(Circulation. 1996;94:1339-1345.)
© 1996 American Heart Association, Inc.
Articles |
Cyclosporine May Affect Improvement of Cognitive Brain Function After Successful Cardiac Transplantation
the Department of Cardiothoracic Surgery (M.G., W.Y., G.L., P.S., N.K., B.B., E.W.); the Fourth Department of Internal Medicine (C.M., L.K., E.E., G.G.); the Department of Medical Computer Science (W.S.); and the Second Department of Internal Medicine (R.P.), University of Vienna, Austria.
Correspondence to Georg Grimm, MD, PhD, Second Department of Internal Medicine, General Hospital Klagenfurt, St Veiterstr 47, A-9020 Klagenfurt, Austria.
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Abstract |
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Background The effects of cardiac transplantation on cognitive brain function are uncertain.
Methods and Results We measured cognitive brain function and quality of life in out-of-hospital cardiac transplant candidates (n=55; ejection fraction, 19.9%; age, 54.8 years [means]). After transplantation, the patients were serially reevaluated at 4 months (n=25) and at 12 months (n=19). Brain function was measured objectively by cognitive P300 evoked potentials. Additionally, standard psychometric tests (Trail Making Test A, Mini-Mental State Examination, and Profile of Mood State test) were performed. Cognitive P300 evoked potentials were impaired in cardiac transplant candidates (359 ms, recorded at vertex) compared with 55 age- and sex-matched healthy subjects (345 ms, P<.01). Trail Making Test A was also abnormal (45 versus 31 seconds in 55 healthy subjects, P<.01). After transplantation, P300 measures were normalized at 4 months (345 ms, P<.05 versus before transplantation) but declined again at 12 months (352 ms, P=NS versus before transplantation). Stepwise multiple regression analysis revealed that cumulative cyclosporine dosage was the only predictor of individual cognitive brain function 4 months (753 mg/kg body wt, P<.05) and 12 months (2006 mg/kg body wt, P<.01) after transplantation, respectively.
Conclusions Objective cognitive P300 auditory evoked potential measurements indicate that cognitive brain function is significantly impaired in patients suffering from stable end-stage heart failure. Successful cardiac transplantation is effective to fully normalize impaired brain function. Subsequent relative long-term decline of cognitive brain function after successful cardiac transplantation is strongly suggested to be related to cumulative cyclosporine neurotoxicity.
Key Words: transplantation • cyclosporine • brain
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Introduction |
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The effect of end-stage heart failure on development of cognitive brain dysfunction is uncertain. Furthermore, it remains to be shown whether successful cardiac transplantation with subsequent normalization of hemodynamics is able to improve impaired cognitive brain function.
Severe depression of cardiac output may substantially affect oxygen and nutrient supply to the brain during end-stage heart failure.1 Chronic impairment of cerebral perfusion leads to progressive loss of neurocognitive processing and causes neurobehavioral disorders.2 3 In patients suffering from severe heart failure, similar findings were reported by extensive psychometric testing of cognitive brain dysfunction.4 5 6 7 Since psychometric testing may be affected by various biases,8 9 10 11 these findings need to be confirmed by objective measures.
Evoked potential measurements detected by cortical leads, representing stable sequences of negative and positive electroencephalogram peaks within a period of several hundred milliseconds, are a highly sensitive and reproducible tool for evaluation of cognitive and neuronal brain dysfunction caused by various disorders.12 13 14 15 Cognitive P300 auditory evoked potentials, elicited by a tone discrimination paradigm, are objective measures related to information and cognitive processing that allow a quantification of cognitive brain dysfunction.15 16 17 The P300 technique was shown to be even more sensitive in detecting subclinical metabolic cognitive impairment than electroencephalography and psychometry, unequivocally confirming the high sensitivity of cognitive P300 auditory evoked potentials.18
The aim of this study was to measure the effects of stable end-stage heart failure and subsequent successful cardiac transplantation on cognitive brain function. Objective cognitive P300 auditory evoked potentials and standard psychometric tests (Mini-Mental State Examination and Trail Making Test A) were studied in patients before and after successful cardiac transplantation. Findings in patients before transplantation were compared with those in age- and sex-matched healthy subjects.
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Methods |
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Patients
Fifty-five consecutive cardiac transplant candidates entered the study. The indication for transplantation in all patients was end-stage heart failure with unacceptable prognosis for survival and unacceptable disability even after careful consideration of all other medical and surgical therapies.19 Only stable, out-of-hospital transplant candidates who were free of significant carotid artery stenosis20 were enrolled. Characteristics of the patients before transplantation (including data from right-heart catheterization) are listed in Table 1
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Thirty of 55 end-stage heart failure patients received transplants within the study period. After transplantation (perioperative death, n=1), 4 patients were excluded from follow-up for severe neurological complications (herpes encephalitis, n=1; perioperative stroke with transient hemiparesis, n=1; cerebral convulsions because of noncompliant cyclosporine abuse at 3.5 and 4 months after transplantation, respectively, n=2). Nine patients on the waiting list died before transplantation, and 16 patients were still on the waiting list at the end of the study period.
Immunosuppression and Follow-up
After transplantation, all patients received a standard quadruple immunosuppressive regimen.21 Induction of therapy was performed with antithymocyte globulin (Thymoglobuline, Merieux, 2 mg/kg for 7 days). Cyclosporin A was progressively adjusted to a target level of 250 to 350 ng/mL (measured by high-performance liquid chromatography in whole blood) for the first 6 months and 150 to 200 ng/mL thereafter. Cyclosporin A dosage adjustments were executed according to creatinine levels (maximal creatinine levels of 150 to 170 µmol/L considered acceptable). Azathioprine was adjusted to maintain a white blood cell count >4000/mL. Prednisolone was initiated at 2 mg·kg-1·d-1 (methylprednisolone) and tapered progressively to a maintenance dosage of 0.2 mg·kg-1·d-1 at 3 weeks. Serial measurements of cardiac function were performed by means of standardized echocardiographic evaluation techniques for cardiac output and fractional shortening.22 23 Scheduled endomyocardial biopsies were performed 1, 2, 3, 4, 8, 16, 24, and 52 weeks after transplantation; cardiac allograft rejections were classified as grade 
2 according to the International Society for Heart and Lung Transplantation.24 Infections were diagnosed by positive cultures and the need for chemotherapy. Clinical characteristics (Table 2) were studied at the times of cognitive P300 auditory evoked potential measurements and psychometric tests.
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Cognitive Brain Function
Cognitive P300 auditory evoked potentials
Cognitive P300 evoked potentials were recorded with Ag-AgCl electrodes on a Nicolet 2000. P300 evoked potentials were generated after a binaurally presented tone discrimination paradigm with frequent (80%) tones of 1000 Hz and rare (20%) target tones of 2000 Hz at 55 dB hearing level. Filter band-pass was 0.01 to 30 Hz. Active electrodes were placed at Cz (vertex) and Fz (frontal), respectively, and referenced to linked earlobe A12 electrodes (10/20 international system).25 During the paradigm, the subjects were instructed to keep a running mental count of the rare 2000-Hz target tones. To verify attention, P300 recordings with a discrepancy of >10% between the actual number of stimuli and the number counted by the subjects were rejected and repeated. P300 evoked potential recording resulted in a stable sequence of positive and negative peaks. Latencies (in milliseconds) of the cognitive P300 peak were assessed. To confirm reproducibility, two sets of P300 measurements (double tracing in Fig 1) were recorded in all patients.20 P300 evoked potential findings were compared with those of 55 age- and sex-matched healthy subjects (mean age, 54.2 years; range, 27 to 70 years) without evidence of heart disease. Measurement of cognitive P300 auditory evoked potentials was performed with the informed consent of the patients and approval of the local ethics commission.
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Psychometric tests
Immediately after P300 recording, Mini-Mental State Examination and Trail Making Test A were performed to test cognitive impairment and psychomotor performance.26 27 To minimize learning effects, five different Trail Making tables were randomly used.
To avoid any influence of biorhythm alterations, all P300 records as well as psychometric tests were performed in the morning under comparable conditions by the same physician.
Quality of Life: Profile of Mood State
The Profile of Mood State test was chosen for objective measurement of mood and mood changes.28 The Profile of Mood State test is a 10-minute, 35-item test presented in multiple-choice format for quantitative evaluation of two important dimensions of mood (depression and fatigue) within the last 24 hours. The patients were able to classify different adjectives (eg, irritation) in a score ranging from 0 (not at all) to 6 (extremely upsetting).
Statistical Analysis
Differences between parameters before and after transplantation (4 and 12 months, respectively) were calculated by 
2 test and paired t test.
ANOVA was performed to test the influence and interaction of absence or presence of end-stage heart failure and age on P300 peak latencies. Values of P300 peak latencies in healthy control subjects and heart failure patients were compared by t test. The course of brain function throughout follow-up was computed as differences of P300 peak latency of the individual patient, and statistical significance was calculated by paired t test.
The influence of all the clinical parameters listed in Table 3 on individual changes of P300 peak latencies was studied by univariate Kendall's tau coefficient of correlation. To test simultaneous influence of predictive variables on changes of P300 peak latencies, all the parameters that exhibited significance in univariate analysis were studied in a stepwise multiple regression analysis (entrance level, 0.15).
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Statistical analysis was performed by use of the Statistic Analysis System (SAS).
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Results |
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Clinical Parameters Before and After Cardiac Transplantation
The clinical parameters of cardiac transplant candidates before transplantation and of the patients who were followed after successful cardiac transplantation are shown in Table 2
. Throughout the follow-up period after cardiac transplantation, New York Heart Association (NYHA) functional status, cardiac output, and fractional shortening improved significantly (P<.01, Table 2). Heart rate was elevated 4 months after transplantation (P<.05), and body mass index increased at 12 months after transplantation (P<.01). The hemoglobin blood level after transplantation was lower than before transplantation (4 months, P<.05 and 12 months, P<.01). Blood levels of creatinine (12 months, P<.0.5), aspartate aminotransferase (P<.05), and alanine aminotransferase (4 months, P<.01 and 12 months, P<.05) were elevated after transplantation.
Parameters in Table 2 that are related to immunosuppressive therapy, rejection, and infection had zero values by definition before transplantation, and therefore, statistical analysis of values after transplantation was not performed.
Cognitive Brain Function
Cognitive P300 auditory evoked potentials (simultaneously recorded at Cz and Fz)
Cognitive P300 peak latencies were prolonged (impaired) in heart failure patients compared with healthy subjects (Cz, 360±29 versus 345±17 ms; Fz, 354±28 versus 342±18 ms; mean±SD, P<.01). ANOVA revealed that the presence of end-stage heart failure is a significant predictor of prolonged P300 peak latencies (P<.01, recorded at Cz and Fz; Fig 2). In both groups, healthy subjects and cardiac transplant candidates, there was significant age dependency of P300 peak latencies (P<.01, Fig 2).
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Four months after cardiac transplantation, P300 peak latencies were fully normalized and significantly improved (decreased) compared with before transplantation (n=25; Cz, 345±30 ms and Fz, 341±26 ms; P<.05, Fig 3). Twelve months after transplantation, P300 peak latencies were prolonged (declined) again (n=19; Cz, 353±29 ms and Fz, 343±22 ms; P=NS versus before transplantation, Fig 3).
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Psychometric tests
Performance of Trail Making Test A was prolonged (impaired) in cardiac transplant candidates compared with 55 healthy subjects (46±18 versus 31±7 seconds, P<.01). Assessment of Mini-Mental State Examination revealed no difference in cardiac transplant candidates compared with 55 healthy subjects (28.3±1.7 versus 29.5±0.7; P=NS, Fig 4). After successful cardiac transplantation, Trail Making Test A tended to improve throughout the study period (at 4 months, 42±16; at 12 months, 41±13; P=NS versus before transplantation). Mini-Mental State Examination improved at 4 months (29.2±1.3; P<.05 versus before transplantation) and was stable at 12 months (29.4±0.7; P=NS versus before transplantation, Fig 4).
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Quality of Life: Profile of Mood State
In end-stage heart failure, numerical scores for depression and fatigue (0.8±0.9 and 2.0±1.3, respectively) were significantly higher (better) than in healthy subjects (depression, 0.2±03; fatigue, 0.7±0.2; P<.05, Fig 5). After successful cardiac transplantation, scores for depression and fatigue decreased (improved) at 4 months (depression, 0.4±0.4; fatigue, 1.0±0.7; P<.01 versus before transplantation). Thereafter, scores remained stable (depression, 0.3±0.3, P<.05, and fatigue, 1.0±1.0, P=NS versus before transplantation) at 12 months (Fig 5).
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Predictors of Individual Changes of Cognitive P300 Peak Latencies
Single linear regression analysis was performed on all parameters listed in Table 3. It revealed that cumulative dosage of cyclosporine (P<.05), actual cardiac output (P<.05), and change of NYHA class (P<.05) were related to individual changes of P300 peak latencies from before through 4 months after cardiac transplantation. At 12 months after transplantation, cumulative dosage of cyclosporine (P<.01), actual cardiac output (P<.05), and actual creatinine blood level (P<.05) were related to individual changes of P300 peak latencies (Table 3).
Multiple linear regression analysis revealed that cumulative dosage of cyclosporine was the only significant predictor of individual changes of P300 peak latencies from before through 4 months after transplantation (P<.05), whereas changes in NYHA class and actual cardiac output did not exhibit significance (Table 4). From before through 12 months after transplantation, cumulative dosage of cyclosporine was the only significant predictor of individual changes of P300 peak latencies (P<.01), whereas actual creatinine blood level and actual cardiac output did not enter the stepwise model (Table 4).
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Discussion |
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As shown by objective cognitive P300 auditory evoked potential measurements, this study indicates that cognitive brain function in stable, end-stage heart failure patients awaiting cardiac transplantation is significantly impaired compared with healthy subjects. Successful cardiac transplantation is effective to fully normalize cognitive measurements. Notably, our findings indicate that improved cognitive brain function may be subclinically affected by long-term cyclosporine immunosuppressive treatment, most likely as a result of cumulative cyclosporine neurotoxicity.
Cognitive brain dysfunction in heart failure patients has been only suggested by psychometric testing.4 5 6 7 However, it is generally accepted that psychometric tests are not without bias, eg, in part because of long performance times (stressing attention), visual impairment, influence of psychomotor function, level of education, or learning effects.8 9 10 11 The latter are of particular interest for follow-up studies.29 Cognitive P300 evoked potentials, elicited by a tone discrimination paradigm, represent an objective and valid measure of cognitive brain function. P300 peak latencies, increasing with age in healthy subjects,15 were shown to be related to cognitive impairment rating,17 rapid evaluation of cognitive function test,30 orientation,31 stimulus evaluation,32 selective attention,33 visual pattern recognition,34 and digit span17 and were shown to be much more sensitive in detecting metabolically induced cognitive brain dysfunction than psychometric tests or electroencephalograms.15 18 20 35 Moreover, P300 technique has a very low intraindividual test-retest variability, with a coefficient of variation of 2%, which further stresses its usefulness for cognitive follow-up studies.15
On the basis of P300 measurements, we were able to show that cognitive brain function is significantly impaired (cognitive P300 peak latency, 359 ms, prolonged) in end-stage heart failure patients compared with age- and sex-matched healthy subjects (345 ms). All P300 recordings were taken repeatedly (double tracing) to confirm reproducibility of measurements. The high SDs of mean P300 peak latencies in patients and in healthy subjects are the result of age dependency of cognitive P300 measurements. Psychometric and quality-of-life tests of this study confirmed recent findings in cardiac transplant candidates5 6 : Mini-Mental State Examination, a standard test of cognitive impairment, was normal in all patients (ranging from 24 to the maximum of 30) even before cardiac transplantation. This indicates that only patients without overt cognitive impairment entered the study. More discriminating were the findings in psychomotor Trail Making Test A: Transplant candidates scored significantly abnormally (46 seconds) compared with healthy subjects (31 seconds). According to Muirhead et al,6 the Profile of Mood State test indicated impaired quality of life (depression and fatigue) in end-stage heart failure patients awaiting cardiac transplantation.
The pathophysiology of brain dysfunction in end-stage heart failure patients depends on cerebral blood flow and on distribution of decreased cardiac output.1 A decreased cerebral arterial blood flow adversely affects neuronal oxygen supply and neuronal glucose utilization.20 36 In stroke patients, chronic impairment of cerebral perfusion results in brain dysfunction, which predominantly involves neurocognitive processing.2 In heart failure patients who are treated with standard vasodilating ACE inhibitors (as are all our patients), cerebral blood flow remains unchanged despite therapeutically induced reduction of blood pressure.37 This effect can be attributed to autoregulation, which is effective in preserving cerebral blood flow constant despite large changes in perfusion pressure.37 Therefore, cognitive impairment related to end-stage heart failure seems to result from overall and local disturbances of complex interactions between neuronal and humoral factors regulating nutrient and oxygen brain supply.1
We showed that successful cardiac transplantation is effective in reversing cognitive impairment of the brain in end-stage heart failure patients. Four months after successful cardiac transplantation, P300 peak latencies were fully normalized (345 ms), indicating significant acceleration of neurocognitive processing. This finding is concordant with significant improvements of physical health (NYHA class, cardiac output) and quality of life (depression, fatigue) 4 months after transplantation. Psychometric testing by Trail Making Test A revealed only a slight tendency to improve. The latter finding is in accordance with recent reports by Schall et al,4 who found that cardiac transplantation failed to improve cognitive scores in psychometric tests. Cyclosporine-induced tremor observed in many of our patients—related not to cognitive but rather to motor processing—was responsible for impaired processing of Trail Making Test A after transplantation, indicating an obvious bias of psychomotor testing. Surprisingly, scores in the Mini-Mental State Examination showed a slight but significant further improvement 4 months after cardiac transplantation. This improvement of cognitive processing after transplantation is most likely to be caused by increased cerebral oxygen and nutrient supply.15 It must be stressed that cognitive improvement can be achieved only in case of neurologically uneventful cardiac transplantation. Four of our series of patients were excluded from follow-up study because of encephalitis, perioperative stroke, or cerebral convulsions induced by cyclosporine abuse. The distinct mechanisms for cognitive improvement after cardiac transplantation may only be speculated upon. Like cardiac transplantation in our study, correction of bradycardia by pacemaker implantation also improves brain function. Both cardiac transplantation and pacemaker implantation result in increases of cardiac output and heart rate, respectively.38 39 For pacemaker patients, Shapiro and Chawla38 speculated that improved cardiac output is responsible for improved brain function, whereas Koide et al39 stressed increased heart rate as the most important factor for improvement of brain function. This seems not to be valid for cardiac transplant recipients, because in our study, cardiac output and heart rate increased significantly at 4 months after transplantation, but neither one was correlated with improvement of cognitive P300 measures in multiple regression analysis.
Despite persistent hemodynamic improvement, cognitive P300 measurements tended to decline again at 12 months after successful cardiac transplantation, which was surprising. Multiple regression analysis revealed that cumulative cyclosporine dosage at 4 and 12 months was the only significant predictor of changes of cognitive evoked potential measurements. All other parameters that we studied and that are listed in Table 4, especially other immunosuppressive agents, failed to predict cognitive measurements. Cyclosporine neurotoxicity is reported to occur in 4% to 54% of transplant recipients.40 Clinically obvious findings such as tremor, paresis, hallucinations, and coma may occur, and cyclosporine-induced morphological abnormalities of the brain may be detected by MRI.40 41 However, these complications are generally believed to occur only at abnormally elevated cyclosporine blood levels. Infusion of a high dosage of cyclosporine in dogs resulted in an acute decrease of cerebral blood flow as well as acute impairment of (noncognitive) somatosensory and auditory brain-stem evoked potentials.40 Considering long-term cyclosporine therapy in animal studies, these authors speculate that cumulative cyclosporine dosage may be responsible for neurotoxicity.40 This is in accordance with our finding that cumulative cyclosporine dosage (but not actual cyclosporine blood levels) at 4 or 12 months revealed predictive power for P300 evoked potential measurements. The mechanism by which cyclosporine affects the brain is unclear. An interaction of lipophilic cyclosporine with calmodulin (affecting blockade of nerve impulses and release of neurotransmitters) is discussed.40 In contrast to cognitive P300 evoked potentials, psychometric tests failed to show any correlation with cyclosporine neurotoxicity (data not shown), indicating that the P300 technique is more sensitive in detecting subclinical cognitive dysfunction than psychometry.15 18 20 35
Study Limitations
The first limitation of this study is the lack of a control group that did not receive cyclosporine after transplantation. Since cyclosporine therapy is the gold standard in treatment after organ transplantation nowadays, it would, of course, be unethical to perform such an ideal study. Second, we studied selected, stable, out-of-hospital transplant candidates exclusively. Unstable, in-hospital transplant candidates on intravenous catecholamine support were excluded. In these patients, this dramatic, life-threatening situation would certainly affect the highly sensitive cognitive P300 measures by various biases, such as impaired ability of concentration in the intensive care unit or application of sedative drugs. Third, we cannot exclude the possibility that there may be other, as yet unknown variables that influence P300 measures. From statistical analysis in our study, we can state only that neither other immunosuppressive agents (azathioprine, steroids), dysfunction of the kidney and liver, nor decrease of hemoglobin affects cognitive P300 measures.
On the basis of objective and sensitive cognitive P300 evoked potential measurements, we conclude that cognitive brain function in stable, out-of-hospital, end-stage heart failure patients is significantly impaired. Cognitive impairment can be fully normalized by successful cardiac transplantation. Long-term follow-up study after transplantation revealed a subsequent decline of cognitive brain function that may be related to cumulative cyclosporine neurotoxicity. The role of cyclosporine treatment on neurocognitive processing needs to be elucidated by further studies.
Received February 20, 1996; revision received April 16, 1996; accepted May 6, 1996.
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