From the Division of Cardiovascular Diseases, Section of Medical Research
Statistics, Division of Cardiothoracic Surgery, Division of Endocrinology,
Mayo Clinic, Rochester, Minn.
Correspondence to Raymond J. Gibbons, MD, 200 First St SW, Rochester, MN 55905.
Methods and Results—Patients evaluated in our cardiac
transplantation clinic between April 1988 and July 1995 were
retrospectively reviewed (n=263). Fifty-two patients were excluded
because they had recent trauma, infection, surgery, myocardial
infarction, corticosteroid use, or history of
malignancy. In the remaining 211 patients, we used Cox proportional
hazards analysis to examine the association between survival
and transplant-free survival with baseline variables.
Univariate analysis showed a significant
association between time to death and %L (P=.004), New
York Heart Association (NYHA) class (P=.002), and
maximal oxygen uptake (P=.05). Univariate
analysis of the end point of survival free from transplantation
yielded similar results. One- and 4-year survival rates for patients
with a low %L (<20.3%) were 78% and 34% compared with 90% and
73% for those with a normal %L. Multivariate
analysis showed NYHA class (P<.008) and %L
(P<.01) were independent predictors of survival and
survival free from cardiac transplantation.
Conclusions The relative lymphocyte concentration is an
inexpensive, readily available, simple prognostic marker in patients
with symptomatic heart failure who do not have recent
trauma, infection, surgery, myocardial infarction,
corticosteroid use, or history of malignancy. It could
be incorporated into clinical models to predict patient outcome and to
aid in the selection of patients for cardiac transplantation.
Elevation of the plasma norepinephrine level may reflect
activation of the sympathetic nervous system in response to systemic
stress. The stress response is also manifest by an elevation of serum
cortisol. Unfortunately, the pharmacodynamics and circadian variation
in the release of cortisol limit its use in the clinical
setting.14 Cortisol results in a known shift in
the leukocyte differential to a lower percentage of
lymphocytes.15 16 This effect can be viewed as a
time-based integral of the cortisol level. Automated differential
analysis, sampling thousands of cells, has greatly improved the
accuracy of the leukocyte differential count.17
We have previously reported on the prognostic utility of the relative
lymphocyte concentration in patients with acute and chronic
coronary artery disease.18 19 20 The
purpose of the present study was to determine whether the relative
lymphocyte concentration was related to outcome in patients with
symptomatic heart failure referred for evaluation of
possible transplantation.
Leukocyte Differential Count
Follow-up
Statistical Analysis
Overall Outcome
Univariate Analysis
Analysis with respect to the end point of time to death
or transplantation yielded similar results. NYHA class
(P=.003), relative lymphocyte concentration
(P=.01), and history of smoking (P=.005) were the
only variables significantly related to the combined end point.
(Current smokers were not offered transplantation, thus decreasing the
number of end points).
Multivariate Analysis
The reduction in the %L, a marker of the stress response and a
possible marker for mortality, is based on well-recognized principles.
Physiological stress results in a marked increase
in systemic cortisol production.14 22
However, the physiological diurnal variation in
plasma cortisol levels, their short half-life, and their pulsatile
pattern of secretion render these levels difficult to use in a clinical
setting.14 Increased cortisol levels result in a
decrease in the relative concentration of
lymphocytes.15 16 Because the adrenal axis is a
sensitive feedback system for adverse physiological
conditions, changes in the %L may be a simple, early marker of
neurohumoral activation. In fact, this test has already been shown to
be an early indicator of acute myocardial infarction and a prognostic
marker for patients with chronic, clinically stable coronary
artery disease, presumably by these
mechanisms.18 19 20
The clinical applicability of this phenomenon was not possible until
the development of the automated differential analyzer, which
has overcome the inherent inaccuracy of the traditional manual
differential analysis by using sample sizes of 1000 to 3000
cells.17 These analyzers are commercially
available and are found in most modern hematology laboratories.
The concept of neurohumoral activation in heart failure is the center
of much attention.5 6 10 13 23 24 25 Increased
levels of circulating catecholamines,
natriuretic peptides, endothelins, and activation of the
renin-angiotensin system are the
pathophysiological correlates of the systemic
response to the failing heart.26 The effects of
all these markers in the hypothalamic-pituitary-adrenal axis have been
described.27 Although the interactions between
the various systems are complex, it is clear that the initial response
to stress includes increased levels of catecholamines and
corticosteroids, probably in response to increases in
corticotropin-releasing hormone.28 Cortisol
results in increased responses to catecholamines, decreased
sympathetic and adrenomedullary outflow, and decreased postsynaptic
uptake of norepinephrine. Catecholamines,
acting primarily by central mechanisms, increase the activity of
adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone.
Vasopressin, angiotensin II, atrial natriuretic
peptide, and endothelin have been implicated as effectors in the
hypothalamic-pituitary-adrenal axis via enhanced ACTH
secretion.29
The relative lymphocyte concentration provides an "assay" for
activation of the hypothalamic-pituitary-adrenal axis. A surprisingly
large percentage (33%) of our patients had abnormal values of the
relative lymphocyte concentration at baseline. This assay is readily
available and inexpensive. Because most patients have a complete blood
count determination as part of their evaluation, the leukocyte
differential and its potential prognostic information adds no extra
cost to the evaluation.
The present study is limited by the fact that we did not measure
cortisol to confirm its elevation in association with a reduction of
the relative lymphocyte count. Determination of serum cortisol would
have to be performed under strictly controlled conditions. Additional
studies are needed to confirm the association between increased levels
of the other neurohormones and the reduction in the relative lymphocyte
concentration.
Because the patient population in the present study was largely
male (159 males, 52 females), we cannot make inferences regarding sex
specificity or generalization of the results to women.
The present study found the relative lymphocyte concentration to be
independently associated with survival in patients with advanced heart
failure. Because this test is widely available and inexpensive, it can
serve as a screening marker for patients with a worse prognosis. It may
help to select patients for more aggressive interventions such as
cardiac transplantation.
Received July 1, 1997;
revision received October 29, 1997;
accepted October 31, 1997.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Predictive Power of the Relative Lymphocyte Concentration in Patients With Advanced Heart Failure
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The
physiological stress suffered by patients with
heart failure results in an increased production of cortisol
and a shift in the leukocyte differential toward a decreased percentage
of lymphocytes (%L). The purpose of this study was to determine the
prognostic significance of a low %L in advanced heart
failure.
Key Words: heart failure • prognosis • transplantation
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Assessment of
prognosis and candidacy for transplantation in individual patients with
symptomatic heart failure has been difficult owing to the
tremendous variability in the course of heart
failure.1 2 3 4 There are numerous clinical markers
and tests that have been proposed for this
purpose.2 4 5 6 7 8 9 10 11 12 13 Of these, the detection and
quantification of neurohumoral activation have gained the most recent
attention. The plasma norepinephrine level is elevated in
patients with asymptomatic left ventricular
dysfunction, is elevated even more in patients with overt heart
failure, appears to respond to treatment, and has been associated with
mortality.5 6 13
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients
All patients referred for consideration of cardiac
transplantation at our institution are evaluated at the cardiac
transplantation clinic. Prospective data are collected to determine the
appropriateness of transplantation. We identified 263 patients referred
from April 1988 through July 1995. The data from these evaluations and
the medical record were reviewed retrospectively. Exclusion
criteria included trauma, surgery, myocardial infarction, infection, or
corticosteroid use within 6 weeks of the evaluation.
Any history of malignancy, chemotherapy, or radiation therapy also
resulted in exclusion from further analysis. A total of 52
patients were excluded, leaving a study group of 211 patients.
The leukocyte differential was determined as part of a complete
blood count during the initial evaluation. This analysis was
performed with the use of a commercially available automated system
that used a sample size of 3000 cells. The percentage of lymphocytes
(%L) is defined as (Total Number of Lymphocytes/Total
Leukocytes)x100. The normal range of the %L in our laboratory is
20.3% to 46.7% as defined by the central 95th percentile in a
separate population of 150 healthy adults from Olmsted County,
Minnesota.21
Follow-up data were obtained by review of the medical
record, mailed questionnaire, or telephone. Death from any cause
was the primary end point. Death or cardiac transplantation was the
secondary end point. All deaths were verified by hospital records
and/or death certificates.
Overall survival and survival free from transplantation were
estimated by use of the Kaplan-Meier method. The relationship of
selected baseline variables (see Table
[tbc]) to these end points
was assessed with Cox proportional hazards analysis on both a
univariate and multivariate basis.
View this table:
[in a new window]
Table 1. Study Group Baseline Characteristics
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
General
Baseline characteristics of the study group are outlined in the
Table
.
Follow-up was 99% complete at a mean duration of 34 months. There
were 46 deaths in the group (patients were censored at time of
transplant), yielding 1- and 4-year survival rates of 86% and 61%,
respectively. For the combined end point of death or transplantation,
there were 136 events (46 deaths, 90 transplantations), yielding a
transplant-free survival rate of 58% at 1 year and 29% at 4
years.
There was a significant relationship between time to death
(censored at transplantation) and New York Heart Association (NYHA)
symptom class (P=.002), peak exercise oxygen consumption
(P=.05), and relative lymphocyte concentration
(P=.004). No other variables were significantly related
to time to death. Survival curves are shown in Fig 1.
View larger version (10K):
[in a new window]
Figure 1. Survival curves for end point of death (with
censoring at the time of transplantation) based on lymphocyte count.
Survival rates for normal vs low lymphocyte count, respectively, were
90% vs 78% at 1 year and 73% vs 34% at 4 years.
P<.001 by log-rank test. %L indicates percentage of
lymphocytes.
Age, left ventricular ejection fraction, NYHA class,
diagnosis of ischemic cardiomyopathy, and
relative lymphocyte concentration were candidate variables in the
multivariate analysis. Only NYHA class
(P=.002 and P=.003) and relative lymphocyte
concentration (P=.004 and P=.01) were independent
predictors of overall survival or transplant-free survival,
respectively. After adjusting for NYHA functional class in the model,
the relative lymphocyte concentration maintained an independent
association with both end points (P=.003 for overall
survival, P=.008 for transplant-free survival). Survival
curves are shown in Fig 2.
View larger version (14K):
[in a new window]
Figure 2. Survival curves for end point of death (with
censoring at the time of transplantation) based on NYHA class and
lymphocyte count. Survival rates for patients with NYHA class I to II
symptoms with normal vs low lymphocyte count, respectively, were 92%
vs 85% at 1 year and 89% vs 47% at 4 years. Survival rates for
patients with NYHA class III to IV symptoms with normal vs low
lymphocyte count, respectively, were 90% vs 76% at 1 year and 62% vs
32% at 4 years. P=.003 by log-rank test. %L indicates
percentage of lymphocytes.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
This investigation reveals that the relative lymphocyte
concentration was significantly and independently related to survival
in the group of patients referred for consideration of cardiac
transplantation. This simple marker is a standard part of the complete
blood count and as such adds minimal expense or time to the evaluation
process.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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