Neuroinflammation as common denominator in heart failure associated mental dysfunction
Gouweleeuw, Leonie
DOI:
10.33612/diss.122192415
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2020
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Gouweleeuw, L. (2020). Neuroinflammation as common denominator in heart failure associated mental
dysfunction: Studies in animal models. University of Groningen. https://doi.org/10.33612/diss.122192415
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CHAPTER 1
General introduction
Myocardial infarction and mental dysfunction - epidemics
Myocardial infarction (MI) and heart failure are associated with a number of different comorbidities, including renal disease, diabetes and hypertension. Another important comorbidity is mental dysfunction; often overlooked or regarded as ”natural response to a life-threatening condition”. Cardiac patients have a higher risk of developing depression, anxiety or cognitive impairment compared to the general population. Vice versa, patients with mental illness are more prone to MI and other forms of cardiac disease. The scope of this thesis, however, is focused on one side of this bilateral neurocardiac interaction; MI leading to mental dysfunction.
The percentage of MI patients suffering from depression varies widely, depending on the study population and the criteria by which depression was scored. Major depression was found in 15-22% of MI patients [1, 2], while a literature review reported symptoms of depression in up to 65% of MI patients [3]. Depression following myocardial infarction should not be considered as an innocent complication. Different studies have shown that depression following MI is associated with higher risk of comorbidities, hospitalizations and all-cause mortality [4, 5]. Unfortunately, treating the depression does not lead to an improved cardiac prognosis. In fact, there is evidence that in women the use of anti-depressant drugs and anxiolytics even worsens cardiac prognosis [6].
Similarly to depression, cognitive impairment is common in MI patients. A recent meta-analysis of 24 studies found an average odds ratio (OR) of 1.45 for cognitive impairment or dementia in patients with coronary heart disease, including MI patients [7]. Results of the separate studies did show high variability, with some studies showing no difference and others a high OR (ranging from 0.97 – 2.58) [8-10]. Studies also showed that OR was sex and age dependant, with higher dementia risk in the male sex and with increasing age [11, 12]. Cognitive impairment is associated with unfavourable disease outcome [13], and MI patients that also have cognitive impairment are more likely to develop dementia [14].
Treatment of mental dysfunction in patients with cardiovascular disease has proven to be difficult. One of the difficulties is that the pathophysiology of the interaction has not been fully elucidated.
Inflammation hypothesis
There are many hypotheses regarding the association between cardiac disease and decreased mental wellbeing. No doubt that psychological and behavioural factors can contribute to mental dysfunction in MI patients. However, many biological factors are proposed to contribute as well. MI evokes a strong neuroendocrine response in order to preserve cardiac function. This can give rise to platelet aggregation, endothelial dysfunction, hypoxia in the central nervous system (CNS) and autonomic nervous system dysfunction [15-17]. These phenomena have been linked to depression, anxiety and cognitive problems. Another major player in the field is inflammation. A schematic overview of mechanisms that contribute to the relationship between cardiovascular disease and depression is giving in Figure 1. Both cardiac disease and mental dysfunction have been linked to elevated levels of cytokines. Several of these cytokines overlap, occurring both in depression and in cardiac disease [18]. Rather than one pathology causing the other, the link between cardiac and mental dysfunction could hence be attributed to inflammation as common underlying factor. This would also explain why treating one of the diseases does not change the prognosis for the other.
Figure 1: Proposed mechanisms involved in the relationship between cardiovascular disease and mental dysfunction.
Inflammation, altered platelet function, endothelial dysfunction and autonomic nervous system dysfunction have been mentioned as involved in both pathologies and can influence and aggravate each other.
The inflammatory reaction following MI is a response to tissue damage, and is needed for proper scar formation [19, 20]. However, circulatory cytokines are raised to long after the healing phase following MI. Clinical studies have found specific inflammatory markers that were more elevated in MI patients with depression compared to MI patients without depression. Among these markers are tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), C-reactive protein (CRP) and Neutrophil-gelatinase-associated lipocalin (NGAL) [21-24]. There are several proposed mechanism by which these factors could exert effects on the CNS, leading to behavioural changes. Either they could enter the CNS at locations not lined by the blood brain barrier, circumventricular organs, or at leaky spots in the blood brain barrier; they could be transported through active transport mechanisms over the blood brain barrier, or they can interact with afferent nerves to reflect the signal into the brain [25]. Moreover, it has been reported that circulatory cytokines can cause local increases in permeability of the blood brain barrier, facilitating the entry of cytokines in the CNS [26]. The latter has been especially well described in the case of TNF-α [27]. MI causes blood brain barrier leakage in rats that can be mimicked by TNF-α infusion [26, 28]. Mice showed blood brain barrier leakage for at least 3 months after MI [29].
Neutrophil gelatinase associated lipocalin
An interesting protein in the association between cardiac disease and mental dysfunction is Neutrophil gelatinase associated lipocalin (NGAL), also known as Lipocalin-2. NGAL is important in anti-microbial defence, primarily through sequestering iron, depleting iron levels needed for bacterial growth [30]. In recent years, NGAL was linked to various disease states and was found to have several pro- and anti-inflammatory actions. Increased levels of NGAL were found in patients with cardiac disease, as well as in animal models of cardiac disease [31-34]. In heart failure patients, higher NGAL levels were associated with unfavourable prognosis [35]. In the nervous system, NGAL expression is altered in relation to different pathologic states, including stroke, MS and Alzheimer’s disease [36-38]. We know that CNS NGAL is upregulated in response to peripheral inflammation, as it is increased upon administration of lipopolysaccharide [39, 40]. NGAL expression by neurons, astrocytes and microglia is upregulated upon stimulation with TNF-α in cell culture experiments, again indicating it responds to inflammatory stimuli [41].
A number of papers regarding NGAL from our group also studied the role of NGAL in the brain and its link with depression. NGAL was identified as a protein highly upregulated in neurons, astrocytes and microglia upon stimulation with TNF-α in cell culture experiments [42]. This indicates NGAL acts downstream of TNF-α and we know that TNF-α is elevated
in heart failure and that TNF-α administration is associated with depressive behaviour [43]. Circulatory NGAL was also found to be elevated in elderly patients with depression [44]. Additionally, NGAL levels measured in post-mortem brain tissue showed differences in expression between Alzheimer’s disease patients with and without depression [36]. Three of our previous studies also focused on the link between NGAL and depression in heart failure patients [24, 45, 46]. These clinical results provide a good foundation to build the experimental work in this thesis on.
In the 2014 publication [24], we measured NGAL and depression in a cohort of heart failure patients, along with cardiovascular parameters at baseline and at 12 months follow-up. Results indicated NGAL was significantly associated with signs depression, both in the self-reported Beck Depression Inventory (BDI), as well as the Hamilton Depression Rating Scale (HAMD) interview (Figure 2). These results were independent of other factors, including age, sex, severity of heart disease and parameters for renal disease. In the multivariate analysis, symptoms of depression according to the BDI were subcategorized into cognitive and somatic symptoms of depression, and NGAL was only statistically associated with total BDI score and BDI somatic score, but not BDI cognitive score. Furthermore, both NGAL levels and depression scores correlated with 6-minute walk test, but not left ventricular ejection fraction. This is an indication that NGAL and depression are both associated with the experienced burden of heart failure, rather than with the clinical measure of disease severity [24].
In 2015, we published another paper on the same cohort of patients [45]. This time, other markers of inflammation (TNF-α, sTNFR1, sTNFR2, IL-6, and hsCRP) were also measured and we investigated whether NGAL correlated with these other inflammatory markers, and whether the correlation between NGAL and somatic depression still held after correcting for these other factors. Results showed that NGAL correlated significantly with TNF-α, sTNF-R1, sTNF-R2, hsCRP and leukocytes. Results also showed that NGAL was significantly associated with somatic symptoms of depression, also after correction for these other inflammatory markers.
The publication from 2016 [46] followed this group of patients for a longer period of time (on average 6.1 years) and investigated inflammatory markers and depression and its association with all-cause mortality. Results showed that depression, NGAL and several other inflammatory markers were associated with all-cause mortality. This association remained after correcting for age, sex and comorbidities.
Figure 2: Correlations between NGAL and depressive symptoms in heart failure patients. BDI baseline r = 0.22,
p = 0.03; 12 months r = 0.391, p = 0.001; HAMD baseline r = 0.25, p = 0.02; 12 months r = 0.18, p = 0.12. Derived from Naudé et al., 2014 [24].
The clinical data presented in these papers shows some very interesting correlations between heart disease, depression and inflammation. To collect more evidence for the role of inflammation linking depressive symptoms to cardiovascular disease, we have set up several animal experiments described in the further chapters of this thesis.
Animal models of MI and neuroinflammation (cardioneural interaction)
Animal models of MI and heart failure are a valuable research tool, most research is carried out in mice and rats. Usually myocardial infarction is induced by ligation of the left coronary artery, leading to an arrest in blood flow to part of the myocardium, which is comparable to the damage that is caused in MI patients. Following the surgery, animals show elevated plasma cytokines, remodelling of the myocardium and scar formation.
Animal models of MI have also been used to study changes in the central nervous system. A publication from 1993 already shows heart failure leads to selectively increased metabolic activity in the paraventricular nucleus of the hypothalamus (PVN) and locus coeruleus in rats [47]. These specific brain areas are involved in tasks including the regulation of blood pressure and sympathetic activity, processes highly involved in MI and heart failure.
Besides increased metabolic activity, there is also evidence for local inflammation in the CNS. The levels of TNF-α were measured over a longer period of time [48]. The investigators found
elevated levels of TNF-α in the heart, plasma and hypothalamus for up to 9 weeks post-MI. TNF-α was also measured in the cortex, here TNF-α levels seemed unaltered, indicating localized rather than general responses.
More proof for neuroinflammation following MI was found in the form of local activation of microglia [49]. The activity score of microglia was increased in the PVN for up to 5 weeks after MI. Notably, this change was only found in the portion of the PVN adjacent to the third ventricle, as there was no change observed in the area of the PVN further away from the third ventricle, where the magnocellular cells are localized.
Neuroinflammatory changes are not confined to areas involved in cardiovascular activity. Rinaldi and colleagues also found changes in microglia and astrocyte morphology in the prefrontal cortex, thalamus and hippocampus [50]. This is interesting, since the prefrontal cortex and hippocampus are also linked to behaviour. Hippocampus is known to be important for cognition and mood [51, 52]. Prefrontal cortex is involved in emotions and decision making and has been linked to the cognitive symptoms of depression [53]. Apoptosis was also found in hippocampus and amygdala areas in rats that received MI [54]. Like the hippocampus and prefrontal cortex, the amygdala has been linked to depression, it is known to play a role in emotions and anxiety [55].
Animal models of MI and behaviour
Animal models have also been used to measure behavioural changes after MI. One of the early studies on behaviour in MI rats revealed that MI rats showed more anxious behaviour and less exploratory behaviour and mobility [56]. Rats also showed decreased social interaction. The combination of these behavioural changes matches the range of behavioural symptoms seen in MI patients. Others also found signs of depressive behaviour in rats [57, 58]. There is also a report showing that depressive like behaviour only occurs in a subset of MI rats [59]. Behavioural changes following MI in rats can be modified by medication, as Schoemaker et al. showed that effective cardiovascular drug treatment could prevent part of the behavioural changes associated with MI [60]. A later study found signs of depression in infarcted rats that could be prevented by treatment with the antidepressant drug sertraline [54]. Similarly, MI induced anhedonia in rats could be reversed by treatment with etanercept, a TNF-α blocker [58].
Experimental heart failure in mice also led to behavioural changes associated with decreased exploration and an impaired short term memory, though changes were mild [61]. Signs of
depression after MI were also found by Ito et al., where behavioural changes were linked to higher sympathoactivation and decreased expression of the sigma-1-receptor [62]. In a study by Hong and colleagues, MI in mice led to cognitive impairment that was associated with changes in β-amyloid metabolism and blood brain barrier leakage [29].
Aim of this thesis
In this thesis we investigated behavioural and inflammatory changes in experimental MI in mice and rats. Special attention was paid to microglia activation as measure for neuroinflammation, and the markers TNF-α and neutrophil-gelatinase-associated lipocalin (NGAL).
Both TNF-α and microglia activation were previously shown to be elevated in experimental MI. However, these studies mostly focused their attention on the PVN and the alterations in blood volume regulation and sympathoactivation, rather than on behavioural changes. TNF-α is an interesting candidate to study, since we know there is elevated expression following MI, and in patients with depression plasma TNF-α is often elevated, while in animal MI models, TNF-α in the brain is also elevated. It is hypothesized that the increased permeability of the blood brain barrier by TNF-α is partly responsible for neuroinflammation and behavioural effects following MI [27]. NGAL is interesting to us, since a study in our group found NGAL as highly upregulated following TNF-α stimulation in neurons, astrocytes and microglia [41]. We later showed plasma NGAL was associated with depressive symptoms in heart failure patients [24].
This thesis will describe changes in behaviour, TNF-α, microglia and NGAL following MI in animal models. The goal is to shed light on neuroinflammatory pathways that might be critically involved in the development of mental dysfunction following MI.
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