Narrative review
Mind injuries after cardiac surgery Daniele Rovaia, Daniela Giannessib, Maria G. Andreassib, Claudio Gentilic, Alessandro Pingitorea, Mattia Glauberd and Angelo Gemignanic After cardiac surgery, delirium, cognitive dysfunction, depression, or anxiety disorders frequently occur, and profoundly affect patients’ prognosis and quality of life. This narrative review focuses on the main clinical presentations of cognitive and psychological problems (’mind injuries’) that occur postoperatively in absence of ascertainable focal neurologic deficits, exploring their pathophysiological mechanisms and possible strategies for prevention and treatment. Postoperative cognitive dysfunction is a potentially devastating complication that can involve several mechanisms and several predisposing, intraoperative, and postoperative risk factors, which can result in or be associated to cerebral microvascular damage. Postoperative depression is influenced by genetic or psychosocial predisposing factors, by neuroendocrine activation, and by the release of several pro-inflammatory factors. The net effect of these changes is neuroinflammation.
Introduction Cardiovascular disease and mind are closely related. It is widely acknowledged that various psychosocial factors (such as acute and chronic stress, depression, or social isolation) are closely associated with an increased risk of acute myocardial infarction,1 anxiety disorders are associated with an increased prevalence of coronary artery disease (CAD),2 and anxiety in youth predicts subsequent coronary heart disease events.3 The relationship between psychosocial factors and cardiac events is even closer in patients who have suffered from cardiac disease. Specifically, depression after acute myocardial infarction or unstable angina is associated with a worse event-free survival,4,5 and anxiety disorders and depression in patients with stable CAD predict greater cardiac events.6 Finally, depressive symptoms are associated with an increased risk of all-cause and cardiovascular death, and this risk is particularly marked in depressive individuals with comorbid CAD.7 After cardiac surgery, impairment in cognitive function, depression, and anxiety disorders frequently occur, profoundly affecting patients’ prognosis and quality of life. For these reasons, we undertook this narrative review in order to focus on the main clinical presentations of cognitive and psychological complications (’mind injuries’) that occur after cardiac surgery in the absence of focal neurologic deficits, and to investigate neural correlates of their pathophysiologic mechanisms. Finally, we will consider current 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
These complex biochemical alterations, along with an aspecific response to stressful life events, might target the function of several brain areas, which are thought to represent a trigger factor for the onset of depression. J Cardiovasc Med 2015, 16:844–851 Keywords: coronary artery bypass grafts, genetics, genomics, inflammatory mediators, neurocognitive deficits a
CNR, Institute of Clinical Physiology, bBiomedicine, CNR, Institute of Clinical Physiology, cClinical Psychology, Department of Surgery, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa and dCardiothoracic Department, Fondazione Toscana G. Monasterio, G. Pasquinucci Heart Hospital, Massa, Italy Correspondence to Daniele Rovai, MD, FESC, CNR, Clinical Physiology Institute, Via Moruzzi 1, 56124 Pisa, Italy Tel: +39 050 3152216; fax: +39 050 315 2166; e-mail: [email protected] Received 14 May 2013 Revised 6 October 2013 Accepted 7 April 2014
achievements that may shed light on possible strategies for prevention and treatment.
Materials and methods A literature search of Medline was conducted on the basis of the following medical subheadings: coronary artery bypass surgery, cardiac surgical procedures, depression, delirium, anxiety disorders, and posttraumatic stress disorders. We selected the articles published in English, French, or Italian language from January 1962 through November 2012; we supplemented this information with articles obtained from journal archives and from personal files. Out of more than 700 papers screened, pertinent articles were selected favoring prospective studies, randomized controlled trials, meta-analysis, or large-scale studies.
Cognitive dysfunction after cardiac surgery Postoperative delirium
Cognitive dysfunction is a common complication after cardiac surgery, and mainly includes postoperative delirium and cognitive decline.8 Postoperative delirium is a confusional state of acute onset characterized by a precipitous drop in attention and cognitive function, including impaired vigilance, memory dysfunction, and delusions. In a recent meta-analysis on 25 selected publications, the incidence of delirium following cardiac surgery was on average 25%.9 In another recent study, out of 8474 patients undergoing coronary artery bypass graft (CABG) surgery at a single center, 6% were reported DOI:10.2459/JCM.0000000000000133
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Mind injuries after cardiac surgery Rovai et al. 845
to develop postoperative delirium.10 This variability likely reflects different diagnostic criteria and patients’ selection. Although generally considered a short-term, transient disorder, delirium can have long-term sequelae. It has been shown that the presence of this disturbance is associated with an increase in perioperative stroke, allcause mortality, prolonged hospitalization, and increased health costs.9 Postoperative cognitive decline
An early, short-term impairment in cognitive performance, characterized by a reduction in memory, attention, language, executive functions, and motor speed, can occur after cardiac surgery. This cognitive decline is subtle and sometimes subthreshold. Thus, it can often be detected only by careful neuropsychological testing by a trained and experienced examiner. Postoperative cognitive decline improves over the following months, being present in 53% of patients at hospital discharge, in 36% at 6 weeks, and in 24–33% of patients at 1 year postoperatively.11,12 The link between postoperative delirium and cognitive decline has been recently demonstrated. On the one hand, the patients in whom delirium developed postoperatively had lower preoperative cognitive function than those in whom delirium did not develop; on the other hand, postoperative delirium was followed by a significant decline in cognitive ability during the first year after surgery.13
Causes of postoperative cognitive dysfunction Predisposing and precipitating factors
Several factors are related to the pathogenesis of postoperative cognitive dysfunction. Compared with patients without postoperative delirium, those with delirium share several predisposing factors, including older age, history of diabetes, history of previous stroke or transient ischemic attack, more depressive symptoms, or lower cognitive function preoperatively.9,14 The precipitating risk factors are related to both the operative phase (as the duration of surgery, prolonged intubation, or intraoperative hyperglycemia) and the postoperative phase (as red blood cell transfusion, elevation in inflammatory markers and plasma cortisol level, or postoperative complications).9,14 The predictors of postoperative cognitive decline can be related to greater comorbidity and fragility, and include preexisting cerebral disease, peripheral vascular disease, postoperative complications, the condition of living alone, and lower levels of education.15 Several intraoperative aspects able to affect postoperative cognitive dysfunction deserve greater attention. Cerebral microemboli
As autopsy of patients who died after cardiac surgery revealed evidence of microemboli in all brains examined,16
cerebral microemboli due to gaseous, organic, or inorganic particles generated during extracorporeal circulation have been hypothesized to be a primary predictor of postoperative cognitive impairment. To measure intraoperative microemboli, transcranial or carotid Doppler ultrasound has been utilized by the analysis of high-intensity transient signals, assumed to reflect particulate or gaseous microembolic particles. However, counting the total number of emboli did not provide a cut-off value, below which there was no risk and above which there was a high risk of postoperative cognitive dysfunction.17 Despite these results, a silent organic brain injury can occur after cardiac surgery, as demonstrated by diffusionweighted magnetic resonance imaging, which has shown brain lesions in 29% of patients studied postoperatively.18 Characteristically, these lesions were multiple and very small, located in all cerebrovascular territories, but more frequently in frontal and watershed border zones. A few of these lesions were associated with overt clinical signs of stroke, whereas other lesions were not. Another open issue is that of the effects of extracorporeal circulation on postoperative cognitive dysfunction. Although several studies reported improved cognitive outcome after off-pump cardiac surgery, no difference in cognitive performance has been found between patients randomized to on-pump and those randomized to off-pump bypass surgery, including a meta-analysis of eight prospective randomized controlled trials.19,20 Conversely, aortic atheroma burden, studied via transesophageal and epiaortic echocardiography, has been shown to predict postoperative cognitive dysfunction at 1 week after surgery.21 Accordingly, a surgical strategy designed to minimize aortic manipulation can significantly reduce the incidence of cognitive deficits in patients with CABG compared with traditional techniques.22 Anesthetic management
Other pathogenetic factors involve the anesthetized patient’s management. In a randomized trial of 180 patients undergoing CABG, propofol anesthesia was associated with an increased incidence of early cognitive dysfunction as compared with desflurane anesthesia, without significant difference in the incidence of postoperative delirium.23 A positive correlation has also been found between early postoperative cognitive dysfunction and intraoperative cerebral oxygen desaturation24 or systemic hypoxia 5 days after CABG.25 Finally, several pieces of evidence suggest a similar pathophysiologic mechanism underlying postsurgical cognitive impairment and Alzheimer’s disease. Similar changes in biomarkers such as amyloid-b beta peptide, tau protein, and S100b have been detected in both plasma and cerebrospinal fluid of patients with Alzheimer’s disease and those with postsurgical cognitive decline.26,27
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In conclusion, cognitive dysfunction after cardiac surgery in the absence of focal neurologic signs is a potentially devastating complication that can involve several mechanisms and several predisposing preoperative, intraoperative, and postoperative risk factors, which often result in cerebral microvascular damage. The latter can trigger changes in anatomical and functional connectivity, the condicio sine qua non for generating cognitive alterations (Fig. 1).
Depression and anxiety disorders after cardiac surgery Depression and depressive symptoms
Undergoing cardiac surgery remains a significant life event that has an important emotional impact on patients and their families. After CABG, from 31 to 60% of patients refer depressive symptoms, whereas 16 to 23% of patients present the clinical picture of major depression.28,29 Although depressive symptoms can be assessed by questionnaires, the diagnosis of major depression is clinical and is based on the observation of several symptoms, including a depressed mood, psychomotor retardation, loss of interest or pleasure in normally enjoyable activities, hopelessness, feelings of failure, and low self-esteem. From a prognostic point of view, postoperative depressive symptoms are associated with a lack of functional improvement 6 months after surgery,30 and DSM IV diagnosis of major depression is associated with an increased risk of new cardiac events during follow-up,31 and with increased mortality up to 5–10 years after CABG.29,32 Furthermore, postoperative depressive symptoms are associated with poorer quality of life, and with an earlier degeneration of venous grafts.33 The negative effects of depression also affect patients Fig. 1
Predisposing risk factors Older age, diabetes, previous stroke or TIA, aortic atheroma burden, peripheral vascular disease, comorbidity, fragility, depressive symptoms, lower cognitive function, low levels of education, living alone
Intraoperative risk factors Prolonged duration of surgery, prolonged intubation, aortic manipulation, propofol anesthesia, intraoperative cerebral oxygen desaturation, intraoperative hyperglycemia, extracorporeal circulation
Cerebral microvascular damage
Postoperative risk factors RBC transfusion, increased inflammatory markers, increased plasma cortisol levels, postoperative complications, systemic hypoxia
Postoperative cognitive dysfunction
Schematic diagram of the factors involved in the pathogenesis of postoperative cognitive dysfunction. RBC, red blood cell.
undergoing cardiac valve surgery.34 On the contrary, patients with personality traits characterized by optimism show a lower rate of rehospitalization after CABG.35 Anxiety disorders
Anxiety disorders are common after cardiac surgery; they include post-traumatic stress disorder (PTSD), generalized anxiety disorder, and panic disorders. PTSD is a severe anxiety disorder often described in combat veterans. It is induced by exposure to an event that involves death or serious injury, and generates intense fear or helplessness. In patients with PTSD, this traumatic event is persistently re-experienced, the stimuli that may trigger such experience are avoided, and symptoms of increased arousal (such as difficulty falling or staying asleep, or concentrating) appear. These symptoms are associated with significantly impaired social or occupational functioning. PTSD can be present in up to 18% of patients after cardiac surgery, and is associated with a poorer quality of life.36 Anxiety symptoms (worry, apprehension, and fearfulness) are very frequent in the preoperative phase of cardiac surgery, involving on average 40% of patients; these symptoms tend to decline weeks and months after surgery. Although the relationship between anxiety and outcome has been less investigated, higher anxiety scores, generalized anxiety disorder (characterized by excessive and uncontrollable anxiety, often disproportionate to the actual source of worry), and panic attack disorder are associated with a worse outcome after CABG or valve surgery.37
Pathophysiology of postoperative depression and anxiety Role of somatic illness
Although the cause and pathophysiology of major depression and other mental disorders are not well clarified, converging evidence suggests that several mechanisms are involved in their pathogenesis. Among the risk factors for depression, a role is played by concomitant physical illness. Patients with a greater degree of depressive symptoms after CABG were more likely to have more comorbid conditions, higher Canadian Cardiovascular Society angina class, higher cardiovascular risk factors, lower physical function, and were to be operated on more often on an emergency basis than those with lower levels of postoperative depressive symptoms.30,33,34 It is noteworthy that left ventricular function, history of cardiac disease, including previous myocardial infarction, angina pectoris, and previous coronary angioplasty procedures, were associated with severity of depression.30 To indicate that the psychological reaction is related to the somatic illness, the term secondary depression has been utilized.38 However, it is a frequent clinical observation that the distress experienced by the patient is often uncorrelated to the severity of physical illness. Thus,
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Mind injuries after cardiac surgery Rovai et al. 847
factors beyond the somatic illness should be considered to explain the complex pathogenetic mechanisms of postoperative depression. Psychosocial factors
A review of 46 studies has shown that the most commonly identified psychological predictors of postoperative depression and anxiety after CABG were preoperative depression and anxiety.39 Furthermore, the patient’s beliefs about their illness before cardiac surgery was an independent predictor of disability, physical functioning, and depressive symptoms 3 months after cardiac surgery.40 Finally, social factors do play a role, because patients who developed postoperative depression were more likely to be less educated, to have less social support, and to live alone than patients who did not develop postoperative depression.30 Neuroendocrine activation
Open heart surgery is associated with the activation of several neuroendocrine systems, such as the hypothalamic–pituitary–adrenal (HPA) axis. HPA activation, with increased cortisol release, has been documented during cardiac surgery, mainly in patients operated with cardiopulmonary bypass.41 A modest association has also been found between major depressive disorder and HPA activation.42 However, a relationship between cortisol concentration and depressive symptoms after CABG has not been consistently demonstrated.43 After cardiac surgery, thyroid hormone changes frequently occur, consisting mainly of decreased triiodothyronine (T3) levels.44 Several studies have documented that altered thyroid hormone profile is a predictor of a worse prognosis in cardiac patients,45 and that the outcome can be counteracted by hormone supplementation.46 Independently of heart disease, low T3 levels are associated with depressive symptoms in psychiatric patients,47 and T3 administration is used as an add-on therapy for depression resistant to serotonin selective reuptake inhibitors in nonhypothyroid patients.48 Despite the above considerations, thyroid homeostasis after CABG has received little attention so far, and its role in postoperative mood disorders is still under investigation. Inflammation
Major depression has been associated with increased inflammatory biomarkers in the peripheral blood.49,50 A meta-analysis of 24 studies measuring cytokine concentration in patients with major depression has found significantly higher concentrations of tumor necrosis factor (TNF)-a and interleukin (IL)-6 in depressed individuals compared with controls.51 In another meta-analysis, depression was positively associated with both IL-6 and with high-sensitivity C-reactive protein in clinical and community samples.52 Finally, in a small series of
depressed patients showing elevated TNF-a and leukocyte count on admission, both TNF-a and leukocyte count decreased to levels comparable to those of controls following antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs).53 Thus, several studies suggest a link between major depression and inflammation. In cardiac surgery, the immune reaction associated with surgical trauma, like other forms of aseptic trauma, initiates a systemic inflammatory response characterized by increased plasma levels of pro-inflammatory and antiinflammatory cytokines, produced by blood cells, the myocardium, and the endothelium.54 In experimental animals, this inflammatory response to surgical trauma has been shown to profoundly affect brain function by inducing neuroinflammation.55 In patients undergoing CABG, preoperative elevated serum levels of highsensitivity C-reactive protein were an independent predictor of postoperative depression.56 Thus, a relationship has been proposed that links surgical trauma, general inflammatory response, neuroinflammation, and depressive symptoms.57 For developing a major depressive episode, these alterations should also interact with a specific multifactorial genetic pattern. Genetic predisposition
Postoperative depression has a genetic component, which should not be regarded as an all-or-nothing phenomenon that is manifested regardless of external conditions. Genetic predisposition is to be understood as a type of reaction (genetically influenced) that occurs when the individual is exposed to stressful events. In the last few decades, alterations in several central nervous system neurotransmitters, including serotonergic neurotransmission, have been shown to play a key role in both the pathophysiology of depression and the mechanisms of action of antidepressant drug treatment.58 The genetic variability in two serotoninrelated gene polymorphisms that influence central nervous system serotonin turnover, and their relationship to depression and adverse cardiac events, has been studied in a group of 427 patients undergoing CABG.59 Neither candidate polymorphism was significantly predictive of postoperative depression in the studied population, which was likely not powered enough to test such a hypothesis (P ¼ 0.06 for each gene polymorphism). However, depressed patients who carry the long (L) allele of the 5HTTLPR polymorphism were more likely than the short/short (S/S) carriers to have an event during follow-up, including repeat coronary revascularization by CABG surgery or percutaneous coronary intervention, myocardial infarction, cardiac arrest, or all-cause mortality. In response to various stimuli, cortisol coordinates metabolic, endocrine, immune, and nervous system responses.
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The effects of cortisol are mainly mediated by the glucocorticoid receptor, which is expressed throughout the body, including the brain.60 In a cross-sectional genetic association study of 526 patients with chronic CAD, four glucocorticoid receptor gene polymorphism and haplotype analyses were conducted and correlated with current or past depression. The prevalence of depression was 24% in the noncarriers, 34% in heterozygotes, and 53% in homozygous for the haplotype 3 allele; these associations persisted after adjusting for confounding factors.61 Finally, an association between polymorphism of the glucocorticoid receptor gene and anxiety, traumatic memories, PTSD symptoms, and health-related quality of life has been shown in 126 patients undergoing cardiac surgery and intensive care unit therapy.62 Specifically, the homozygous carriers of the BcL G allele were more likely to present anxiety and PTSD symptoms than heterozygous carriers or noncarriers. Furthermore, homozygous carriers did not show any significant improvement in health-related quality of life 6 months after cardiac surgery, whereas heterozygous carriers or noncarriers did. Finally, genetic variants of the binding protein that modulates the glucocorticoid receptor function (FK506) and brain-derived neurotrophic factor (BDNF) are suggestively associated with depression in a Swedish population-based cohort.63 All of the above considerations support the concept that genetic predisposition is a risk factor for developing elevated depressive symptoms and for greater adverse events after cardiac surgery. Brain and abnormal response to stress
Within the brain, a complex neural network determines what is threatening and thus stressful to the individual. This network includes some subcortical structures such as hypothalamus, hippocampus, and amygdaloid complex, as well as cortical areas such as the prefrontal cortex. Recently, it has been pointed out that the hippocampus seems to be a crucial structure for linking abnormal stress reaction (allostatic load) to mental dysfunctions. The hippocampus is a complex and highly organized brain structure involved in learning and memory, in processing the contextual aspects of emotional events, and regulating visceral functions, including the HPA axis.64,65 The hippocampus contains receptors for adrenal steroids and for major metabolic hormones, and it appears to be particularly vulnerable to the effects of stress. Mild and short-lasting stress often enhances hippocampal function, whereas prolonged or severe stress may alter the structure and function of the hippocampus. This altered hippocampal function includes a reduction (retraction) in the branching of cell dendrites and a reduction in the formation of new neurons in the adult hippocampus, a phenomenon referred to as adult hippocampal neurogenesis.66 Recently, several studies have provided evidence that the hippocampus is a specific target of various hormones and pro-inflammatory
substances induced by stressful experiences, thus supporting the idea that the hippocampus is involved in the regulation of mood.67,68 Thus, a neurogenesis hypothesis of depression has been put forward linking a suppressed rate of adult hippocampal neurogenesis to the pathophysiology of depression. In conclusion, the complex biochemical changes that occur during cardiac surgery, including neuroendocrine activation and inflammation, along with an aspecific response to stressful life events, might target hippocampal function and represent a risk factor or a trigger factor for the onset of depression in these patients (Fig. 2).
Possible strategies for prevention and treatment Antidepressants
Because of their favorable risk profile and effects on depression, anxiety disorders, and PTSD, SSRIs are considered the antidepressants of choice in patients with CAD. In a meta-analysis of six randomized controlled trials, CAD patients on SSRIs showed a significantly greater improvement in depression symptoms compared with controls, without significant differences in mortality or CHD readmission rates.69 Despite these premises, studies on SSRIs in patients undergoing CABG have generated conflicting results. In a retrospective study on 4794 patients who underwent CABG, 5% of whom were already receiving SSRIs before surgery, the SSRI group had an increased risk of mortality after adjustment for baseline differences.70 In a more recent study on 4136 patients who underwent CABG, 2.5% of whom were on SSRIs or serotonin–noradrenaline reuptake inhibitors, the antidepressant treatment was not associated with cardiac mortality or all-cause mortality. However, the use of the above medications was significantly associated with an increased risk of renal dysfunction requiring dialysis and prolonged ventilation after CABG.71 In a previous study on 1380 patients who received either SSRIs (78% of patients) or non-SSRI antidepressant (22% of patients) before CABG, the preoperative use of SSRIs was not associated with increased risk for bleeding or inhospital mortality after CABG.72 Faced with these diverging results, prospective randomized trials on the optimal medical treatment of mood disorders after cardiac surgery would be desirable. Statins
An interesting association between postoperative depression and statin therapy has been observed in a small sample of 193 patients hospitalized for angioplasty, myocardial infarction, or CABG. The use of statins (in 81% of patients) was associated with significantly decreased risk of depression.73 As statins have known effects on inflammatory cytokines, and they also reduce markers of oxidative stress, this observation could support the inflammatory and oxidative hypothesis of depression.
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Mind injuries after cardiac surgery Rovai et al. 849
Fig. 2
Predisposing psychological risk factors
Predisposing genetic factors
Pre-operative depression and anxiety, patient’s beliefs about their illness
Serotonin-related gene and glucocorticoid receptor gene polymorphism
Predisposing social risk factors
Somatic illness
Low levels of education, low social support, living alone
Comorbidity, angina class, CV risk factors, low physical function, emergency operations
Surgical trauma
Neuroendocrine activation
Inflammation
HPA axis activation →cortisol release Low T3 syndrome
Pro-inflammatory cytokines High-sensitivity-CRP
Neuroinflammation Hippocampus, amygdala, prefrontal cortex
Postoperative depression
Schematic diagram of the factors involved in the pathogenesis of postoperative depression. CRP, C-reactive protein; CV, cardiovascular; HPA, hypothalamic–pituitary–adrenal; T3, triiodothyronine.
In a larger study on 1059 cardiac surgical patients, the preoperative use of statins had a protective effect on the risk of early postoperative delirium.74 These findings suggest the possibility of novel therapies different from conventional antidepressants in the prevention and treatment of postoperative depression and cognitive dysfunction. However, further studies are needed to prove such a hypothesis. Cognitive behavioral therapy
Interesting results on the prevention and treatment of postoperative mind injuries involve nonpharmacological treatment tailored to improve patient knowledge and stress management. In a recent study, 100 patients with symptoms of depression or anxiety before CABG were randomly assigned to receive the usual treatment or a brief cognitive behavioral therapy. This intervention improved depressive symptoms at time of discharge, as well as quality of life after 1 month.75 In another study, 123 patients with major or minor depression within 1 year after surgery were randomized to cognitive behavioral therapy, supportive stress management, or usual care. Even after surgery, the two nonpharmacological strategies were efficacious for treating depression after CABG, compared with the usual care.76 Recently, the effectiveness of telephone-delivered collaborative care has been evaluated in 302 patients after CABG.77 Compared with usual care, telephone-delivered care resulted in improved health-related quality of life, physical functioning, and depressive symptoms at 8-month follow-up.
Enriched environment hypothesis
Several studies have shown that exposure to a cognitively and socially stimulating environment (a combination known as ‘enriched environment’) and physical exercise exert beneficial effects on brain function. Specifically, exercise and exposure to an enriched environment improve cognitive performance, slow down decline in the elderly, increase cortical synaptic plasticity, and reduce the risk of developing dementia and depression.78–80 Furthermore, it has been shown that an enriched environment yields a significant increase in hippocampal neurogenesis, counterbalancing the detrimental effects of stress-related substances.78 Because of the similarities in pathophysiological mechanisms, one might propose translating the enriched environment strategy to the postoperative theatre. In this view, interaction between patient and family members, nurses, and medical personnel should be encouraged as much as possible. Furthermore, the patient might take advantage of being exposed to pleasant visual stimuli and to pleasant acoustic stimuli or odors. Finally, the patient’s mental recovery might be favored by an early rehabilitation program, so as to train the patient’s body and mind.
Limitations Because of the complexity of this issue and the large amount of literature available, an in-depth analysis of individual studies could not be reported in this narrative review. This wide topic was chosen to underlie the continuum and possible interrelationship between different types of cognitive dysfunction and mood
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850 Journal of Cardiovascular Medicine 2015, Vol 16 No 12
disorders, as well as any common favoring factors, precipitating factors, and pathogenetic mechanisms.
Conclusion
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The relationship between cardiovascular disease and mental disorders is close and bidirectional. On the one hand, stress, depression, and social isolation are independent risk factors for the development of CAD. On the other hand, heart disease and cardiac surgery produce a stress reaction that induces the activation of several neuroendocrine pathways, and the release of several pro-inflammatory factors. The net effect of these changes is neuroinflammation. Consequently, a reduction in the function of several brain areas occurs, and is thought to be responsible for depressive mood. Furthermore, postoperative mind injuries are influenced by factors that existed prior to the intervention, such as genetic predisposition or psychosocial factors. Prevention of postoperative mental disorders through optimization of pre and/or postsurgery treatment by new pharmacological and/or nonpharmacological strategies could be worthwhile for improving patient’s prognosis and quality of life.
Acknowledgements
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This study was supported by institutional grants of the CNR Institute of Clinical Physiology. The authors gratefully acknowledge Ms Alison Frank for the English revision of the article.
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There are no conflicts of interest. 25
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Sze´kely A, Balog P, Benko¨ E, et al. Anxiety predicts mortality and morbidity after coronary artery and valve surgery: a 4-year follow-up study. Psychosom Med 2007; 69:625–631. Bech P. Mood and anxiety in the medically ill. Adv Psychosom Med 2012; 32:118–132. McKenzie LH, Simpson J, Stewart M. A systematic review of preoperative predictors of postoperative depression and anxiety in individuals who have undergone coronary artery bypass graft surgery. Psychol Health Med 2010; 15:74–93. Juergens MC, Seekatz B, Moosdorf RG, et al. Illness beliefs before cardiac surgery predict disability, quality of life, and depression 3 months later. J Psychosom Res 2010; 68:553–560. Hoda MR, El-Achkar H, Schmitz E, et al. Systemic stress hormone response in patients undergoing open heart surgery with or without cardiopulmonary bypass. Ann Thorac Surg 2006; 82:2179–2186. Vreeburg SA, Hoogendijk WJ, van Pelt J, et al. Major depressive disorder and hypothalamic–pituitary–adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry 2009; 66:617–626. Dowlati Y, Herrmann N, Swardfager W, et al. Relationship between hair cortisol concentrations and depressive symptoms in patients with coronary artery disease. Neuropsychiatr Dis Treat 2010; 6:393–400. Sabatino L, Cerillo AG, Ripoli A, et al. Is the low tri-iodothyronine state a crucial factor in determining the outcome of coronary artery bypass patients? Evidence from a clinical pilot study. J Endocrinol 2002; 175:577–586. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007; 167:1526–1532. Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2008; 93:1351–1358. Premachandra BN, Kabir MA, Williams IK. Low T3 syndrome in psychiatric depression. J Endocrinol Invest 2006; 29:568–572. Abraham G, Milev R, Stuart Lawson J. T3 augmentation of SSRI resistant depression. J Affect Disord 2006; 91:211–215. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65:732–741. Schmidt HD, Shelton RC, Duman RD. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropyschopharmacology 2011; 36:2375–2394. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67:446–457. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171–186. Tuglu C, Kara SH, Caliyurt O, et al. Increased serum tumor necrosis factoralpha levels and treatment response in major depressive disorder. Psychopharmacology 2003; 170:429–433. Franke A, Lante W, Fackeldey V, et al. Proinflammatory and antiinflammatory cytokines after cardiac operation: different cellular sources at different times. Ann Thorac Surg 2002; 74:363–370. Terrando N, Eriksson LI, Ryu JK, et al. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol 2011; 70:986–995. Yang L, Wang J, Zhang L, et al. Preoperative high-sensitivity C-reactive protein predicts depression in patients undergoing coronary artery bypass surgery: a single-center prospective observational study. J Thorac Cardiovasc Surg 2012; 144:500–505. Poole L, Dickens C, Steptoe A. The puzzle of depression and acute coronary syndrome: reviewing the role of acute inflammation. J Psychosom Res 2011; 71:61–68. Risch SC, Nemeroff CB. Neurochemical alterations of serotonergic neuronal systems in depression. J Clin Psychiatry 1992; 53:3–7. Phillips-Bute B, Mathew JP, Blumenthal JA, et al. Perioperative Genetics and Safety Outcomes Investigative Team. Relationship of genetic variability and depressive symptoms to adverse events after coronary artery bypass graft surgery. Psychosomat Med 2008; 70:953–959.
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DeRijk R, de Kloet ER. Corticosteroid receptor genetic polymorphisms and stress responsivity. Endocrine 2005; 28:263–270. Otte C, Wu¨st S, Zhao S, et al. Glucocorticoid receptor gene and depression in patients with coronary heart disease: the Heart and Soul Study-2009 Curt Richter Award Winner. Psychoneuroendocrinology 2009; 34:1574–1581. Hauer D, Weis F, Papassotiropoulos A, et al. Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy. Crit Care Med 2011; 39:643–650. Lavebratt C, Aberg E, Sjo¨holm LK, Forsell Y. Variations in FKBP5 and BDNF genes are suggestively associated with depression in a Swedish population-based cohort. J Affect Disord 2010; 125: 249–255. McEwen BS, Gianaros PJ. Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann N Y Acad Sci 2010; 1186:190–222. Maras PM, Baram TZ. Sculpting the hippocampus from within: stress, spines, and CRH. Trends Neurosci 2012; 35:315–324. Lucassen PJ, Meerlo P, Naylor AS, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur Neuropsychopharmacol 2010; 20:1–17. Samuels BA, Hen R. Neurogenesis and affective disorders. Eur J Neurosci 2011; 33:1152–1159. Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci Biobehav Rev 2010; 35:2–16. Pizzi C, Rutjes AW, Costa GM, et al. Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. Am J Cardiol 2011; 107:972–979. Xiong GL, Jiang W, Clare R, et al. Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting. Am J Cardiol 2006; 98:42–47. Tully PJ, Cardinal T, Bennetts JS, Baker RA. Selective serotonin reuptake inhibitors, venlafaxine and duloxetine are associated with in hospital morbidity but not bleeding or late mortality after coronary artery bypass graft surgery. Heart Lung Circ 2012; 21:206–214. Kim DH, Daskalakis C, Whellan DJ, et al. Safety of selective serotonin reuptake inhibitor in adults undergoing coronary artery bypass grafting. Am J Cardiol 2009; 103:1391–1395. Stafford L, Berk M. The use of statins after a cardiac intervention is associated with reduced risk of subsequent depression: proof of concept for the inflammatory and oxidative hypotheses of depression? J Clin Psychiatry 2011; 72:1229–1235. Katznelson R, Djaiani GN, Borger MA, et al. Preoperative use of statins is associated with reduced early delirium rates after cardiac surgery. Anesthesiology 2009; 110:67–73. Dao TK, Youssef NA, Armsworth M, et al. Randomized controlled trial of brief cognitive behavioral intervention for depression and anxiety symptoms preoperatively in patients undergoing coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 2011; 142:e109–e115. Freedland KE, Skala JA, Carney RM, et al. Treatment of depression after coronary artery bypass surgery: a randomized controlled trial. Arch Gen Psychiatry 2009; 66:387–396. Rollman BL, Belnap BH, LeMenager MS, et al. Telephone-delivered collaborative care for treating post-CABG depression: a randomized controlled trial. JAMA 2009; 302:2095–2103. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002; 25: 295–301. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol 2004; 3:343–353. Nithianantharajah J, Hannan AJ. Enriched environments, experiencedependent plasticity and disorders of the nervous system. Nat Rev Neurosci 2006; 7:697–709.
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Mind injuries after cardiac surgery Daniele Rovaia, Daniela Giannessib, Maria G. Andreassib, Claudio Gentilic, Alessandro Pingitorea, Mattia Glauberd and Angelo Gemignanic After cardiac surgery, delirium, cognitive dysfunction, depression, or anxiety disorders frequently occur, and profoundly affect patients’ prognosis and quality of life. This narrative review focuses on the main clinical presentations of cognitive and psychological problems (’mind injuries’) that occur postoperatively in absence of ascertainable focal neurologic deficits, exploring their pathophysiological mechanisms and possible strategies for prevention and treatment. Postoperative cognitive dysfunction is a potentially devastating complication that can involve several mechanisms and several predisposing, intraoperative, and postoperative risk factors, which can result in or be associated to cerebral microvascular damage. Postoperative depression is influenced by genetic or psychosocial predisposing factors, by neuroendocrine activation, and by the release of several pro-inflammatory factors. The net effect of these changes is neuroinflammation.
Introduction Cardiovascular disease and mind are closely related. It is widely acknowledged that various psychosocial factors (such as acute and chronic stress, depression, or social isolation) are closely associated with an increased risk of acute myocardial infarction,1 anxiety disorders are associated with an increased prevalence of coronary artery disease (CAD),2 and anxiety in youth predicts subsequent coronary heart disease events.3 The relationship between psychosocial factors and cardiac events is even closer in patients who have suffered from cardiac disease. Specifically, depression after acute myocardial infarction or unstable angina is associated with a worse event-free survival,4,5 and anxiety disorders and depression in patients with stable CAD predict greater cardiac events.6 Finally, depressive symptoms are associated with an increased risk of all-cause and cardiovascular death, and this risk is particularly marked in depressive individuals with comorbid CAD.7 After cardiac surgery, impairment in cognitive function, depression, and anxiety disorders frequently occur, profoundly affecting patients’ prognosis and quality of life. For these reasons, we undertook this narrative review in order to focus on the main clinical presentations of cognitive and psychological complications (’mind injuries’) that occur after cardiac surgery in the absence of focal neurologic deficits, and to investigate neural correlates of their pathophysiologic mechanisms. Finally, we will consider current 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
These complex biochemical alterations, along with an aspecific response to stressful life events, might target the function of several brain areas, which are thought to represent a trigger factor for the onset of depression. J Cardiovasc Med 2015, 16:844–851 Keywords: coronary artery bypass grafts, genetics, genomics, inflammatory mediators, neurocognitive deficits a
CNR, Institute of Clinical Physiology, bBiomedicine, CNR, Institute of Clinical Physiology, cClinical Psychology, Department of Surgery, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa and dCardiothoracic Department, Fondazione Toscana G. Monasterio, G. Pasquinucci Heart Hospital, Massa, Italy Correspondence to Daniele Rovai, MD, FESC, CNR, Clinical Physiology Institute, Via Moruzzi 1, 56124 Pisa, Italy Tel: +39 050 3152216; fax: +39 050 315 2166; e-mail: [email protected] Received 14 May 2013 Revised 6 October 2013 Accepted 7 April 2014
achievements that may shed light on possible strategies for prevention and treatment.
Materials and methods A literature search of Medline was conducted on the basis of the following medical subheadings: coronary artery bypass surgery, cardiac surgical procedures, depression, delirium, anxiety disorders, and posttraumatic stress disorders. We selected the articles published in English, French, or Italian language from January 1962 through November 2012; we supplemented this information with articles obtained from journal archives and from personal files. Out of more than 700 papers screened, pertinent articles were selected favoring prospective studies, randomized controlled trials, meta-analysis, or large-scale studies.
Cognitive dysfunction after cardiac surgery Postoperative delirium
Cognitive dysfunction is a common complication after cardiac surgery, and mainly includes postoperative delirium and cognitive decline.8 Postoperative delirium is a confusional state of acute onset characterized by a precipitous drop in attention and cognitive function, including impaired vigilance, memory dysfunction, and delusions. In a recent meta-analysis on 25 selected publications, the incidence of delirium following cardiac surgery was on average 25%.9 In another recent study, out of 8474 patients undergoing coronary artery bypass graft (CABG) surgery at a single center, 6% were reported DOI:10.2459/JCM.0000000000000133
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Mind injuries after cardiac surgery Rovai et al. 845
to develop postoperative delirium.10 This variability likely reflects different diagnostic criteria and patients’ selection. Although generally considered a short-term, transient disorder, delirium can have long-term sequelae. It has been shown that the presence of this disturbance is associated with an increase in perioperative stroke, allcause mortality, prolonged hospitalization, and increased health costs.9 Postoperative cognitive decline
An early, short-term impairment in cognitive performance, characterized by a reduction in memory, attention, language, executive functions, and motor speed, can occur after cardiac surgery. This cognitive decline is subtle and sometimes subthreshold. Thus, it can often be detected only by careful neuropsychological testing by a trained and experienced examiner. Postoperative cognitive decline improves over the following months, being present in 53% of patients at hospital discharge, in 36% at 6 weeks, and in 24–33% of patients at 1 year postoperatively.11,12 The link between postoperative delirium and cognitive decline has been recently demonstrated. On the one hand, the patients in whom delirium developed postoperatively had lower preoperative cognitive function than those in whom delirium did not develop; on the other hand, postoperative delirium was followed by a significant decline in cognitive ability during the first year after surgery.13
Causes of postoperative cognitive dysfunction Predisposing and precipitating factors
Several factors are related to the pathogenesis of postoperative cognitive dysfunction. Compared with patients without postoperative delirium, those with delirium share several predisposing factors, including older age, history of diabetes, history of previous stroke or transient ischemic attack, more depressive symptoms, or lower cognitive function preoperatively.9,14 The precipitating risk factors are related to both the operative phase (as the duration of surgery, prolonged intubation, or intraoperative hyperglycemia) and the postoperative phase (as red blood cell transfusion, elevation in inflammatory markers and plasma cortisol level, or postoperative complications).9,14 The predictors of postoperative cognitive decline can be related to greater comorbidity and fragility, and include preexisting cerebral disease, peripheral vascular disease, postoperative complications, the condition of living alone, and lower levels of education.15 Several intraoperative aspects able to affect postoperative cognitive dysfunction deserve greater attention. Cerebral microemboli
As autopsy of patients who died after cardiac surgery revealed evidence of microemboli in all brains examined,16
cerebral microemboli due to gaseous, organic, or inorganic particles generated during extracorporeal circulation have been hypothesized to be a primary predictor of postoperative cognitive impairment. To measure intraoperative microemboli, transcranial or carotid Doppler ultrasound has been utilized by the analysis of high-intensity transient signals, assumed to reflect particulate or gaseous microembolic particles. However, counting the total number of emboli did not provide a cut-off value, below which there was no risk and above which there was a high risk of postoperative cognitive dysfunction.17 Despite these results, a silent organic brain injury can occur after cardiac surgery, as demonstrated by diffusionweighted magnetic resonance imaging, which has shown brain lesions in 29% of patients studied postoperatively.18 Characteristically, these lesions were multiple and very small, located in all cerebrovascular territories, but more frequently in frontal and watershed border zones. A few of these lesions were associated with overt clinical signs of stroke, whereas other lesions were not. Another open issue is that of the effects of extracorporeal circulation on postoperative cognitive dysfunction. Although several studies reported improved cognitive outcome after off-pump cardiac surgery, no difference in cognitive performance has been found between patients randomized to on-pump and those randomized to off-pump bypass surgery, including a meta-analysis of eight prospective randomized controlled trials.19,20 Conversely, aortic atheroma burden, studied via transesophageal and epiaortic echocardiography, has been shown to predict postoperative cognitive dysfunction at 1 week after surgery.21 Accordingly, a surgical strategy designed to minimize aortic manipulation can significantly reduce the incidence of cognitive deficits in patients with CABG compared with traditional techniques.22 Anesthetic management
Other pathogenetic factors involve the anesthetized patient’s management. In a randomized trial of 180 patients undergoing CABG, propofol anesthesia was associated with an increased incidence of early cognitive dysfunction as compared with desflurane anesthesia, without significant difference in the incidence of postoperative delirium.23 A positive correlation has also been found between early postoperative cognitive dysfunction and intraoperative cerebral oxygen desaturation24 or systemic hypoxia 5 days after CABG.25 Finally, several pieces of evidence suggest a similar pathophysiologic mechanism underlying postsurgical cognitive impairment and Alzheimer’s disease. Similar changes in biomarkers such as amyloid-b beta peptide, tau protein, and S100b have been detected in both plasma and cerebrospinal fluid of patients with Alzheimer’s disease and those with postsurgical cognitive decline.26,27
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In conclusion, cognitive dysfunction after cardiac surgery in the absence of focal neurologic signs is a potentially devastating complication that can involve several mechanisms and several predisposing preoperative, intraoperative, and postoperative risk factors, which often result in cerebral microvascular damage. The latter can trigger changes in anatomical and functional connectivity, the condicio sine qua non for generating cognitive alterations (Fig. 1).
Depression and anxiety disorders after cardiac surgery Depression and depressive symptoms
Undergoing cardiac surgery remains a significant life event that has an important emotional impact on patients and their families. After CABG, from 31 to 60% of patients refer depressive symptoms, whereas 16 to 23% of patients present the clinical picture of major depression.28,29 Although depressive symptoms can be assessed by questionnaires, the diagnosis of major depression is clinical and is based on the observation of several symptoms, including a depressed mood, psychomotor retardation, loss of interest or pleasure in normally enjoyable activities, hopelessness, feelings of failure, and low self-esteem. From a prognostic point of view, postoperative depressive symptoms are associated with a lack of functional improvement 6 months after surgery,30 and DSM IV diagnosis of major depression is associated with an increased risk of new cardiac events during follow-up,31 and with increased mortality up to 5–10 years after CABG.29,32 Furthermore, postoperative depressive symptoms are associated with poorer quality of life, and with an earlier degeneration of venous grafts.33 The negative effects of depression also affect patients Fig. 1
Predisposing risk factors Older age, diabetes, previous stroke or TIA, aortic atheroma burden, peripheral vascular disease, comorbidity, fragility, depressive symptoms, lower cognitive function, low levels of education, living alone
Intraoperative risk factors Prolonged duration of surgery, prolonged intubation, aortic manipulation, propofol anesthesia, intraoperative cerebral oxygen desaturation, intraoperative hyperglycemia, extracorporeal circulation
Cerebral microvascular damage
Postoperative risk factors RBC transfusion, increased inflammatory markers, increased plasma cortisol levels, postoperative complications, systemic hypoxia
Postoperative cognitive dysfunction
Schematic diagram of the factors involved in the pathogenesis of postoperative cognitive dysfunction. RBC, red blood cell.
undergoing cardiac valve surgery.34 On the contrary, patients with personality traits characterized by optimism show a lower rate of rehospitalization after CABG.35 Anxiety disorders
Anxiety disorders are common after cardiac surgery; they include post-traumatic stress disorder (PTSD), generalized anxiety disorder, and panic disorders. PTSD is a severe anxiety disorder often described in combat veterans. It is induced by exposure to an event that involves death or serious injury, and generates intense fear or helplessness. In patients with PTSD, this traumatic event is persistently re-experienced, the stimuli that may trigger such experience are avoided, and symptoms of increased arousal (such as difficulty falling or staying asleep, or concentrating) appear. These symptoms are associated with significantly impaired social or occupational functioning. PTSD can be present in up to 18% of patients after cardiac surgery, and is associated with a poorer quality of life.36 Anxiety symptoms (worry, apprehension, and fearfulness) are very frequent in the preoperative phase of cardiac surgery, involving on average 40% of patients; these symptoms tend to decline weeks and months after surgery. Although the relationship between anxiety and outcome has been less investigated, higher anxiety scores, generalized anxiety disorder (characterized by excessive and uncontrollable anxiety, often disproportionate to the actual source of worry), and panic attack disorder are associated with a worse outcome after CABG or valve surgery.37
Pathophysiology of postoperative depression and anxiety Role of somatic illness
Although the cause and pathophysiology of major depression and other mental disorders are not well clarified, converging evidence suggests that several mechanisms are involved in their pathogenesis. Among the risk factors for depression, a role is played by concomitant physical illness. Patients with a greater degree of depressive symptoms after CABG were more likely to have more comorbid conditions, higher Canadian Cardiovascular Society angina class, higher cardiovascular risk factors, lower physical function, and were to be operated on more often on an emergency basis than those with lower levels of postoperative depressive symptoms.30,33,34 It is noteworthy that left ventricular function, history of cardiac disease, including previous myocardial infarction, angina pectoris, and previous coronary angioplasty procedures, were associated with severity of depression.30 To indicate that the psychological reaction is related to the somatic illness, the term secondary depression has been utilized.38 However, it is a frequent clinical observation that the distress experienced by the patient is often uncorrelated to the severity of physical illness. Thus,
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Mind injuries after cardiac surgery Rovai et al. 847
factors beyond the somatic illness should be considered to explain the complex pathogenetic mechanisms of postoperative depression. Psychosocial factors
A review of 46 studies has shown that the most commonly identified psychological predictors of postoperative depression and anxiety after CABG were preoperative depression and anxiety.39 Furthermore, the patient’s beliefs about their illness before cardiac surgery was an independent predictor of disability, physical functioning, and depressive symptoms 3 months after cardiac surgery.40 Finally, social factors do play a role, because patients who developed postoperative depression were more likely to be less educated, to have less social support, and to live alone than patients who did not develop postoperative depression.30 Neuroendocrine activation
Open heart surgery is associated with the activation of several neuroendocrine systems, such as the hypothalamic–pituitary–adrenal (HPA) axis. HPA activation, with increased cortisol release, has been documented during cardiac surgery, mainly in patients operated with cardiopulmonary bypass.41 A modest association has also been found between major depressive disorder and HPA activation.42 However, a relationship between cortisol concentration and depressive symptoms after CABG has not been consistently demonstrated.43 After cardiac surgery, thyroid hormone changes frequently occur, consisting mainly of decreased triiodothyronine (T3) levels.44 Several studies have documented that altered thyroid hormone profile is a predictor of a worse prognosis in cardiac patients,45 and that the outcome can be counteracted by hormone supplementation.46 Independently of heart disease, low T3 levels are associated with depressive symptoms in psychiatric patients,47 and T3 administration is used as an add-on therapy for depression resistant to serotonin selective reuptake inhibitors in nonhypothyroid patients.48 Despite the above considerations, thyroid homeostasis after CABG has received little attention so far, and its role in postoperative mood disorders is still under investigation. Inflammation
Major depression has been associated with increased inflammatory biomarkers in the peripheral blood.49,50 A meta-analysis of 24 studies measuring cytokine concentration in patients with major depression has found significantly higher concentrations of tumor necrosis factor (TNF)-a and interleukin (IL)-6 in depressed individuals compared with controls.51 In another meta-analysis, depression was positively associated with both IL-6 and with high-sensitivity C-reactive protein in clinical and community samples.52 Finally, in a small series of
depressed patients showing elevated TNF-a and leukocyte count on admission, both TNF-a and leukocyte count decreased to levels comparable to those of controls following antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs).53 Thus, several studies suggest a link between major depression and inflammation. In cardiac surgery, the immune reaction associated with surgical trauma, like other forms of aseptic trauma, initiates a systemic inflammatory response characterized by increased plasma levels of pro-inflammatory and antiinflammatory cytokines, produced by blood cells, the myocardium, and the endothelium.54 In experimental animals, this inflammatory response to surgical trauma has been shown to profoundly affect brain function by inducing neuroinflammation.55 In patients undergoing CABG, preoperative elevated serum levels of highsensitivity C-reactive protein were an independent predictor of postoperative depression.56 Thus, a relationship has been proposed that links surgical trauma, general inflammatory response, neuroinflammation, and depressive symptoms.57 For developing a major depressive episode, these alterations should also interact with a specific multifactorial genetic pattern. Genetic predisposition
Postoperative depression has a genetic component, which should not be regarded as an all-or-nothing phenomenon that is manifested regardless of external conditions. Genetic predisposition is to be understood as a type of reaction (genetically influenced) that occurs when the individual is exposed to stressful events. In the last few decades, alterations in several central nervous system neurotransmitters, including serotonergic neurotransmission, have been shown to play a key role in both the pathophysiology of depression and the mechanisms of action of antidepressant drug treatment.58 The genetic variability in two serotoninrelated gene polymorphisms that influence central nervous system serotonin turnover, and their relationship to depression and adverse cardiac events, has been studied in a group of 427 patients undergoing CABG.59 Neither candidate polymorphism was significantly predictive of postoperative depression in the studied population, which was likely not powered enough to test such a hypothesis (P ¼ 0.06 for each gene polymorphism). However, depressed patients who carry the long (L) allele of the 5HTTLPR polymorphism were more likely than the short/short (S/S) carriers to have an event during follow-up, including repeat coronary revascularization by CABG surgery or percutaneous coronary intervention, myocardial infarction, cardiac arrest, or all-cause mortality. In response to various stimuli, cortisol coordinates metabolic, endocrine, immune, and nervous system responses.
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The effects of cortisol are mainly mediated by the glucocorticoid receptor, which is expressed throughout the body, including the brain.60 In a cross-sectional genetic association study of 526 patients with chronic CAD, four glucocorticoid receptor gene polymorphism and haplotype analyses were conducted and correlated with current or past depression. The prevalence of depression was 24% in the noncarriers, 34% in heterozygotes, and 53% in homozygous for the haplotype 3 allele; these associations persisted after adjusting for confounding factors.61 Finally, an association between polymorphism of the glucocorticoid receptor gene and anxiety, traumatic memories, PTSD symptoms, and health-related quality of life has been shown in 126 patients undergoing cardiac surgery and intensive care unit therapy.62 Specifically, the homozygous carriers of the BcL G allele were more likely to present anxiety and PTSD symptoms than heterozygous carriers or noncarriers. Furthermore, homozygous carriers did not show any significant improvement in health-related quality of life 6 months after cardiac surgery, whereas heterozygous carriers or noncarriers did. Finally, genetic variants of the binding protein that modulates the glucocorticoid receptor function (FK506) and brain-derived neurotrophic factor (BDNF) are suggestively associated with depression in a Swedish population-based cohort.63 All of the above considerations support the concept that genetic predisposition is a risk factor for developing elevated depressive symptoms and for greater adverse events after cardiac surgery. Brain and abnormal response to stress
Within the brain, a complex neural network determines what is threatening and thus stressful to the individual. This network includes some subcortical structures such as hypothalamus, hippocampus, and amygdaloid complex, as well as cortical areas such as the prefrontal cortex. Recently, it has been pointed out that the hippocampus seems to be a crucial structure for linking abnormal stress reaction (allostatic load) to mental dysfunctions. The hippocampus is a complex and highly organized brain structure involved in learning and memory, in processing the contextual aspects of emotional events, and regulating visceral functions, including the HPA axis.64,65 The hippocampus contains receptors for adrenal steroids and for major metabolic hormones, and it appears to be particularly vulnerable to the effects of stress. Mild and short-lasting stress often enhances hippocampal function, whereas prolonged or severe stress may alter the structure and function of the hippocampus. This altered hippocampal function includes a reduction (retraction) in the branching of cell dendrites and a reduction in the formation of new neurons in the adult hippocampus, a phenomenon referred to as adult hippocampal neurogenesis.66 Recently, several studies have provided evidence that the hippocampus is a specific target of various hormones and pro-inflammatory
substances induced by stressful experiences, thus supporting the idea that the hippocampus is involved in the regulation of mood.67,68 Thus, a neurogenesis hypothesis of depression has been put forward linking a suppressed rate of adult hippocampal neurogenesis to the pathophysiology of depression. In conclusion, the complex biochemical changes that occur during cardiac surgery, including neuroendocrine activation and inflammation, along with an aspecific response to stressful life events, might target hippocampal function and represent a risk factor or a trigger factor for the onset of depression in these patients (Fig. 2).
Possible strategies for prevention and treatment Antidepressants
Because of their favorable risk profile and effects on depression, anxiety disorders, and PTSD, SSRIs are considered the antidepressants of choice in patients with CAD. In a meta-analysis of six randomized controlled trials, CAD patients on SSRIs showed a significantly greater improvement in depression symptoms compared with controls, without significant differences in mortality or CHD readmission rates.69 Despite these premises, studies on SSRIs in patients undergoing CABG have generated conflicting results. In a retrospective study on 4794 patients who underwent CABG, 5% of whom were already receiving SSRIs before surgery, the SSRI group had an increased risk of mortality after adjustment for baseline differences.70 In a more recent study on 4136 patients who underwent CABG, 2.5% of whom were on SSRIs or serotonin–noradrenaline reuptake inhibitors, the antidepressant treatment was not associated with cardiac mortality or all-cause mortality. However, the use of the above medications was significantly associated with an increased risk of renal dysfunction requiring dialysis and prolonged ventilation after CABG.71 In a previous study on 1380 patients who received either SSRIs (78% of patients) or non-SSRI antidepressant (22% of patients) before CABG, the preoperative use of SSRIs was not associated with increased risk for bleeding or inhospital mortality after CABG.72 Faced with these diverging results, prospective randomized trials on the optimal medical treatment of mood disorders after cardiac surgery would be desirable. Statins
An interesting association between postoperative depression and statin therapy has been observed in a small sample of 193 patients hospitalized for angioplasty, myocardial infarction, or CABG. The use of statins (in 81% of patients) was associated with significantly decreased risk of depression.73 As statins have known effects on inflammatory cytokines, and they also reduce markers of oxidative stress, this observation could support the inflammatory and oxidative hypothesis of depression.
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Mind injuries after cardiac surgery Rovai et al. 849
Fig. 2
Predisposing psychological risk factors
Predisposing genetic factors
Pre-operative depression and anxiety, patient’s beliefs about their illness
Serotonin-related gene and glucocorticoid receptor gene polymorphism
Predisposing social risk factors
Somatic illness
Low levels of education, low social support, living alone
Comorbidity, angina class, CV risk factors, low physical function, emergency operations
Surgical trauma
Neuroendocrine activation
Inflammation
HPA axis activation →cortisol release Low T3 syndrome
Pro-inflammatory cytokines High-sensitivity-CRP
Neuroinflammation Hippocampus, amygdala, prefrontal cortex
Postoperative depression
Schematic diagram of the factors involved in the pathogenesis of postoperative depression. CRP, C-reactive protein; CV, cardiovascular; HPA, hypothalamic–pituitary–adrenal; T3, triiodothyronine.
In a larger study on 1059 cardiac surgical patients, the preoperative use of statins had a protective effect on the risk of early postoperative delirium.74 These findings suggest the possibility of novel therapies different from conventional antidepressants in the prevention and treatment of postoperative depression and cognitive dysfunction. However, further studies are needed to prove such a hypothesis. Cognitive behavioral therapy
Interesting results on the prevention and treatment of postoperative mind injuries involve nonpharmacological treatment tailored to improve patient knowledge and stress management. In a recent study, 100 patients with symptoms of depression or anxiety before CABG were randomly assigned to receive the usual treatment or a brief cognitive behavioral therapy. This intervention improved depressive symptoms at time of discharge, as well as quality of life after 1 month.75 In another study, 123 patients with major or minor depression within 1 year after surgery were randomized to cognitive behavioral therapy, supportive stress management, or usual care. Even after surgery, the two nonpharmacological strategies were efficacious for treating depression after CABG, compared with the usual care.76 Recently, the effectiveness of telephone-delivered collaborative care has been evaluated in 302 patients after CABG.77 Compared with usual care, telephone-delivered care resulted in improved health-related quality of life, physical functioning, and depressive symptoms at 8-month follow-up.
Enriched environment hypothesis
Several studies have shown that exposure to a cognitively and socially stimulating environment (a combination known as ‘enriched environment’) and physical exercise exert beneficial effects on brain function. Specifically, exercise and exposure to an enriched environment improve cognitive performance, slow down decline in the elderly, increase cortical synaptic plasticity, and reduce the risk of developing dementia and depression.78–80 Furthermore, it has been shown that an enriched environment yields a significant increase in hippocampal neurogenesis, counterbalancing the detrimental effects of stress-related substances.78 Because of the similarities in pathophysiological mechanisms, one might propose translating the enriched environment strategy to the postoperative theatre. In this view, interaction between patient and family members, nurses, and medical personnel should be encouraged as much as possible. Furthermore, the patient might take advantage of being exposed to pleasant visual stimuli and to pleasant acoustic stimuli or odors. Finally, the patient’s mental recovery might be favored by an early rehabilitation program, so as to train the patient’s body and mind.
Limitations Because of the complexity of this issue and the large amount of literature available, an in-depth analysis of individual studies could not be reported in this narrative review. This wide topic was chosen to underlie the continuum and possible interrelationship between different types of cognitive dysfunction and mood
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disorders, as well as any common favoring factors, precipitating factors, and pathogenetic mechanisms.
Conclusion
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The relationship between cardiovascular disease and mental disorders is close and bidirectional. On the one hand, stress, depression, and social isolation are independent risk factors for the development of CAD. On the other hand, heart disease and cardiac surgery produce a stress reaction that induces the activation of several neuroendocrine pathways, and the release of several pro-inflammatory factors. The net effect of these changes is neuroinflammation. Consequently, a reduction in the function of several brain areas occurs, and is thought to be responsible for depressive mood. Furthermore, postoperative mind injuries are influenced by factors that existed prior to the intervention, such as genetic predisposition or psychosocial factors. Prevention of postoperative mental disorders through optimization of pre and/or postsurgery treatment by new pharmacological and/or nonpharmacological strategies could be worthwhile for improving patient’s prognosis and quality of life.
Acknowledgements
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This study was supported by institutional grants of the CNR Institute of Clinical Physiology. The authors gratefully acknowledge Ms Alison Frank for the English revision of the article.
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There are no conflicts of interest. 25
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