(Circulation. 2001;103:2784.)
© 2001 American Heart Association, Inc.
Brief Rapid Communications |
Prognostic Significance of Cerebral Metabolic Abnormalities in Patients With Congestive Heart Failure
From the Departments of Medicine (C.W.L., H.S.Y., M.-K.H., J.-K.S., S.-W.P., S.-J.P., J.-J.K.) and Radiology (T.-H.L.) and the Asan Institute for Life Science (J.H.L.), Asan Medical Center, University of Ulsan, Seoul, Korea.
Correspondence to Jae-Joong Kim, MD, PhD, Department of Medicine, University of Ulsan, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul, 138-736,Korea. E-mail jjkim{at}www.amc.seoul.kr
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Abstract |
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Background—Cerebral metabolic abnormalities were proposed as a potential marker of disease severity in congestive heart failure (CHF), but their prognostic significance remains uncertain.
Methods and Results—We
investigated the prognostic value of cerebral metabolic
abnormalities in 130 consecutive patients with advanced CHF (100 men
aged 42.6±11.9 years; left ventricular ejection fraction,
22.2±6.2%). Proton magnetic resonance spectroscopy data were obtained
from localized regions (
8 mL) of the occipital gray matter and the
parietal white matter. The primary end point was the occurrence of
death after the proton magnetic resonance spectroscopy. During
follow-up (18.5±14.4 months), 21 patients died and 15 underwent urgent
heart transplantation. In the Cox proportional model, occipital
metabolites (N-acetylaspartate, creatine, choline, and myoinositol),
parietal N-acetylaspartate level, and the duration of CHF symptoms
(>12 months) were validated as univariate predictors of
death. In multivariate Cox analyses, however,
the occipital N-acetylaspartate level was an independent predictor of
death (hazard ratio, 0.52; 95% CI, 0.41 to 0.67;
P<0.001). An analysis
with respect to the combined end point of death or urgent
transplantation showed similar results. The best cutoff value (9.0
mmol/kg) for occipital N-acetylaspartate level had 75% sensitivity and
67% specificity to predict mortality.
Conclusions—The occipital N-acetylaspartate level is a powerful and independent predictor of CHF mortality, suggesting that cerebral metabolic abnormalities may be used as a new prognostic marker in the assessment of patients with CHF.
Key Words: brain • heart failure • magnetic resonance imaging • prognosis • spectroscopy
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Introduction |
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Anumber of clinical markers and tests have been described to determine prognosis in patients with congestive heart failure (CHF).1 2 3 Despite the use of these tools, however, an assessment of prognosis remains difficult. Thus, the search for new markers is clinically important for accurate risk stratification. Cerebral metabolic abnormalities were proposed as a potential marker of disease severity in CHF,4 but their prognostic significance remains uncertain. In the present study, we assessed the prognostic value of cerebral metabolic abnormalities in a large group of ambulatory patients with advanced CHF.
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Methods |
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Study Population
The study population consisted of 130 consecutive patients (age
60 years) with advanced CHF (left
ventricular ejection fraction 35%) who were screened for
heart transplantation. All the patients were stable and had been on
standard medication in the previous 4 weeks (digoxin, 96.9%;
angiotensin-converting enzyme inhibitors,
93.8%; and diuretics, 90.8%). Exclusion criteria included
cerebrovascular disease, a history of drug or alcohol abuse, chronic
liver disease, or chronic renal failure. The study was approved by the
institutional review committee of our hospital, and the subjects gave
informed consent.
Clinical and Laboratory Evaluation
All the patients were evaluated using a standardized
protocol that included clinical evaluation, laboratory studies, and
echocardiography.
Proton Magnetic Resonance Spectroscopy
Localized in vivo proton magnetic resonance
spectroscopy was performed on a 1.5T SIGNA system (General Electric
Medical System), as described
previously.4 Image-guided
water-suppressed spectra were obtained in 2 locations (voxel volume, 7
to 9 mL), one with mostly parietal white matter (PWM) and one with
mostly occipital gray matter (OGM), using the following spectral
acquisition parameters: repetition time (TR), 3.0 s;
echo time (TE), 30 ms; and number of scans, 36 averages in the
stimulated echo acquisition mode sequence incorporated into proton
brain examination (PROBE). All raw PROBE data were processed according
to the method described by Kreis et
al.5 Peaks were identified
with known chemical shifts, as follows: N-acetylaspartate, 2.02 ppm;
creatine, 3.03 ppm; choline, 3.22 ppm; and myoinositol, 3.56 ppm. The
absolute concentrations of the cerebral metabolites were calculated
using the brain water signal as an internal reference from the PROBE
data and expressed as mmol/kg wet weight, as described by Soher et
al.6 All spectra were
reviewed by a person who was blinded to clinical
data.
Follow-Up and Study End Points
Follow-up information was obtained by chart reviews
or telephone calls, and all patients were followed for >9 months. The
primary end point was all-cause mortality; patients who received heart
transplantation were censored on their transplantation date. The
combined end point was death or urgent transplantation (United
Network for Organ Sharing [UNOS] status
1).1
Statistical Analysis
Data are expressed as mean±SD for continuous
variables and as frequencies for categorical variables. A Cox
proportional hazard analysis was used to assess the association
between variables and mortality. A receiver-operating
characteristics (ROC) curve analysis was performed to determine
the best prognostic cutoff for survival.
P<0.05 was considered
statistically significant.
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Results |
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As shown in Table 1
, idiopathic dilated
cardiomyopathy predominated as the cause of CHF,
and all the patients had marked left ventricular
dysfunction. Baseline characteristics were similar between survivors
and nonsurvivors, with the exception of cerebral metabolite levels and
the duration of CHF symptoms
(Table 1).
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During follow-up (18.5±14.4 months), 21 patients died (cardiac deaths, n=20), yielding 1- and 2-year survival rates of 88.2±3.1% and 80.5±4.4%, respectively. Thirty-six patients underwent heart transplantation during the study (urgent, n=15; elective, n=21). For the combined end point of death or urgent transplantation, there were 36 events, yielding an event-free survival rate of 76.6±3.9% at 1 year and 67.6±4.8% at 2 years.
A Cox proportional hazard analysis showed a
significant relationship between the length of time to death and
cerebral metabolite levels and the duration of CHF symptoms
(Table 2). No other variables were significantly related
to the length of time to death. An analysis with respect to the
combined end point revealed similar results. The choline (hazard ratio
[HR], 0.11; 95% CI, 0.03 to 0.41;
P=0.001), creatine (HR, 0.55;
95% CI, 0.43 to 0.71;
P<0.001), myoinositol (HR,
0.68; 95% CI, 0.53 to 0.87;
P=0.002), and N-acetylaspartate
levels (HR, 0.59; 95% CI, 0.49 to 0.73;
P<0.001) in the OGM and the
duration of CHF symptoms >12 months (HR, 4.60; 95% CI, 2.09 to 10.10;
P=0.001) were the variables
that significantly related to death or urgent transplantation. On a
multivariate analysis, however, the occipital
N-acetylaspartate level (HR, 0.52; 95% CI, 0.41 to 0.67;
P<0.001) was the only
independent predictor of death. Likewise, the occipital
N-acetylaspartate level (HR, 0.59; 95% CI, 0.49 to 0.73;
P<0.001) was independently
related to death or urgent transplantation.
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Kaplan-Meier survival curves using the optimal cutoff value
are shown in
Figure 1. A ROC analysis revealed that the occipital
N-acetylaspartate had a good prognostic value in predicting death (ROC
area, 0.78±0.06; 95% CI, 0.67 to 0.89;
P<0.001) and reasonable
prognostic value in predicting death or urgent transplantation (ROC
area, 0.75±0.05; 95% CI, 0.65 to 0.84;
P<0.001;
Figure 2). The best cutoff value for occipital
N-acetylaspartate (9.0 mmol/kg) had 75% sensitivity and 67%
specificity to predict all-cause mortality.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study shows that the occipital N-acetylaspartate level was independently related to survival in the group of patients referred for consideration of heart transplantation, suggesting that cerebral metabolic abnormalities may be used as a new, powerful prognostic marker in the assessment of these patients.
The brain circulation is characterized by the autoregulation
of blood flow over a wide range of perfusion
pressures.7 Blood flow to the
brain is usually preserved at the expense of peripheral
perfusion, but it decreases in the advanced stages of
CHF.8 This may have serious
consequences for the function of the brain and, eventually, for the
patient’s life. We previously reported that cerebral
metabolism in CHF is variably deranged, with regional
differences reflecting the severity of
disease.4 Interestingly, the
metabolite levels in the OGM were more closely related to CHF mortality
than those in the PWM. The reasons for this remain unknown, but they
may represent regional susceptibility to cerebral
hypoperfusion. In general, the metabolic abnormalities seem
to develop earlier and progress more rapidly in gray matter than in
white matter.9 Thus, the
metabolite levels in the OGM may be more useful for the prediction of
CHF mortality than those in the PWM because the former are more
susceptible to hypoxic
injury.10 N-acetylaspartate
is a neuronal marker, and loss of N-acetylaspartate is generally
accompanied by neuronal
loss.9 In this study, the
reduction of the occipital N-acetylaspartate level (institution
normal,4 10.57±1.23 mmol/kg)
was the strongest predictor of CHF mortality, suggesting that neuronal
damage in gray matter may represent terminal
metabolic response to the failing heart and a bad
prognostic sign. The best cutoff value of occipital
N-acetylaspartate was 9 mmol/kg.However, the cutoff value
of 8 mmol/kg may be more acceptable to identify a high-risk
subgroup who faces very poor short-term prognosis (1-year survival,
50.9±13.7%), and heart transplantation should be considered in this
group.
The identification of patients with CHF who are at a higher risk of death has become an area of active investigation in the last 2 decades, and a number of factors have been proposed as potential prognostic markers in this complex disease.1 2 3 In fact, left ventricular ejection fraction is a powerful predictor of death in a heterogeneous population of CHF patients; however, its prognostic value loses strength when applied to potential transplantation candidates. Neurohumoral markers were also found to be important predictors of survival, but they are not routinely used due to diurnal variability and differences between studies.2 11 Until now, peak oxygen consumption has been widely used to select candidates for heart transplantation. However, it can also be influenced by noncardiac factors such as skeletal muscle abnormalities, motivation, obesity, or exercise training,12 and it may yield misleading prognostic information. In contrast, proton magnetic resonance spectroscopy has been well validated in several clinical conditions, and the narrow individual variation in cerebral metabolites may render this technique reliable for patients with advanced CHF.9 10 Furthermore, it is simple to perform and readily available in all magnetic resonance laboratories.
In this study, cerebral blood flow was not measured and, therefore, the relationship between the regional blood flow and metabolic changes could not be evaluated. Furthermore, additional studies may be needed to clarify the interactions between the known prognostic markers and this new index. Nevertheless, our data suggest that cerebral metabolism may provide a new prognostic insight for patients with advanced CHF.
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Acknowledgments |
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This study was supported by a grant from the Korean Society of Circulation (#99-8) and by a grant from the Asan Institute for Life Science (#2001-075).
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Footnotes |
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The first 2 authors contributed equally to this article.
Received February 23, 2001; revision received April 12, 2001; accepted April 18, 2001.
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