Tilburg University
Taking care of the failing heart
Kessing, Dionne
Publication date:
2016
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Citation for published version (APA):
Kessing, D. (2016). Taking care of the failing heart: A comprehensive view on self-care. Ridderprint.
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Take down policy
: A comprehensive view on self-care
Dionne Kessing
Voor de openbare verdediging
van mijn proefschrift
TAKING CARE OF
THE FAILING HEART
A comprehensive view on
self-care
Op vrijdag 5 februari 2016
om 14.00 uur
in de aula van Tilburg University,
Warandelaan 2, Tilburg
Aansluitend bent u van harte
welkom op de receptie in
Grand Café Esplanade ter plaatse
OF THE FAILING HEART
A comprehensive view on self-care
ISBN:
978-94-6299-279-5
Cover design:
Dionne Kessing, Nikki Vermeulen
Lay-out and printing:
Ridderprint BV - www.ridderprint.nl
© Dionne Kessing, 2015, Utrecht, the Netherlands
OF THE FAILING HEART
A comprehensive view on self-care
Proefschrift
ter verkrijging van de graad van doctor
aan Tilburg University
op gezag van de rector magnificus,
prof. dr. E.H.L. Aarts,
in het openbaar te verdedigen ten overstaan van een
door het college voor promoties aangewezen commissie
in de aula van de Universiteit
op vrijdag 5 februari 2016 om 14.15 uur
door
Dionne Ennie Francis Kessing,
Prof. dr. J.W.M.G. Widdershoven
Copromotor:
Dr. H.M. Kupper
Overige leden: Prof. dr. A.W.M. Evers
Prof. dr. M.J.M. Geenen
Prof. dr. D.E. Grobbee
Dr.
V.
Janssen
Prof. dr. F. Pouwer
PART I
DETERMINANTS OF HEART FAILURE SELF-CARE:
IN SEARCH OF EVIDENCE
Chapter 2
How are depression and Type D personality associated with
outcomes in chronic heart failure patients?
25
Chapter 3
Fatigue and compliance with self-care behavior in patients with
chronic heart failure
43
Chapter 4
Positive affect, anhedonia and self-care behavior in patients with
chronic heart failure
57
Chapter 5
Psychological determinants of self-care in patients with chronic
heart failure: systematic review and meta-analysis
73
PART II
THE COMPLEXITY OF HEART FAILURE SELF-CARE
AND OUTCOMES
Chapter 6
Self-care and patient reported outcomes: a longitudinal analysis of
health-related quality of life in patients with chronic heart failure
121
Chapter 7
Self-care and pathophysiological outcomes in patients with chronic
heart failure
135
Chapter 8
Self-care and all-cause mortality in patients with chronic heart failure
153
Chapter 9
Summary and general discussion
167
Appendix
Nederlandse samenvatting (Dutch summary)
179
Dankwoord (Acknowledgements)
List of publications
About the author
General introduction
1
HEART FAILURE
Chronic heart failure is an incurable and progressive syndrome that approximately affects 2-3% of the population worldwide.1 It is associated with poor prognosis which is comparable to that of
cancer, i.e. the mortality rate of patients with heart failure has been estimated at approximately 60% within 5 years after diagnosis.2 Prevalence rates of heart failure have increased tremendously over
the past decades and are still expected to rise as a result of medical advances, improved survival after myocardial infarction, and increased longevity in Western developed countries.2 Moreover, heart
failure is associated with frequent hospital admissions, therefore imposing a substantial economic burden on the health care systems.2-4
The clinical syndrome of chronic heart failure is defined by characteristic symptoms and objective evidence of a structural or functional cardiac abnormality.1 Common precursors of heart failure are
coronary artery disease and chronic hypertension. Other well-known causes are diabetes, valve dysfunction, arrhythmia, pericardial disease, congenital heart disease, cardiomyopathy (e.g., dilated, hypertrophic, alcoholic, idiopathic), infections (e.g., viral, rheumatic fever), toxins, anemia, thyroid disorders, and treatments for cancer such as radiation and chemotherapy.1, 2
There are two clinical subtypes: heart failure with (a) reduced and (b) preserved ejection fraction, often referred to as systolic and diastolic heart failure, respectively (Figure 1). In systolic heart failure, there is reduced contraction and impaired emptying of the left ventricle which dilates. In diastolic heart failure, the left ventricle fails to relax properly between beats which leads to filling difficulties of the heart. Despite significant differences in etiological features and response to treatment, there is great overlap in signs (e.g., elevated jugular venous pressure, pulmonary crackles) and symptoms (e.g., dyspnea, fatigue, peripheral edema).1 Fluid retention is also common in heart failure which may cause
weight gain, frequent urinating, coughing (particularly when laying down), and / or acute pulmonary edema (i.e. fluid overload in lungs) which requires medical treatment.
Main goals of heart failure management include treatment of (the) underlying cause(s), reduction of symptoms, prevention of further disease progression, prolongation of life, and achieving optimum quality of life.1 Treatment usually involves pharmacological therapy and behavioral modifications,
FIGURE 1. The structural abnormalities of the heart in systolic and diastolic heart failure in comparison with a
healthy heart.
The burden of chronic heart failure
Chronic heart failure is associated with poor quality of life which is even more severely impaired in comparison with many other chronic diseases.5, 6 The decline in quality of life is largely due to the
progressive and malignant nature of the condition, increased morbidity, frequent hospitalizations, and poor long-term survival. A high proportion of patients with heart failure suffers from other (chronic) comorbid conditions, such as diabetes, anemia, and renal dysfunction.7, 8 Patients are likely
to experience hampering consequences of their condition that are both direct and indirect, such as dyspnea, fatigue, social isolation, living in fear, losing sense of control9, limitations in daily activities10,
and sexual dysfunction11. Moreover, treatment of chronic heart failure requires a vast amount of
self-care, which places a great burden on the daily life of patients.
Pathways linking psychological factors and outcomes
Accordingly, it may not be surprising that psychological distress such as depression is common among patients with heart failure, and has been associated with a variety of adverse health outcomes.12, 13 Studies have shown that depression is at least as important as cardiac function in determining
health-related quality of life.13 Moreover, a recent meta-analysis has demonstrated that major, and
not minor depression predicts all-cause mortality in patients with chronic heart failure.14 Examination
of potential mechanisms linking psychological distress to poor outcomes in coronary heart disease has been subject of many studies, and can generally be categorized into a pathophysiological (e.g., immune dysfunction / inflammation, autonomic nervous system) and behavioral (e.g., poor self-care, unhealthy lifestyle behaviors such as smoking) pathway.15 In heart failure, however, less mechanistic
1
HEART FAILURE SELF-CARE
The number of studies on self-care in heart failure has increased tremendously over the past few decades. Self-care can be defined as “the actions by an individual to capture or maintain a desired level of health and well-being”16 to actively manage symptoms, treatment, and lifestyle changes
inherent in living with a chronic medical condition.17 It has also been referred to as a naturalistic
decision-making process, which suggests that self-care is the result of rational decision-making that
underlies the “choice of positive health care practices and the behaviors used to manage signs and symptoms of the disease” in the real-world setting.18 Self-care in heart failure includes the following:
medication adherence, following a low sodium diet, limiting fluid intake, regular physical exercise, daily monitoring of weight and other critical symptoms as indicators of acute disease progression. Moreover, patients are required to continuously interact with their health care professionals as the care for heart failure is ongoing.17 There is heterogeneity in the conceptual definition and assessment
of heart failure self-care. Some researchers advocate a distinction between self-care maintenance, i.e. actions used to maintain physiological stability including treatment adherence and symptom monitoring, and self-care management, i.e. the decision-making response to heart failure symptoms.19
While others tend to focus more on most recommended lifestyle and consultation behaviors.17
What determines heart failure self-care?
A multitude of factors are known to affect heart failure self-care.18 Studies have repeatedly shown
that self-care is suboptimal, in particular for exercise and weight monitoring.20 According to the
2009 Scientific Statement from the American Heart Association, complicating factors of self-care in patients with systolic heart failure are comorbid conditions, depression, anxiety, older age, poor health literacy, cognitive impairment, and sleep disturbances.21 Other complicating factors are low education
and socio-economic status, poor social support and social isolation, poor heart failure and self-care knowledge, polypharmacy, and lack of experience with the disease.22-25 Gender differences in
self-care have also been described, but it is unclear whether this is caused by gender or gender-related differences.26-29
Yet, poor self-care is not merely the result of patient-related factors. Problems within the health care system also contribute to the level of self-care including variations between health care professionals in their perception of and attention given to self-care education30, treatment of heart failure as an
isolated condition while many patients suffer from multiple conditions, and poor communication (between providers).21
Critically, systematic evidence on determinants of self-care is not as straightforward as perhaps assumed. A systematic review on determinants of self-care in heart failure found little evidence for any of the aforementioned factors.31 In this review, only determinants of self-care included length of
Psychological and other risk factors of self-care
The adverse relationship between psychological distress and health outcomes in chronic heart failure has been subject of numerous studies in recent decades. Prior research has primarily focused on negative mood states, of which depression and Type D personality are two well-studied psychological risk factors.32 Type D personality can be defined as the combination of having an increased tendency to
experience negative emotions while being socially inhibited, thus not able to express these emotions in an adequate manner in social interaction.33 Depression and Type D are important predictors of
poor health related quality of life in chronic heart failure, but evidence remains inconsistent for their adverse effects on heart failure prognosis. Identification of shared and distinct pathophysiological and behavioral pathways linking both psychological factors to disease progression may provide guidance for clinicians in optimizing clinical care.
Adequate psychological resources seem essential to provide patients with the necessary motivation and energy to effectively engage in self-care. Fatigue, however, may hinder patients from successful behavioral change or in being able to sustain in daily self-care activities. Fatigue is a complex phenomenon and one of the most prevalent symptoms in heart failure that has been associated with depression, decreased exercise capacity, dyspnea, poor performance of daily activities,10 and poor
quality of life.34-37 Yet, no studies have examined its relation with self-care, while, given these relations,
one can imagine that it may exert negative effects on self-care.
Positive psychological factors and self-care
At large, there is a dearth of evidence on cardiovascular health effects of positive psychological factors. In terms of self-care, research suggests that self-care confidence or self-efficacy and perceived control facilitate self-care.26 However, little is known on the role of positive affective factors despite the
growing evidence that positive affect is not simply the opposite of negative affect as both states can be experienced simultaneously.38, 39 Accumulating empirical evidence shows that positive affect and
well-being is associated with improved (cardiovascular) health40-44 and pathophysiological function
such as reduced inflammation.41, 45 Moreover, positive affect has been associated with enhanced
physical activity,41 which hints toward a potential, but so far neglected role in self-care.
The prognostic value of heart failure self-care
As self-care is primarily targeted at reducing heart failure symptoms to improve the physical condition of patients, one might expect that it would benefit health outcomes by improving quality of life and pathophysiologic function and decreasing risk for hospitalizations and mortality. The available evidence, however, is rather inconsistent which seems largely but not entirely attributable to methodological weaknesses and heterogeneity within the research field.46
Regarding quality of life, findings from observational studies have yielded inconsistent results with studies reporting a positive47-49 or no relation50-52 with care. Similarly, a review on the effects of
1
function, it has been proposed that self-care is likely to benefit outcomes via neurohumoral and inflammatory function.55 To date, only one cross-sectional study has been published exploring these
relations in which only self-care management, and not self-care maintenance, was related to reduced levels of myocardial stress and inflammation.56 Replication and extension of these findings is needed
in a larger and prospective study.
Results from prior studies support a beneficial relationship between self-care and event-free survival, but this seems highly attributable to fewer hospitalizations and not decreased mortality per se.57, 58 Same patterns have been found for effects of heart failure targeted disease management
programs, i.e. they are shown effective to decrease hospital readmission, but not in mortality rates.59
One study did show that poor weight monitoring was associated with increased mortality but no support was found for the remaining elements of self-care.60 Other studies that focused on distinct
heart failure self-care behaviors showed that medication non-adherence was associated with increased risk for adverse cardiac events61 while low sodium intake was associated with increased
event free survival (i.e. hospitalization or death).62 However, methodological limitations (e.g., short
period of follow-up or small samples) may contribute to the lack of evidence in terms of mortality. Clearly, a closer examination of its prognostic value in terms of long-term mortality in a large cohort seems warranted.
AIMS AND OUTLINE OF DISSERTATION
The first aim of this dissertation is to study the complexity of psychological factors in their associations with self-care among patients with chronic heart failure. The second aim is to examine how self-care is related to health related quality of life, pathophysiologic function, and mortality as important outcomes. In our empirical studies, self-care was assessed with the European Heart Failure Self-care Behavior scale, which is a 9-item, well-validated and widely-used instrument that assesses most important self-care behaviors.17, 63, 64 These include limiting fluids, daily weight monitoring, medication adherence,
following a low sodium diet, regular exercise, and consultation behavior in case of worsening of heart failure signs and symptoms. An overview of chapters is graphically presented in Figure 2.
Part 1 Determinants of heart failure self-care:
in search of evidence
Given their inconsistent prognostic value in chronic heart failure, a close examination is presented on the current evidence of the association of depression and Type D personality and their association with medical and patient-related outcomes in chapter 2. This includes a detailed discussion of common and distinct relations with pathophysiological processes as well as self-care as potential underlying mechanisms of disease. In chapter 3, it is prospectively examined whether fatigue is associated with HF self-care. The impact of poor sleep65, 66 and psychological distress66-69 are taken
in response to stimuli that were previously experienced as rewarding”70) with self-care are examined
in chapter 4. Several affect measures were used since there is no gold standard for measuring positive affect. Similar to fatigue, it is examined how heart failure disease severity, depressive symptoms, or other explaining factors contribute to these associations. Finally, a fully comprehensive systematic review and meta-analysis is presented in chapter 5 on the current evidence of psychological factors as determinants of heart failure self-care including medication adherence.
Part II The complexity of heart failure self-care and
outcomes
Chapter 6 assesses the longitudinal association of (changes within) self-care and patient reported
outcomes while accounting for the role of psychological distress (depression, anxiety, and Type D personality). As for pathophysiological function, a prospective examination is provided in chapter
7 on the associations of heart failure self-care with serum levels of tumor necrosis factor alpha,
interleukin-6, and interleukin-10 as markers of inflammation, estimated glomerular filtration rate of creatinine and hemoglobin as markers of renal and hematological function. Finally, chapter 8 examines the association of self-care with long-term all-cause mortality. Post-hoc analyses are performed to examine the association of each separate element of self-care with mortality.
To conclude this dissertation, a summary of the main findings will be presented in a comprehensive discussion in chapter 9. Moreover, directions for future research and implications for clinical practice will be provided.
Chapters 6-8
PSYCHOLOGICAL DETERMINANTS
Depression Anxiety Positive affect vs
anhedonia Fatigue
HEART FAILURE SELF-CARE
Health-related quality of life Pathophysiology Mortality
PA RT II : S el f-ca re a nd o ut co m es PA RT I: D et er m in an ts o f s el f-ca re OUTCOMES Chapter 6 Type D Chapter 2 Chapter 6 Other determinants, e.g., clinical, sociodemographic Chapters 2-8 Chapter 5 Chapters
2, 5, 6 Chapters 5, 6 Chapter 4 Chapter 3
Chapter 7 Chapter 8
Chapters 2, 5, 6
1
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Determinants of
heart failure
self-care:
in search of evidence
How are depression and Type D
personality associated with outcomes
in chronic heart failure patients?
Jos Widdershoven
Dionne Kessing
Angélique Schiffer
Johan Denollet
Nina Kupper
CURRENT HEART FAILURE REPORTS, 2013; 10:244-53
ABSTRACT
2
INTRODUCTION
Cardiovascular disease (CVD) remains the leading cause of death and disability in the world, with almost 23.6 million people dying from CVDs worldwide by 2030.1 The clinical syndrome of chronic
heart failure (HF) is the most symptomatic expression of CVD. HF is caused by an underlying cardiac defect in, usually, elderly patients frequently treated for other medical problems. HF patients often suffer from multiple somatic comorbidities, not only related to the cause of chronic HF (e.g., hypertension, diabetes) and age but also to its consequences (e.g., arrhythmias, renal disease) and treatment.2 Furthermore, emotional distress is highly prevalent in chronic HF patients.
The interrelationship between psychological factors and adverse health outcomes, as well as mechanisms explaining these relations, has been subject of numerous studies. In this context, depression and Type D personality are two often-studied psychological risk factors (Table 1).
TABLE 1. Depression and Type D personality
Negative emotions Social inhibition Duration
Depression Depressed affect in general Not specified <2 years; episodic
Type D Negative affect in general Elevated levels (non-expression) >2 years; chronic
Depression
Definition: a state primarily characterized by persistent low mood and loss of interest and a range of
associated emotional, cognitive, physical, and behavioral symptoms. Clinically important episodes of depression that at least exist for two weeks are called major depressive episodes.
Examples of symptoms: persistent sadness, fatigue, sleeping problems, feelings of hopelessness
Type D personality
Definition: the tendency to experience a variety of negative emotions, such as anger, sadness, fear,
across time and situations (i.e., the personality trait negative affectivity), together with the tendency not to share these emotions in social interactions, because of fear of rejection or disapproval (i.e., the personality trait social inhibition).3
Examples of symptoms: frequent worrying, scanning the world for danger, insecure when with
others
Comparison of depression and Type D personality
It has been proposed that depression and Type D are equivalent.4 However, clear conceptual
differences exist. While depression is episodic in nature, Type D personality is a trait characteristic that is stable over long periods of time,5 and is predictive of episodic stress such as depressive
episodes.6 Moreover, studies that have examined both together report only a small overlap in
Up to 40% of HF patients experiences clinical levels of depression.8 Depression is more prevalent
in HF patients than in healthy elderly and HF patients have a greater risk of developing new onset depression.9 Type D prevalence in HF may be up to 31%.10 Research suggests that health-related
behaviors, such as treatment adherence and lifestyle factors, may be associated with emotional distress and may be important for maintaining health in HF. Moreover, there are pathophysiological communalities between HF and respectively depression and Type D, which might be involved in exacerbating disease progression in HF patients with emotional distress as compared to non-distressed HF patients.
The aim of this review is to describe the up-to-date evidence of the association of depression and Type D personality with medical and patient-related outcomes, as well as self-care in chronic HF patients. Moreover, existing evidence on shared pathophysiological processes and assessment issues in chronic HF patients are reviewed.
OUTCOMES
Mortality and readmission
Depression – A 2006 meta-analysis reported that chronic HF patients with depressive symptoms or
a clinical depression had >2-fold increased risk of death and associated clinical events. However, included studies were heterogeneous with respect to characteristics of study population, depression assessment, and follow-up duration.11 Since then, several studies have been published that examined
the depression-mortality association in HF but found less impressive or no significant hazard ratios (HR) at all. For instance, clinically significant symptoms of depression were associated with an increased HR of 1.56 for death or cardiovascular hospitalization.8 In a prospective study of 1,006 HF patients
with a 2.7 year mean follow-up, depression was independently associated with increased mortality (HR = 1.3).12 In another large study in elderly HF patients, patients treated with antidepressants had
increased all-cause mortality rates (HR = 1.2) at 1-year follow-up, while readmissions for HF were not increased.13 Most recently, it was demonstrated that depression was significantly associated with
diminished survival in a sample of 985 HF patients over a median 4.4 year follow-up (HR = 1.4).14
The aspect of timing of depressive symptoms has been addressed by showing that HF patients with recently developed depressive symptoms showed a significantly higher risk of hospitalization and patients developing depressive symptoms after re-hospitalization were at higher risk of all-cause mortality three years later.15 Null-findings have been reported as well, as several studies reported no
effect of depression on mortality in HF patients.4, 16, 17
2
Type D – A recent meta-analysis on Type D and hard medical outcomes reported that, in contrary to
coronary artery disease (CAD), there is no evidence for an association between Type D personality and mortality in HF.18 One study reporting a positive association between Type D and mortality was not
included in this meta-analysis, possibly due to the specific subsample of HF patients, i.e. HF patients who underwent cardiac transplantation in which Type D was associated with early allograft rejection and increased mortality.19 It should be noted that the studies reporting no association between Type
D and mortality, also report the same null-finding for depression.
Explaining heterogeneity and null-findings – With evidence for a mortality link with psychological risk
factors being mixed at best, it is important to identify sources of heterogeneity, so that more definite conclusions may be drawn. Differences in HRs between studies may be related to major differences in included patient groups with respect to diagnosis, prevalence of depression and Type D, time-course of depression, and follow-up duration. A source of noise includes the assessment of depression and Type D. Regarding depression, future studies may want to take symptom profiles and dimensions, persistence of depression, confounding with somatic symptoms, and timing in relation to index cardiac event into account. With respect to Type D, there is discussion about the combination of two stable traits into one risk factor, and the use of a dichotomized score to classify persons as having Type D. Another vital aspect concerns the multifactorial nature of HF, and we should question whether psychological risk factors in this end stage of cardiovascular disease play a minor role due to the complexity of multisystem failure and the lower prevalence of cardiac deaths in HF patients. A recent very large clinical trial in 6975 patients revealed that in addition to NYHA functional class, older age and renal dysfunction were the most powerful predictors of mortality in HF patients.20
Another factor in explaining heterogeneity and decreasing effect sizes is that cardiologic treatment has improved over time. Nowadays, patients with myocardial infarction (MI) are treated with primary percutaneous coronary intervention with a subsequent focus on complete revascularization, drug treatment has been intensified and formalized, and the use of device therapies for HF has become standard practice. All these therapeutic changes may have resulted in differences in characteristics and outcomes of HF patient populations over time. Selection bias may also play a role, since the increased mortality risk in CAD may result in fewer CAD survivors with depression or Type D. Future studies may want to take these factors into account.
Patient-centered outcomes
The assessment of outcomes such as quality of life (QOL) or health status (HS) is a key component of patient-centered care.21 Improvements in medical treatment may lead to an extension of HF patients’
life, but QOL in HF is more impaired than in the general population.22 Furthermore, impaired QOL/
health status has negative prognostic value for HF progression.23 However, comparison between
essence of QOL, but are actually measuring health status.24 The World Health Organization defines
QOL as follows: “individuals’ perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns”.25 Since
most studies discussed below do not use this definition when referring to QOL, we decided to use the term health status in describing the results of these studies.
Depression - One study has shown that treating depressive symptoms with Paroxetine resulted in
significant decreases in depression in HF patients, and these reductions significantly correlated with improvements in generic mental, but not with physical health status.26 Others, however, reported the
negative impact of depression on physical health status, also when using measures for depression that do not contain somatic items to prevent overlap in depression measures and measures of physical health status in HF.27 Several studies have indicated that health status may depend more
on the presence of depression than on (somatic measures of ) disease severity.e.g., 28 However, the
high prevalence of depression in HF seems closely linked to various somatic features of the disease.29
Furthermore, a dose-relationship between physical symptoms of HF and depression with health status has been reported.30 Depression and health status in HF are associated but their interrelationship
and associations with (indicators of ) disease-severity seem to be complex. Until now, studies do not provide a clear, consistent understanding of these relationships.
Type D - Only few studies focused exclusively on the associations between Type D and HS in HF.31
A prospective study on the effect of Type D on a broad health status measure in HF patients found Type D to predict disease-specific mental health status, sub-domains of generic health status, and general health at 12-month follow-up.32 The association between Type D and mental health status
was confirmed in a study of 251 HF patients, with Type D as an independent determinant of mental, but not of physical health status at 9 months.33 Another study showed that Type D and non-Type D
anhedonic HF patients, as compared to non-anhedonic non-Type D patients, reported lower levels of general mental, but not of physical health status at 12-month follow-up.34 In conclusion, results
suggest that Type D is an important independent predictor of impaired health status in HF, but that relationships are mainly restricted to the mental/emotional domains of health status.
MAINTAINING HEALTH THROUGH SELF-CARE
Maintaining health in chronic diseases, which is broader than mortality and morbidity, is achieved by managing self-care and lifestyle behaviors. How well patients adapt these behaviors may be affected by their psychological functioning.35 Effective HF self-care, healthy lifestyle behavior, and medication
adherence have been associated with enhanced medical and patient-centered outcomes in HF.36-38
There are several factors associated with effective HF self-care behaviors and self-care confidence, such as self-efficacy39, social support,e.g., 40 and coping41, that may be affected by depressed mood or
2
Self-care
Depression - Depression in HF has been associated with poor self-care behaviors,35 non-completion of
cardiac rehabilitation,42 a longer delay between worsening of HF symptoms and contacting a medical
professional,43 and unhealthy lifestyle behaviors, such as physical inactivity and smoking.44 Notably,
in one study, minor depression but not major depression was associated with poor HF self-care, with the underlying mechanism remaining unclear.45 In some studies, no relationship between depression
and self-care has been found,e.g., 46, 47, 48 potentially due to methodological reasons related to sample
size or social desirability bias (as self-care is often assessed by means of self-report). In HF, depression has also been associated with self-reported medication non-adherence,e.g., 49 but the association
between depression and objectively measured non-adherence is inconsistent. Some studies have found no association49, 50, while others have shown a relationship between depression and objectively
measured medication non-adherence,13, 51 without a clear explanation for these differences. While
it seems likely that poor medication adherence plays a role in the interaction between depression and HF, no firm conclusions can be drawn. Future prospective research may benefit from the use of objective self-care measures; for instance, objectively measured, but not self-reported medication adherence is associated with improved clinical outcomes in HF.52
Type D – To date, two prospective studies have investigated the link between Type D and HF self-care,
and have shown Type D to be associated with poor consultation behavior,53, 54 despite an increased
perception of cardiac symptoms and more worrying about health.53 Perhaps the social inhibition
component of Type D may drive the decreased tendency to contact a medical professional once symptoms worsen. While no studies have examined the relationship between Type D and other relevant self-care behaviors, lifestyle factors or medication adherence, an association with poor treatment compliance has been observed in a study among patients with obstructive sleep apnea syndrome.55 Moreover, Type D has been associated with a higher display of unhealthy behaviors (i.e.
smoking, less physical exercise, and poorer dietary habits) in both healthy participants and cardiac patients,56-58 as well as with medication non-adherence in patients with acute coronary syndrome59
and post-MI patients.60
Self-efficacy, coping, and social support as mediators
of effective self-care
Depression – Depressed HF patients tend to have more maladaptive coping styles, such as denial
and behavioral disengagement.e.g., 61, 62 In a study among 254 HF patients, the relationship between
poor social support, depression, and treatment non-adherence was shown to be fully mediated by self-efficacy.63 Depressive symptoms and poor social support appeared to have a synergistic negative
effect on event-free survival in 220 HF patients,64 although another study (n = 84) failed to find such
Type D – While there is a lack of evidence for the HF population, Type D has been associated with
maladaptive coping and lower self-efficacy among CVD patients, mediating the relationships between Type D and worse perceived health66 and medication non-adherence.59 In non-cardiac
populations, avoidant and passive coping and poor social support have been reported as mediators of the relationship between Type D and physical symptoms.e.g., 67
In conclusion, the evidence for a behavioral pathway through which both psychological risk factors are supposed to link with poor health can be considered rather moderate, since findings reviewed here are mixed and studies on Type D in HF populations are lacking. Future studies are encouraged to examine the association of Type D personality with behavioral mechanisms in HF. One major limitation when examining relevant health behaviors is that mostly self-report measures are used. We recommend future research to use both objective and self-report measurement methods.
PATHOPHYSIOLOGICAL PROCESSES
In CVD, shared pathophysiological mechanisms have been identified that may explain the relation of depression and Type D with disease progression.68 In HF patients, less mechanistic research has been
performed. Identifying shared pathophysiological pathways in HF is important, because this provides guidance for clinicians by showing through which pathophysiological pathways psychological risk factors exacerbate disease progression.
Autonomic nervous system dysregulation
Depression – HF patients are characterized by alterations in autonomic nervous system (ANS) function,
reflected in increased sympathetic and decreased parasympathetic cardiac drive. Such an imbalance in the ANS is also observed in depression69. Sympathetic dominance increases the risk of cardiac
fibrillation, arrhythmias and sudden death70. One of the methods for assessing autonomic cardiac
regulation is by assessing heart rate variability (HRV). One study in HF patients reported smaller Low Frequency-HRV values with increasing clinical depression scores,71 while another study in ICD patients
with impaired pump function reported depression to be related to decreased parasympathetic control.72 This is congruent with most73 but not all studies in CAD patients. e.g., 74
Type D - Type D has been related to ANS dysregulation in both healthy75 and patient populations. In
HF, Type D patients may have a maladaptive, blunted heart rate response to mental stress,76 and a
reduced heart rate recovery after exercise.77 In ICD patients with an impaired pump function, Type D
was associated with an overall lower autonomic cardiac control,72 and an increased risk of sympathetic
2
Inflammation
Depression – Inflammation plays a pivotal role in the etiology of CVD, and in HF it is associated with
impaired cardiac contractility.79 There is evidence for increased levels of pro-inflammatory markers
associated with depression in HF. Apart from one smaller study,80 cross-sectional and prospective
studies suggested the involvement of the Tumour Necrosis Factor (TNF)-α system.e.g., 81 With respect
to other markers of inflammation, evidence is mixed. One prospective study (n = 517) suggested C-reactive protein (hsCRP) and interleukin-6 to be elevated in depressed HF patients,82 but in another
prospective study, the association with hsCRP was not significant.81
Type D – Cross-sectional and prospective studies have shown that Type D is associated with increased
levels of inflammatory markers, especially sTNFR1 and sTNFR2 in patients with HF.e.g., 83 One recent
mediation analysis showed that inflammatory biomarkers mediated a small part of the association between Type D and the change in self-reported physical HS over 1.5 years.84
Endothelial function
Depression - The endothelium has an important role in tissue perfusion and may therefore be an
important prognostic marker in HF.85 In healthy individuals86 and CAD patients,87 endothelial
dysfunction seems to be impaired in individuals with depression. No studies examining this association have been performed in HF patients.
Type D - With respect to Type D, one study in HF patients has examined the relationship with
endothelial progenitor cells playing an important role in endothelial preservation. Findings showed that circulating endothelial progenitor cells were reduced in Type D HF patients.88 In the general
population, no Type D associated differences in endothelial function were found.89
Neurohumoral mechanisms and anemia
Depression - Neurohumoral processes, especially involving the renin-angiotensin-aldosterone system
(RAAS), are important in the etiology and progression of HF. Moreover, high levels of cortisol have been shown to increase the mortality risk in HF90 and depressed men with
hypothalamic-pituitary-adrenal (HPA) axis hyperactivity have an increased risk of cardiac mortality.91
Depression and chronic stress may be associated with activation of the RAAS.e.g., 92 Interestingly,
aldosterone seems to be mostly increased in patients with atypical depression characteristics.92 To
With respect to cortisol, Studies in CAD patients have reported flatter cortisol rhythm curves93 and
higher 24-hour cortisol output94 in association with depression, but unaltered levels were reported as
well.95 One reason for these inconsistent results may be related to depression profiles, as they relate
differently to HPA axis function.96 In HF, depression has not been related to cortisol levels yet.
Type D - It is known that renal dysfunction is a common comorbidity in HF patients and that a vicious
circle exists between renal functioning, cardiac functioning, and anemia. In a recent study in HF patients, Type D was prospectively associated with reduced hemoglobin levels, and this effect was mediated by deterioration of renal function. Anxious depression was unrelated to anaemia.97
With respect to HPA axis function, no study has examined the relation between Type D and HPA axis function in HF patients. Based on studies in patients with ACS, it may be hypothesized that the HPA axis is overactive in Type D HF patients as well, since ACS patients with Type D demonstrated an elevated daytime cortisol output.e.g., 95
Oxidative stress
Depression - One study assessed Xanthine oxidase (XO), which affects contractile function and
myocyte hypertrophy in HF, and Heat shock protein (Hsp) 70, playing a role in myocyte protection, in a sample of 110 HF patients. Results showed that depression was unrelated to these markers.98 A
recent study, using a marker of lipid peroxidation, showed that it was elevated in clinically depressed HF patients.99 The inconsistent findings with respect to oxidative stress in relation to depression in
HF patients may be due to differences in markers used, as they reflect different bodily processes and pathophysiological pathways.
Type D personality – In one study of 110 HF patients, Type D was associated with an increased oxidative
stress burden, apparent in the decreased antioxidant levels and an increased oxidative stress ratio.98
2
NETWORK OF EFFECTS
With respect to behavioral and pathophysiological mechanisms, a great deal of work still needs to be done. For Type D, much of the evidence suggesting a behavioral link with poor outcomes has been conducted in other populations than HF and therefore, future prospective studies are needed to study these mechanisms in HF. Figures I displays the behavioral and pathophysiological relations found in HF (indicated by bold lines) and other populations (dashed lines) for both depression and Type D. Most mechanistic studies have been performed in CAD patients, and it is not certain that these mechanisms can be extrapolated to HF, because about half of the HF patients have a non-ischemic etiology. Not all mechanisms are shared between depression and Type D, suggesting that part of their adverse effect on health may be going through different pathways. Health behaviors may be associated with pathophysiological processes since the association of depression with cytokines and acute phase proteins may be mediated by health behavioral factors, such as physical inactivity, smoking, and body mass index (BMI).81 On the other hand, there is evidence to suggest that depressed
mood is a reflection of sickness behavior induced by chronic inflammation.100
Depression
Type D
Disease progression
ANS dysregulation
Endothelial dysfunction HPA axis dysfunction
Inflammation Oxidative stress Renin-Angiotensin Aldosterone System B. Anemia Depression Type D Patient centred outcomes Medical outcomes Poor consultation behavior / delay
Low self -efficacy Inadequate coping
Poor social support
Poor self -care, medication non-adherence, and
unhealthy lifestyle
A.
FIGURE 1. The behavioral (A) and pathophysiological (B) relations found in HF and other populations for both
RESEARCH IMPLICATIONS
Future research on the effect of depression and Type D on prognosis, health status and self-care may want to take the described medical and psychological complicating and obscuring factors into account. Moreover, it is important that research considers a more comprehensive multisystem multi marker approach. Stress mediators (i.e. HPA axis and norepinephrine) that are affected in depression and Type D have a pervasive influence on many aspects of bodily functioning. Chronic cortisol exposure affects erythropoietin mRNA expression in the kidneys,101 and may increase the risk of anemia. Moreover,
cortisol and sympathetic activation regulate the immune system.102 The parasympathetic nervous
system is involved in immune regulation, i.e. in immune to brain communication.103
There is overlap in mechanisms, but unique behavioral and pathophysiological pathways have also been identified. Research is needed to examine whether a cluster of psychological constructs can be viewed as one overarching risk factor, or whether psychological factors have unique influences on behavioral and biological pathways, and therefore could be best evaluated individually. Moreover, behavioral and pathophysiological processes are intrinsically intertwined, and future research is recommended to examine these moderating and mediating effects more intensely.
CLINICAL IMPLICATIONS
The potential mechanisms that have been summarized in the current review provide guidance to possible intervention and treatment programs that may be tailored to the needs of the HF patient with depression or Type D personality. There are important differences in self-care, health behaviors, and shared pathophysiological pathways that could be addressed by clinicians. While behavioral and pathophysiological interventions could be developed to modify the pathways shared by depression and HF, clinicians should treat their depressed patients according to the existing guidelines for depression, irrespective of their heart condition. Until now, there have been two small (n = 34 and n = 146) intervention studies that have examined the effect of stress reduction, either enhancing coping with stress or mindfulness-based stress reduction, on Type D characteristics. Both studies showed reductions for the continuous subscale scores as a result of the intervention.104, 105 No intervention has
2
CONCLUSION
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