Relation of Systemic Sympathetic
Nervous System Activation to
Echocardiographic Left Ventricular Size
and Performance and Its Implications in
Patients With Mitral Regurgitation
Rajendra H. Mehta, MD, Mark A. Supiano, MD, Hakan Oral, MD,
P. Michael Grossman, MD, Janet A. Petrusha, RN, Daniel G. Montgomery,
Kerri A. Briesmiester, BS, Marla J. Smith, BS, and Mark R. Starling, MD
We have previously demonstrated that the systemic
sympathetic nervous system (SNS) is activated in pro-
portion to an increase in cineventriculographic left ven-
tricular (LV) end-systolic volume and decrease in ejection
fraction (EF) in patients with chronic mitral regurgitation
(MR). However, the relation between noninvasive echo-
cardiographic measures of LV size and performance and
systemic SNS activation and their clinical implications in
patients with MR is not known. We studied 17 MR
patients with echocardiography, arterial norepinephrine
(NE) sampling, and [3H]-NE infusions and arterial blood
sampling to determine NE kinetic parameters using a
2-compartment analysis, including extravascular NE re-
lease rates (NE2, index of SNS activity) and the meta-
bolic clearance rate from the vascular compartment. The
arterial NE values correlated with LV end-systolic dimen-
sions (r 5 0.50, p 5 0.04), but not with LV end-diastolic
B oth cineventriculographic and 2-dimensional
echocardiographic left ventricular (LV) size and
performance have been shown to correlate with post-
operative LV dysfunction and poor outcome after
mitral valve repair or replacement in patients with
chronic mitral regurgitation (MR).1– 6 The systemic
sympathetic nervous system (SNS) is one of the many
neurohormonal mechanisms postulated to contribute
to postoperative LV contractile dysfunction and poor
outcome after mitral valve surgery in patients with
MR. Noninvasive methods, such as echocardiography,
have not been previously used to determine whether
simple echocardiographic correlates of SNS activity
exist. This is an important observation, since recent
data suggest that an echocardiographic LV end-sys-
tolic dimension of $40 mm can identify early, occult
From The University of Michigan and Veterans Affairs Medical Cen-
ters, Ann Arbor, Michigan. This study was supported by Grant NIH
RO1-HL36450 from the National Heart, Lung, and Blood Institute,
and Grant MM-RR00042 from the Kughn Clinical Research Center,
National Institutes of Health, Bethesda, Maryland, and by Veterans
Affairs, Washington, DC. Manuscript received March 3, 2000; re-
vised manuscript received and accepted June 1, 2000.
Address for reprints: Mark R. Starling, MD, Cardiology, 7E 111A,
2215 Fuller Road, Ann Arbor, Michigan 48105. E-mail: mrstar@
umich.edu.
©2000 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 86 December 1, 2000
BS,
dimensions, and EF or fractional shortening measures.
The NE2 values correlated with LV end-systolic dimen-
sions (r 5 0.53, p 5 0.03) and inversely with LVEF (r 5
20.45, p 5 0.07) and fractional shortening (r 5 0.43,
p 5 0.08) measures, but not with LV end-diastolic di-
mensions. The metabolic clearance rate values showed
an inverse correlation with LV end-diastolic (r 5 20.52,
p 5 0.03) and end-systolic (r 5 20.49, p 5 0.04)
dimensions, but not with LV performance measures. The
increase in NE2 values was progressive as the LV end-
systolic dimensions increased and more marked at LV
end-systolic dimensions >40 mm. Thus, activation of the
SNS is related to an increase in echocardiographic LV
end-systolic dimensions and a decrease in LV perfor-
mance measures in chronic MR. Q2000 by Excerpta
Medica, Inc.
(Am J Cardiol 2000;86:1193–1197)
LV contractile impairment and predict the LV size and
performance response to mitral valve surgery in pa-
tients with MR.7 Whether echocardiographic parame-
ters of LV size and performance can identify systemic
SNS activation and provide a link to LV contractile
impairment is not known. The present study was un-
dertaken to test the hypothesis that activation of the
systemic SNS could be identified by simple 2-dimen-
sional echocardiographic measures of LV size and
performance.
METHODS
Patient selection: The study group consisted of 17
patients (14 men and 3 women, aged from 34 to 76
years, mean 54 6 12) referred to the University of
Michigan or Veterans Affairs Medical Centers for an
assessment of the severity of their chronic MR, who
had a high-quality 2-dimensional transthoracic echo-
cardiogram at our institutions targeted for the assess-
ment of LV size and performance. The cineventricu-
lographic data from these subjects have been reported
in a preliminary fashion elsewhere.8,9 A patient was
excluded from the study if he/she had coronary artery
disease, atrial fibrillation, significant aortic valve dis-
ease, or concomitant mitral stenosis. Seven patients
were in New York Heart Association functional class
0002-9149/00/$–see front matter 1193
PII S0002-9149(00)01201-7
I, 7 were in functional class II, and the remaining 3
TABLE 1 Relation of Arterial NE to Echocardiographic
patients were in functional class III. At the time of Parameters
cardiac catheterization, medical treatment included:
an angiotensin-converting enzyme inhibitor in 7 pa- Echocardiographic
Parameters Correlation (r) p Value
tients, a diuretic in 2 patients, a b-adrenergic blocking
agent in 3 patients, and a nitrate or digoxin in 1 patient Arterial NE (pg/ml)
each. The b-adrenergic blocking agents, diuretics, LVEDD (mm) 0.33 0.18
LVESD (mm) 0.50 0.04
digoxin, and angiotensin-converting enzyme inhibi- LVFS (%) 20.28 0.27
tors, were all discontinued at least 24 to 48 hours, LVEF (%) 20.23 0.38
whereas the nitrate was discontinued at least 12 hours
EDD 5 end-diastolic diameter; ESD 5 end-systolic diameter; FS 5 fractional
before the investigative study. All patients provided shortening.
written informed consent on forms previously ap-
proved by the institutional review boards at the Uni-
versity of Michigan or Veterans Affairs Medical Cen-
ters, Ann Arbor, Michigan. TABLE 2 Relation of NE Kinetic Parameters to
Study design: A 2-dimensionally targeted echocar- Echocardiographic Parameters
diogram was recorded to measure LV chamber dimen- Echocardiographic
sions and calculate LV ejection fraction (EF) and Parameters Correlation (r) p Value
fractional shortening. SNS activity was then assessed 2
NE2 (mg/min/m )
using a 3H-norepinephrine ([3H]-NE) infusion with LVEDD (mm) 0.25 0.34
multiple arterial blood samples to provide data for a LVESD (mm) 0.53 0.03
2-compartment modeling analysis of NE kinetics.10 LVFS (%) 20.46 0.07
Echocardiography: Echocardiography was per- LVEF (%) 20.45 0.07
formed in multiple orthogonal 2-dimensional imaging MCR1 (liters/min/m2)
planes, and M-mode and Doppler (conventional and LVEDD (mm) 20.52 0.03
LVESD (mm) 20.49 0.05
color Doppler) examinations were performed after LVFS (%) 0.07 0.80
first having a reference from the 2-dimensional im- LVEF (%) 0.05 0.83
ages. LV wall thickness (interventricular septum and NESF (mg/min/m2)
posterior wall) and end-diastolic and end-systolic di- LVEDD (mm) 20.18 0.50
mensions were measured on-line using standard crite- LVESD (mm) 20.46 0.07
ria established by the American Society of Echocar- LVFS (%) 0.38 0.13
diography.11 Fractional shortening of the left ventricle LVEF (%) 0.46 0.07
(%) was calculated as the difference in LV end-dia- R21 (mg/min/m2)
stolic and end-systolic diameter 4 by end-diastolic LVEDD (mm) 0.09 0.72
LVESD (mm) 0.23 0.36
diameter 3 100. EF was calculated on-line by a pack- LVFS (%) 20.23 0.36
age available on all standard echocardiographic equip- LVEF (%) 20.20 0.45
ment that uses LV volumes. This involved tracing of
MCR1 5 metabolic clearance rate; NESF 5 NE spillover fraction from
LV endocardial borders at end-diastole and end-sys- compartment 2 to 1; R21 5 the rates of NE appearance into compartment 1;
tole in the apical 4- and 2-chamber views to calculate other abbreviations as in Table 1.
LV end-diastolic and end-systolic volumes, respec-
tively. Then, EFs were calculated as the difference
between LV end-diastolic and end-systolic volume 4
by end-diastolic volume 3 100. LV mass index was obtained from the 10- and 20-minute decay time
calculated using the Schiller method.12 All measure- points. Chilled plastic tubes containing ethylenedia-
ments were averaged over 5 cardiac cycles. minetetraacetic acid and glutathione were used to col-
Sympathetic nervous system activity: The protocol lect the arterial blood samples, which were then stored
adapted for this analysis was based on our previously on ice. Plasma was obtained by centrifuging the blood
published procedures.10,13–19 The protocol consisted samples at 4°C. These samples were then stored at
of an intravenous infusion of [3H]-NE, approximate –70°C until the assays were performed. Arterial NE
specific activity 18.8 Ci/mmol (New England Nuclear; was determined by a single isotope derivative radioen-
Boston, Massachusetts), calculated to deliver 0.35 zymatic assay.19 Each subject’s samples were mea-
mCi/min/m2 at a rate of 0.2 ml/min using an infusion sured in the same assay. The intra-assay coefficient of
pump. Ascorbic acid (1 mg/ml) was added to the variation for this measurement in our laboratory is 5%
infusion to prevent the oxidation of NE. The infusion for NE. Then, [3H]-NE concentrations were deter-
was given for 1 hour to achieve a steady-state level of mined following alumina extraction of plasma (recov-
[3H]-NE. Arterial blood samples were taken from the ery approximately 60%) within 24 hours of the study.
LV catheter at 40, 50, and 60 minutes during the Liquid scintillation counting of the radiolabeled cate-
infusion to determine arterial NE and [3H]-NE con- cholamine was subsequently performed to determine
centrations. The infusion was stopped at 1 hour, and [3H]-NE concentration.
additional arterial blood samples were collected at 1, The systemic NE kinetic parameters were derived
2, 4, 6, 8, 10, 14, 16, 18, and 20 minutes to measure using a 2-compartment model developed by Linares
[3H]-NE concentrations. Arterial NE levels were also and colleagues.10 This involved determining simulta-

1194 THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 86 DECEMBER 1, 2000

 index of systemic SNS activity in our pa-
tients with MR.
Statistical analysis: The values are pre-
sented as mean 6 1 SD. Pearson correlation
matrixes were used to establish univariate
correlations in our patients with MR between
arterial NE levels and NE kinetic parameters
and LV end-diastolic and end-systolic diam-
eters, fractional shortenings, EFs, and masses.
A p value ,0.05 was required to indicate a
significant relation.

RESULTS
[3H]-NE kinetic data: The mean arterial NE
value in these patients with MR was 278 6
75 pg/ml. The NE kinetic parameters in these
patients were as follows: the average NE2
was 2.04 6 0.61 mg/min/m2; NE spillover
fraction was 13% 6 2%; the metabolic clear-
ance rate from compartment 1 was 0.95 6 11
L/min/m2; the rate of appearance of NE into
FIGURE 1. Relation between arterial NE and echocardiographically mea-
compartment 1 was 0.29 6 0.09 mg/min/m2;
sured LV end-systolic diameter (ESD). and the volume of distribution of NE in
compartment 1 was 2.77 6 1.44 L/m2. There
was a relation between the arterial NE and
neous fits of the tracee (arterial NE) and tracer ([3H]- NE2 values (r 5 0.78, p ,0.001), but not between the
NE) systems by the method of weighted nonlinear values for NE and the metabolic clearance rates from
least squares.20,21 In this 2-compartment model, com- compartment 1 (r 5 20.14, p 5 0 .56) in these
partment 1 represents the vascular compartment, and patients.
is therefore accessible to sampling. On the other hand, Echocardiographic data: The echocardiographic
compartment 2 represents the extravascular compart- mean LV dimensions were as follows: LV end-dia-
ment into which NE is released from nerve terminals stolic diameter, 57 6 9 mm; LV end-systolic diame-
and exchanges with the vascular compartment, and is ter, 39 6 5 mm; LV fractional shortening, 32% 6 5%;
therefore not accessible for sampling. The NE kinetic LVEF, 58% 6 8%. All of these patients with MR had
parameters estimated by this model included: the rates an EF of $50%. LV mass index was increased in
of NE appearance into compartment 1 (mg/min/m2) these patients to an average of 157 6 57 g/m2.
and into compartment 2 (NE2, mg/min/m2); the met- Relation between echocardiographic data and arte-
abolic clearance rate from compartment 1 (L/min/m2); rial NE and NE kinetic parameters (Tables 1 and 2): The
the NE spillover fraction from compartment 2 to 1 arterial NE levels showed a positive relation to LV
(%); and the volume of distribution of NE in compart- end-systolic diameters (r 5 0.50, p 5 0.04, Figure 1),
ment 1 (L/m2).10 The values for NE2 were used as our but not to LV end-diastolic diameters (r 5 0. 34, p 5

FIGURE 2. Relation between the extravascular NE release rates (NE2) and various echocardiographic parameters is shown. Note the
direct relation between NE2 and end-systolic diameter (ESD, left panel), suggesting that as ESD increases, there is a progressive in-
crease in NE2, our index of SNS activity. Note also the weak but inverse relation between NE2 and LV fractional shortening (FS) (mid-
dle panel) and EF (right panel), suggesting that as FS and EF decreases, there is a progressive increase in NE2, our marker of SNS
activity.

VALVULAR HEART DISEASE/SYMPATHETIC NERVOUS SYSTEM ACTIVATION IN MR 1195

FIGURE 3. Relation between the metabolic clearance rate of norepinephrine (MCR1) and echocardiographically measured LV end-
diastolic diameter (EDD, left panel) and LV end-systolic diameter (ESD, right panel) is shown.
0.18), LV fractional shortenings (r 5 20.28, p 5
0.27), or LVEF (r 5 20.23, p 5 0.38) (Table 1). The
NE2 values showed a positive relation to LV end-
systolic diameters (r 5 0.53, p 5 0.03), a weak
inverse relation to LV fractional shortenings (r 5
20.45, p 5 0.07) and LVEF (r 5 20.46, p 5 0.07),
but not to LV end-diastolic diameters (r 5 0.25, p 5
0.34) (Table 2, Figure 2).
The metabolic clearance rates from compartment 1
showed an inverse relation to LV end-diastolic diam-
eters (r 5 20.52, p 5 0.03, Figure 3) and end-systolic
diameters (r 5 20.49, p 5 0.05, Figure 3), but not to
LV fractional shortenings (r 5 0.07, p 5 0.80) or
LVEF (r 5 0.05, p 5 0.83) (Table 2).
The NE spillover fractions from compartment 2 to
1 showed a weak inverse relation to LV end-systolic
diameters (r 5 20.46, p 5 0.07) and a weak direct
relation to LVEF (0.46, p 5 0.07). The NE spillover
fractions from compartment 2 to 1 values did not
correlate with either LV end-diastolic dimensions (r 5
20.18, p 5 0.50) or fractional shortenings (r 5 0.38,
p 5 0.13) (Table 2).
Finally, the rates of NE appearance into compart-
ment 1 showed no significant relation to any measure
of LV size or performance (Table 2).
DISCUSSION
Our study documents that the systemic SNS is
activated in patients with chronic MR. Further, this
activation of the systemic SNS occurs early in the
disease process and is progressive as manifest by
increased NE release rates into the extravascular com-
partment (NE2) as echocardiographic LV end-systolic
diameters increase. Our study also demonstrates that
there is an inverse relation, although weak, between
the NE2 values and LV fractional shortenings and EF,
to the extent that there appears to be progressive
activation of the systemic SNS as LV systolic perfor-
mance declines. These data are similar to our prior
1196 THE AMERICAN JOURNAL OF CARDIOLOGYT
preliminary study using cineventriculography where
systemic SNS activation was shown to be proportional
to an increase in LV end-systolic volumes and reduc-
tion in EF.8 Thus, this study suggests that a simple
noninvasive echocardiographic measure of LV end-
systolic diameter and performance can be linked to the
degree of systemic SNS activity. Although this finding
is similar to that seen in patients with heart fail-
ure,22–25 activation of the SNS seems to occur at much
smaller LV end-systolic diameters and at relatively
preserved performance measures in patients with MR.
Although the mean LV end-systolic diameter was
39 6 5 mm and EF was 58 6 8% (LVEF .50% in all
patients), the mean NE2 values were elevated beyond
the average value previously reported in control sub-
jects.9,14
The metabolic clearance rates of NE from com-
partment 1 were shown to be inversely related to both
LV end-diastolic and end-systolic diameters, suggest-
ing that a decrease in clearance of NE from the vas-
cular space occurs as LV dimensions increase. A
similar inverse relation was demonstrated with NE
spillover fractions from compartment 2 to 1 and LV
end-systolic dimensions. These data collectively sug-
gest that there is a decrease in NE clearance from the
vascular space and an enhanced clearance of NE from
the extravascular space as the echocardiographic LV
dimensions increase and performance declines. Fur-
ther, these relations provide an explanation for the
lack of a significant relation between the rates of NE
appearance into compartment 1 and echocardio-
graphic measures of LV size or performance (i.e.,
although NE2 increases as LV end-systolic diameter
increases and LV fraction shortening and EF decline,
the rates of NE appearance into compartment 1 do not
demonstrate parallel changes due to the concurrent
decline in NE spillover fractions from compartment 2
to 1). This suggests the possibility that NE uptake
VOL. 86 DECEMBER 1, 2000
mechanisms are altered in chronic MR, in addition to
the decrease in the metabolic clearance rates from
compartment 1.
Can a measure of SNS activity be used to help
identify patients with early LV intrinsic contractile
dysfunction in the presence of preserved, commonly
used indexes of LV function such as EF? Unfortu-
nately, simple measures of SNS activity such as arte-
rial NE levels are not significantly different in patients
with MR compared with control subjects, limiting the
utility of measuring arterial NE levels.9 Although NE2
levels have been shown to be significantly higher in
patients with MR than in control subjects for any
given LV end-systolic volume,9 NE2 estimation re-
quires a prolonged and complex infusion protocol.12
Moreover, these higher extravascular secretion rates
are mitigated by the reduced NE spillover and through
either heightened metabolism or reuptake of NE into
the nerve terminal in the extravascular space. There-
fore, its clinical use, especially as a method of follow-
ing patients with MR over time, may be limited. The
finding in this study that SNS activity correlates with
a progressive increment in LV end-systolic diameter
provides support for the use of this simple noninvasive
index for identifying patients with SNS activation who
may benefit from early surgical intervention.
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