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Mind-Body Medicine in Chronic Heart Failure

2010; Lippincott Williams & Wilkins; Volume: 3; Issue: 6 Linguagem: Inglês

10.1161/circheartfailure.110.951509

1941-3297

Sitaramesh Emani, Philip F. Binkley,

Mindfulness and Compassion Interventions

HomeCirculation: Heart FailureVol. 3, No. 6Mind-Body Medicine in Chronic Heart Failure Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMind-Body Medicine in Chronic Heart FailureA Translational Science Challenge Sitaramesh Emani and Philip F. Binkley Sitaramesh EmaniSitaramesh Emani From The Ohio State University Division of Cardiovascular Medicine and the Dorothy Davis Heart and Lung Research Institute, Columbus, Ohio. and Philip F. BinkleyPhilip F. Binkley From The Ohio State University Division of Cardiovascular Medicine and the Dorothy Davis Heart and Lung Research Institute, Columbus, Ohio. Originally published1 Nov 2010https://doi.org/10.1161/CIRCHEARTFAILURE.110.951509Circulation: Heart Failure. 2010;3:715–725IntroductionThe connection between the mind and body has often been regarded by Western medicine as something ascribed to the mystical and a topic residing outside the scope of scientific thought. However, it has been a long-term integral tenet in the medical practice of many other cultures.1 It could be argued that the reliance of Western thought on the concept of dualism in which Plato, Aristotle, and other classical philosophers separated the body as a physical entity from the mind as a "spiritual" force has ultimately discouraged health care professionals from serious consideration of what has appeared to be a vague and even mysterious connection between the mind and body.2 Nevertheless, a growing body of research has progressively identified the mechanistic building blocks that demystify the reciprocal mind-body interaction and show that it is clearly a physical rather than mystical connection. Descriptions of neurovisceral changes in which readily demonstrated structural alterations in the brain, heart, and other organ systems arise in response to stress and a variety of emotional states provide further demonstration of the true organic mind-body connection. Perhaps the most abundant mechanistic data pertain to the brain-heart interaction under both conditions of health and a variety of cardiovascular disease states. The increasing body of evidence for these important interactions has in fact led to the call for dedicated integrated fields such as neurocardiology or behavioral cardiology.3–5It is therefore important to examine the current state of our understanding of mind-body interactions including the experimental evidence identifying the physiological basis for these interactions and their impact on clinical outcomes. As will be shown, there is a significant overlap between the pathophysiologic mechanisms of congestive heart failure and the major effectors of mind-body connections. This provides the basis for potential new therapies that incorporate mind-body medicine. However, it must be determined whether our current understanding of the mechanisms governing mind-body interactions is sufficient to proceed with routine application of mind-body therapies in patients with heart failure. Further, are patients with heart failure amenable to interventions that act on the "heart-mind" axis in the same way as those without heart failure? This review will examine this understanding in an effort to determine whether current evidence justifies incorporation of mind-body medicine in the treatment of patients with congestive heart failure. Does the current value or future potential of heart/brain medicine in fact justify the creation of a new transdisciplinary and translational scientific field of study and realm of clinical practice?The Mechanistic Building Blocks Governing Mind-Heart InteractionsThe Autonomic Nervous SystemThe autonomic nervous system is probably the earliest and most closely studied effector limb of the mind-heart interaction. As early as 1915, Eppinger and Hess3 proposed that behaviors may differ between individuals because of a predominance of sympathetic or parasympathetic activity. This predominance determined the physiological as well as behavioral responses to environmental stimuli and could predispose individuals to disease states such as hypertension or asthma. As discussed in excellent reviews by Samuels,5,6 the impact of stress and intense emotion on cardiovascular function was submitted to credible scientific thought and investigation in 1942 by Walter Cannon7 in a report reviewing what has been called "Voodoo Death." This report described episodes of sudden death recounted from a variety of cultures which were apparently secondary to profound fear or emotion often inspired by superstitious beliefs. Cannon speculated that death resulted from enhanced sympathetic nervous system and adrenal responses to intense emotional stress and a belief in a power over which the victim had no control. The events discussed in his article are in fact early descriptions of what has come to be known as sudden unexpected death, and a myriad of evidence has supported the major role of the sympathetic nervous system in mediating these episodes.5,6Foundation evidence for the role of the autonomic nervous system in stress-induced sudden cardiac death has been provided by a variety of animal models. A wide range of stressors have been shown to be associated with sudden death.5,8,9 In general, interventions that interrupt release of intracardiac but not circulating norepinephrine prevent stress-induced sudden death.Autonomically mediated mind-body interactions constitute one of the fundamental links between emotional states and cardiovascular disease in human beings.9–11 Perhaps the most dramatic example of this connection is in the so-called "broken heart syndrome" or Takotsubo cardiomyopathy.3,5,12 This syndrome of acute and generally reversible heart failure with a characteristic pattern of ventricular contraction abnormalities appears due in part to increased sympathetic activity producing either direct myocardial damage or contractile dysfunction resulting from diffuse coronary vasospasm. A variety of other stress and distress related conditions have been similarly shown to be characterized by significant abnormalities of the autonomic nervous system. Prominent among these is depression, which has been shown to be associated with sympathetic and parasympathetic imbalance and accordingly an environment that can promote coronary artery disease, congestive heart failure, and sudden death.10,13–22Although sustained increases in sympathetic activity are known to adversely affect cardiovascular function, inappropriately enhanced activity of the parasympathetic nervous system may be similarly damaging. ECG recordings obtained in some rat models of stress show that sudden death is mediated by profound bradycardia progressing to asystole.5,6,8 This suggests that extreme stress may produce an "autonomic storm" characterized by excessive activation of both the sympathetic and parasympathetic nervous systems. Such malignant parasympathetic activity has been shown to play a role in human disease. In a study by Luu et al,23 62% of deaths in patients with advanced heart failure awaiting cardiac transplantation were due to profound bradycardia, suggesting malignant vagotonia as a cause of death.The autonomic control of mind-body interactions has special relevance to patients with heart failure who characteristically have marked parasympathetic/sympathetic imbalance.24,25 Can stress produce autonomic imbalance that in fact leads to the occurrence or progression of ventricular failure? In turn, can the autonomic imbalance in heart failure that parallels that found in stress states in fact promote distress? The significant coincidence of congestive heart failure and depression13,26 and data indicating that depression may precede the appearance of congestive heart failure27,28 suggest that this may be the case. Mind-body interactions that interrupt this reciprocal autonomic dysfunction may therefore benefit both conditions.How Are Emotions and Stress Connected to the Heart?The autonomic nervous system is classically regarded as an "involuntary" system regulated by hypothalamic centers and thus beyond direct conscious control.5,29,30 Nevertheless, it appears that conscious effort can alter cardiovascular function acting through the so-called involuntary autonomic nervous system.5,30,31 However, the question remains how an involuntary nervous system may mediate the cardiovascular responses that characterize conscious mind-heart interactions and the physiological response to various mental states. Increasing understanding of the relationship of cortical function to autonomic control centers provides insight into possible mechanisms for volitional control of cardiovascular function.5,29,32–39Recognition of the role of cortical control of autonomic function dates to at least 1869 when John Hughlings Jackson40,41 observed significant cardiovascular changes during major motor seizure activity. He reasoned that cortical centers governed not only voluntary motor movements but vasomotion and visceral motor activity. Over the years, a variety of stimulation, ablation, and neuroanatomic studies have defined cortical regions that have projections to centers having direct control over sympathetic and parasympathetic activity.40 These cortical regions include the insular cortex, the somatic and motor sensory cortex, the medial prefrontal cortex, and the anterior cingulate cortex. As an example, the insular cortex has been shown to have a "representation of the autonomic nervous system5" as well as "viscerotopic sensory inputs,"29 including those from the cardiovascular system. Studies in animal models using both insular cortex stimulation and localized destructive lesions and studies in humans who have had insular strokes suggest that the right posterior insular cortex modulates cardiovascular sympathetic control and the left posterior insular cortex modulates parasympathetic function.29,37–39,42–47 In these models and in human subjects, stimulation of the left insular cortex produced ST changes, widening of the QRS complex, complete heart block leading to asystolic death, and contraction band necrosis (see below).42–44 The cardiovascular regulatory capacity of the insular cortex suggests one pathway for volitional cardiovascular control that may be operative in mind-heart interactions. Similarly, the anterior cingulated cortex (ACC) has been shown to serve as an interface between cognitive and emotional inputs with projections to autonomic control centers.40,48 It therefore plays a critical role in adaptive responses to the internal and external environment and has been shown to mediate these responses through autonomic pathways. The ACC is functionally, anatomically, and histologically designed to integrate the emotional and cognitive activity of the mind with the physiological responses of the cardiovascular system as well as other organ systems.Functional imaging studies in humans have demonstrated that cortical centers such as the ACC and prefrontal cortex constitute a network integrating emotional and cognitive components of the mind with autonomic cardiovascular control.49 Integrative body-mind training has been shown to increase parasympathetic activity, increase electroencephalographic theta waves originating from these regions, and increase blood flow to these central nervous system centers. Therefore, changes in cognitive and emotional state produce changes in autonomic cardiovascular control producing what some authors have called "brain-body harmony."49 These functional changes can be accompanied by structural central nervous system changes as evidenced by destructive lesions in the ACC in patients with depression who have had a myocardial infarction.50Data for more than a century have confirmed that cortical centers integrating emotional responses and cognitive states, which constitute in part what is regarded as the "mind," have a direct connection to autonomic function. Autonomic control is not simply based on reflex responses but is tightly linked to cortical function. It would therefore be surprising if positive and negative emotional and cognitive states did not have an impact on cardiovascular function and the evolution of cardiovascular diseases. The cortical influence over autonomic centers supports the belief that cardiovascular function and disease risk can be altered through conscious efforts.Inflammatory and Neuroimmune PathwaysBoth cardiovascular disease and mental distress are associated with activation of proinflammatory mechanisms. The commonality of these mechanisms identifies inflammatory pathways as a major mediator of reciprocal mind-heart interactions. In addition, inflammation and autonomic activity are closely tied promoting states of neuroimmune activation that are operative in governing both psychological and cardiovascular function.Although the end-organ effects of proinflammatory cytokines are well recognized, the immune system also serves as a communication network between the central nervous system and other organ systems.51–54 Cytokines produced and released in the periphery can diffuse into the central nervous system, where they in many ways function as neurotransmitters.51,55–59 Importantly, proinflammatory cytokines, either from the periphery or produced within the central nervous system, can stimulate the production of norepinephrine and sympathetic activity.60,61 However, beyond the role of circulating cytokines which must diffuse through the blood-brain barrier to the central nervous system, Tracey and other have shown that proinflammatory cytokines convey signals through the peripheral nervous system constituting a system of rapid communication from the periphery to the central nervous system.54 It is apparent that cytokine signaling via the Vagus nerve can occur with cytokine concentrations that fall well below the circulating levels required to cross the blood-brain barrier.54,62–64In response to peripheral signaling by cytokines, the autonomic nervous system can in turn activate both proinflammatory and antiinflammatory mechanisms. Bierhaus et al65 showed that stress-induced increases in catecholamines and cortisol rapidly increase NF-κβ expression in peripheral blood monocytes that subsequently increase cytokine production. Further, NF-κβ production could be inhibited by α- and β-adrenergic blockade demonstrating the role of sympathetic activation in triggering proinflammatory states.The description of a "cholinergic antiinflammatory reflex" exemplifies the orchestration of the mind-body communication network integrating inflammation and autonomic function.54,66 Studies by Tracey et al54,55,66 have shown that stimulation of the efferent Vagus nerve reduces both cytokine production and release by cells of the reticuloendothelial system. The inflammatory reflex consists of stimulation of vagal afferent fibers by cytokines, as discussed above, resulting in an augmentation of central parasympathetic outflow via the Vagus nerve and consequent reduction of cytokine production and release. This system constitutes a servocontrol mechanism that keeps inflammation in check preventing the deleterious effects of excessive proinflammatory stimulation. Conversely, reduced parasympathetic activity, as occurs in disease states such as congestive heart failure, can result in a failure to inhibit proinflammatory cytokine production enhancing the risk of end-organ inflammatory damage and has been shown to be a possible cause of increased proinflammatory cytokines in human subjects.67The evidence is clear that unrestrained proinflammatory stimulation is associated with cognitive and mood changes. A variety of animal models have shown that acute or chronic stress results in increased proinflammatory cytokine production accompanied by behavioral changes and cognitive impairment.55,68,69 These studies parallel investigations in human subjects that show a significant association between distress and depression and immune activation.70,71 Similar to animal studies, administration of cytokines to human subjects, such as interferon-α, or stimulation of the immune system through vaccination results in depressed mood and activation of the central nervous system in regions known to affect cognitive function and mood.72–74Studies by Kiecolt-Glaser and Glaser73,75–77 exemplify the connection between chronic stress conditions in human subjects and increases in proinflammatory cytokines. Aging care givers of patients with dementia were followed over a 6-year period with measurement of circulating concentrations of interleukin-6 (IL-6). Progressive increases in IL-6 concentrations were seen in all patients over time, but the rate of increase was significantly higher in members of the care giver cohort, who were under increased stress.76 Similar increases in IL-6 were seen in other stress states such as marital discord.73,77 These and similar studies demonstrate one pathway by which acute or chronic stress can lead to immune system activation with resultant inflammatory cardiovascular damage. Especially considering the apparent role of inflammation in the pathogenesis of congestive heart failure,78,79 these data suggest an intriguing link between stress and the evolution of ventricular dysfunction. Preliminary data from Ferketich et al80 support this link in a study in which patients with symptomatic reduction in ventricular systolic function were screened for symptoms of depression using the Beck Depression Inventory (BDI). In these patients, there was a significant linear correlation between BDI score and concentration of tumor necrosis factor-α. It can be safely said that the coincidence of depression and heart failure likely creates a proinflammatory environment that can promote the progression of both disorders.A variety of effectors of both the proinflammatory cascade and autonomic nervous system likely play a role in patients with congestive heart failure. As an example, nitric oxide, which is dysregulated in congestive heart failure, plays a role in modulating autonomic function and in mediating inflammation.81 Reduction in nitric oxide production in congestive heart failure has been associated with abnormalities in autonomic balance.82–87 Recent studies of a loss of function polymorphism of the promoter for nitric oxide synthase demonstrate that it is indeed tightly linked to autonomic function in patients with congestive heart failure.88 Therefore, nitric oxide exemplifies a family of mediators of both inflammatory and autonomic pathways that regulates mind-body interactions and that is especially relevant in patients with congestive heart failure.Environmental Factors Contributing to Mind-Heart InteractionsAlthough mind-body interactions are often considered a self-contained, closed-loop process, there is evidence that external factors, such as infectious agents, may play a role in governing these interactions. A progression of studies has shown a role for Epstein-Barr virus (EBV) infection in mediating altered mood through cytokine stimulation.75,89–93 An early viral protein, dUTPase, produced even during incomplete replication of EBV, has been shown to stimulate peripheral blood mononuclear cells to produce IL-6 and other cytokines. A strong association between the titer of dUTPase antibody and concentration of circulating IL-6 was found in the above noted study of caregiver stress. Therefore, reactivation of EBV, which is a common latent infection, appears to result in stimulation of production of IL-6 and other proinflammatory cytokines that can mediate both depression and cardiovascular injury. This provides a model by which an external infectious agent may modulate mind-body interactions through promotion and even initiation of the inflammatory "network of communication."Neurovisceral Regulation: Anatomic Consequences of Mind-Heart InteractionsAnatomic and structural changes in the heart and the brain accompany states of mental stress as well as different states of concentration and meditation. These anatomic changes solidify the physical connection between the mind and body further demonstrating the reality of these interactions.In the myocardium, psychological stress has been demonstrated to produce classic changes of contraction band necrosis. Studies of hypothalamic stimulation in animal models demonstrated ECG changes resembling those seen in humans with central nervous system hemorrhage or infarction followed by arrhythmic death. Examination of the myocardium in these animals demonstrated what may be interpreted as contraction band necrosis resembling the lesions seen in ischemic infarction.5,6,94,95 Similar lesions have been produced without central nervous stimulation but with psychic stress.5,96 Studies in human subjects have reported these myocardial lesions in patients with psychiatric illness or subarachnoid hemorrhage.97,98 The finding of increased troponin levels in patients with intracerebral hemorrhage and the demonstration of wall motion abnormalities in patients without coronary artery disease who have had an insular stroke further speak to the structural myocardial damage that can be mediated by the central nervous system.38,39Conversely, structural changes in the central nervous system have been shown to accompany differing psychological states. Chronic depression has been associated with decreased hippocampal volume, which is related to the duration of depression.99,100 In contrast to the damage and volume loss that may accompany stress, practitioners of various forms of meditation have increased cortical thickening, especially in centers involved with attention and sensory processing including the prefrontal cortex and the right insular cortex.101,102 Corresponding to these observations, functional magnetic resonance studies have shown increased activity in specific regions of the brain in subjects who have practiced mediation for differing periods of time as compared with control subjects.102Associated with these anatomic changes is evidence for a remodeling of mind-body interactions, which evolves with repeated or sustained stress. This remodeling may "prime" the systems governing mind-body interactions to produce an exaggerated responses to stressful stimuli (Figure). The existence of this remodeling process is supported by studies showing that subjects with early life trauma have significant increases in baseline and stress-induced neuroimmune activation.71 A variety of investigations have shown that episodes of depression are not isolated but demonstrate a pattern of repetition suggesting evolution of pathways that progressively facilitate depressed mood.10 Indeed, many of the same mediators of mind-heart and mind-body interactions are operative in central nervous system structural remodeling. Chief among them are cytokines that are known to act as neural trophic factors but which can over time mediate apoptosis and reduction of tissue volume.55Download figureDownload PowerPointFigure. Proposed remodeling of mind-heart interactions leads to progressive increases in neuroimmune activation in response to stress. In a state such as depression, there is increased sympathetic activity, decreased parasympathetic activity, and activation of proinflammatory pathways. In response to stress, there is further activation of the sympathetic nervous system and proinflammatory pathways and further withdrawal of parasympathetic activity. This results in an environment that promotes sudden cardiac death and vascular and myocardial injury.It may be speculated that remodeling of mind-heart interactions results in an increasing magnitude of stress responses that lead to permanent detrimental end organ damage. As an example, if repeated stress produces even small areas of contraction band necrosis over time, could this ultimately result in ventricular systolic dysfunction and dilation? Further, would such remodeling of mind-heart interactions make patients less susceptible to the potential beneficial effects of interventions such as biofeedback, meditation, or other mind-body therapies?Interventions Targeting Mind-Heart InteractionsA rich mechanistic foundation for mind-body and mind-heart interactions has now been established. This then raises the question as to whether there are volitional modifications of these interactions that can prevent and treat disease states. There is now a wealth of clinical, mechanistic and outcome trials that attempt to address this issue although the quality of these investigations is highly variable.103 Relatively few of these specifically address prevention or treatment of congestive heart failure, although many have addressed risk factors for cardiovascular diseases in general, and may lead to further observations in the setting of ventricular failure. The mind-body interventions that have been explored include biofeedback methods, meditation techniques, and relaxation therapies.BiofeedbackBiofeedback interventions can be broadly defined as those in which the subject learns to consciously regulate a given physiological "target" variable.104 Often, the ability to regulate this specific variable is accompanied by modification of other elements of the mind-heart interaction.One of the most detailed studies of biofeedback is an investigation by Moser et al105 performed in patients with advanced congestive heart failure. Participants were randomized to either biofeedback intervention or to control conditions. The biofeedback cohort successfully increased skin temperature, and compared with control subjects, significantly increased cardiac output, reduced systemic vascular resistance, and decreased respiratory frequency. The mechanism by which the biofeedback intervention produced these changes in hemodynamic variables is not certain but may have resulted from biofeedback associated alterations in autonomic vascular control.Similarly, short-term studies of slow breathing in patients with congestive heart failure have shown immediate changes in baroreflex sensitivity measured by the interaction of heart rate and blood pressure variability.106 For the congestive heart failure group as a whole, there was a decrease in systolic and diastolic blood pressure during slow breathing. This and other studies suggest that there is the capacity to consciously regulate autonomically governed mind-heart interactions through alteration of baroreflex function.104,107–109Meditation and Relaxation TechniquesMeditation and relaxation techniques have been investigated as other methods to beneficially alter mind-body interactions. Meditation techniques may be broadly classified in three categories. First are those techniques that require concentration on a specific external object or internal sensation (such as breathing) in preparation for focused reflection, exclusion of unwanted thoughts, or a quiet state of awareness.103,110,111 Transcendental meditation may be the most commonly recognized form of this category of meditation. Second are those that rely on increased awareness or mindfulness of the external and internal environment and exclusion of conscious interpretations or evaluations of events and sensations in these environments. Third is compassion mediation which incorporates stages of the above practices with the ultimate goal of eliminating negative evaluations and fostering positive attitudes toward the self and progressively to others in one's surroundings.110 All of these require self-monitoring and progressive practice to achieve a desired state of awareness.Other techniques rely on eliciting the relaxation response, which shares many features of the above mediation techniques. In essence, relaxation techniques consist of focused attention, a passive nonevaluative approach to thoughts, relaxation of muscle tone, and a nondistracting environment.112–114 The hallmark of the relaxation response is a reduction in sympathetic nervous system activity.Only a relatively small number of outcome studies have examined the above or related mind-body interventions in patients with congestive heart failure. However, a number of studies have investigated both cardiovascular and clinical outcomes following programs of meditation or relaxation techniques. For example, it is estimated that there have been more than 600 studies published examining the impact of transcendental meditation on cardiovascular disease.115 A review of selected studies of these techniques in patients without heart failure provides proof of concept that they may be effective in altering mind-heart interactions in patients with ventricular failure.Barnes et al116 examined blood pressure and noninvasively measured cardiac output in adults without known cardiovascular disease who practiced transcendental meditation. Compared with a control group using relaxation methods, those practicing transcendental meditation had decreases in systolic and diastolic blood pressures, increases in cardiac output, and decreases in systemic vascular resistance during meditation. Similar results have been reported in adolescents with blood pressures in the upper percentiles of normal.117,118 The capacity to alter vascular tone and blood pressure may extend to perhaps all forms of meditation. A 6-week trial of yoga and meditation demonstrated significant reductions in heart rate and blood pressure and evidence for endothelium-dependent vasodilation in the intervention group.119It is probable that mediation exerts its effect on vascular control through autonomic mechanisms. This has been specifically examined by measurement of heart rate variability and noninvasive measures of the preejection period (a surrogate for sympathetic activity) in a study of mindfulness meditation.119 In subjects practicing this form of meditation, there was coactivati