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doi: 10.1111/j.1742-1241.2007.01640.x REVIEW ARTICLE New insights into the link between cardiovascular disease and depression S. A. Mosovich,1 R. T. Boone,2 A. Reichenberg,1 S. Bansilal,1 J. Shaffer,3 K. Dahlman,1 P. D. Harvey,4 M. E. Farkouh5 Linked Comment: Puri. Int J Clin Pract 2008; 62: 355–7. 1 SUMMARY Review Criteria Introduction: Although the association between depression and cardiovascular disease (CVD) is well documented, the underlying mechanisms for this relationship remain unclear. In this paper, we present three possible models which account for the comorbidity between depression and cardiovascular disease. Models: The first model outlines depression as a risk factor for CVD and the second model presents CVD as a risk factor for depression. The third model proposes a common underlying pathway related to the effects of chronic stress on the body in manifesting as depression or cardiovascular disease. Conclusions: If the proposed model holds true, it may be possible that an intervention initiated before overt manifestations of CVD or depression become apparent, may delay or prevent the onset of these serious clinical entities. Introduction The association between depression and vascular disease is well documented. Meta-analyses have indicated that depression is associated with an increased risk of developing coronary heart disease (CHD) in healthy individuals (1,2). Early longitudinal studies of CHD mortality found that, in many patients, depression or other mood disorders preceded death from myocardial infarction (MI) (3–5). Forty-five per cent of postmyocardial patients suffered from either minor or major depression symptoms (6,7), and it has been estimated that between 17% and 27% of patients with coronary artery disease (CAD) suffer from major depression, and a significantly larger percentage has subsyndromal symptoms of depression. The precise mechanisms by which depression and vascular disease are linked remain largely unknown. In particular, the direction of causation is not understood, and numerous studies conducted in recent years have suggested both that depression is a risk factor for cardiovascular disease (CVD) and that CVD is a risk factor for depression. Such a reciprocal relationship allows for three possibilities: (i) CVD causes depression (Figure 1A); (ii) depression causes CVD (Figure 1B) or (iii) both CVD and depression are caused by a common underlying factor (Figure 1C). Statistically, it is impossible to disentan- Our theory emerged from authors’ extensive clinical practice, reading of recent journals and feedback from reviewers. Message for the Clinic Cardiovascular disease and depression may be linked via a common underlying process. Specifically, pro-inflammatory cytokines may disrupt serotonin levels and subsequent platelet aggregation, causing both depression and arteriosclerosis. gle the first two models as the correlation between CVD and depression is bi-directional in cross-sectional research. Further, the picture can be further clouded as the relationship between depression and vascular disease is likely to be influenced by lifestyle choices that affect each independently. For example, behaviours such as smoking, sedentarism or poor diet can contribute, either directly or indirectly, to the development of both vascular disease and depression (8–10). Nevertheless, the robust comorbidity of vascular disease and depression invites conceptual models to explain the pathophysiological processes underlying both illnesses. A common underlying factor that leads to both CVD and depression, if the appropriate mechanism is identified, provides a more comprehensive and parsimonious explanation than trying to determine whether CVD causes depression or vice versa. Indeed, if common biological mechanisms for both disorders can be demonstrated, then their interrelationship may be better understood, leading to more effective prevention and treatment of these conditions. Further, such a model also offers new theoretical directions for understanding individual differences in the manifestation of these disorders. In this paper, we present three possible models that account for the comorbidity between depression and cardiovascular disease. The first model which outlines depression as a risk factor for CVD; the ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA 2 Department of Psychology, University of Massachusetts, Dartmouth, MA, USA 3 Department of Psychology, St. Johns University, Jamaica, NY, USA 4 Department of Psychiatry, Emory University, Atlanta, GA, USA 5 Department of Cardiology, Mount Sinai School of Medicine, New York, NY, USA Correspondence to: R. Thomas Boone, PhD, Department of Psychology, University of Massachusetts, Dartmouth, 285 Old Westport Road, North Dartmouth, MA 02747, USA Tel.: + 1 508 999 8440 Fax: + 1 508 999 9169 Email: [email protected] Disclosure The authors have no conflicts of interest to declare as regards this manuscript. 423 424 Link between cardiovascular disease and depression A CVD Depression B Depression CVD C Depression It seems that depression may not only contribute to the onset of CVD, but also heighten its severity (14). Patients with a depressive episode in the month before the first MI have been shown to have a twofold higher risk of cardiac failure compared with non-depressed subjects (19). Even mild depressive symptoms of depression increase mortality risk after acute MI (20). CVD Model no. 2: CVD as a risk factor for depression Common underlying factor (Cytokine and inflammatory response to stress) Figure 1 Three models for comorbidity of cardiovascular disease (CVD) and depression second model which presents CVD as a risk factor for depression and finally a third model which proposes a common underlying factor which leads to depression and CVD. We critically discuss the strengths and limitations and present potential biological correlates for each model. Model no. 1: Depression as a risk factor for CVD Several studies have suggested that a prior history of depression or depressive symptoms is strongly associated with subsequent development of ischaemic heart disease and MI (11–14). Frasure-Smith and Lesperance (15) performed a review of 143 articles on this topic and concluded that depression is a likely cardiac risk factor, although their conclusions were somewhat qualified as they were unable to systematically control for other risk factors, as covariates across the studies included in their analyses. Risk of MI is significantly elevated for up to 10 years after the onset of the first depressive episode (16). Community-based studies have found that pre-existing depressive symptoms predicted not only CHD but also stroke. In a 10-year prospective study, subjects with baseline depressive symptoms were almost three times more likely to suffer an ischaemic stroke during the follow-up period than non-depressed subjects, even after controlling for other cardiovascular risk factors including systolic blood pressure, diabetes, cholesterol level and smoking status (17). Another study with a 16-year average follow-up period reported similar results (18). Research has also suggested that CVD precedes the onset of depression. A study of 222 patients who had experienced MI found that 16% tested for major depression between 5 and 10 days after their initial hospitalisation (21). Hance et al. (22) found that 17% patients who were receiving catheterisation and angiography had major depression and another 17% qualified for minor depression. While the effect was only true for males, Hippisley-Cox et al. (13) found using a community sample in an ambulatory setting that 20% of the CAD subjects had depression, compared with 12% of matched controls with an odds ratio of two, even after controlling for smoking, diabetes, hypertension and socioeconomic status (SES). Several studies have also found increased rates of depression following a stroke event. Robinson et al. (23,24) studied both the short (postevent) and longterm (1–2 years) effect of stroke on depression. They found that 27% of 103 patients qualified for major depression after the stroke event, while follow-up tests of 65 patients showed that 14% continued to have major depression up to 2 years later, although, interestingly, levels of depressed symptoms for diagnosed depression seemed stable while levels of depressed symptoms for the subclinical group appeared to increase. Indeed, another 18% of patients followed over time met criteria for minor depression. Other studies have examined depression in the interim duration (2–6 months) after a stroke. Pohjasvaara et al. (25) evaluated 277 patients for major depression and found that 4 months after stroke, 27% had major depression and 14% had minor depression. In another study, Gainotti et al. (26) found that an increase in the incidence of depressive symptoms as more time elapsed after the stroke. Other studies, which compared poststroke subjects to controls, found that there were significantly higher rates of depression in the stroke group (27–31). Models explaining the mechanism underlying this association have emerged from the imaging literature. Based on imaging studies in geriatric ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 Link between cardiovascular disease and depression populations, it has been hypothesised that depression is a direct outcome of subcortical brain lesions on strategic brain areas caused by cerebral atherosclerosis. Specifically, the lesions may disrupt the striatopallido-thalamo-cortical pathways (32,33). Thus, a possible mechanism linking vascular disease and depression may lie in structural changes resulting from vascular lesions in the prefrontal cortex, subcortical regions, the hippocampus and amygdala – all have been linked to the pathophysiology of depression (32). However, relating CVD to depression using the localisation of lesions in the brain offers no explanation for cases where depression has been shown to precede vascular diseases (34). Another model posits that the relationship between vascular disease and depression results from the way in which blood-borne mediators, activated by stress, profoundly influence mood through effects on brain targets (35). This model takes into consideration a series of events initiated by an initial insult (stress) with systemic implications. Model no. 3: Integrated model, a common underlying factor for cardiovascular disease and depression We have described above evidence for the association between depression and vascular disease. Given the nature of this research, namely correlational, it is statistically impossible to infer the direction of causality. What is needed is a better understanding of the biochemical processes that link these two diseases. However, attempts to pinpoint the biochemical explanation for this association have thus far proved unsatisfactory. Rather than limiting ourselves to the causal, bi-directional relationships described above, we propose a new model; that depression and CVD share a common underlying cause; the two illnesses are two possible outcomes that result from prior stress related insult to the body (36). This third possibility has not been explored in CVD and depression despite the abundant examples for such relationships in medicine. For instance, craniofacial abnormalities are comorbid with mental retardation; however, we do not talk about craniofacial abnormalities causing mental retardation, or vice-versa. As recently uncovered in 1970s, when this coupling occurs, it is often the result of fetal alcohol syndrome. A more classic example is the work of Koch who in 1882 recognised that the four disparate symptoms of pyrexiae, locales, neuroses and cachexiae described by Cullen were caused in their entirety by tuberculosis (37). Platelet activation, in its critical role in generating atherosclerotic plaque, is clearly related to CVD. A reduction in the baseline level of serotonin is a chem- ical marker of depression. Both phenomena can result from a cascade of pathways initiated by a stressor. We would like to propose that the specific mechanism that underlies CVD and depression rests on the presence of an initial stressor that sets off a chain of local and systemic events, mediated by immune intercellular messengers, which lead to neurotoxicity and decreased production of serotonin. Stress Stress is a general term that refers to any demand on the body which is, leads to a disruption of the homeostatic systems and signals, a disparity between what is optimal for the body and what actually exists (37). Stress can take many shapes and can have drastically different magnitudes: it can be psychological, such as exam stress or the death of a spouse; inflammatory, such as rheumatoid arthritis; infectious, such as influenza; traumatic, such as brain injury; metabolic, such as diabetes; or cancerous. Individuals’ proclivity to express a pathological response to these commonplace stressors is a result of their genetic vulnerability and their behaviours combined. When there is stress, the body recognises, evaluates and adapts to the adverse events by initiating an immune reaction meant to both eradicate the stressor and to return the body to homeostatic balance. One level of defense in the immune reaction comes from macrophages, which circulate in the bloodstream and in the glial cells of the brain as shown in Figure 2. When they encounter stress, macrophages induce the production of cytokines as part of an attempt to summon other immune defenses against that stressor. Cytokines Cytokines are hormone-like messengers that facilitate communication between different parts of the immune system. They have been implicated [interleukin (IL)-1, IL-6, tumour necrosis factor-(TNF)alpha] in the central control of response to systemic disease and other stressors and in the activation of neuroendocrine, immune and behavioural responses (38–40). Some cytokines and their receptors are also expressed in neuronal glial cells even under noninflammatory conditions. After infection or trauma, cytokines are expressed in much larger quantities, and excessive secretion of cytokines is thought to be involved in many pathological processes within the brain, possibly contributing the development of various neuropsychiatric conditions (14,41–43). Cytokines and the brain response During stress, the body secretes cortisol excessively, which is associated with the ‘fight or flight’ response. ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 425 426 Link between cardiovascular disease and depression Figure 2 Stress-immunochallenge-functional disruption of a neuron acting on susceptible individuals Hypothalamus Corticotrophin releasing hormone Pituitary Suppresses immune system cytokines Activates immune system, more cytokine induction Adrenocorticotrophin hormone Glucocorticoids Adrenal glands Epinephrine Norepinephrine Alters metabolism Figure 3 Regulation of homeostasis via hypothalamopituitary axis Cytokines have receptors in the hypothalamus, which in turn produces cortisol releasing factor (CRF), which then stimulates cortisol adrenocorticotropic hormone (ACTH) and cortisol production from the adrenal gland (44). Under normal circumstances, this secretion of corticosteroids works to suppress the cytokine response that initiated the cycle (45), thus returning the system to a homeostatic balance (Figure 3). However, when stress persists for a longer duration, the cytokine response becomes maladaptive, diminishing the immune system’s sensitivity to glucocorticoid hormones that normally terminate the inflammatory cascade (46). When the negative feedback loop is disrupted, the central action of cytokines may also account for the hypothalamic– pituitary axis hyperactivity that is frequently seen in depressive patients (14,47,48). This excess cortisol, in conjunction with unchecked cytokine production because of cortisol, changes the normal pathway of serotonin synthesis. Normally, tryptophan, an essential amino acid, is converted to 5-hydroxy tryptamine (5-HTP) and serotonin (5HT) in the brain (Figure 4). However, the metabolism of tryptophan can be switched to the kynurenine pathway in the presence of elevated levels of the glucocorticoids and cytokines, which are both produced as a result of stress. This alternate pathway, the kynurenine pathway, results in quinolinic acid, which has neurotoxic effects on neuronal targets (49). In addition, the production of serotonin is also ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 Link between cardiovascular disease and depression Figure 4 Alteration of tryptyophan synthesis by immune challenge (acting on susceptible individuals) diminished, as the system is lacking the tryptophan that would have produced under normal circumstances. Because of the pathway switch, the reduced tryptophan limits the biosynthesis of serotonin and consequently may relate to an increased susceptibility for depressive mood (50). The products of the tryptophan–kynurenine pathway display various functions in the brain. For example, high doses of a form of kynurenine act as cytotoxic on cultures of neuronal cells (51). Thus, excess cortisol and a cytokine response that is not ‘turned’ off can lead to depression by affecting serotonin levels through a disruption of the serotonin precursor tryptophan. However, the impact of the disregulated cytokine response has other dramatic effects. Specifically, in addition to effects on the brain, cytokines play four important roles in the body. Cytokines and the systemic response Oxidative stress and cell death. In the body, cytokines initiate a series of events that eventually lead to the death of cells, including serotonin-producing cells. Blood-borne cytokines stimulate the activity of cyclooxygenase within cells, leading to the synthesis of thromboxane A2 (TXA2), prostacyclin and prostaglandins (PGE2) as shown in Figure 5. An increase in plasma and cerebrospinal fluid concentrations of PGE2 has been reported in patients with depression and may contribute to the decrease in brain biogenic amine function by affecting the synthesis of the amines (52). Some evidence has shown that PGE2 formed as a result of the cyclo-oxygenase pathway are potential inducers of intracellular oxidative stress – composed of nitric oxide and free radicals – which leads to cell degeneration and death (53). Nitric oxide can have toxic effects on neurons and other cells (54,55), leading to the death of cells that specialise in the synthesis neurotransmitters such as serotonin. Thus, cytokines’ impact and resultant oxidative stress has been directly linked to CVD and depression. Acute phase reactants. Cytokines also travel to the liver and induce increased production of acute phase reactants (APRs), a response of the organism to disturbances of its homeostasis because of stressors (56) as shown in Figure 6. Black and Garbutt (57) hypothesise that repeated episodes of stress, may lead to chronic inflammatory process or progression of atherosclerosis. The APRs produced include coagulation factors such as fibrinogen and prothrombin, which when converted, respectively, to the forms of fibrin and thrombin, provide a structurally sound meshwork for thrombus formation (58). Neopterin. On activation by cytokines, neopterin is released by macrophages and monocytes. Increased ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 427 428 Link between cardiovascular disease and depression Figure 5 Prostaglandin synthesis as mediator of neurotoxicity leading to depression levels of neopterin are found when individuals have infections, inflammatory disease and surgical stress (59). Neopterin may enhance oxidative stress and induce apoptosis in neuronal, astrocytic and microglial cells (60). Neopterin derivatives, combined with the immune stimuli and cortisol referenced in the section on cytokines and the brain response, are involved in the degradation of tryptophan, thereby restricting the biosynthesis of serotonin (61) as shown in Figure 4. Infections in the vascular bed. Many investigations have demonstrated that pre-existing infectious agents, such as viral and bacterial pathogens, embedded in vascular tissue may act as inflammatory stressors, evoking immune changes similar to the ones we have already described (62,63). In brief, these agents initiate cytokine-mediated cascade of events leading to the attenuation of serotonin synthesis in one case as well as to neuronal degeneration and cell death. The vascular bed and platelet aggregation. Research has shown that stress, including the psychosocial variety, can induce structural changes in healthy blood vessels. Stressors also activate the sympathetic nervous system, which increases blood pressure and heart rate, which in turn puts pressure on parts of the endothelial wall, leaving them vulnerable to atheromatous plaques. Stress may also play a role in endothelial cell synthesis of molecules important in promoting atherosclerosis, such as adhesion molecules and clotting factors. Under conditions of chronic stress, the overexpression of adhesion molecules, which were initially intended to stem an acute condition by attracting white blood cells, leads to an increased adhesiveness of the vascular wall, culminating in the accumulation of a pathological number of macrophages and lymphocytes. Even in individuals with no symptoms of disease, the presence of adhesions in the blood indicate an ongoing or intermittent inflammatory process that may consist of repetitive or chronic stress and repetitive endothelial damage (64,65). As stress contributes to modifications in the vascular bed, decreased serotonin levels, which, in this case, resulted from the brain response to cytokines, increase platelet activation. Platelets both store and release serotonin, and serotonin plays an important role in platelet activation (66,67). A weak platelet agonist itself, serotonin increases the effects of several other platelet agonists, such as adenosine diphosphate, TXA2, thrombin and catecholamines (68). ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 Link between cardiovascular disease and depression Figure 6 Central and systemic response to stress induced immune challenge Platelets are also embryologically related to serotonin neurons (69). There is evidence that lower levels of serotonin are associated with factors in the determination of vascular disease and acute coronary syndromes. The exact mechanisms are still debated, but it is possible that lower levels of plasma-bound 5-HT induce platelet receptor upregulation, which in turn increases platelet reactivity and the aggregation response (69–71). In addition, selective serotonin reuptake inhibitors (SSRIs), which increase the amount of plasma-bound serotonin, have been shown to decrease platelet aggregability and reduce risk of acute coronary syndromes, further connecting serotonin to vascular disease processes (72). Thromboxane A2, which is derived from the cyclo-oxygenase pathway, plays vasoconstrictive role by promoting platelet aggregation, which in pathological states leads to thrombosis (73). Among many other effects, chronic stress has been shown to increase intracellular calcium, which, in conjunction with platelet agonists like TXA2, causes further platelet aggregation. In addition, a greater resting level of calcium has been found in the platelets of both depressed and hypertensive patients in comparison with controls (74–76). Cytokines can also lead to other cellular imbalances. When induced by stress, cytokines increase the concentration of various lipids such as triglycerides, cholesterol and free fatty acids. Certain cytokines, such as TNF-alpha and interferon-gamma, stimulate lipolysis in animals, which contribute to the free fatty acid pool (77). These lipid changes generally occur quickly after the onset of stress and last as long as the stress. If conditions such as high blood pressure and/or endothelial damage resulting from acute stress exist simultaneously to the short-term elevation atherogenic lipids, then the effects may be of clinical relevance. During stress, increases in corticosteroids (see section above) sensitise adipose tissue, causing a subsequent increase in fatty acids, which become part of the fatty acid pool (78). An injured endothelium (which can be caused by hypertension or other factors in addition to stress) reacts by releasing molecules that attract white blood cells that adhere to adhesion molecules on the endothelial wall, so that they can attend to the source of the immune distress. In addition, cytokines and the glucocorticoids they cause (see above) may induce adhesion molecules on the damaged endothelium. Blood vessels that are already compromised by atherosclerosis can have an even greater response to ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 429 430 Link between cardiovascular disease and depression stress, which, if chronic, can lead to further endothelial injury in those vessels. These combined effects of stressors and cytokines on endothelial cells, adhesion molecules, platelets and plasma lipid concentration will, under conditions of chronic stress, lead to vascular disease, such as plaque buildup leading to atherosclerosis. Evidence for cytokine and inflammatory response as underlying factor The proposed integrative model that cytokines and inflammatory response might be the common underlying factor that connects CVD and depression has only recently been getting attention from researchers (36). To date, our proposed model is the one that offers the most detailed description of the process, identifying the specific role of cytokines and serotonin de-regulation. The connections detailed in the model above are based upon correlations and an attempt to integrate a pattern of findings. Collectively, these relationships are consistent with our model, but are not definitive proof. To fully support our model, a prospective study in which data on cytokines, serotonin, atherosclerosis, depression and CVD are monitored over a period of time would be required. Such a study will simultaneously allow for testing our integrated model vs. the other models, CVD causes depression and depression causes CVD. In lieu of this study, there is some indirect evidence that the common underlying factor model is the best explanation. Our integrated model identifies the effects of cytokines and serotonin de-regulation as part of an inflammatory process. As there are other illnesses that also fall under inflammatory processes, notably asthma and rheumatoid arthritis, our model would predict that depression should also be comorbid with these inflammatory diseases. A recent meta-analysis (J. S. Shaffer, R. T. Boone, S. A. Mosovich, A. Riechenberg, M. Farkouh, St. John’s University, Manuscript submitted for publication) demonstrates just that. Finally, the role of parsimony must be considered. CVD and depression are clearly related to one another. In detailing our integrated model, we have also shown that inflammatory processes related to cytokines and serotonin brought on as a reaction to stress are also related to both depression and CVD. While the directionality of depression and CVD is logically ambiguous, it is less likely that CVD or depression cause a stress-produced inflammatory process. Thus, our integrated model captures the inter-relatedness of all three of these processes and offers a logical time sequence that makes sense. Clinical implications If our proposed integrative model holds true, it may be possible that an intervention initiated when cytokine levels are elevated and before overt manifestations of CVD or depression become apparent in individuals at risk, may delay or prevent the onset of these serious clinical entities. Therapies targeted at this common underlying mechanism for depression and CVD require further evaluation in randomised clinical trials. Use of anti-depressants for treating cardiac patients, particularly those that target serotonin, has already demonstrated clinical efficacy (79). The common underlying factor model also offers some interesting theoretical directions for further research, most notably on individual differences in susceptibility to specific disease. In short, our model offers a mechanism for how stress can cause a broad range of illnesses. The higher than chance levels of comorbidity across these illnesses supports our model, but the failure to see higher rates of comorbidity suggests that there are mediators that operate on an individual level. Future research can be directed to identify the biological markers for who is likely to develop CVD alone, who is likely to develop depression alone and who is likely to develop both illnesses. In addition to looking for biological markers, future research could also consider the effects of different types of stress. Specifically, some stressors may be more likely to lead to some illnesses more than others. There may also be a threshold level of stress required, along with individual differences for such a threshold, before the inflammatory processes can have pathogenic effects. Finally, while stress, even chronic stress, is fairly ubiquitous, there may be specific processes, such as a learned helplessness reaction, that yields activation of the damaging inflammatory process. Summary In summary, a cytokine-mediated chain of events initiated by chronic stress leads to biodynamic outcomes (e.g. serotonin dysfunction, platelet hyper-reactivity) that, over time, can manifest themselves in severe clinical outcomes: depression, and /or CVD. The chain of events described in Model no. 3 is not a series of staggered occurrences that take place sequentially, but rather a simultaneous collection of wellestablished biological events, which, once they are initiated, overwhelm the body’s defenses and lead to effects throughout the body. The results of the various cytokine-mediated pathways described in this paper do not exist in isolation; instead, the total effect of the stressor on the body is the cumulative result of ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, March 2008, 62, 3, 423–432 Link between cardiovascular disease and depression all of these established steps. In this way, via a series of biochemical events, a systemic response to a stressor leads to an expression of vascular disease on the endothelial wall. Conversely, the local site of disease in itself, as we mentioned, can set off a systemic response, thus perpetuating these events. 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