Heart failure is a clinical syndrome that affects 5.7 million adults 20 years or older. The incidence of heart failure is approximately 10 per 1000 population after 65 years of age.1 Among ambulatory care visits for a circulatory disorder, heart failure is the primary diagnosis for 41.6% of visits to primary care offices and 21% of hospital emergency department visits.2 Symptoms, subjective reports of abnormal physical, emotional, or cognitive conditions, trigger an individual to enter the healthcare system.3 Dyspnea and fatigue are frequently reported symptoms by individuals seeking emergency care for heart failure4 and in patients followed in cardiology clinics.5 A growing public health concern, heart failure is a progressive and symptomatic illness, with published reports suggesting that, on average, patients with heart failure experience anywhere from 2 to 9 symptoms.5–7
Whereas symptom research has focused on the study of single symptoms, interest is growing in the examination of relationships among symptoms that share a common etiology.8 Heart failure, for example, provides a common etiology for symptoms such as dyspnea, fatigue, and edema, which may occur together in an individual who has heart failure. Symptom relationships may be direct or indirect. For example, as the level of 1 symptom increases, the level of another symptom increases or a symptom may influence another symptom, which in turn influences a third symptom.9 Relationship among symptoms may be demonstrated both clinically and statistically.10 Bivariate correlation, factor analysis, and cluster analysis are examples of statistical procedures used to demonstrate relationships among symptoms11 Examining relationships among symptoms may uncover different approaches to understanding symptoms.10 A group of 3 or more symptoms occurring concurrently that are related to one another is known as a symptom cluster.12 The establishment of a relationship among a group of symptoms is a precursor to the identification of symptom clusters.13 Therefore, the purpose of this systematic review was to summarize what is known about relationships among heart failure symptoms, a precursor to the identification of heart failure symptom clusters, as well as to examine studies specifically addressing symptom clusters described in this population.
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, which outline a methodology for performing systematic reviews in healthcare, were followed in the conduct of this systematic review.14 PubMed, PsychINFO, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Database were searched for relevant articles. The search term was heart failure in combination with a pair of symptoms. Specific symptoms used in the literature searches were dyspnea, fatigue, depression, edema, anxiety, sleep disturbances, pain, loss of appetite, and cognitive impairment. These symptoms were selected as the focal point of this review because of their prevalence and distressing nature in heart failure patients.5,15,16 Studies were included in the review if they were published in the English language between 2000 and 2010 and reported a significant relationship among 2 or more heart failure symptoms in subjects 18 years or older. A total of 1316 studies were identified from database and ancestry searches. Studies were excluded if they included conditions in addition to heart failure, evaluated the efficacy of an intervention for the treatment of heart failure, or did not examine relationships among individual heart failure symptoms. Seventy-nine studies were screened. Thirty-four studies meeting the inclusion criteria were included in this systematic review. The search and screening results are reported in the Figure.
The methodological quality of the studies was evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria.17 The STROBE criteria consist of 22 items that should be included in descriptive observational studies and in studies investigating associations between exposures and health outcomes. The specific criteria refer to the title and abstract, introduction, methods, reporting of the results, discussion sections of the report, and reporting of study funding. A score of 1 was given for each of the criteria on the checklist that was present in the study report. Possible methodological quality scores range from 0 to 22. A score of 22 indicates a high level of clarity and reporting of the details about the conduct of the study. Studies included in this systematic review and the scientific quality score assigned using the STROBE criteria may be found in Table, Supplemental Digital Content 1, http://links.lww.com/JCN/A4. Scientific quality scores for the studies included in this systematic review ranged from a low score of 14 to a high score of 22. The median quality score was 18.
A total of 34 studies were included in the systematic review. Many of the studies reported relationships between pairs of symptoms; however, there were a few studies that observed relationships among 3 or more symptoms. Dyspnea, fatigue, and depression were the symptoms most often included as symptom relationships reported in these studies.
Dyspnea, a classic heart failure symptom, has been reported to be related to both fatigue and depression. Fatigue intensity and exertional fatigue are specific characteristics of fatigue that were related to dyspnea.18,19 Dyspnea was observed by Ramasamy et al20 (r = 0.40; df = 46; P < .01) and Sullivan et al21 (r = 0.43–0.56; P < .001) to have a positive relationship with depression. Similarly, Bekelman et al5 found 5:1 odds that a participant with probable depression would be quite a bit or very much distressed by shortness of breath compared with study participants who did not have depression (odds ratio [OR], 5.28; P < .05). When relationships between more than 2 symptoms were considered, dyspnea, fatigue, and depression, along with the symptoms bloating and swelling, were observed by Hertzog et al22 to be related.
Investigators studied the relationships between dyspnea and edema, anxiety, or sleep in individuals with heart failure. Webel et al23 observed moderate positive correlations over a 30-day period between dyspnea and edema (r = 0.45–0.63; P ≤ .001). As well, dyspnea and weight gain have been associated with fatigue.24 Variability in the relationships between dyspnea and anxiety or sleep has been observed. Redeker25 found a relationship between dyspnea and anxiety (r = 0.22–0.35; P = .001–.02); however, Ramasamy et al20 did not find a relationship between these same variables. Yu et al26 observed an inverse correlation between dyspnea and anxiety/depression (r = −0.17; P < .05) using the Hospital Anxiety and Depression Scale (HADS). Higher scores on the dyspnea subscale of the instrument used by these investigators indicate lesser severity of dyspnea so that as anxiety and depression increase, dyspnea also increases. Paroxysmal nocturnal dyspnea has been reported to have a weak relationship with the sleep characteristics of sleepiness (r = 0.161; P = .02) and insomnia (r = 0.279; P = .004).27 Dyspnea has been reported to have a nonsignificant relationship with sleep disturbances, which include falling asleep, staying asleep, and feeling unrefreshed after sleeping.20 The relationship between sleep disordered breathing (eg, obstructive and central sleep apnea) and sleep quality or excessive daytime sleepiness has been found to be nonsignificant.28
In summary, when the relationship between dyspnea and one other heart failure symptom is considered, increases in dyspnea are related to increases in symptoms such as depression, fatigue, and edema. The relationships between dyspnea and sleep characteristics such as sleepiness, insomnia, sleep disturbances, and sleep disordered breathing are small. However, when relationships among 3 or more symptoms were evaluated, sleep characteristics were observed to be related to dyspnea.22,29,30
Relationships between fatigue and symptoms of anxiety, pain, and/or sleep disturbances were contingent on the particular characteristics of fatigue being examined. For example, in some studies, anxiety was associated with general measures of fatigue (r = 0.42–0.49; P < .001)25,31 and mental fatigue (R2 = 0.254; F = 36.2; β = .39; P < .001).32 Yu et al26 detected a relationship between fatigue and anxiety/depression assessed using HADS (r = −0.50; P < .001). However, in the investigation by Falk et al,32 who used the HADS, anxiety was not related to the characteristics of general fatigue, physical fatigue, reduced activity, or reduced motivation. General fatigue related to cardiac pain (r = 0.44; P < .001)19 and to pain distress (β = .22; P < .05)32 has been reported. Not surprisingly, cardiac pain has been reported to be related to exertional fatigue (r = 0.42; P < .001),19 whereas pain distress was related to physical fatigue (β = .22; P < .05).32 It may be that symptoms such as pain accentuate feelings of fatigue32 or, as in the case of cardiac pain, are related to poor tissue perfusion associated with ischemic heart disease. Difficulty with sleep was not related to fatigue intensity (r = 0.20; P < .05)18 but was related to general fatigue (r = 0.42; P < .001) and to exertional fatigue (r = 0.29; P < .001).19 Redeker et al28 noted a nonsignificant relationship between global fatigue and severity of sleep disordered breathing. These researchers observed that this finding may be related to the nonspecific nature of fatigue. Relationships between fatigue and symptoms less typical of heart failure patients have been observed. Stephen18 observed a relationship between fatigue intensity and nocturia (r = 0.36; P < .01), which may be associated with interrupted sleep. Falk et al32 reported that physical fatigue was related to poor appetite (β = .26; P < .01), whereas nausea was related to general fatigue (β = .18; P < .05) and reduced activity (β = .23; P < .05). These investigators point out that less typical heart failure symptoms, such as nausea and poor appetite, may add to overall symptom burden and may lead to an increase in the perceived burden of fatigue. Song et al7 found that lack of energy, the most prevalent and the most distressful symptom in this study, lack of appetite, and difficulty sleeping formed a symptom cluster and was associated with a higher risk for cardiac rehospitalization. The relationship of fatigue to an array of symptoms underscores the need to assess for the presence of both typical and less typical symptoms when evaluating fatigue in individuals with heart failure.
The relationship between depression and fatigue has frequently been studied by investigators, who report that as depression increases, fatigue increases (r = 0.34–0.77; P < .001–.01).21,25,31,33–35 Fatigue characteristics reported to be related to depression include exertional fatigue (r = 0.33; P < .001),19 reduced activity (R2 = 0.178; F = 23.0; β = .37; P < .001),32 and reduced motivation (R2 = 0.110; F = 13.7; β = .40; P < .001)32 The characteristics of physical fatigue and mental fatigue were not reported to be related to depression.32 When considered as components of a symptom cluster, depression and fatigue were related to excessive daytime sleepiness and nonrestorative sleep.36
Investigators examined the relationships between depression and several other symptoms occurring in individuals with heart failure. The relationship between depression and anxiety (r = 0.52–0.74; P < .01–.001) persists across studies irrespective of the instrument used to measure these symptoms.37–41 In a number of studies, depression has been related to sleep characteristics such as difficulty initiating and maintaining sleep (OR, 5.09; 95% confidence interval, 2.41–10.75),42 sleep quality (r = 0.40–0.71; P < .001),43–44 and sleep disordered breathing, which included Cheyne-Stokes respirations and obstructive apnea (r = 0.88; P < .001),43 but not to severity of sleep disordered breathing, which is characterized as the number of apnea or hypopnea episodes during sleep.28 Goebel et al6 observed a relationship between depression and pain (r = 0.32; P = .002). Sullivan et al21 found that depression was related to chest pain (r = 0.38 to 0.43; P < .001) and that as depression increased, bodily pain also became worse (r = −0.37 to −0.47; P < .001). Depression has been reported to be related to appetite loss (OR, 2.28; 95% confidence interval, 1.58–4.33; P = .001)45 and to decreased vitality (r = −0.40 to −0.44; P < .001).21 The findings with respect to the relationship of depression and heart failure symptoms highlight the broad association that depression may have not only with heart failure but also with other chronic illnesses.
Cognitive impairment associated with ischemic heart disease and heart failure is reported to be associated with loss of gray matter volume assessed by magnetic resonance imaging.46 Sloan and Pressler47 observed that individuals with heart failure relate awareness of cognitive impairments such as difficulty with memory and concentration. A relationship was not detected between cognitive impairment and symptoms, such as depression,48,49 anxiety,49 or pain.49 Jurgens et al29 and Smith et al50 observed, however, that difficulty concentrating was included in a heart failure symptom cluster that also included depression and worry or fatigue. These findings suggest that cognitive impairment in patients with heart failure may co-occur and be related to both neurological and psychological factors.
Sources of Variations in Symptom Relationships
As illustrated in the summation of symptom relationships presented in this review, the particular symptom characteristic studied was observed to be a source of variability in the observed symptom relationships. Because instruments may measure unique (or multiple) symptom characteristics, instrument selection may influence the nature of the symptom relationships discovered. For example, depression evaluated using the Short-Form Geriatric Depression Scale, Beck Depression Inventory, the Center for Epidemiologic Studies Depression Scale, or the Profile of Mood States (POMS) Depression/Dejection scale correlated with sleep quality (r = 0.402; P < .001),44 sleep disturbance (r = 0.39–0.53; P < .001),25 or fatigue (r = 0.34–0.64; P < .001–.01).25,34 However, investigators reported that depression assessed using the HADS depression subscale was not related to sleep disturbance (r = 0.19–0.26; P = .06–<.11)20,25 or excessive daytime sleepiness (r = -0.02; P = .855).25 Chen et al31 observed a relationship between depression assessed using the HADS depression scale and fatigue assessed using the shortened Piper Fatigue Scale, which evaluates the severity and temporal fatigue domains (r = 0.5; P < .001). Ramasamy et al20 and Redeker25 did not observe a relationship between depression, assessed using the HADS depression subscale, and fatigue.
Each of the instruments used to evaluate depression approaches the evaluation of depression in a different manner. The items in the HADS concentrate on the anhedonic state.51 The Beck Depression Inventory measures behavioral manifestations of depression.52 The POMS assesses transient distinct mood states.53 The Geriatric Depression Scale concentrates on the evaluation of the psychological aspects of depression.54 The findings with respect to the evaluation of depression suggest that as further studies about heart failure symptom clusters are designed, careful consideration needs to be given to the particular facet of depression that is appropriate for the study. For example, the anhedonic state associated with depression and evaluated by the HADS was not consistently associated with other heart failure symptoms. Investigators did, however, report a more consistent association between other depression characteristics (eg, behaviors, mood states or psychological features) and heart failure symptoms such as sleep,25,42–45 dyspnea,5,25 or fatigue.25,33,34
The sample size and the proportion of individuals in the sample who experienced the symptom of interest may have influenced the study results. For example, 7 of the 34 studies reported nonsignificant relationships between some or all of the symptoms studied. Four of these studies had sample sizes between 50 and 70 subjects and used Pearson correlation to detect symptom relationships. Two studies with sample sizes of 100 or more observed a low prevalence of the symptoms of interest. For example, Akomolafe et al,48 who studied depression and cognitive impairment in a sample of 100 heart failure patients, reported that 23% of the sample had depression and only 10% reported cognitive impairment. This investigation did not detect a relationship between depression and cognitive impairment. Falk et al,32 who studied relationships between fatigue, anxiety, and depression, reported that the prevalence of depression and anxiety in the sample of 112 individuals with heart failure was 18% and 10%, respectively. Nonsignificant relationships were observed between anxiety and the fatigue characteristics of general fatigue, physical fatigue, reduced activity, and reduced motivation. A significant relationship was detected between anxiety and mental fatigue. Falk et al32 also detected nonsignificant relationships between depression and the fatigue characteristics of physical fatigue and mental fatigue. However, relationships were detected between depression and the fatigue characteristics, general fatigue, reduced activity, and reduced motivation. Redeker et al28 did not detect relationships among symptoms studied in a sample of 170 individuals with heart failure in which the prevalence of the symptoms of interest was between 46% and 85%. The 3 studies with samples of 100 or more study participants used regression analysis to examine symptom relationships.28,32,48 Although there were statistically significant findings in these studies, a greater prevalence of a symptom in the sample would add credibility to the conclusions reached by the investigators.
Some heart failure symptoms were weakly correlated. This may be caused by a narrow range of scores on a variable with a restricted sample.55 For example, the sample in the study by Principe-Rodriguez et al27 was composed of new patients referred to a heart failure program. This sample may not have included the full spectrum of responses on a variable that might have been available if the sample had not been restricted to new patients in the heart failure program. Smith et al19 included only heart failure patients 80 years or younger and who had an left ventricular ejection fraction at or below 40% in their sample. The sample for the study reported by Stephen18 was composed of heart failure patients 65 years or older who had compensated heart failure. These restrictions on these study samples could have contributed to the weak correlations between heart failure symptoms observed by these investigators.
As the study of heart failure symptom relationships proceeds, it will be important to be aware of the symptom characteristics measured by the instrument selected to measure the symptoms of interest as well as the prevalence of the symptom in the sample. Perhaps, the variation in symptom relationships uncovered when different symptom characteristics are evaluated is leading symptom assessment for heart failure symptom cluster development toward an emphasis on symptom characteristics rather than the overall symptom construct. Low symptom prevalence and restricting the sample may limit the ability to detect symptom relationships. Thus, careful consideration of inclusion criteria and symptom characteristics will be crucial in the design of studies to identify symptom clusters.
Summary and Conclusions
This systematic review of studies reporting heart failure symptom relationships provides a description of associations among symptoms in individuals with heart failure. Dyspnea and depression, fatigue and pain, depression and fatigue, depression and anxiety, and depression and pain are some symptoms for which relationships were established by investigators. Depression is related to several symptoms experienced by individuals with heart failure, suggesting to clinicians that there is a need to be alert to the possibility that an individual with heart failure, who is experiencing a number of heart failure symptoms, may have depression. Some symptom relationships, such as the relationship between dyspnea and sleep, did not become evident until these symptoms were evaluated in a group of 3 or more symptoms. A notable finding of this systematic review is the differences in relationships when symptom characteristics are considered. For example, anxiety was related to mental fatigue but not to general fatigue, physical fatigue, reduced activity, or reduced motivation. There was an association between depression and difficulty initiating and maintaining sleep, sleep quality, and sleep disordered breathing; however, depression was not related to severity of sleep disordered breathing. Relationships between depression and sleep or fatigue did not persist when the HADS depression scale was used to assess depression, in contrast to when the Beck Depression Inventory, Center for Epidemiologic Studies Depression Scale, or POMS Depression/Dejection scale was used to evaluate depression. This finding suggests that as work on heart failure symptom cluster identification continues, consideration should be given to examining the relationships among the various symptom characteristics in addition to relationships among general measures of the symptom. Studies that define the phenotype of individual heart failure symptoms may be needed before the identification of heart failure symptom clusters.
This systematic review provides a description of heart failure symptom relationships that may be useful when assessing individuals with heart failure. Advancing the science of heart failure symptom phenotyping and heart failure symptom cluster identification has the potential to lead to more effective interventions that target a group of symptoms rather than a single symptom to facilitate better heart failure symptom self-management.
What’s New and Important?
Summary and Implications
- This systematic review observed relationships among several heart failure symptom pairs, for example, depression and anxiety, depression and fatigue, depression and pain, fatigue and pain, dyspnea and depression, and dyspnea and sleep.
- Relationships among heart failure symptoms differ when symptom characteristics are considered.
- Instrument selection may influence the persistence of relationships among heart failure symptoms.
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