(Circulation. 1999;99:2396-2401.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of NO Donors on LV Diastolic Function in Patients With Severe Pressure-Overload Hypertrophy
From the Division of Cardiology, University Hospitals Zurich and Bern, Switzerland.
Correspondence to Otto M. Hess, MD, Professor of Cardiology, Swiss Heart Center, University Hospital, CH-3010 Bern, Switzerland. E-mail otto.martin.hess{at}insel.ch
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Abstract |
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Background—Previous experimental studies have shown that nitric oxide (NO) modulates cardiac function by an abbreviation of systolic contraction and an enhancement of diastolic relaxation. However, the response to NO donors of patients with severe pressure-overload hypertrophy and diastolic dysfunction is unknown.
Methods and Results—Intracoronary NO donors were
given to 17 patients with severe aortic stenosis. A
dose-response curve was obtained with nitroglycerin
(30, 90, and 150 µg) in 11 patients and sodium nitroprusside (1, 2,
and 4 µg/min) in 6. Left ventricular (LV) high-fidelity
pressure measurements with simultaneous LV angiograms were
performed at baseline and after the maximal dose of NO. The
dose-response curve for intracoronary NO donors showed a marked
fall in LV end-diastolic pressure, from 23 to 14
mm Hg (-39%; P<0.0001), whereas LV peak
systolic pressure fell only slightly, from 206 to 196
mm Hg (-4%; P<0.01). End-diastolic
chamber stiffness decreased from 0.12 to 0.07 mm Hg/mL
(P<0.0001) and end-systolic stiffness from 1.6
to 1.3 mm Hg/mL (P<0.01). Heart rate, right
atrial pressure, LV ejection fraction, the time constant of isovolumic
pressure decay (
), and LV filling rates remained unchanged.
Conclusions—In patients with severe pressure-overload hypertrophy, intracoronary NO donors exert a marked decrease in LV end-diastolic pressure without affecting LV systolic pump function. Thus, the hypertrophied myocardium appears to be particularly susceptible to NO donors, with a marked improvement in diastolic function.
Key Words: nitric oxide • nitroglycerin • sodium nitroprusside • hypertrophy • diastole
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Nitric oxide (NO) is known to be an important determinant in the control of vascular tone.1 However, its influence as a modulator of myocardial function (reviewed in Reference 22 ) has only recently been appreciated. Smith et al,3 Brutsaert and Andries,4 and Ramaciotti et al5 pioneered the research investigating the role of the endocardial and vascular endothelium to modulate myocardial contraction and relaxation. These and subsequent studies have shown that NO- and/or cGMP-releasing substances increase diastolic cell length, decrease contractility, shorten ejection period, diminish contractile response to ß-adrenergic agonists, and slow heart rate.6 7 8 These findings have been confirmed in the human myocardium, demonstrating a reduction in left ventricular (LV) pressure and an improvement in LV diastolic distensibility after intracoronary administration of NO-releasing compounds in patients with normal LV function9 and in transplant recipients.10 However, the effect of NO donors on LV function in patients with severe pressure-overload hypertrophy and accompanying diastolic dysfunction is still unknown.
Thus, the purpose of the present study was to evaluate the effect of intracoronary NO donors on LV contraction and relaxation in patients with severe aortic stenosis.
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Methods |
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Patient Characteristics
Fifteen men and 2 women (age, 58±10 years) were included in the present analysis. Eleven patients received intracoronary nitroglycerin (NTG) and 6, intracoronary sodium nitroprusside (SNP). All patients underwent diagnostic cardiac catheterization for symptomatic aortic stenosis (NYHA class, 2.2±0.3; mean gradient, 66±17 mm Hg; valve area, 0.7±17 cm2; muscle mass index, 175±64 g/m2). There were no significant differences between patients receiving either NTG or SNP with regard to baseline characteristics. Patients with significant coronary artery disease (>50% diameter stenosis), hypotension (systolic blood pressure <100 mm Hg), moderate to severe congestive heart failure (NYHA class III to IV) or age >75 years were excluded from the present analysis. The study protocol was approved by the local ethics committee, and informed consent was obtained from all patients.
Study Protocol
All vasoactive drugs were withheld for 
24 hours before the
procedure. Right and left heart catheterization was
performed according to our protocol (Figure 1
). Right-sided pressures were measured
by a 6F Cournand catheter introduced from the right femoral vein and
left-sided pressure by a 6F pigtail catheter introduced from the right
femoral artery. Coronary angiography was carried out with
nonionic contrast material (Iopamiro, Iopamidol 300; Sintetica
AG). At the end of diagnostic angiography, an interval of
15 minutes was allowed for dissipation of contrast effects. LV
pressure was measured with a transseptally introduced 3F Millar
catheter (Figure 2). A 6F
coronary artery infusion catheter was placed in the left main
coronary artery for intracoronary drug administration.
Its position was confirmed at the beginning and at the end of the study
by contrast injection. A dose-response curve was obtained for both NTG
(Perlinganit, Schwarz Pharma AG) injections with increasing doses of
30, 90, and 150 µg and for SNP infusions with doses of 1, 2, and 4
µg/min (Nipride, Roche). Simultaneous biplane LV
angiograms in the right and left anterior oblique projections were
performed at baseline and after the maximal dose of the
intracoronary NO donor with 40 to 50 mL of the nonionic
contrast material (injection rate, 12 mL/s). Filming rate was 25 (n=7)
or 50 (n=10) frames per second. The LV angiograms of 3 patients could
not be quantitatively analyzed because of premature
ventricular contractions (2 patients receiving NTG, 1 SNP).
LV volumes were analyzed on a frame-by-frame basis by the
area-length method.11 LV muscle mass was calculated
according to the method of Rackley et al.12
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Data Analysis
LV systolic function was determined from LV
systolic pressure, peak positive dP/dt, LV systolic
volume, and LV ejection fraction. Systolic ejection time was
calculated as the time interval from the beginning of the Q wave in the
standard ECG to end systole, which was defined as the time of pressure
crossover of the LV and aortic pressure curves.
LV diastolic function was estimated from LV
diastolic pressure, peak negative dP/dt, LV
diastolic volume, the time constant of isovolumic pressure
decay (), and early and late peak filling rates. Rate of relaxation
was calculated from the linear relationship between LV pressure and
negative dP/dt by use of a shifting asymptote13 :
P=P0 ·
e-t/T+PB, where
P=LV pressure (mm Hg), P0=pressure at the time
of peak negative dP/dt, t=time after peak negative dP/dt (ms), T=time
constant of isovolumic pressure decay (ms), and
PB=pressure asymptote. LV
diastolic filling was measured from instantaneous LV
volumes. Early peak filling rate (mL/s) was determined during the first
half of diastole and late peak filling rate during the
second half. Passive-elastic properties were determined from the
diastolic pressure-volume (Figure 3) and stress-strain relationships by use
of an elastic model with shifting asymptote: P=a* ·
ebV+c* and S=a ·
eß
+c, where P=LV pressure
(mm Hg), a*=elastic constant (mm Hg), b=constant of chamber
stiffness, V=LV volume (mL), c*=pressure asymptote (mm Hg),
S=LV midwall circumferential wall stress
(kdyne/cm2), a=elastic constant
(kdyne/cm2), ß=constant of myocardial
stiffness, =La Grangian strain, and c=stress asymptote
(kdyne/cm2). End-diastolic and
end-systolic chamber stiffness was calculated from the
instantaneous pressure-volume relationship at end diastole
and end systole: End-diastolic CS=LVEDP/EDV and
end-systolic CS=LVESP/ESV, where CS=chamber stiffness, LVEDP=LV
end-diastolic and LVESP=end-systolic pressure
(mm Hg), and EDV=end-diastolic and
ESV=end-systolic volume (mL). The chamber stiffness constant b
was derived from the exponential curve fit to the diastolic
portion of the LV pressure-volume relation.14 The
myocardial stiffness constant ß was calculated from the curve fit to
the diastolic portion of the stress-strain
relation.14
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Statistics
Hemodynamic and angiographic data at baseline
and after intracoronary NO donors were compared by a paired
Student's t test. Intragroup comparisons of the
dose-response curve were carried out by a 2-way ANOVA for repeated
measurements. Results are reported as mean±SD.
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Results |
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LV Pressure Response to Intracoronary NO Donors
A representative pressure recording before and after intracoronary administration of NTG is shown in Figure 2
. The dose-response curve (Figure 4) revealed a marked decrease of LV
end-diastolic pressure with increasing doses of
intracoronary NO donors (maximally -39% of baseline,
P<0.0001). LV peak systolic pressure fell slightly
but significantly (-4% of baseline, P<0.01).
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P<0.05,
P<0.01, *P<0.001,
**P<0.0001 vs baseline.
LV Systolic Parameters
In addition to the fall in LV end-diastolic and
peak-systolic pressure, there was a decrease in LV
end-systolic pressure (P<0.0001) and in peak
ejection rate (P<0.05) after NO administration (Table 1).
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Heart rate, right atrial pressure, LV ejection time, peak positive dP/dt, LV developed systolic pressure, LV end-diastolic volume, LV ejection fraction, and early and late peak filling rates remained unchanged after the NO donor.
LV Diastolic Function Parameters
Peak negative dP/dt decreased in parallel to the reduction in LV
peak systolic pressure after intracoronary
administration of the NO donor (Table 2).
LV end-systolic chamber stiffness decreased slightly
(P<0.01), whereas end-diastolic chamber
stiffness decreased markedly (P<0.0001) after the NO donor.
There was also a significant reduction in end-diastolic
wall stress (P<0.01) and the stress asymptote c
(P<0.05) after the NO donor. The time constant of LV
pressure decay (), end-systolic wall stress, and LV chamber
and myocardial stiffness remained unaffected, whereas the pressure
asymptote c* of the diastolic pressure-volume
relation decreased slightly. However, there was a downward shift of the
LV diastolic pressure-volume curve in 7 of 17 patients
(Figure 3). Furthermore, there was a significant correlation
between LV end-diastolic pressure and pressure
asymptote c* (r=0.593; P<0.026) or
stress asymptote c (r=0.637;
P<0.015).
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The nitrovasodilators NTG and SNP are known to differ in their
biotransformation of NO and the magnitude of their effects on preload
and afterload after systemic administration.15 The use of
intracoronary NTG and intracoronary SNP allowed the
exclusion of such differences (Table 3).
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Discussion |
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Diastolic dysfunction is a common finding in patients with severe aortic stenosis.16 Its pathogenesis is manifold but can be explained by severe LV hypertrophy with a reduced Ca2+ reuptake into the sarcoplasmic reticulum, resulting in a defective excitation-contraction coupling; by elevated angiotensin II levels; or by a reduced capillary density and/or an increased collagen content.17 18 19 20 21
Therapeutic approaches have been used to reduce LV diastolic filling pressure (dyspnea on exertion) and to improve subendocardial perfusion (angina pectoris) to ameliorate clinical symptoms and ultimately diastolic dysfunction. In severe aortic stenosis, valve replacement is the therapy of choice.22 Nevertheless, aortic valve obstruction with moderate to severe LV hypertrophy may profit from therapy that is able to improve LV diastolic function.
The major findings of the present study were (1) that intracoronary NO donors improve diastolic function in patients with severe pressure-overload hypertrophy, with a decrease in LVEDP and a reduction in LV end-diastolic chamber stiffness and (2) that the hypertrophied myocardium seems to be particularly susceptible to NO donors, with a marked improvement in diastolic function.
Pathophysiological Mechanisms
Recent reports have underlined the role of NO as a modulator of
cardiac function.2 In isolated cardiomyocytes
and papillary muscles, NO- and cGMP-releasing substances are associated
with a decrease in systolic cell length and an improvement in
diastolic relaxation.3 23 This has been
attributed to either a desensitization of myofilaments to
Ca2+,6 reaction of NO with oxygen
radicals to form toxic peroxynitrites,24 or binding of NO
to the iron-containing proteins, such as those in the respiratory chain
of the mitochondria.25 26
Similar data have been obtained in Langendorf preparations7 and animal models27 after administration of NO-releasing compounds, revealing a decrease in systolic contraction and an improvement in diastolic relaxation. Complementary results were reported by Paulus and coworkers after bicoronary administration of SNP in healthy patients9 or infusion of substance P in transplant recipients,10 with a decrease in LV filling pressure and an increase in LV distensibility.
Effect of NO Donors in LV Hypertrophy
In contrast to the previous findings of Paulus et
al,9 NO donors led to a pronounced decrease in LV
end-diastolic pressure but had no effect on LV
systolic pump function.
Similar observations have been reported with the use of intracoronary ACE inhibitors in patients with pressure-overload LV hypertrophy.28 A decrease in LV filling pressure with an improvement in regional LV relaxation was found after intracoronary enalapril. These effects may be in part NO-mediated by the reduced degradation of bradykinin.29 Other studies have shown a link between ACE inhibition and NO effects under in vitro30 and in vivo conditions.31 Thus, NO may contribute to the beneficial effects of ACE inhibitors with regard to LV diastolic function. However, the physiological relevance of NO in this setting remains speculative.
It must be pointed out that in our patients with pressure-overload
hypertrophy, administration of intracoronary NO
decreased LV filling pressures without affecting LV volumes. This
combination suggests a parallel downward shift of the LV
pressure-volume relation (Figure 3), which was seen in nearly
half of our patients and which implies a change in LV distensibility.
This trend was supported by a decrease in LV end-diastolic
chamber stiffness, 
P/V. However, the chamber and myocardial
stiffness constant b or ß did not show a significant change after NO
donors. This apparent contradiction can be explained by the fact that
there was a parallel downward shift of the pressure-volume relation
without a change in slope (resulting in an unchanged b or ß), whereas
the pressure asymptote c* decreased slightly and the stress
asymptote c significantly (Table 3). Furthermore, there
was a significant correlation between LV end-diastolic
pressure and the pressure asymptote c* or stress
asymptote c. Taken together, these findings support the concept
of a downward shift of the diastolic pressure-volume curve
in response to intracoronary NO donors, which was also observed
by Paulus et al.9
LV end-diastolic pressure is known to be influenced by external forces, such as the pericardium and right ventricular filling pressure.32 33 Thus, biventricular interaction may account for the parallel decrease of both right ventricular and LV filling pressures in the context of pure preload reduction.34 However, to avoid systemic effects, NO donors were administered by the intracoronary route, and the fall in LV end-diastolic pressure was not achieved by a change in right atrial pressure, suggesting a direct effect of NO on the myocardium.
There were minor changes in LV systolic function after NO donors. A decrease in peak systolic pressure and peak ejection rate would ordinarily suggest a decline in contractility. However, developed pressure and LV ejection fraction remained stable, indicating no change in LV contractile state. Accordingly, a decline in peak ejection rate associated with a decrease in end-diastolic wall stress and stable end-diastolic volume may be caused by an effect via the Frank-Starling mechanism.
Role of NO in LV Hypertrophy
Why does the hypertrophied myocardium differ from the
normal myocardium in its response to NO donors? Is
constitutive NO synthase (NOS) activity impaired in the hypertrophied
myocardium compared with the normal heart, or are some of
the downstream signals of NO altered in LV hypertrophy?
Two recent reports from animal models of pressure-overload hypertrophy may provide some explanations. The authors administered SNP to isolated rat cardiomyocytes35 and demonstrated a decrease in systolic contraction and an increase in diastolic cell length in normal but not in hypertrophied myocytes. These findings were explained by a blunting of the downstream signaling effect of cGMP on the sodium proton exchange. In normal cardiomyocytes, this leads to an increase in contraction, whereas this response is impaired in hypertrophied cardiomyocytes.
In a canine model of pressure-overload hypertrophy, basal
and stimulated myocardial cGMP levels after the NO donor
morpholinosynonimine were higher in LV hypertrophy than in
controls.29 However, the NOS inhibitor
N
-nitro-L-arginine
methyl ester had no effect on cGMP levels in either group. It is of
interest that LV mechanics remained unaffected after the NO donor in
the group with hypertrophy, whereas it changed in the
control group. These findings suggest that animals with
hypertrophy have increased myocardial cGMP levels that are
independent of NOS activity.
No data on myocardial NOS activity in pressure-overload hypertrophy in humans are available. The levels of constitutive NOS levels could not be determined because no myocardial biopsies were performed in the present study.
Taken together, the data derived from the animal experiments support our findings, which showed no effect of NO donors on contraction or relaxation in patients with severe pressure-overload hypertrophy. They suggest that the downstream targets of NO in the hypertrophic myocardium may be less responsive to NO than the normal one.
Clinical Implications
Our data show that NO donors improve diastolic
function in patients with severe LV hypertrophy. LVEDP
dropped by 39% after small intracoronary doses of NO donors,
whereas systolic pump function remained unchanged. In contrast,
Paulus and coworkers9 reported a 21% decrease in baseline
peak LVEDP after 4 µg/min SNP in patients without cardiac disease.
Because the hypertrophied myocardium is associated with a
high incidence of LV diastolic dysfunction,16
NO donors may be particularly suitable for decreasing elevated
diastolic filling pressures. Thus, nitrovasodilators may be
able to reduce lung congestion and dyspnea on exertion on a short-term
basis. Their long-term effect remains to be determined.
Study Limitations
1. SNP and NTG were used as NO donors for the purpose of the
present study. These substances differ in their biotransformation
of NO. NTG requires the presence of S-thiol enzymes, whereas
SNP liberates NO spontaneously.15 It is known that
nitrovasodilators do not accurately mimic endothelial
or myocardial NO release. However, these compounds are widely used in
clinical application for acute and chronic treatment of
coronary and valvular heart disease.
2. Single coronary administration of the NO donors was used instead of bicoronary infusions. This may have led to an underestimation of the NO donor effect, but systemic side effects may have been minimized.
3. A control group of patients with administration of vehicle was not included. A previous collaborative study from our laboratory showed no effect on diastolic function with the intracoronary infusion of vehicle (normal saline) and repeated angiography in patients with severe aortic stenosis.28
Conclusions
The present study shows that administration of small
intracoronary doses of NO donors leads to a marked decrease in
LV filling pressure, suggesting that the hypertrophied
myocardium appears to be particularly susceptible for
exogenously administered NO donors. This may be explained by either a
reduced production or release of NO by the
endothelium in the hypertrophied
myocardium.
In contrast to previous studies in healthy volunteers, the hypertrophied ventricle shows no effect of intracoronary NO donors on LV contraction and relaxation. This effect may be explained by a blunting of the downstream signaling effects of cGMP in the hypertrophied cardiomyocytes due to an increased constitutive NOS activity35 and/or increased guanylate cyclase activity.29
Received October 16, 1998; revision received February 3, 1999; accepted February 16, 1999.
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J. G. F. Bronzwaer, C. Heymes, C. A. Visser, and W. J. Paulus Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H10 - H16. [Abstract] [Full Text] [PDF]
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 S. Mak, E. R. Azevedo, P. P. Liu, and G. E. Newton Effect of Hyperoxia on Left Ventricular Function and Filling Pressures in Patients With and Without Congestive Heart Failure Chest, August 1, 2001; 120(2): 467 - 473. [Abstract] [Full Text] [PDF]
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S. M Bryant, C. E Sears, L. Rigg, D. A Terrar, and B. Casadei Nitric oxide does not modulate the hyperpolarization-activated current, If, in ventricular myocytes from spontaneously hypertensive rats Cardiovasc Res, July 1, 2001; 51(1): 51 - 58. [Abstract] [Full Text] [PDF]
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 W. Grossman Defining Diastolic Dysfunction Circulation, May 2, 2000; 101(17): 2020 - 2021. [Full Text] [PDF]
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L. Mandinov, F. R. Eberli, C. Seiler, and O. M. Hess Diastolic heart failure Cardiovasc Res, March 1, 2000; 45(4): 813 - 825. [Abstract] [Full Text] [PDF]
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