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type D personality and increased incidence of cardiovascular events in patients with known. IHD [54–56]. Moreover, some reports have demonstrated that type D ...
Riccardo Proietti1, Daniela Mapelli2, Biancarosa Volpe3, Stefano Bartoletti4, Antonio Sagone5, Lucia Dal Bianco6 & Luciano Daliento†6 Cardiology. ‘A Uboldo’ Hospital, Cernusco s/N, Milano, Italy Department of General Psychology, University of Padua, Italy Cardiac,Thoracic & Vascular Department, University of Padua,Italy 4 Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, Italy, 5 Electrophysiology Laboratory, ‘L Sacco’ Hospital, Milano, Italy 6 Cardiology Department, University of Padua, Via Giustiniani 2, Italy † Author for correspondence: Tel.: +39 049 821 1780 n Fax: +39 049 876 1764 n [email protected] 1 2 3

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The connection between cardiovascular disease and psychosocial risk factors has been the subject of an ever-growing body of literature over the last 50 years. Studies on the role of negative emotions, personality traits, chronic stress and social determinants have brought to light their possible role in triggering acute coronary syndromes, although further studies are required to clarify controversial results regarding the association between cardiovascular risk and important psychological problems such as depression and anxiety. The recognition of the role of emotional events in acute coronary syndromes paved the way for provocation experiments, aimed at inducing mental stress in a controlled setting and then documenting reversible impairment of myocardial perfusion, depolarization anomalies and arrhythmias. This ultimately led to the formalization of the concept of mental stressinduced myocardial ischemia. Accumulating evidence on the mechanistic bases of such phenomena, outline a wide range of central and peripheral physiological changes associated with emotions and behaviors, whose effects are exerted on the cardiovascular system, sympathetic nervous system and the hypothalamushypophysis neuroendocrine axis. This article outlines the main steps in the identification of psychological aspects as cardiovascular risk factors and emphasizes the relevance of emotional stress as a trigger of acute cardiovascular events. Finally, a description is provided of the pathophysiological mechanisms behind mental stress-induced myocardial ischemia and pathways connecting the heart and brain.

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Mental stress and ischemic heart disease: evolving awareness of a complex association

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Cardiovascular disease (CVD) is the most prev­ alent public health problem on a worldwide scale [1,2] . Dyslipidemias, smoking, diabetes mellitus, arterial hypertension, obesity, a positive family history for early coronary artery disease and a sedentary lifestyle are well established risk fac­ tors for the development of CVD. The preven­ tion and treatment of these risk factors signifi­ cantly reduced morbidity and mortality [1–3] . Nevertheless, CVD remain the main cause of illness and death in the world [1,2] . It is just as clearly established in the relevant literature that a high number of cardiovascular events occur in people with one or no risk factor at all [4–6] . Moreover, although the risk factors for atheroma formation are known, much less information is available on the factors which act upon the vascular lesion at different stages in its patho­ biological history, determining its clinical evolu­ tion towards a catastrophic acute event [5] . The impact of psychological aspects as cardio­ vascular risk factors, while amply described, was 10.2217/FCA.11.13 © 2011 Future Medicine Ltd

certainly underplayed in comparison with tradi­ tional risk factors [7] . Initially, studies were prevalently oriented to the description of pernicious personality traits in atherogenesis [7–73] , then broadened their scope to the role of negative reactions to personal or community relationships or events in triggering acute coronary syndrome [81–94] . These studies led to the identification of mental stress as an important variable in the pathogenesis of myo­ cardial ischemia. This article aims to outline the main land­ marks in the identification of psychological aspects as cardiovascular risk factors and empha­ size the relevance of emotional stress as a trigger of acute cardiovascular events. It will also discuss mental stress-provoking procedures and how they can induce, in different laboratory models, reversible impairment of myocardial perfusion, depolarization anomalies and arrhythmias. The article will also describe the pathophysiologi­ cal mechanisms behind mental stress-induced Future Cardiol. (2011) 7(3), xxx–xxx

Keywords emotional trigger ischemic heart disease n mental stress ischemia n psychological factors n n

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ISSN 1479-6678

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myocardial ischemia (MSIMI) and will illustrate the pathways connecting the heart and brain through which such mechanisms can exert their influence. Psychological factors & cardiovascular risk

A wide range of social and psychological factors have been correlated with the pathogenesis and presentation of ischemic heart disease (IHD), demonstrating a link between emotions and car­ diovascular health [7] . Available evidence applies particularly to four main psychosocial aspects: n Negative emotions (depression, anxiety, h­ostility and rage); Personality traits;

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Chronic stress (work and family related);

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Social determinants (social isolation and c­onflicts) [7] . Interest in the role played by negative emo­ tions on the development of CVD has grown exponentially, focusing in particular on the role of depression and depressive symptoms, of anxi­ ety, anger and hostility. Numerous trials have demonstrated a sig­ nif icant correlation between depression and increased cardiovascular risk: in 1993, Anda  et  al. reported that in a population of 2800 individuals followed-up for over 12 years, symptoms of depression (assessed through the General Health Questionnaire) were associated with a significant risk of fatal or nonfatal IHD, independent of traditional cardiovascular risk factors [8] . Subsequent epidemiological studies investigated the association between depression and IHD in a population of healthy subjects [9–15] and in people with known heart disease, [16–26] consistently demonstrating a correlation between major depressive episodes and increased incidence of cardiovascular events. The most striking aspect emerging from these studies is the presence of a gradient between severity of depression and future cardiovascular events: the risk of IHD associated with depres­ sion follows a continuous spectrum that is pro­ portional to the extent of depressive symptoms [16] . However, a growing body of studies have failed to detect a relation in CHD patients between depression and adverse cardiovascu­ lar events or mortality [27–31] . There is a longstanding interest in examining the relationship between cardiovascular events and depression, although the fact that different trials tend to use

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different depression scales (e.g., PHQ-9, BDI and HADS) makes comparison between stud­ ies difficult. In fact the incidence of depression in some studies, report data that may be some­ what lower than expected. This discrepancy on incidence of depression in cardiovascular disease patient populations could be owing to the rigor of screening criteria for classifying participants as depressed. According to current DSM-IV-TR criteria, major depressive disorder (MDD) is best diagnosed on psychiatric interview, when the patient reports five or more of the follow­ ing symptoms during the same 2-week period (and when they represent a change from previous functioning): at least one of either of the symp­ toms of depression depressed mood or loss of interest or pleasure. In addition, the patient must report: depressed mood, a significantly reduced level of interest or pleasure in most or all activi­ ties, a considerable weight loss or gain, difficulty falling or staying asleep (insomnia) or sleeping more than usual (hypersomnia), behavior that is agitated or slowed down, feeling fatigued or having a diminished energy, thoughts of worth­ lessness or extreme guilt, reduction in ability to think, concentrate or make decisions and fre­ quent thoughts of death or suicide (with or with­ out a specific plan) or attempt of suicide. Minor depression disorder, is a clinical syndrome often described for research purpose, the signs are sim­ ilar to those of MDD but with fewer symptoms less impairments and dysthymia is a chronically depressed mood state for at least 2 years without meeting the criteria for MDD. As mentioned, the clinical interview is the best tool for diag­ nosis of depression, but in the research studies self-reported questionnaires are also often used, for example, the Beck Depression Inventory. It is worth noting that self-reported questionnaires, strictly speaking, do not assess depressive dis­ order per se, but instead are aimed at identify­ ing depressive symptoms. The majority of these depressive symptoms represent mood disorders due to a general medical condition, which often resolve spontaneously following remission or hospital discharge. The combination of enhanced sympathetic tone, hypercortisolism and platelet dysfunc­ tion observed during depression, constitute the pathophysiological bases of its pro-atherogenic effects [32–37] . Moreover, clinical depression is associated with several significant alterations in cellular immunity [38,39] . This dysregulation does not seem to be corrected by pharmacological and cogni­ tive-behavioral treatments for depression, as

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of fear of rejection or disapproval [52] . In their study, they demonstrated that type D personal­ ity was an independent risk factors for cardiovas­ cular events in a population of 315 patients with known heart disease, followed-up for 5 years [53] . Subsequent studies drew a correlation between type D personality and increased incidence of cardiovascular events in patients with known IHD [54–56] . Moreover, some reports have demonstrated that type D personality is a vulnerable factor in healthy individuals for developing mental health problems (e.g., symptoms of depression, anxiety, post-traumatic stress disorder and work-related stress) or physical health problems (notably metabolic syndrome) [57] , which can in turn be associated with mechanisms promoting cardio­ vascular disease [58] . The INTERHEART study investigated the presence of traditional risk factors and psycho­ logical stress in 11,119 patients with IHD and 13,648 healthy subjects enrolled at 262 centers in 52 different nations and observed that indi­ viduals with work- or home-related permanent stress had a doubled relative risk of acute MI [59] . In particular, as far as work-related cardio­ vascular risk is concerned, there appears to be an association between high work load and low reward (intended as low compensation, insuffi­ ciently gratifying role, scarce career opportuni­ ties precarious job positions). The Whitehall II Cohort study that enrolled 6895 men and 3413 women, demonstrated an imbalance between perceived job effort and reward and restricted decisional space associated with a significant risk of coronary disease at a 5-year follow-up [60] . A comparison between work- and familyrelated stress was the object of the MRFIT study, which observed in males with known heart dis­ ease an increased risk of cardiovascular events associated with family-related stress compared with work-related stress [61] . Orth-Gomer et al. described similar results in the female popula­ tion [62] . Published evidence also indicates that social isolation and lack of interpersonal support are independent cardiovascular risk factors [63] ; even more striking, mortality triples in socially isolated patients with known heart disease and a perceived lack of social support [7] . Few studies have investigated the efficacy of a cognitive behavioral therapy on outcomes of cardiovascular disease: those performed by Blumenthal and colleagues demonstrated the efficacy of a cognitive behavioral approach for stress management as part of secondary pre­ vention in patients with known IHD [64–66] .

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demonstrated in the two large SADHART [40] and ENRICHD [41] trials, where respectively sertraline and cognitive-behavioral therapy was demonstrated to be both safe and effective in treating symptoms of depression, but ultimately ineffective in decreasing major end point such as mortality and morbidity. Results of both studies were hugely disappointing to researchers as the findings demonstrated that depression measured in hospitalized acute post-myocardial infarction (MI) patients, does not mediate cardiac risk. An association between anxiety disorders and cardiac death was demonstrated in studies performed on large populations of both people with known heart disease [42] and healthy sub­ jects [43–46] . Strik et al. [28] and Shibeshi et al. [47] demonstrated in two different trials that general anxiety is an independent predictor of major adverse cardiovascular events in patients who had suffered a previous MI; both authors conclude that anxiety should be considered dur­ ing risk stratification of post-MIs patients. In a cohort study enrolling 947 patients with known coronary artery disease, Watkins et al. reported phobic anxiety as a risk factor for heart-related mortality and sudden cardiac death in women [48] . Anxiety also confers a worse prognosis in patients with previous cardiac bypass surgery, as shown in different works by Tully et al. [29] and Székely et al. [30] . A more recent meta-analysis highlights anxiety as an independent risk fac­ tor for future cardiovascular events and cardiac mortality in healthy subjects [49] . Having largely abandoned the notion that development of IHD correlated with type A behavioral pattern (mainly characterized by hos­ tility, intense ambition, competitive spirit, con­ stant preoccupation over deadlines and general sense of urgency) [50] , greater attention was paid to the consideration of certain peculiar aspects, such as hostility, rage or tendency to feel nega­ tive emotions and to deny them through social inhibition. Chida and Steptoe recently performed a metaanalysis on studies that had individually con­ sidered rage and hostility in relation to cardio­ vascular risk and observed a significant increase in cardiovascular events in healthy subjects and a worse prognosis in people with known heart disease [51] . In the late 1990s, Denollet and colleagues first described type D personality (letter D stands for distressed), to describe individuals that have the tendency to experience increased negative emo­ tions across time and situations and that tend not to share these emotions with others, because

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Furthermore, additional experiences from other groupes, have described different treatment modalities, such as relaxation and behavioral techniques that have been shown to exert a ben­ eficial effect on the control of blood pressure and other hemodynamic parameters dependent on the autonomic nervous system [67–72] . Recently, the Swedish CBT trial showed that a cognitive behavioral therapy, focused on stress management, has a positive effect in patients with a previous heart attack in reducing reoccurrence of adverse cardiovascular events and improving psychological health [73] . Acute coronary syndromes & emotional events

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The critical event in acute coronary syndromes is destabilization of a coronary plaque and sub­ sequent thrombus formation within the arterial lumen. Plaque rupture is the most common form of destabilization and occurs in 70% of fatal MI and sudden cardiac deaths [74] . Numerous stud­ ies have been conducted on the immune–inflam­ matory mechanisms involved in the rupture process and on the identification of biohumoral markers capable of predicting such an event. However, we still remain unable to define the pathophysiological evolution of an atheroscle­ rotic lesion, nor do we know the determinants that act upon it, to prompt its rupture or the factors that instead contribute to a prolonged subclinical existence of the plaque [75] . A variety of factors are involved on a so-called ‘vulnerable’ plaque and can lead to its rupture: hemodynamic activation owing to blood flow abnormalities, sympathetic system activation capable of mediating coronary vasoconstriction and imbalances between prothrombotic and thrombolytic factors, which act on the hemo­ static profile of circulating blood [75–77] . This sequence of events can occur spontaneously, although in some cases a trigger can be identified at the start of the pathophysiological chain of events which ends in the acute cardiac event [78] . A trigger must be sought among those stimuli that occur 1–2 h before the clinical onset of an acute coronary syndrome. This trigger can take many forms, including physical exertion, exces­ sive heat or cold, infections or stimulant drugs such as cocaine [79] . Emotional triggers are also thought to exist and have been generally the subject of retrospec­ tive studies belonging to two typical method­ ological approaches [80] . The first approach is the study of the impact of extraordinary natural or social events (e.g., earthquakes, terrorist attacks,

industrial disasters or even high-profile sports events) on the incidence of admissions for acute coronary syndromes or of sudden death. The second approach consists in the individual study of a single patient who suffered an acute cardiac event in order to investigate whether the hour just before saw the presence of any particularly intense emotional event. An increased incidence of MI was first reported after the January 1994 Northridge earthquake in Los Angeles (USA): in the week of the earth­ quake, accesses to emergency departments for acute MI increased to 201 from the 149 of the preceding week, while the occurrence of sudden death increased to an average of 24 cases per day in the week of the earthquake from 4.6 cases per day in the preceding week [81] . A similar find­ ing of increased admissions for acute MI was also observed during the 1995 Hanshin-Awaji earthquake in Japan [82] . On the other hand, the fact that no such increases were reported in the 1989 Loma Prieta earthquake in San Francisco (USA), led observ­ ers to suppose that other factors interfere with the possibility that natural disasters may precipi­ tate acute cardiac events [83] , probably the added stress of abrupt awakening in the Los Angeles earthquake contributed to trigger the event. Meisel et al. documented an increased incidence in acute MI and sudden death in the Tel Aviv area during the initial phase of the first Gulf War [84] . The 9/11 terrorist attacks increased the frequency of emergency department accesses for MI in the subsequent 2 months in Brooklyn hospitals [85–86] . Even avidly followed sports events have been correlated with an increased incidence of MI. For example, Carroll et al. described an increase in the number of admissions for MI on a day when the England national football team lost to Argentina in the 16th round of the 1998 FIFA World Cup [87] . Recently, Wilbert-Lampen et al. described an increased incidence of cardiac emergencies in the male German population during the days when Germany was playing in the Munich 2006 FIFA World Cup [88] . The first large study to evaluate individu­ ally the impact of emotional triggers was the study Multicenter Investigation of Limitation of Infarct Size (MILIS), which included 849 patients interviewed within 18 h of the onset of MI: 18% of these reported an emotional stress in the period immediately preceding the onset of symptoms [89] . Of the patients enrolled in the Triggers and Mechanisms of Myocardial Infarction (TRIMM) study, 35% reported an emotional

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harassment, carrying out verbal and color-based cognitive tasks, public discussion of an emotion­ ally embarrassing subject [105] . The adequacy of these tests was evaluated not just in terms of their ability to induce ischemia, but also on grounds of their reproducibility. Kim et al. reported a 75% reproducibility with the public discussion test [106] , while Jain et al. found a 90% reproducibility with the anger recall test, which entails the recall of a particularly intense emotional event and then its retelling out loud [107] . Different diagnostic techniques have been used to detect ischemia, including ECG change and left ventricle dyskinesias on an ECG. Yet, MSIMI can still fluctuate and often myocardial perfusion imaging techniques are the most sensi­ tive way to recognize this [105] . Various studies to date have brought to light the prognostic impact of MSIMI. The first study to do so enrolled 30 patients in secondary pre­ vention, who were observed for the onset of ven­ tricular dysfunction after mental stress. A 2-year follow-up, the 15 patients who had tested posi­ tive had an increased incidence of cardiovascu­ lar events (e.g., reinfarction, hospitalization for angina and revascularization procedures) com­ pared with those who had tested negative [108] . A subsequent study by Jiang et al. evaluated 126 patients with known IHD over a 5-year follow-up period, testing for ventricular dys­ function on radionuclide ventricular scanning, induced by mental stress [109] . Those who had tested positive had a significantly wore prognosis for fatal and nonfatal cardiovascular events. Krantz et al. investigated the prognostic sig­ nificance of MSIMI as evidenced by wall dys­ kinesias in 96 patients [110] . On a 4-year followup, a total of 28 events occurred and among the patients who had tested positive, 45% had an event, whereas less than 25% of those who had tested negative had one. The strongest study to show an impact of MSIMI on mortality in a cohort of patients with known IHD was the PIMI trial, which included 196 patients followed-up for 5 years. The authors demonstrated that wall dyskinesias after men­ tal stress occurred in 40% of patients who died during follow-up, as opposed to only 17% of those who survived [111] . The exact mechanisms behind this association remained unidentified, however, it is conceivable that coronary hyper reactivity may result in frequent episodes of silent myocardial ischemia during daily life and social interactions, predisposing to further cata­ strophic cardiovascular events.

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stress in the hour before acute MI [90] . In a metaanalysis including 17 studies, Culic et al. con­ cluded that 6.8% of patients suffered an emo­ tional stress before the onset of acute MI [79] . Anger, as moderate or extreme outburst, is the most widely reported emotional trigger of acute coronary syndromes. In the Determinant of Myocardial Infarction Onset study, 2.4% of patients reported excessive irritation in the two h preceding acute MI [91] . A study performed by Strike et al. in London on 295 patients reported an incidence of 17.4% of episodes of acute emo­ tional upset in the 2 h preceding symptom onset, including arguing with relatives or neighbours [92] . Acute stressor effects have been evaluated as possible triggers in the SHEEP study, which found that stressors such as particularly demand­ ing work-related deadlines were associated with a substantial increase in the risk of cardiac events in the next 24 h [93] . Steptoe et al. evaluated the incidence of epi­ sodes of acute depression in the 2 h preceding the onset of symptoms of acute coronary syndromes [94] . They found that depressive episodes were reported by 18% of patients. However, it must be acknowledged that these retrospective studies may be influenced by several biases which interfere with the interpretation of results. The patient’s recall of an emotional event can be markedly influenced by the importance of the clinical event he/she suffered, to the point that the latter is justified by the amplification in hindsight of emotional events that may have oth­ erwise hold little relevance [80] . In order to limit the influence of this bias, a case-crossover analy­ sis is used, whereby events are investigated that occurred in the 2 h preceding the clinical event and those that occurred in the same hour of the day before [80] . Despite their limits, these stud­ ies demonstrated that the association between emotional events and acute coronary syndromes is consistent and is most likely to occur in people with a lower socioeconomical level [80] .

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Myocardial ischemia & mental stress

Over the last decades, scientific evidence has demonstrated consistently that myocardial ischemia could be induced through various kinds of mental stress induced by provokating procedures (stress induced in the laboratory); this phenomenon was labeled with the MSIMI acronym [95–104] . A wide range of provocative tests have been employed to induce a mental and emotional effort capable of determining myocardial isch­ emia, such as time-capped arithmetic tasks with future science group

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abnormal in patients with IHD and a stronger, more prolonged hypertensive response exists. Data suggest that the extent of hemodynamic response correlates with the degree of induced ischemia [116] . The effector systems which medi­ ate this response include the sympathetic nervous system and adrenal medulla, the parasympathetic nervous system, the hypothalamic–pituitary– adrenocortical axis, renin–angiotensin–aldoste­ rone and vasopressin systems. The occurrence of mental stress-induced endothelial dysfunction was described in normal individuals, in patients with IHD and hyperten­ sion. The link between endothelial dysfunction and mental stress is supported by the role played by the sympathetic nervous system in regulating vascular tone [116] . In addition, acute stress aug­ ments the activity of the hypothalamus–pitu­ itary–adrenocortical system, increasing plasma and tissue catecholamines [116] . Inflammatory markers such as IL-6 and TNF-α rise after intense physical exertion. It has been observed that platelet activation is particularly strong during mental stress, with a more pronounced and prolonged response in individuals with known IHD compared with controls [116] . Platelet activation was detected via an increase in b-thromboglobulin, platelet factor 4 and ADP [116] . The concentration of aggregation-inducing adrenergic receptors on platelets can be altered by a variety of psycho­ logical conditions and psychiatric disorders. Therefore, MSIMI is characterized by a com­ bination of endothelial dysfunction, changes in coronary vasoreactivity and hemodynamic effect caused by an autonomic stimulus [116] . These features, together with the well-documented ability to increase inflammatory activation and platelet aggregation, compel investigators to include mental stress as an important factor in the understanding of the pathobiology of acute coronary syndromes.

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Recent scientific evidence stress how dif­ ferent the mechanism responsible for MSIMI and that behind ischemia induced by physical exercise are [112] . Ischemia induced by physi­ cal exertion develops following the inability to meet increased oxygen demand when coronary stenosis impairs an adequate increase in blood flow. On the other hand, MSIMI correlates with anomalous coronary vessel reactivity and height­ ened vasoconstrictive response to stress. During mental stress, diastolic pressure and systemic vascular resistance rise. Direct angiographic evidence of constric­ tion of epicardial vessels was documented dur­ ing mental stress [113] . Moreover, the abnormal coronary response correlates with a paradoxical vasoconstrictive response after intracoronary acetylcholine injection [113] . Lacy et al. showed how abnormal vasomotor response to mental stress is more important in arterial segments that are devoid of significant stenosis [114] . Burg et al. emphasized that, while the intensity of physical exertion and the severity of IHD are the essential determinants of exercise-induced myocardial ischemia, personality traits are the most important aspects in MSIMI [95] . They observed that high levels of hostility, rage and type A personality are markers of susceptibil­ ity to MSIMI, whereas the severity of coronary artery disease on angiography or the severity of exercise-induced ischemia were not. Individual heritable differences may exist in the degree of adrenergic stimulation triggered by mental stress. Hassan et al. recently reported that individual responses to mental stress may partly stem from polymorphisms in b1 adren­ ergic receptors (ADRB1) genes [115] . They dem­ onstrated that in patients who are homozygous for the Ser49 allele of the ADRB1 gene had a threefold increase in their probability of experi­ encing MSIMI, as detected by myocardial perfu­ sion imaging, compared with people who car­ ried other alleles. Much work remains regarding the identification of other genetic determinants underlying the individual variations in neuro­ hormonal activation in MSIMI. Psychological stress causes a wide range of response which may induce myocardial isch­ emia: some of these occur only in patients with coronary artery disease, while others occur in its absence [116] . An intense mental stress causes a hemodynamic response, primarily by increasing heart rate, blood pressure and cardiac output, which can deter­ mine myocardial perfusion deficit [116] . There is evidence that this hemodynamic response is

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Cerebral activation patterns in mental stress inducing myocardial ischemia

The central autonomic network is a flexible network of brain areas that regulate the physi­ ological effects of emotions by way of peripheral effectors (Figure 1) . Involved regions include the prefrontal cortex (involved in decision planning and complex cognitive behaviors), amygdala (important in the processing of fear-inducing stimuli) and anterior cingulate gyrus (includ­ ing a dorsal segment involved in inhibiting emo­ tional responses and a ventral segment involved in processing and integrating emotions) [117] . future science group

Mental stress & ischemic heart disease

Lateral lobes

Emotional processing

Frontal and prefrontal lobes

Thalamus

Limbic system

Hypothalamus

Hippocampal complex

Amygdala

NE Locus coeruleus

NE Rostral/lateral medulla

Ang II

Sympathetic and parasympathetic nervous system

Adrenal gland

Coronary vasoreactivity

Inflammatory response

Endothelial injury

Platelet activation

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Cingulate girus

Arrhythmias

Pathophysiological response

Cerebral cortex

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Figure 1. Central autonomic network, a flexible network of interconnected brain areas that regulate the physiological effects of emotions by way of the neuro-hormonal autonomic nervous system. Ang: Angiotensin II; NE: Norepinephrine.

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The brain response to everyday situations is an integrated, hierarchical process starting from the prefrontal and frontal cortex, which is con­ nected to primary sensory and motor areas, as well as to structures involved in memory and emotion (e.g., hippocampus, cingulus, amygdala and temporal cortex). Sensory inputs are filtered by the thalamus, which possesses widespread anatomical projections to the cortex, the hypo­ thalamus and parts of the limbic system. The latter includes the hypothalamus (which controls a variety of biological functions), the hippocam­ pus complex (mainly involved in memory), the amygdala (which integrates emotion-related information from other brain regions) and the cingulate gyrus (which contributes to the con­ scious perception of emotions). This system inte­ grates emotions with memory, particularly with long-term recall and learned experience, which in turn self-modulate the frequency and extent of the hypothalamic-limbic response [117,118] . The integrated brain response to psychological stress allows sensory information to be assessed and learned on the basis of its relation to previous experience, to generate a coordinated peripheral response that results in a more effective behavior future science group

for the individual. Peripheral changes exerted through the hypothalamus–pituitary–neuroen­ docrine axis and the sympathetic–adrenomed­ ullary system are ultimately responsible for the increase in heart rate and blood pressure. The sympathetic system richly innervates the coro­ nary arteries and myocardium, whose b1 and b2 adrenergic receptors are also directly activated by circulating catecholamines released during stress. In order to study the role of the CNS in MSIMI, Soufer et al. performed a PET study of the CNS during mental stress induced by math­ ematical tasks: activation patterns in response to mental stress differed between people with known heart disease and healthy subjects [119] . The frontal and limbic systems involved in cog­ nitive and affective mechanisms were activated in people with heart disease but not in healthy subjects. These results lend themselves to mul­ tiple interpretations: a stronger activation in cortical areas may indicate that mathematical calculations in people with known heart dis­ ease require greater effort compared with nor­ mal subjects. An alternative explanation may be that these data demonstrate the contribution

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effects on vasomotor tone and function, which make patients vulnerable to myocardial ischemia and/or to ventricular arrhythmias. These results fit well with the more recent find­ ings by Kop et al., who reported that mental cal­ culation and recalling rage may cause a transient increase in inflammatory markers such as CRP and IL-6 in patients with IHD [123] . Baseline inflammatory markers were elevated in patients with IHD than in controls, as expected. Patients with a stronger catecholaminergic response to mental stress were also shown to have an exag­ gerated increase in these inflammatory markers. The authors commented that individuals who reacted to mental stress with higher epineph­ rine and norepinephrine levels may be at higher risk for coronary artery disease progression and atherosclerotic plaque rupture owing to higher circulating concentrations of proinflammatory cytokines and CRP [123] .

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of emotional variables, which seem prevalent in people with IHD. Moreover, hemispheric activa­ tion is more asymmetrical in people with IHD, who appear to activate the left hemisphere more and the right one less than healthy subjects [119] . In addition, within the group of people with known IHD, those who had MSIMI had a sig­ nificantly stronger activation of the left hippo­ campus, consistently with the idea that memory plays a central role in the physiological cardiovas­ cular response to mental stress [108] . Women also appear to have a stronger response than men [120] . The results of these reports are particularly interesting, because they implicate for the first time, a clear identification of cerebral areas involved in the pathogenic mechanisms of CVD, drawing an evident connection between heart– brain interactions and demonstrated inducible myocardial ischemia. A subsequent study from Soufer and col­ leagues demonstrated that the cerebral activa­ tion patterns differ between patients in whom myocardial ischemia could be induced by mental stress, compared with those with dobutamineinduced ischemia [121] . From these data it can be inferred that cerebral activation in patients with stress-inducible myo­ cardial ischemia occurs in area that determine an increased sympathetic tone and a decreased parasympathetic tone, tipping the balance in favor of the former [122] . Afferent signals carried by the vagus nerve can activate an efferent response that inhibits cyto­ kine release, known as the inflammatory reflex. Acetylcholine interacts with nicotinic recep­ tors on tissue macrophages, which then inhibit release of TNF-α, IL-1, endothelin-1 and other cytokines. The reduction in parasympathetic activity observed during mental stress leads to opposite results, for example to the secretion of proin­ flammatory cytokines and their concomitant

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Conclusion

A considerable amount of scientific evidence demonstrates that emotions, personality traits and stress have an impact on CVD. Not only do psychological aspects constitute well-documented risk factors in the primary and secondary preven­ tion of cardiovascular events, but intense emotions can trigger acute coronary syndromes, as first noticed during natural and social events of par­ ticular significance and then shown by epidemio­ logical studies. The creation of laboratory models allowed the documentation of the occurrence of MSIMI and evidenced how it correlates with a more severe prognosis in secondary prevention. The cumulative evidence leads to the con­ cept of mental stress as a pathway of emotional processing, in which involved brain areas could activate stressor effector systems and thereby provide a milieu of increased vulnerability to the heart. The brain transduction of emo­ tional events leads to a learning history in the

Executive summary A wide range of social and psychological factors have been correlated with the pathogenesis and presentation of ischemic heart disease, demonstrating a link between emotions and cardiovascular health. n Several studies demonstrated that intense emotional events can trigger acute coronary syndrome. A trigger must be sought among the stimuli that occur 1–2 h before the clinical onset of an acute clinical event and can be pathophysiologically connected with it. n Over recent decades, scientific evidence has demonstrated consistently that myocardial ischemia could be induced through various kinds of mental stress induced by provokating procedures (stress induced in the laboratory); this phenomenon was labeled as mental stress-induced myocardial ischemia. n A range of central and peripheral physiological changes are associated with emotions and behaviors, whose effects are exerted on the cardiovascular system, sympathetic nervous system and the hypothalamus-hypophysis neuroendocrine axis. n A considerable amount of scientific evidence demonstrates that emotions, personality traits and stress have an impact on cardiovascular disease. It is desirable that the international cardiological community will pay more attention to the assessment of the impact of psychological factors on cardiovascular disease and their management. n

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Over the next decade, it is anticipated that the international cardiology community will pay greater attention to the assessment of the impact of psychological factors on CVD and their man­ agement. For such a development to occur, new clinical protocols will have to be developed to include the assessment of emotional and cogni­ tive factors within cardiovascular risk estimates and as part of secondary prevention approaches in patients with known heart disease. An important impulse will have to be provided by therapeutic studies, which for example may demonstrate the possible benefits of cognitive behavioral therapy in improving prognosis, par­ ticularly in secondary prevention of IHD. It is also strongly hoped that the laboratory model of mental stress is standardized [118] and may be translated into clinical practice; after all, considering the routine use of stress testing in cardiological practice, despite its low sensitivity and specificity, why should we not entertain the idea of a standardized test of mental stress in clinical practice? Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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hierarchical mobilization of a programmed stress response, which is very individualized and heav­ ily drawn on past experience. As a result, this brain-initiated mobilization can occur chroni­ cally throughout one’s daily life, resulting in progressive cardiovascular damage or eventually causing a multiorgan chain sequence leading to an acute cardiovascular effect Despite this indisputable evidence, the evalua­ tion of the patient’s psychological profile and the influence of mental stress is usually neglected in the stratification of cardiovascular risk and in the management of the patient with known heart disease. This is reflected in the fact that while observational studies on this matter abound, experimental studies are harder to come by. Even though the interrelation between the ortho- and para-sympathetic nervous systems, changes in hemodynamic parameters and pos­ sible cardiovascular consequences appear intui­ tive, there are much more complex underlying pathogenic mechanisms, involving elaboration of emotions by the CNS and the activation of a systemic vasoactive and proinflammatory response, which may determine both short- and long-term cardiovascular effects. While the background of clinical cardiologists does contemplate the notion of the influence of the autonomic nervous system on vascular response, it seems to not include full awareness of the strong interaction between the brain and heart in cardiovascular homeostasis and seems quite far from translating into clinical practice the important advances that scientific research achieved in this field.

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