Prognostic Significance of Cerebral Metabolic Abnormalities in Patients With Congestive Heart Failure
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.
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.
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
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.
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⇓).
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.
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.
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.
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).
The first 2 authors contributed equally to this article.
- Received February 23, 2001.
- Revision received April 12, 2001.
- Accepted April 18, 2001.
- Copyright © 2001 by American Heart Association