INTRODUCTION

Heart failure (HF) has been associated with increased prevalence of cognitive dysfunction in older populations.¹ The issue of so called “cardiogenic dementia” has been renewed by recent findings of the effects of pacemaker implantation and cardiac transplantation on cognitive function^2,3; in some studies; increasing age and lower indices of left ventricular function were associated with worsening cognitive performance. However the linkage between aging, left ventricular systolic function, and cognitive performance remains elusive.^2-7

Advances in our understanding of the pathophysiology of HF have moved us away from seeing it in purely hemodynamic terms to an appreciation of its multisystem nature.⁸ Patients with HF have evidence of inflammatory cytokine activation, which may play a crucial role in the pathogenesis of this syndrome^8-10. However, recently, cytokine dysregulation has also been associated with cognitive disorders and dementia^11-16.

Aim of the work:

The aim of this study was to investigate the relationship between inflammatory cytokine levels and cognition in patients with congestive heart failure.

PATIENTS AND METHODS

This was a prospective cross sectional study done on 40 consecutive patients with congestive heart failure (CHF) presented to Hai AL Jamea Hospital, Jeddah. Complete history taking including history of complications was done. Thorough physical and neurological examinations were performed. Transthoracic echo-cardiography for evaluation of left ventricular ejection fraction (2D, M mode) and ECG were performed to all patients.

New York heart association (NYHA) criteria¹⁷ were used to evaluate the degree of heart failure.  Accordingly the patients were classified into two groups, group A (20 patients) included NYHA class I & II, and group B (20 patients) included NYHA class III & IV. 

Cognitive function was assessed for all patients using the Hodkinson Abbreviated Mental Test (AMT).¹⁸ Serum IL-6 and TNF-α were measured. Informed consent was obtained from all the patients.

Patients were excluded from the study if they had:

1-                  Acute infection.

2-        Rheumatoid disease.

3-        severe renal failure (creatinine > 250 mmol/L)

4-        Myocardial infarction within the previous 12 months

5-        Suspected of having malignancy.

6-        History and/or symptoms or signs of cerebrovascular strokes.

7-        Dementia

Measurement of cognitive function:²

Cognitive performance was assessed using the Hodkinson Abbreviated Mental Test (AMT).¹⁸ This test can be performed easily and rapidly by a non-specialized personnel; it does not need writing or reading tests and is consistent with other screening tests for dementia. This test has also been proved reliable for detecting both mild cognitive impairment and dementia in older population.^19-21

The AMT includes 10 items; What is your present age? What year is it? Please count from 20 backwards to 1? What is the time? When is your birthday? Could you repeat the address which I gave you? When did the First World War begin? What is the name of this place? What is the name of the President of the Republic? Can you recognize these … people? In this study, question number 7 (When did the First World War begin?) was replaced by (When did the First Gulf War begin?) and questions number 9 (What is the name of the President of the Republic?) was replaced by (What is the name of the King?). This test explores three cognitive domains; information, memory, and concentration. The score is 1 for each correct answer, and 0 for wrong answer.

Laboratory Analysis:

Baseline serum samples for inflammatory markers were drawn into plain red-top tubes. To prevent erroneous results due to the presence of fibrin, complete clot formation was left to take place prior to centrifugatiuon of the samples. Next, samples were spun at 3000 g for 20 minutes, and then frozen at -20^o for later analysis; for maximum 6 months. Serum IL-6 and TNF-α were measured in duplicate using Immulite fully automated machine for immunoassay by solid-phase, enzyme-labeled, chemiluminescent sequential immunometric assay.

Statistics:

Statistics were done using the SPSS program 12 for windows (USA). Descriptive statistics including mean and standard deviation were computed for continuous variables (e.g., age). Frequency and percentage were computed for numeric variables (e.g., sex). Independent sample t-test was used to compare between two continuous variables.

To study the factors that affected the cognitive abilities of the patients, the analysis was done on two steps; first the effect of each variable on cognition was studied independent of the other variables (Bivariate correlation; Pearson correlation), then the degree of the effect of each variable on cognition was studied in the presence of the other variables (stepwise linear regression analysis)

RESULTS

There was no statistical significant difference in the distribution of sex between both groups (Pearson Chi-Square = 0.1, p>0.05).  Also, there was no statistical significant difference between the mean age between both groups (t-test = 0.627, p>0.05) (Table 1).

The frequencies of co-morbid diseases were statistically equal in both groups (p>0.05). Patients in group A used beta-blockers more frequently (p <0.05), while patients in group B used digitalis, diuretics and ACEI more frequently (p<0.05). The mean left ventricular ejection fraction and the systolic blood pressure is significantly higher in group A than in group B (t-test = 3.1, p<0.01 & t-test = 2.9, p<0.01 respectively) (Table 1).

Both groups had a mean score on AMT test denoting the presence of cognitive impairment, however, group B had a significantly lower mean scores than group A (group A; 6.97±1.39, group B; 5.9±1.44) (t test = 2.38, p<0.05) (Table 1).

The serum levels of sodium, potassium and creatinine were not statistically different in both groups (p>0.05). However, the serum levels of TNF-α were significantly higher in group B than in group A (t-test = -3.8, p <0.005). Also, the serum levels of IL-6 were also significantly higher in group B than in group A (t-test = -3.55, p < 0.005) (Table 1).

Bivariate correlation analysis revealed the presence of significant negative correlations between AMT scores and the serum levels of IL-6 and TNF-α and there were significant positive correlations between the AMT scores and the LVEF and systolic blood pressure (Table 2). Stepwise linear regression analysis was executed using IL-6, TNF, systolic blood pressure and LVEF as independent variables and the AMT scores as the dependent variable. R square was 0.812 indicating a successful linear model. Only the serum IL-6 level was found to significantly predict the AMT scores. The other variables were excluded from the model. The regression model obtained was: (AMT score =11.839 −0.439 × serum IL-6) (Fig. 1).

Table 1: showing the demographic, clinical, cognitive and laboratory findings for both groups.

Table 2. Showing the results of bivariate correlation analysis.

*               p < 0.05

**            p < 0.001

Fig. (1): Showing the mean AMT in relation of the serum IL-6 levels.

DISCUSSION

Cognitive dysfunction is a frequent finding among older patients with left ventricular dysfunction.^1-7 Zuccala et al.¹ studied the association between cognitive dysfunction and disability in 1583 patients with heart failure. They also used the Hodkinson abbreviated mental test to study cognitive abilities. They reported that cognitive dysfunction (as detected by abbreviated mental test <7) was detected in 57% in severe cases and in 13% in mild cases. These findings were also found in the present study; patients with heart failure had cognitive impairment that was significantly higher in patients with severe heart failure. In addition, similar findings were reported by other authors as well.^2-7

However, the pathogenesis of cognitive impairment in patients with heart failure has always been controversial. Two main hypothesis have been postulated, multiple cerebral emboli and cerebral hypoperfusion. Authors who supported the first hypothesis postulated that left ventricular dysfunction leads to increased end diastolic volume and stasis, predisposing to thrombus formation. In patients with heart failure, ejection fraction is a risk factor for cerebral infarction and ventricular thrombus formation.²² Obvious clinical stroke was excluded in most studies that examined for the cognitive impairment in patients with heart failure, as it was also the case in the current study, suggesting that multiple stroke could not be responsible for the cognitive impairment.

Cerebral hypoperfusion as a cause of the cognitive impairment in patients with heart failure was suggested on the other hand because systolic dysfunction of the left ventricle was found to reduce the cardiac ejection fraction and blood flow to the cerebral arteries. Using 133xenon, cerebral blood flow was found to be lower in patients with cardiac failure.^23,24 Also, a correlation was found between the Mini-Mental State Examination score and left ventricular ejection fraction in elderly patients with chronic heart failure.⁷ The findings of the present study did not fully support this hypothesis. LVEF was significantly lower in group II than in group I and it showed significant positive correlation with the cognitive abilities as it was reported previously.⁷ However, LVEF was excluded from the stepwise linear regression model in predicting the AMT scores of patients with CHF. This means that the effect of LVEF independent of other variables that was shown by bivariate correlation analysis was statistically insignificant when it was examined in the presence of other factors that had a significantly much more influence on cognition.

On the other hand, in this study, stepwise linear regression analysis showed that the serum IL-6 level was the only factor that could predict significantly the AMT scores in patients with CHF. Also, the mean serum IL-6 and TNF-α levels were significantly higher in group II than in group I and both showed significant negative linear correlation with the AMT scores. These findings signify that IL-6 had a strong influence on cognition when it was studied independently and in the presence of the other variables. These findings suggest an important role of IL-6 in the pathogenesis of cognitive impairment in patients with heart failure.

To the best of our knowledge, the current study is the first that associates cytokines activation with the pathogenesis of cognitive impairment in patients with heart failure. However the negative role of inflammatory cytokines, especially IL-6, in the development of cognitive impairment and dementia has been recently reported in both animal and human studies.^12-16 It is hypothesized that these molecules influence cognition via diverse mechanisms. Peripheral cytokines penetrate the blood-brain barrier directly via active transport mechanisms or indirectly via vagal nerve stimulation. Peripheral administration of certain cytokines as biological response modifiers produces adverse cognitive effects in animals and humans. There is abundant evidence that inflammatory mechanisms within the central nervous system contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells.²⁵

Whether or not the administration of anti IL-6 or anti TNF-α to patients with heart failure could improve the cognitive impairment is an open question that needs further study.

Conclusion:

The current study showed that patients with heart failure had cognitive impairment that worsened with the severity of heart failure. It also showed that the serum levels of IL-6 and TNF-α were significantly elevated in severe cases with heart failure (NYHA classification III & IV) more than in milder cases (NYHA classification I&II).  Both cytokine levels were negatively correlated with the cognitive impairment, however, only serum IL-6 levels could predict the degree of cognitive impairment in patients with heart failure.

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