
CI-55
HEMODYNAMIC RESPONSEJLund-Johansen
decrease in HR. However, this was compensated by
increase in SV and CO was unchanged.
Thus, the calcium antagonists (like the diuretics)
maintain BP control by partial correction of the hemodynamic disturbances: only partial because the subnormal CO during exercise is not corrected.
Downloaded from http://hyper.ahajournals.org/ by guest on April 30, 2017
Hemodynamic Responses to Prolonged Drug
Treatment (5-6 Years)
Since at least some of the hemodynamic abnormalities in established hypertension are thought to be due to
structural changes in the heart and in the resistance
vessels, it could be hoped that permanent blood pressure control could induce regression of these changes
and also further normalization of central hemodynamics during prolonged treatment. We have studied
groups of patients treated with different beta-blockers
(alprenolol, atenolol, or metoprolol) and with labetalol
who have had a third hemodynamic study after 3-5
years. The results from the atenolol study (fig. 7) show
that the systemic hemodynamics were practically unchanged from 1 year until 5 years after the start of
therapy. Somewhat disappointingly there was no tendency for an increase in CO and SV or a decrease in
TPRI. On the other hand, no obvious deterioration had
taken place.31 Similar changes were seen with alprenolol and with metoprolol. The reduction of the workload
on the heart was maintained.
We have recently completed a 6-year follow-up on
15 patients with moderate hypertension treated with
labetalol for 6 years. The responses were somewhat
different from those seen on prolonged beta-blocker
therapy. BP was controlled over these 6 years and did
not change significantly. However, TPR had fallen at
rest as well as during exercise, and after 6 years TPR
was less than after 1 year on therapy (fig. 8). CI after 6
years was slightly higher than after 1 year, but the
differences between the 1 -year and 6-year results were
CI I
10
150
100500
1000
500
500
1000
VO2 ml min"1rri2
HR beats mirr,-1
1000
HRx MAP beats min"1mm Hg
•103
28
150
1
SI ml stroke" rri
2
20
60
100
50
10
40
30
50
>•
500
XXX)
500
1000
VO2 ml min~1rn2
,_
500
XXX)
FIGURE 8. Hemodynamic changes induced by 6-year therapy on labetalol in 15 men. Solid line = studied before therapy; dashed
line = studied after I year; and dotted line = studied after 6 years. Mean values and SEM. Stars show differences between thefirstand
the second study. Note the gradualfall in total peripheral resistance (TPRI) and a slight increase in stroke index (SI) and cardiac index
(CI) during the 5 years between the second and the third study.
111-56
RESPONSE TO HYPERTENSION THERAPY
SUPP III HYPERTENSION VOL 5, No 5, SEPTEMBER-OCTOBER 1983
not statistically significant. However, the results point
to a greater normalization of central hemodynamics on
prolonged labetalol therapy than with prolonged betablocker treatment.
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Hemodynamic Characteristics and Responses in
Patients with Severe Therapy-Resistant
Hypertension
Anderson et al.32 studied a group of patients who had
shown resistance to treatment with conventional antihypertensive agents (triple therapy with diuretics,
beta-blockers, and vasodilators). When therapy was
stopped and blood pressure increased, the characteristic hemodynamic disturbance was a marked increase in
TPR associated with a subnormal SV and CO. The BP
was very high (about 230/140 mm Hg during rest). In a
similar group of patients, we have confirmed these
hemodynamic characteristics at rest and during mild
exercise (Omvik and Lund-Johansen, 1983, unpublished results). Since, apart from structural changes in
the resistance vessels, the high resistance could also
theoretically be due to an overactivity in the reninangiotensin system (not measured), the patients were
treated with captopril and a diuretic. Most of the patients responded with a substantial drop in BP, with a
few practically reaching normotensive levels. During
rest, the BP was reduced through a drop in TPR, with
little change in CO. During exercise, a decrease in CO
was also seen. Similar responses during rest have been
reported by others.33"34
Discussion and Conclusion
This review has shown that most of the commonly
used antihypertensive agents may control BP, but often only by partially correcting the hemodynamic disturbances. Particularly the beta-blockers will usually
maintain a subnormal cardiac output at rest and during
exercise, and of course a subnormal HR. The arteriovenous oxygen difference is increased at rest as well as
during exercise. A greater degree of normalization of
central hemodynamics is achieved by diuretics and
calcium antagonists, but complete normalization of
CO is usually not achieved. In our experience, the
greatest normalization of central hemodynamics was
achieved by the alpha-blocker, prazosin.
During prolonged treatment for 5-6 years, the betablockers prevented a further decrease in SV and a
further increase in TPR, and thus seem to arrest or stop
the changes that could have been expected in untreated
subjects. Prolonged therapy with combined alpha- and
beta-blockade (by the use of labetalol) induced a gradual decrease in TPR and a slight increase in CO at rest
as well as during exercise. Thus, combined alpha- and
beta-blockade might induce more adequate responses
than beta-blockers alone.
This short review discusses only the typical response in patients with mild to moderate essential hypertension. Most of these patients generally seemed to
tolerate the chronic reduction in CO induced by the
beta-blockers surprisingly well, generally with little
restriction in their physical activity. However, in spe-
cial subgroups of patients, the use of a wrong antihypertensive agent may induce inadequate responses:
i.e., a decrease in CI in patients with hypertension and
peripheral vascular disorders. In patients with very
severe therapy-resistant hypertension, converting-enzyme inhibitors are sometimes particularly useful, at
least partly normalizing central hemodynamics
through reduction in TPR.
Finally, it should be emphasized that, although the
responses to antihypertensive agents vary greatly from
a hemodynamic point of view, other effects of the
antihypertensive agents might of course have greater
significance for the clinical outcome. However, at
least when dealing with relatively young patients with
mild to moderate essential hypertension where many
years (perhaps life-long) therapy might be necessary,
restoration of a normal circulatory system would seem
to be the most logical way of treating this condition.
References
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111-57
25. Fagard R, Lijnen P, Amery A: Response of the systemic pulmonary circulation to labetalol at rest and during exercise.
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Discussion
DISCUSSANTS: S. JULIUS
P. LUND-JOHANSEN
MUIESAN
P. SLEIGHT
Are lowering the cardiac output and raising the
vascular resistance necessarily bad? And is lowering
the vascular resistance always good for the body?
For example, if one pools all the blood to the skin
the vascular resistance may be low but the renal
blood flow may be decreased. Tarazi's study suggests that hydralazine causes cardiac hypertrophy in
site of the fact that it lowers the vascular resistance.
LUND-JOHANSEN: My philosophy is that the cardiac
output should be tailored so that it gives a normal
perfusionof the body. So in "healthy" patients with
essential hypertension 1 aim at making things as
normal as possible. Possibly this philosophy is
wrong and it Could even be better to lower the cardiac output and heart rate at rest and during exercise
by, say, 20%. But the pay-off is an increased arteriovenous oxygen difference. Patients with mild to
moderate essential hypertension seem to tolerate
both of these latter features surprisingly well. Finally, this type of treatment has now been in use for 20
JULIUS:
years, but there haven't been any reports of a mysterious hypoperfusion syndrome.
MUIESAN: Which doses of nifedepine and labetalol did
you use?
LUND-JOHANSEN: With nifedepine we started with 20
mg of the long acting form twice daily, raising this
to a maximum total daily dose of 80 mg. With labetalol the initial dose was 100 mg twice daily increasing to 1200 mg maximum.
Could you enlarge on your statement that patients with a reduced cardiac output and a raised
resistance felt surprisingly well.
LUND-JOHANSEN: Some of these subjects certainly felt
dizzy and had "heavy legs" and muscular fatigue
the first two to three weeks of therapy, but thereafter
these sensations disappeared. Most of the subjects
could participate in rather vigorous physical exercise (skiing, mountain hiking) without feeling any
change in their physical working performance.
SLEIGHT:
Hemodynamic response: decrease in cardiac output vs reduction in vascular resistance.
P Lund-Johansen
Hypertension. 1983;5:III49
doi: 10.1161/01.HYP.5.5_Pt_2.III49
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