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Curr Med Chem. Author manuscript; available in PMC 2016 June 27.
Published in final edited form as:
PMCID: PMC4922792
NIHMSID: NIHMS794021

Disturbed Tryptophan Metabolism in Cardiovascular Disease

Abstract

Atherosclerosis (AS), a major pathologic consequence of obesity, is the main etiological factor of cardiovascular disease (CVD), which is the most common cause of death in the western world. A systemic chronic low grade immune-mediated inflammation (scLGI) is substantially implicated in AS and its consequences. In particular, pro-inflammatory cytokines play a major role, with Th1-type cytokine interferon-γ (IFN-γ) being a key mediator. Among various other molecular and cellular effects, IFN- γ activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, dendritic, and other cells, which, in turn, decreases serum levels of the essential amino acid tryptophan (TRP). Thus, people with CVD often have increased serum kynurenine to tryptophan ratios (KYN/TRP), a result of an increased TRP breakdown. Importantly, increased KYN/TRP is associated with a higher likelihood of fatal cardiovascular events. A scLGI with increased production of the proinflammatory adipokine leptin, in combination with IFN-γ and interleukin-6 (IL-6), represents another central link between obesity, AS, and CVD. Leptin has also been shown to contribute to Th1-type immunity shifting, with abdominal fat being thus a direct contributor to KYN/TRP ratio. However, TRP is not only an important source for protein production but also for the generation of one of the most important neurotransmitters, 5-hydroxytryptamine (serotonin), by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. In prolonged states of scLGI, availability of free serum TRP is strongly diminished, affecting serotonin synthesis, particularly in the brain. Additionally, accumulation of neurotoxic KYN metabolites such as quinolinic acid produced by microglia, can contribute to the development of depression via NMDA glutamatergic stimulation. Depression had been reported to be associated with CVD endpoints, but it most likely represents only a secondary loop connecting excess adipose tissue, scLGI and cardiovascular morbidity and mortality. Accelerated catabolism of TRP is further involved in the pathogenesis of the anemia of scLGI. The pro-inflammatory cytokine IFN-γ suppresses growth and differentiation of erythroid progenitor cells, and the depletion of TRP limits protein synthesis and thus hemoglobin production, and, through reduction in oxygen supply, may contribute to ischemic vascular disease. In this review we discuss the impact of TRP breakdown and the related complex mechanisms on the prognosis and individual course of CVD. Measurement of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio will contribute to a better understanding of the interplay between inflammation, metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorable outcome in patients with CVD. The review leads to a novel framework for successful therapeutic modification of several cardinal pathophysiological processes leading to adverse cardiovascular outcome.

Keywords: Anemia, cardiovascular disease, chronic immune activation syndrome, mood alteration, tryptophan breakdown

INTRODUCTION

L-tryptophan (TRP) is an essential amino acid for the biosynthesis of proteins. The following products of TRP are involved in other important biologic processes: (i) 5-hydroxytryptamine, serotonin, formed by TRP 5-hydroxylase (T5H) following decarboxylation, (ii) kynurenine, formed by TRP 2,3-dioxygenase (TDO); and indoleamine 2,3-dioxygenase (IDO) (Fig. 1).

Fig. 1
Tryptophan metabolism. Tryptophan 5-hydoxylase (T5H) catabolizes the synthesis of 5-hydroxytryptamin (serotonin); tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) initiate the formation of kynurenine.

Tryptophan 2,3-dioxygenase and IDO initiate the first step in the catabolism of TRP. This is called the “kynurenine-pathway” leading to nicotinic acid, the vitamin niacin, and nicotinamide adenine dinucleotides, as end products [1]. Tryptophan 2,3-dioxygenase originates predominantly in the liver and can be induced by a variety of molecules (e.g. cortisol). Indoleamine 2,3-dioxygenase is expressed by various cells, and its main inducer is the Th1-type cytokine IFN-γ [25]. Both, TDO and IDO catalyze the first step in TRP breakdown, leading to the formation of N-formylkynurenine which is subsequently deformylated to kynurenine (KYN). Interferon-γ is the most potent in vitro and in vivo stimulator for IDO. Tryptophan 2,3-dioxygenasebreakdown was detected in antigen-presenting cells like monocyte-derived macrophages, dendritic cells, fibroblasts and other cells [25] (Fig. 2) as well as in humans after injection of IFN-γ [6].

Fig. 2
The Th1 cytokine interferon-γ (IFN-γ) is released during the innate and adaptive immune response. It induces the enzyme indoleamine 2,3-dioxygenase (IDO) in macrophages, dendritic and other cells.

Although less effective, other cytokines or lipopolysaccharides may also induce IDO [68]. An in vivo, enhanced cytokine-induced breakdown of TRP is usually seen in context of a cellular Th1-weighted immune response. Thus, a decrease of the serum TRP concentration is accompanied by increased KYN or other TRP catabolites [6, 9, 10]. Under physiologic conditions, the KYN levels are related to TRP concentrations. A reduced nutritional intake of TRP decreases endogenous TRP levels, and lower KYN blood levels are detected. The KYN/TRP ratio is a reasonable indicator of the TRP breakdown, and provides a better approach than the analysis of the absolute TRP or KYN concentrations. A concomitant immune system activation is essential to refer TRP breakdown to the activation of IDO and not to TDO [11, 12]. Thus, activated IDO is present when KYN/TRP and immune activation parameters, especially IFN-γ are positively correlated. Neopterin, which can be easily measured in body fluids or cell culture supernatants, is another sensitive diagnostic marker to monitor a Th1-type immune activation in humans and animal models [13].

Elevated neopterin concentration is also an independent marker for CVD and a predictor of future cardiovascular events in patients with coronary artery disease [12]. In patients with stable angina pectoris, systemic markers of IFN-γ activity, plasma neopterin, and plasma KYN/TRP provide similar risk estimates for major coronary events and mortality. Interferon-γ levels were positively correlated with acute atherosclerotic complications [14], and KYN/TRP levels at admission predicted the later outcome in patients with acute stroke [15]. Obesity and metabolic syndrome (MetS) are important conditions associated with an increased cardiovascular risk. We showed recently that the TRP-KYN metabolism was found to be essentially dysregulated in obese persons in dependence of age and parameters of the MetS [16].

TRYPTOPHAN METABOLISM IS INVOLVED IN ENDOTHELIUM DERIVED BLOOD PRESSURE CONTROL AND MICROVASCULAR REACTIVITY IN SEPSIS AND STROKE

Blood pressure control has a major influence on the clinical course of CVD. Induction of endotoxemia in mice led to increased endothelial expression of IDO, constitutively expressed in all endothelial cells, with decreased TRP/KYN and reduced blood pressure [17]. Pharmacological inhibition of IDO increased blood pressure in these mice but not in mice deficient in either IDO or IFN-γ which is required for IDO induction [17]. Further, both TRP and KYN dilated preconstricted porcine coronary arteries [17]. Whereas the dilating effect of TRP required the presence of active IDO and an intact endothelium, the effect of KYN was endothelium independent. The KYN induced arterial relaxation was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Thus, IDO mediated TRP metabolism may be centrally involved in the regulatory mechanisms of the vascular tone [17]. On the other hand, it was shown that an increased IDO activity (measured by KYN/TRP ratio in patients suffering from sepsis) caused a potent inhibition of the inducible nitric oxide synthase (iNOS) [18]. Obviously, there is a complex interaction between the vasodilatators NO and IDO which appear to reciprocally inhibit each other. This interaction may have a major contribution to the microvascular reactivity in serious clinical conditions like myocardial infarction, sepsis and stroke. Specifically, activation of IDO and higher concentrations of several KYN metabolites have been observed post-stroke, where they have been associated with increased mortality and the development of post-stroke cognitive impairment [19]. It sounds inconsistent that despite IDO and KYN act as arterial relaxing factors [20] they are associated with increased post-stroke mortality and cognitive impairment. A probable explanation is that both IDO and KYN are produced due to inflammation as a kind of feedback mechanism to counteract the vasoconstriction mediated by proinflammatory events. Nevertheless, this beneficial effect is probably too weak to achieve a sustained compensation of the negative effects of local and systemic inflammation in the wake of severe stroke events.

TRYPTOPHAN METABOLISM, MOOD DISORDER, AND CARDIOVASCULAR EVENTS - “CHICKEN OR THE EGG?”

Tryptophan breakdown leads to reduced serotonin availability. Thus, increased TRP catabolism was proposed as a pathway leading to mood dysregulation [1]. Furthermore, syndromal depression and adjustment disorder with depressed mood were proposed as contributors to CVD and myocardial infarction (“broken heart syndrome”) [21, 22]. Moreover, increased cardiovascular comorbidity and adverse cardiovascular eventendpoints have been reported in subjects with depressive mood disorders [2325]. Reciprocally, evidence exists that an immune-mediated scLGI like seen in CVD, is also involved in the pathophysiology of mood disorders [25, 26], and in turn, episodes of mood disorders can result in elevated inflammation markers [27, 28]. This is confirmed by the observation that a sucessful treatment of depression and mania with antidepressive and antipsychotic drugs leads to a decreased activity of the systemic inflammation seen in these patients [29, 30].

Obesity and MetS are known contributors to increased mortality in patients with bipolar disorders [3133]. Moreover, obesity worsens the course and prognosis of mood disorders, with longer episodes, shorter inter-episode intervals, and higher rates of suicidality [34]. Proposed underlying mechanisms include a Th1-weighted T-helper cell activation shunting TRP from production of serotonin to KYN and its neuroactive metabolites. Details of the complex involvement of TRP metabolism in serotonin availability, mood alterations, inflammation and CVD are shown in (Fig. 3).

Fig. 3
The complex involvement of TRP metabolism in serotonin availability, mood alterations, T-cell mediated inflammation and clinical endpoints of CVD.

Multiple studies found evidence for TRP depletion as well as IDO activation in mood disorders [3537]. Consistently, we recently reported that patients with bipolar disorder have elevated KYN and KYN/TRP ratios than mentally healthy control participants [38]. Moreover, concentrations of KYN and KYN/TRP were significantly increased in overweight compared to normal-weight bipolar patients [38]. Other studies demonstrated activated T-cells, presumably of the Th1 subtype, over the whole course of manic-depressive illness [39]. Notably, the catabolic KYN pathway contributes to the neuroprotective–neurodegenerative/neurotoxic changes via production of kynureninic acid and quinolinic acid [40]. Additionally, activation of the KYN pathway promotes generation of ROS and lipid peroxidation essentially involved in the oxidative stress as a consequence of chronic inflammation [41]. These molecular changes, involved in both AS and mood disorders could underlie the bi-directional association between mood disorders and cardiovascular disease, as well as other inflammation-mediated medical conditions [42].

Considering the IDO-mediated interplay between TRP breakdown, Th1-type immune activation, and neuroendocrine alterations, it appears that mood alterations in CVD subjects are more likely the “egg” laid by a “hen” named cLGI caused by the atherosclerotic vascular burden and an obesogenic lifestyle.

Nevertheless, ascribe the mood alterations in CVD only on scLGI is not rigorous. In addition, the feeling of helplessness or lack of social support can also play important roles [4347] although the disturbed neurotransmitter environment may again represent an important determinant which increases the susceptibilty for improper handling of such psychologic traits.

TRYPTOPHAN METABOLISM AND MELATONIN: SPECIFIC LINKS TO CARDIOVASCULAR DISEASE

Melatonin, being derived from L-tryptophan, is produced by the pineal gland during the biological (“internal”) night driven by the master circadian pacemaker in the hypothalamus, and released in dim light or darkness [48]. Impaired melatonin synthesis has been shown to be associated with age-related conditions including CVD [4951]. A disrupted maturation of the photoneuroendocrine system caused by a genetic absence or mutation of genes involved in melatonin synthesis (including TRP hydroxylase) has been shown to cause an imbalance in the crosstalk among serotonin, progesterone, catecholamines and intracellular calcium [52]. Hence, an impaired TRP catabolism with successive melatonin deficiency may favor CVD by abnormal hormone levels (e.g. blood pressure increase through water retention by aldosterone) [53]. In addition, evidence is cumulating that melatonin has anti-inflammatory, antioxidant, antihypertensive, and possibly antilipidemic properties [54]. For example, treatment with melatonin ameliorated the symptoms of MetS and decreased blood levels of low-density lipoprotein cholesterol (LDL-C) [55]. Further, melatonin has been shown to significantly suppress the formation of cholesterol and reduce LDL-C in isolated human mononuclear leucocytes [56]. In vitro studies have given evidence for antioxidant actions of melatonin on LDL-C oxidation [57]. In keeping with this, Dominguez-Rodriguez et al. [58] reported a relationship between nocturnally elevated oxidized serum LDL-C and reduced circulating melatonin levels in patients with acute myocardial infarction. Hence, treatment with melatonin reduces blood pressure in rodents [59] and humans [55, 60]. Integrating the previously described evidence, it may be possible that decreased melatonin secretion secondary to increased TRP breakdown could represent an additional pathophysiological pathway towards CVD in patients with scLGI of various cause, including obesity.

TRYPTOPHAN METABOLISM, ANEMIA, CHRONIC INFLAMMATION, AND CARDIOVASCULAR DISEASE

Pro-inflammatory cytokines like IFN-γ and TNF-α suppress the growth and differentiation of erythroid progenitor cells [61]. Patients with anemia of chronic inflammation had decreased TRP plasma levels positively correlated with a drop in hemoglobin [62]. Thus, IFN-γ induced TRP deprivation may play a central role in the cytokine induced suppression of hematopoieses seen in patients with chronic systemic inflammation. With respect to scLGI in patients in coronary artery disease, anemia is probably “a player” rather than a “bystander” because it worsens the oxygenation of the myocardial tissue already reduced by the mechanical process of coronary obstruction [63]. Additionally, the tachycardia of anemia increases the myocardial oxygen demand. This paves the way for a higher probability of fatal outcomes. Taken together, scLGI, anemia and immune (T-cell) dysfunction, based on an insufficient TRP supply due to IDO activation, may have a robust effect on mortality in CVD patients.

TRYPTOPHAN METABOLISM, AGING, IMMUNE FUNCTION, AND CARDIOVASCULAR RISK

Systemic chronic low grade immune-mediated inflammation in aging induces alterations in two enzymatic pathways, the IDO and the guanosine-triphosphate-cyclohydrolase-1 (GTP-CH1) pathways, both involved in the biosynthesis of monoamines [64] and potential neuropsychiatric symptoms. KYN/TRP was found significantly higher in nonagenarians compared with controls [65]. In a similar way elevated neopterin levels have been described in nonagenerians and being associated with a shorter residual life span [66]. Further, IDO activity predicted subsequent mortality in nonagenarians [65]. As an important regulatory mechanism in the immune system, increased IDO activity downregulates T cell functions. As aging of the immune system has been previously associated with a decline in T cell function [67], it seems justified to consider increased IDO activity as an important mechanism involved in the decline of T cell responses in immunosenescence [65]. Thus, accelerated TRP catabolism could be a modifiable step on this causal pathway. As T-cells play an important role in the process of progression of CVD towards MI, a suppressed T cell function is expected to be beneficial rather than detrimental to the incidence of coronary events, conceptually supported by the low MI rates in subjects > 85 years. On the other hand, IDO may have a detrimental role in early AS, particularly in young female adults [68]. In these subjects, IDO activity correlated significantly with several risk factors for AS, i.e. with LDL-cholesterol, BMI, and inversely with HDL-C and triglyceride. Thus, IDO may be involved in the immune regulation of AS in a gender and age dependent way.

TRYPTOPHAN METABOLISM AND GENETIC LINKAGE TO IFN-γ CODING GENES

Raitala et al. reported that the TRP catabolism appears to be genetically moderated by the IFN-γ gene and may thus be operative in disease conditions associated with certain IFN-γ gene polymorphisms [69]. Specifically, interferon-γ+874(T/A) genotypes are known to have an effect on IFN-γ production. The high producer T allele was associated with an increased IDO activity (i.e. elevated KYN/TRP) in females. Hence, it would be worthwhile to investigate if the previously reported IDO associated increased AS risk factors seen in young females [68] are associated with the IFN-γ risk alleles [69].

THERAPEUTIC CONSIDERATIONS

To achieve a normalization of the TRP metabolism would be an important goal for the treatment of related symptoms in patients suffering from CVD. For instance, administration of the IDO-inhibitor 1-methyl tryptophan [70] may represent a relevant pharmacological approach to be considered for future investigation. However, IDO is well known for its immunosuppressive properties, and inhibiting it may prove detrimental, as it may boost proinflammatory mechanisms. Likewise, an elevated KYN/TRP ratio might represent a natural response of the human immune system to counteract inflammation. Also anti-inflammatory drugs such as aspirin and salicylic acid [71] but also statins [72] may affect the IDO mediated pathways. Specifically, Atorvastatin suppresses INF-γ-induced neopterin formation and TRP depletion in human peripheral blood mononuclear cells and in monocytic cell lines [72]. Moreover, immunosuppressants like rapamycin [73] counteract IDO induction during the pro-inflammatory response in vitro. The same is true for several natural compounds with anti-inflammatory properties and with immunosuppressant capacity in vitro, e.g., resveratrol [74]. Finally, melatonin seems to have cardioprotective properties via its direct free radical scavenger and its indirect antioxidant activity [75].

CONCLUDING REMARKS

Within this review we generated substantial evidence that the Th1-type cytokine IFN-γ causes increased IDO activity which ultimately decreases serum levels of the essential amino acid TRP. As a scLGI with activation of certain T-cell subsets (Th1, less Th2) [76] is usually present in patients with CVD, these subjects have an increased IDO activation leading to an increased TRP breakdown with an increased KYN/TRP ratio. Importantly, elevated KYN and KYN/TRP indicate a higher likelihood of cardiovascular fatalities. As shown in our recently published observations [77], increased production of the proinflammatory adipokine leptin in combination with interleukin-6 (IL-6), represents another link between obesity and early occurrence of mediators of AS. Leptin has also been shown to upregulate Th1-type immunity, and increased abdominal fat, an important source of leptin, leads to increased KYN/TRP [16].

In prolonged states of scLGI, availability of free serum TRP is persistently diminished, and thus, serotonergic functions are affected. Accumulation of neuroactive KYN metabolites such as quinolinic acid is neurotoxic and may contribute to mood dysregulation, previously implicated in increased likelihood of myocardial infarction. However, the data reviewed in this article suggest that mood disorders appear to more likely be a consequence of scLGI/and an epiphenomenon rather than a mediating step of cardiovascular events.

More importantly for CVD, accelerated catabolism of TRP is centrally involved in the pathogenesis of the anemia of scLGI. IFN-γ suppresses erythroid progenitor cells, and the depletion of TRP decreases hemoglobin production. Anemia caused by scLGI and increased TRP breakdown add to the detrimental effects of pre-existent reduced vascular reserves.

Measurement of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio are important predictors of an unfavourable outcome in patients with CVD. It will be important to investigate if these parameters can provide a basis for more successful and precise biologically grounded therapeutic protocols to further reduce cardiovascular morbidity and mortality.

Acknowledgments

This work was supported by funding under the european FP7 program “NanoAthero”- NMP4-LA-2012-3099820. We want to thank further Dr. Florian Prueller, Clinical Institute of Medical and Chemical Laboratory Diagnosis, Graz, Austria for the expert technical assistance.

Footnotes

CONFLICT OF INTEREST

The author(s) confirm that this article content has no conflicts of interest.

References

1. Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta. 2006;364(1–2):82–90. [PubMed]
2. Yoshida R, Imanishi J, Oku T, Kishida T, Hayaishi O. Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc Natl Acad Sci USA. 1981;78(1):129–132. [PubMed]
3. Werner ER, Bitterlich G, Fuchs D, Hausen A, Reibnegger G, Szabo G, Dierich MP, Wachter H. Human macrophages degrade tryptophan upon induction by interferon-gamma. Life Sci. 1987;41(3):273–280. [PubMed]
4. Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol. 2000;164(7):3596–3599. [PubMed]
5. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 1991;5(11):2516–2522. [PubMed]
6. Byrne GI, Lehmann LK, Kirschbaum JG, Borden EC, Lee CM, Brown RR. Induction of tryptophan degradation in vitro and in vivo: a gamma-interferon-stimulated activity. J Interferon Res. 1986;6(4):389–396. [PubMed]
7. Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H. Characteristics of interferon induced tryptophan metabolism in human cells in vitro. Biochim Biophys Acta. 1989;1012(2):140–147. [PubMed]
8. Weiss G, Murr C, Zoller H, Haun M, Widner B, Ludescher C, Fuchs D. Modulation of neopterin formation and tryptophan degradation by Th1- and Th2-derived cytokines in human monocytic cells. Clin Exp Immunol. 1999;116(3):435–440. [PubMed]
9. Schroecksnadel K, Frick B, Winkler C, Fuchs D. Crucial role of interferon-gamma and stimulated macrophages in cardiovascular disease. Curr Vasc Pharmacol. 2006;4(3):205–213. [PubMed]
10. Wirleitner B, Rudzite V, Neurauter G, Murr C, Kalnins U, Erglis A, Trusinskis K, Fuchs D. Immune activation and degradation of tryptophan in coronary heart disease. Eur J Clin Invest. 2003;33(7):550–554. [PubMed]
11. Fuchs D, Moller AA, Reibnegger G, Stockle E, Werner ER, Wachter H. Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. J Acquir Immune Defic Syndr. 1990;3(9):873–876. [PubMed]
12. Widner B, Werner ER, Schennach H, Wachter H, Fuchs D. Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clin Chem. 1997;43(12):2424–2426. [PubMed]
13. Murr C, Gerlach D, Widner B, Dierich MP, Fuchs D. Neopterin production and tryptophan degradation in humans infected by Streptococcus pyogenes. Med Microbiol Immunol. 2001;189(3):161–163. [PubMed]
14. Pedersen ER, Midttun O, Ueland PM, Schartum-Hansen H, Seifert R, Igland J, Nordrehaug JE, Ebbing M, Svingen G, Bleie O, Berge R, Nygard O. Systemic markers of interferon-gamma-mediated immune activation and long-term prognosis in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2011;31(3):698–704. [PubMed]
15. Brouns R, Verkerk R, Aerts T, De Surgeloose D, Wauters A, Scharpe S, De Deyn PP. The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke. Neurochem Res. 2010;35(9):1315–1322. [PubMed]
16. Mangge H, Summers KL, Meinitzer A, Zelzer S, Almer G, Prassl R, Schnedl WJ, Reininghaus E, Paulmichl K, Weghuber D, Fuchs D. Obesity-related dysregulation of the Tryptophan-Kynurenine metabolism: Role of age and parameters of the metabolic syndrome. Obesity (Silver Spring) 2014;22(1):195–201. [PubMed]
17. Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF, Jr, Hunt NH, Stocker R. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med. 2010;16(3):279–285. [PMC free article] [PubMed]
18. Darcy CJ, Davis JS, Woodberry T, McNeil YR, Stephens DP, Yeo TW, Anstey NM. An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function. PLoS One. 2011;6(6):e21185. [PMC free article] [PubMed]
19. Gold AB, Herrmann N, Swardfager W, Black SE, Aviv RI, Tennen G, Kiss A, Lanctot KL. The relationship between indoleamine 2,3-dioxygenase activity and post-stroke cognitive impairment. J Neuroinflammation. 2011;8:17. [PMC free article] [PubMed]
20. Hofmann F. Ido brings down the pressure in systemic inflammation. Nat Med. 2010;16(3):265–267. [PubMed]
21. Benninghoven D, Kaduk A, Wiegand U, Specht T, Kunzendorf S, Jantschek G. Influence of anxiety on the course of heart disease after acute myocardial infarction - risk factor or protective function? Psychother Psychosom. 2006;75(1):56–61. [PubMed]
22. Lewis S. Broken heart syndrome: perspectives from East and West. Adv Mind Body Med. 2005;21(2):3–5. [PubMed]
23. Kuehl LK, Penninx BW, Otte C. Depression: risk factor for cardiovascular disease. Nervenarzt. 2012;83(11):1379–1384. [PubMed]
24. Goldstein MM. Depression–An independent risk factor for cardiovascular disease. JAAPA. 2006;19(9):40–42. 44, 46. [PubMed]
25. Patel A. Review: the role of inflammation in depression. Psychiatr Danub. 2013;25(Suppl 2):S216–S223. [PubMed]
26. Langan C, McDonald C. Neurobiological trait abnormalities in bipolar disorder. Mol Psychiatry. 2009;14(9):833–846. [PubMed]
27. Wium-Andersen MK, Orsted DD, Nielsen SF, Nordestgaard BG. Elevated C-reactive protein levels, psychological distress, and depression in 73, 131 individuals. JAMA Psychiatr. 2013;70(2):176–184. [PubMed]
28. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37(1):137–162. [PMC free article] [PubMed]
29. Baune BT, Eyre H. Anti-inflammatory effects of antidepressant and atypical antipsychotic medication for the treatment of major depression and comorbid arthritis: a case report. J Med Case Rep. 2010;4:6. [PMC free article] [PubMed]
30. Alikhan SM, Lee JA, Dratcu L. Mirtazapine treatment of a severe depressive episode and resolution of elevated inflammatory markers. Case Rep Psychiatr. 2013;2013:697872. [PMC free article] [PubMed]
31. Kupfer DJ. The increasing medical burden in bipolar disorder. JAMA. 2005;293(20):2528–2530. [PubMed]
32. McIntyre RS. Overview of managing medical comorbidities in patients with severe mental illness. J Clin Psychiatr. 2009;70(6):e17. [PubMed]
33. McIntyre RS, Soczynska JK, Beyer JL, Woldeyohannes HO, Law CW, Miranda A, Konarski JZ, Kennedy SH. Medical comorbidity in bipolar disorder: re-prioritizing unmet needs. Curr Opin Psychiatr. 2007;20(4):406–416. [PubMed]
34. Goldstein BI, Liu SM, Schaffer A, Sala R, Blanco C. Obesity and the three-year longitudinal course of bipolar disorder. Bipolar Disord. 2013;15(3):284–293. [PMC free article] [PubMed]
35. Myint AM, Bondy B, Baghai TC, Eser D, Nothdurfter C, Schule C, Zill P, Muller N, Rupprecht R, Schwarz MJ. Tryptophan metabolism and immunogenetics in major depression: a role for interferon-gamma gene. Brain Behav Immun. 2013;31:128–133. [PubMed]
36. Myint AM, Kim YK. Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Prog Neuropsychopharmacol Biol Psychiatr. 2014;48:304–313. [PubMed]
37. Rosenblat JD, Cha DS, Mansur RB, McIntyre RS. Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatr. 2014 [PubMed]
38. Reininghaus EZ, McIntyre RS, Reininghaus B, Geisler S, Bengesser SA, Lackner N, Hecht K, Birner A, Kattnig F, Unterweger R, Kapfhammer HP, Zelzer S, Fuchs D, Mangge H. Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report. Bipolar Disord. 2013 [Epub Ahead of Print] [PubMed]
39. Breunis MN, Kupka RW, Nolen WA, Suppes T, Denicoff KD, Leverich GS, Post RM, Drexhage HA. High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder. Biol Psychiatr. 2003;53(2):157–165. [PubMed]
40. Myint AM. Kynurenines: from the perspective of major psychiatric disorders. FEBS J. 2012;279(8):1375–1385. [PubMed]
41. Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yucel M, Gama CS, Dodd S, Dean B, Magalhaes PV, Amminger P, McGorry P, Malhi GS. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35(3):804–817. [PubMed]
42. Wirleitner B, Neurauter G, Schrocksnadel K, Frick B, Fuchs D. Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr Med Chem. 2003;10(16):1581–1591. [PubMed]
43. Carney RM, Blumenthal JA, Freedland KE, Stein PK, Howells WB, Berkman LF, Watkins LL, Czajkowski SM, Hayano J, Domitrovich PP, Jaffe AS. Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch Intern Med. 2005;165(13):1486–1491. [PubMed]
44. Duivis HE, de Jonge P, Penninx BW, Na BY, Cohen BE, Whooley MA. Depressive symptoms, health behaviors, and subsequent inflammation in patients with coronary heart disease: prospective findings from the heart and soul study. Am J Psychiatr. 2011;168(9):913–920. [PubMed]
45. Elderon L, Whooley MA. Depression and cardiovascular disease. Prog Cardiovasc Dis. 2013;55(6):511–523. [PubMed]
46. House JS. Social isolation kills, but how and why? Psychosom Med. 2001;63(2):273–274. [PubMed]
47. Robles TF, Kiecolt-Glaser JK. The physiology of marriage: pathways to health. Physiol Behav. 2003;79(3):409–416. [PubMed]
48. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev. 1991;12(2):151–180. [PubMed]
49. Sakotnik A, Liebmann PM, Stoschitzky K, Lercher P, Schauenstein K, Klein W, Eber B. Decreased melatonin synthesis in patients with coronary artery disease. Eur Heart J. 1999;20(18):1314–1317. [PubMed]
50. Altun A, Yaprak M, Aktoz M, Vardar A, Betul UA, Ozbay G. Impaired nocturnal synthesis of melatonin in patients with cardiac syndrome X. Neurosci Lett. 2002;327(2):143–145. [PubMed]
51. Yaprak M, Altun A, Vardar A, Aktoz M, Ciftci S, Ozbay G. Decreased nocturnal synthesis of melatonin in patients with coronary artery disease. Int J Cardiol. 2003;89(1):103–107. [PubMed]
52. Weissbluth L, Weissbluth M. Sudden infant death syndrome: a genetically determined impaired maturation of the photoneuroendocrine system. A unifying hypothesis. J Theor Biol. 1994;167(1):13–25. [PubMed]
53. Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, Emoto N, Okuno Y, Tsujimoto G, Kanematsu A, Ogawa O, Todo T, Tsutsui K, van der Horst GT, Okamura H. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nat Med. 2010;16(1):67–74. [PubMed]
54. Dominguez-Rodriguez A, Abreu-Gonzalez P, Sanchez-Sanchez JJ, Kaski JC, Reiter RJ. Melatonin and circadian biology in human cardiovascular disease. J Pineal Res. 2010;49(1):14–22. [PubMed]
55. Kozirog M, Poliwczak AR, Duchnowicz P, Koter-Michalak M, Sikora J, Broncel M. Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. J Pineal Res. 2011;50(3):261–266. [PubMed]
56. Muller-Wieland D, Behnke B, Koopmann K, Krone W. Melatonin inhibits LDL receptor activity and cholesterol synthesis in freshly isolated human mononuclear leukocytes. Biochem Biophys Res Commun. 1994;203(1):416–421. [PubMed]
57. Kelly MR, Loo G. Melatonin inhibits oxidative modification of human low-density lipoprotein. J Pineal Res. 1997;22(4):203–209. [PubMed]
58. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez M, Ferrer-Hita J, Vargas M, Reiter RJ. Elevated levels of oxidized low-density lipoprotein and impaired nocturnal synthesis of melatonin in patients with myocardial infarction. Atherosclerosis. 2005;180(1):101–105. [PubMed]
59. Kawashima K, Miwa Y, Fujimoto K, Oohata H, Nishino H, Koike H. Antihypertensive action of melatonin in the spontaneously hypertensive rat. Clin Exp Hypertens A. 1987;9(7):1121–1131. [PubMed]
60. Cagnacci A, Soldani R, Yen SS. Melatonin enhances cortisol levels in aged women: reversible by estrogens. J Pineal Res. 1997;22(2):81–85. [PubMed]
61. Fuchs D, Hausen A, Reibnegger G, Werner ER, Werner-Felmayer G, Dierich MP, Wachter H. Immune activation and the anaemia associated with chronic inflammatory disorders. Eur J Haematol. 1991;46(2):65–70. [PubMed]
62. Weiss G, Schroecksnadel K, Mattle V, Winkler C, Konwalinka G, Fuchs D. Possible role of cytokine-induced tryptophan degradation in anaemia of inflammation. Eur J Haematol. 2004;72(2):130–134. [PubMed]
63. Leshem-Rubinow E, Steinvil A, Rogowski O, Zeltser D, Berliner S, Weitzman D, Raz R, Chodick G, Shalev V. Hemoglobin nonrecovery following acute myocardial infarction is a biomarker of poor outcome: A retrospective database study. Int J Cardiol. 2013;169(5):349–353. [PubMed]
64. Capuron L, Schroecksnadel S, Feart C, Aubert A, Higueret D, Barberger-Gateau P, Laye S, Fuchs D. Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol Psychiatr. 2011;70(2):175–182. [PubMed]
65. Pertovaara M, Raitala A, Lehtimaki T, Karhunen PJ, Oja SS, Jylha M, Hervonen A, Hurme M. Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality. Mech Ageing Dev. 2006;127(5):497–499. [PubMed]
66. Solichova D, Melichar B, Blaha V, Klejna M, Vavrova J, Palicka V, Zadak Z. Biochemical profile and survival in nonagenarians. Clin Biochem. 2001;34(7):563–569. [PubMed]
67. Palmer DB. The Effect of Age on Thymic Function. Front Immunol. 2013;4:316. [PMC free article] [PubMed]
68. Pertovaara M, Raitala A, Juonala M, Lehtimaki T, Huhtala H, Oja SS, Jokinen E, Viikari JS, Raitakari OT, Hurme M. Indoleamine 2,3-dioxygenase enzyme activity correlates with risk factors for atherosclerosis: the Cardiovascular Risk in Young Finns Study. Clin Exp Immunol. 2007;148(1):106–111. [PubMed]
69. Raitala A, Pertovaara M, Karjalainen J, Oja SS, Hurme M. Association of interferon-gamma +874(T/A) single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals. Scand J Immunol. 2005;61(4):387–390. [PubMed]
70. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281(5380):1191–1193. [PubMed]
71. Schroecksnadel K, Winkler C, Wirleitner B, Schennach H, Fuchs D. Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro. Clin Exp Immunol. 2005;140(1):41–45. [PubMed]
72. Neurauter G, Wirleitner B, Laich A, Schennach H, Weiss G, Fuchs D. Atorvastatin suppresses interferon-gamma -induced neopterin formation and tryptophan degradation in human peripheral blood mononuclear cells and in monocytic cell lines. Clin Exp Immunol. 2003;131(2):264–267. [PubMed]
73. Schroecksnadel S, Sucher R, Kurz K, Fuchs D, Brandacher G. Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells. Transpl Immunol. 2011;25(2–3):119–123. [PubMed]
74. Jenny M, Klieber M, Zaknun D, Schroecksnadel S, Kurz K, Ledochowski M, Schennach H, Fuchs D. In vitro testing for anti-inflammatory properties of compounds employing peripheral blood mononuclear cells freshly isolated from healthy donors. Inflamm Res. 2011;60(2):127–135. [PubMed]
75. Tengattini S, Reiter RJ, Tan DX, Terron MP, Rodella LF, Rezzani R. Cardiovascular diseases: protective effects of melatonin. J Pineal Res. 2008;44(1):16–25. [PubMed]
76. Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Cytokine network and T cell immunity in atherosclerosis. Semin Immunopathol. 2009;31(1):23–33. [PubMed]
77. Stelzer I, Zelzer S, Raggam RB, Pruller F, Truschnig-Wilders M, Meinitzer A, Schnedl WJ, Horejsi R, Moller R, Weghuber D, Reeves G, Postolache TT, Mangge H. Link between leptin and interleukin-6 levels in the initial phase of obesity related inflammation. Transl Res. 2012;159(2):118–124. [PubMed]