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Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease logoLink to Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
. 2026 Aug 7;15(16):e046789. doi: 10.1161/JAHA.125.046789

General and Exertional Fatigue, Quality of Life, and Risk of Incident Clinical Heart Failure in Those With Pre‐heart Failure in the ARIC Study

Noelle V Pavlovic 1,✉, Martha Abshire Saylor 2, Cheryl R Himmelfarb 2,3,4, Christopher S Lee 1, Amil M Shah 5, Patricia P Chang 6, Sabra Lewsey 4, Yvonne Commodore‐Mensah 2,3, Kunihiro Matsushita 3,4, Chiadi E Ndumele 4
PMCID: PMC13695721  PMID: 42568054

Abstract

Background

General and exertional fatigue are associated with worse outcomes in clinical heart failure (HF). Little is known about their prognostic importance in stage B HF.

Methods

We included 2972 individuals at visit 5 (2011–2013) of the ARIC (Atherosclerosis Risk in Communities) study without clinical HF but with echocardiographic or biomarker evidence for stage B HF. Using general and exertional fatigue scale scores, individuals were categorized as low/no fatigue, high general fatigue only, high exertional fatigue only, or high general and high exertional fatigue. We determined their associations with quality of life and incident HF events using adjusted linear and Cox regression, respectively.

Results

Participants were 60% female, 18% Black, with a mean age of 76 years. Compared with low/no fatigue, all fatigue categories were associated with lower quality of life, with high general and high exertional fatigue having the lowest scores (physical: β=−11.48 [95% CI, −12.80 to −10.17]; mental: β=−5.97 [95% CI, −7.03 to −4.92]). There were 338 incident HF events over a median of 8.4 years. Compared with low/no fatigue, increased incident HF overall was found for high exertional fatigue only (hazard ratio [HR], 1.86 [95% CI, 1.39–2.49]) and high general and high exertional fatigue (HR, 2.16 [95% CI, 1.46–3.20]) but not general fatigue only (HR, 1.42 [95% CI, 0.99–2.04]). All 3 categories were independently associated with increased risk of incident HF with preserved ejection fraction but not with HF with reduced ejection fraction.

Conclusions

General and exertional fatigue demonstrate prognostic importance in pre‐HF and appear to be linked to underrecognized poor quality of life before the onset of clinical HF.

Keywords: fatigue, heart failure, patient‐reported outcomes, pre‐heart failure, symptoms

Subject Categories: Heart Failure, Quality and Outcomes

Nonstandard Abbreviations and Acronyms

ARIC

Atherosclerosis Risk in Communities

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

IR

incidence rate

MRC

Medical Research Council

PROMIS

Patient Reported Outcome Information System

Clinical Perspective.

What Is New?

  • This study evaluated the association of patient‐reported general and exertional fatigue on risk of incident heart failure (HF) in individuals with stage B HF.

  • In those with stage B HF, general and exertional fatigue were independently associated with worse physical and mental quality of life and increased risk of incident clinical HF with preserved ejection fraction.

What Are the Clinical Implications?

  • Although fatigue is not currently routinely addressed clinically as a target for primary HF prevention, the results of this study highlight the prognostic significance of general and exertional fatigue in stage B HF and assessment of fatigue may identify individuals with stage B HF at high risk for developing HF with preserved ejection fraction.

Heart failure (HF) manifests on a continuum, with HF stages A–D reflecting the progression from preclinical (stages A and B) to clinical HF (stages C and D). 1 Whereas historically most HF research and clinical attention has focused on the treatment and associated outcomes of clinical HF (Stages C and D), there is now growing emphasis on prevention among individuals with pre‐HF (stage B HF). Approximately 24% to 36% of the US population has stage B HF 1 , 2 and these individuals are at elevated risk for developing clinical HF. Therefore, there is a need to better characterize this group to identify individuals most at risk of disease progression and to inform preventative strategies.

Clinical HF is characterized by a high symptom burden, with fatigue symptoms being one of the most common and distressing. 3 These fatigue symptoms present as 2 types, general and exertional fatigue, that are distinct 4 , 5 but can co‐occur. 6 , 7 General fatigue in multiple chronic conditions, including HF, has been described as a persistent sensation of a need for rest that is not a result of exertion and not relieved by rest. 4 Exertional fatigue is described as the sensation of a need for rest that is directly related to exertion, is relieved by rest, and is often linked with exertional dyspnea. 8 In clinical HF, general fatigue, exertional fatigue and their co‐occurrence are associated with poorer quality of life (QOL) and increased risk of HF hospitalization and mortality. 9 However, little is known about general and exertional fatigue in stage B HF.

Even in the absence of clinical HF, subclinical cardiac dysfunction, a defining feature of stage B HF, is associated with objectively measured impaired exercise capacity that, in turn, is associated with increased risk of incident clinical HF. 10 , 11 , 12 Thus, it is possible that individuals with stage B HF experience general or exertional fatigue symptoms. However, the distribution and clinical implications of patient‐reported fatigue symptoms in stage B HF are currently uncharacterized. General and exertional fatigue symptoms may be partially reflective of functional capacity and cardiorespiratory fitness, thus, understanding the association of these subjective symptoms with incident HF risk may have implications for screening and monitoring in clinical practice. Therefore, the purpose of this analysis was to determine the association of general and exertional fatigue, and their co‐occurrence, with QOL and incident clinical HF among community‐dwelling older adults with stage B HF in the ARIC (Atherosclerosis Risk in Communities) study.

METHODS

The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. However, the ARIC study data are publicly available through the database of Genotypes and Phenotypes and the National Heart, Lung, and Blood Institute Biological Specimen and Data Repository Information Coordinating Center. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.

The ARIC study is an ongoing, prospective cohort study that enrolled 15 792 participants between 1987 to 1989 from 4 US communities in North Carolina, Mississippi, Minnesota, and Maryland. 13 Participants were subsequently examined at serial study visits and followed continuously to monitor for clinical events. The ARIC study was approved by institutional review boards at each participating site. All participants provided written informed consent.

In this analysis, we included 2972 participants at visit 5 (2011–2013) of the ARIC study with stage B HF, complete data on general and exertional fatigue survey items as well as key covariates, and who reported Black or White race (Figure S1). The ARIC study visit 5 was selected for this analysis because it was the visit where general and exertional fatigue were assessed and was the first visit after the initiation of HF adjudication in 2005.

Measures

Stage B HF

Our definition of stage B HF was based on the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines 14 and was defined as the absence of prevalent clinical HF at or before visit 5 plus the presence of at least 1 of the following: (1) structural heart disease, (2) evidence for increased filling pressures by echocardiogram, or (3) presence of HF risk factors and elevated cardiac biomarkers (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide] or hs‐troponin T [high‐sensitivity cardiac troponin T]) (Table S1). Echocardiography in the ARIC study was acquired using standardized equipment and protocols, the methods of which have been previously described. 15

General Fatigue

General fatigue is a persistent sensation of a need for rest that is not a result of exertion and is not relieved by rest. 4 As a result, general fatigue may affect the initiation of activity but is not necessarily triggered by activity. We used the Patient‐Reported Outcomes Measurement Information System (PROMIS) fatigue scale items measured in ARIC at the first semiannual follow‐up call post visit 5 (since 2012) to operationalize general fatigue. The PROMIS fatigue item bank is psychometrically validated in diverse populations to measure general fatigue. 16 The summative score from the 5 items ranges from 5 to 25, with higher score indicating greater severity of general fatigue. This score was standardized to a mean of 50 and SD of 10 (Table S2) as designed by PROMIS for comparability across populations and studies. 17

Exertional Fatigue

Exertional fatigue is the sensation of a need for rest that is directly related to the execution of an exertional activity and is relieved by rest. 8 We used the modified Medical Research Council (MRC) breathlessness scale measured at visit 5 (2011–2013) to operationalize exertional fatigue. The MRC breathlessness scale is considered a proxy for exertional fatigue in this study as this is the scale that most closely approximates the construct of exertional fatigue in the ARIC study. 7 This scale is validated for the measurement of dyspnea on exertion, and exertional dyspnea is used to determine fatigue level and patient‐perceived exertion in cardiopulmonary exercise testing. 18 , 19 , 20 , 21 Score on the MRC breathlessness scale ranges from 0 to 5 with increasing score indicating increasing breathlessness with exertion (Table S3).

Quality of Life

Data on QOL were collected at visit 5 and measured using the 12‐Item Short Form Health Survey. 22 , 23 This scale is composed of 2 component summary scale scores, physical and mental QOL, that both range from 0 to 100 with higher score indicating better QOL.

Incident HF Events

The baseline time point for prospective analyses was the first semiannual follow‐up after visit 5, the time point at which fatigue data were complete. Incident HF was ascertained prospectively with administrative censoring at December 31, 2020 for this analysis. Incident HF was defined as a new diagnosis of definite or probable acute decompensated HF. 24 Ascertainment of incident HF was performed by active surveillance of all hospitalizations and death from hospital records using identification of International Classification of Diseases (ICD) codes of HF hospitalization or HF death (code 428 or I50 in any position) and subsequent adjudication of these codes by an expert panel. 24 , 25 , 26 Incident HF events classified as definite or probable acute decompensated HF were included in this analysis. 25 Using left ventricular ejection fraction (EF) from hospitalization record data abstraction, when available, incident HF events were further categorized as HF with preserved EF (HFpEF) for left ventricular EF of ≥50% and as HF with reduced EF (HFrEF) for left ventricular EF of <50%.

Demographic and Clinical Characteristics

Covariates included age, sex, race, level of education, smoking status, alcohol intake, body mass index, systolic blood pressure, use of antihypertensive medications in the past 4 weeks, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation, 27 depressive symptoms (Center for Epidemiologic Studies Depression Scale), 28 triglycerides, total cholesterol, diabetes (hemoglobin A1c value of ≥6.5%, use of diabetes medication, or self‐reported diagnosis of diabetes), coronary heart disease (self‐reported coronary heart disease or silent myocardial infarction at visit 1 or adjudicated myocardial infarction or coronary revascularization procedure between visit 1 and visit 5 29 ), and atrial fibrillation (from ECG or hospital discharge records before visit 5). Covariates were assessed using standardized questionnaires, physical exam, and laboratory testing at visit 5, except for education level which was assessed at visit 1 (1987–1989). Covariates were selected a priori based on existing literature and their associations with fatigue 3 , 30 , 31 , 32 , 33 , 34 , 35 , 36 or risk of incident HF. 14 , 37 , 38 , 39 , 40 , 41 , 42 , 43

Statistical Analysis

General and exertional fatigue scale scores were dichotomized into (1) none to mild or (2) moderate to severe categories based on score cutoffs previously defined in the literature. 17 , 44 None to mild general fatigue was defined as a score < 52.5 on the PROMIS fatigue scale, and moderate to severe general fatigue as a score ≥ 52.5. The PROMIS fatigue scale has been validated to have a threshold score of 52.5 for the presence of clinically meaningful levels of fatigue. 17 None to mild exertional fatigue was defined as a score of 0 to 1 on the MRC Breathlessness Scale, and moderate to severe exertional fatigue as a score of ≥2, a threshold which has been previously defined in the ARIC study as indicating the presence of exertional dyspnea. 45 We used these thresholds to cross‐categorize individuals based on both their general and exertional fatigue scores to capture general and exertional fatigue individually, and their co‐occurrence. Our primary exposure for this analysis was the cross‐categorization of these general and exertional fatigue score categories into (1) low/no general and exertional fatigue, (2) high general fatigue only, (3) high exertional fatigue only, and (4) high general and high exertional fatigue (Figure 1).

Figure 1. Fatigue categories definitions based on general and exertional fatigue scale score.

Figure 1

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Individuals were cross‐categorized based on their scores on both general and exertional fatigue scale scores previously established in the literature. General fatigue was measured using the PROMIS Fatigue scale and exertional fatigue with the MRC Breathlessness scale. MRC indicates Medical Research Council; and PROMIS, Patient Reported Information System Outcomes System.

We applied descriptive statistics of central tendency, dispersion, and frequency including means±SD for normally distributed continuous variables, medians (quartile 1, quartile 3) for skewed continuous variables, and percentages. We compared characteristics across fatigue categories using global chi‐square tests, ANOVA, and the Kruskal–Wallis H test where appropriate. Levene's test was used to determine the appropriateness of ANOVA based on homogeneity of variances across fatigue categories. Alpha was set a priori at 0.05 and all inference tests were 2 sided. We estimated the crude incidence rates and associated 95% CIs for HF events across general and exertional fatigue categories. In cross‐sectional analyses, we used linear regression to determine the relationship of fatigue categories with physical and mental QOL. In prospective analyses, we used Cox proportional hazard regression to determine the prospective association of fatigue categories with incident clinical HF, with tests for statistical interaction between general and exertional fatigue. We further used competing risks regression to assess associations of fatigue categories with incident HFpEF and HFrEF. Competing events included the other HF phenotype (HFpEF, HFrEF, undefined phenotype), and death. The proportional hazards assumption was checked using Schoenfeld residuals.

Regression models were adjusted for age, race, education level, sex, smoking status, alcohol intake, body mass index, use of antihypertensive medications, systolic blood pressure, diabetes, coronary heart disease, atrial fibrillation, depressive symptoms, estimated glomerular filtration rate, triglycerides, and total cholesterol. For analyses of the mental QOL outcome, depressive symptoms were removed from the covariate adjustment model in order to avoid adjusting for the outcome itself as depressive symptoms are included in the composite mental QOL subscale of the Short Form‐12. Analyses were performed on complete cases and no data were imputed.

We performed sensitivity analyses estimating the association of fatigue categories with risk of HF events, including (1) stratifying on sex and race; with tests for interaction (2) additionally adjusting for physical activity level 46 ; (3) excluding individuals with early incident HF events within the first 3 years of follow‐up; (4) excluding individuals with an outpatient clinical HF diagnosis at or before ARIC visit 5 by linking the ARIC data set with Centers for Medicare & Medicaid Services HF diagnosis codes (Table S4); and (5) excluding individuals with NT‐proBNP levels ≥450 pg/mL, ≥ 300 pg/mL, and ≥ 125 pg/mL. Physical activity level was defined using the American Heart Association Physical Activity Guidelines for Americans recommendations with recommended defined as ≥75 min/week of vigorous or ≥ 150 min/week of moderate intensity physical activity, intermediate as >0 min/week of moderate/vigorous physical activity but less than ideal, and poor as 0 min/week of moderate/vigorous physical activity. 46 These physical activity categories have been shown to be strongly associated with risk of incident HF in the ARIC study. 47 , 48

RESULTS

Of the 2972 participants in this study population, 60% were female, 18% were Black, and they had a mean age 76 ± 5 years. The majority of the sample (71%, N=2097) had low/no general and exertional fatigue, 10% (N=306) had high general fatigue only, 12% (N=370) had high exertional fatigue only, and 7% (N=199) had high general and high exertional fatigue (Table 1). Compared with the low/no general and exertional fatigue category, all other categories were more likely to be female and Black adults, have a lower level of education, and have a higher frequency of diabetes and use of anti‐hypertensive medication. They also on average had lower estimated glomerular filtration rate, higher body mass index, and higher levels of depressive symptoms (Table 1).

Table 1.

Sociodemographic and Clinical Characteristics of 2972 Adults With Stage B HF at Visit 5 (2011–2013) of the Atherosclerosis Risk in Communities Study by General and Exertional Fatigue Categories

Overall Low/no fatigue High general fatigue High Eexertional fatigue High general and high exertional fatigue
No. 2972 2097 (71%) 306 (10%) 370 (12%) 199 (7%) P value
Age, y 76 ± 5 76 ± 5 76 ± 5 76 ± 5 77 ± 5 0.022
Female sex 1778 (60%) 1166 (56%) 232 (76%) 227 (61%) 153 (77%) <0.001
Black race 535 (18%) 313 (15%) 68 (22%) 96 (26%) 58 (29%) <0.001
Education level <0.001
Some high school or less 339 (11%) 202 (10%) 38 (12%) 55 (15%) 44 (22%)
High school or vocational 1293 (44%) 900 (43%) 148 (48%) 155 (42%) 90 (45%)
At least some college 1340 (45%) 995 (47%) 120 (39%) 160 (43%) 65 (33%)
Alcohol intake (g/wk) 31 ± 67 34 ± 70 25 ± 59 26 ± 56 19 ± 56 0.002
Smoking status
Current 179 (6%) 113 (5%) 19 (6%) 33 (9%) 14 (7%) 0.130
Former 1432 (48%) 1011 (48%) 144 (47%) 169 (46%) 108 (54%)
Never 1226 (41%) 879 (42%) 130 (42%) 146 (39%) 71 (36%)
Unknown 135 (5%) 94 (4%) 13 (4%) 22 (6%) 6 (3%)
Depressive symptoms 2 (1, 4) 2 (1, 3) 4 (2, 6) 3 (1, 5) 5 (3, 8) <0.001
Systolic blood pressure, mm Hg 132 ± 18 132 ± 18 132 ± 19 133 ± 19 133 ± 21 0.700
Antihypertensive medications 2290 (77%) 1567 (75%) 243 (79%) 312 (84%) 168 (84%) <0.001
Diabetes 818 (28%) 497 (24%) 89 (29%) 132 (36%) 100 (50%) <0.001
Coronary heart disease 341 (11%) 243 (12%) 25 (8%) 51 (14%) 22 (11%) 0.150
Atrial fibrillation 170 (6%) 112 (5%) 20 (7%) 28 (8%) 10 (5%) 0.330
Body mass index, kg/m2 29 ± 6 28 ± 5 29 ± 5 31 ± 7 32 ± 7 <0.001
Estimated glomerular filtration rate, mL/min/1.73m2 59 (47–73) 62 (49–75) 59 (45–72) 54 (42–67) 50 (39–63) <0.001
Total cholesterol, mg/dL 179 (152–207) 180 (153–208) 183 (163–214) 168 (145–202) 173 (150–209) <0.001
Triglycerides, mg/dL 111 (84–150) 110 (83–149) 114 (85–156) 110 (87–145) 117 (91–160) 0.130
Left ventricular ejection fraction (%) 66 (62–69) 66 (62–69) 66 (63–69) 66 (62–69) 66 (62–69) 0.850
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Values are presented as mean ± SD for normally distributed variables, median (IQR) for skewed variables, and n (%) for frequencies.

Individuals with high general and high exertional fatigue had the lowest physical QOL scores with an 11.5 point lower score on average than those with low/no general and exertional fatigue (β −11.48 [95% CI, −12.80 to −10.17]). High general fatigue only (β −4.98 [95% CI, −6.01 to −3.94]) and high exertional fatigue only (β −5.60 [95% CI, −6.57 to −4.63]) were also associated with lower physical QOL scores on average compared with the low/no general and exertional fatigue category, although to a lesser degree than the co‐occurrence of the 2. We saw similar trends for mental QOL for all categories, though of lesser magnitude, with the high general and high exertional fatigue category associated with the lowest average mental QOL score compared with the low/no general and exertional fatigue category (β: −5.97 [95% CI, −7.03 to −4.92]) (Figure 2).

Figure 2. Cross‐sectional association of general and exertional fatigue on physical and mental quality of life.

Figure 2

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The association of fatigue category with QOL was determined using adjusted linear regression and estimates are reported as adjusted mean difference in QOL score (95% CI) on the Short Form‐12 health‐related QOL scale compared with the low/no fatigue category. Regressions are adjusted for age, race, education level, sex, smoking status, alcohol intake, body mass index, use of antihypertensive medications, systolic blood pressure, diabetes, coronary heart disease, atrial fibrillation, depressive symptoms, estimated glomerular filtration rate, triglycerides, and total cholesterol. Depressive symptoms were removed for mental QOL analyses. QOL indicates quality of life.

Over a median follow‐up time of 8.4 years, there were 338 incident clinical HF events. Crude incidence rates (IR) of clinical HF per 1000 person‐years increased stepwise from the low/no general and exertional fatigue category (IR, 12.2 [95% CI, 10.6–14.0]), to the high general fatigue only category (IR, 16.3 [95% CI, 11.9–22.6]) to the high exertional fatigue only category (IR, 25.7 [95% CI, 20.3–32.7]), to the high general and high exertional fatigue category (IR, 28.0 [95% CI, 20.3–38.7]) (Table 2). Cox proportional hazards regression showed independent associations with incident clinical HF of any phenotype for those with high exertional fatigue only (hazard ratio [HR], 1.86 [95% CI, 1.39–2.49]) and the co‐occurrence of high general and high exertional fatigue (HR, 2.16 [95% CI, 1.46–3.20]) compared with those with low/no general and exertional fatigue (Figure 3). When general and exertional fatigue were examined individually, not cross‐categorized, there was no statistically significant interaction between general and exertional fatigue on the risk of incident HF of any phenotype (P=0.459).

Table 2.

Crude Incidence Rates of Clinical HF Events by General and Exertional Fatigue Categories From Visit 5 Through 2020.

Low/o fatigue High general fatigue High exertional fatigue High general and high exertional fatigue
No. No.=2097 No.=306 No.=370 No.=199
All HF Events 197 (9%) 37 (12%) 67 (18%) 37 (19%)
IR/1000 py 12.2 (10.6–14.0) 16.3 (11.9–22.6) 25.7 (20.3–32.7) 28.0 (20.3–38.7)
HF with preserved EF Events 89 (4.24%) 21 (6.96%) 39 (10.54%) 24 (12.06%)
IR/1000 py 5.49 (4.46–6.76) 9.29 (6.06–14.25) 14.99 (10.95–20.51) 18.18 (12.18–27.12)
HF with reduced EF Events 93 (4.43%) 15 (4.90%) 25 (6.76%) 10 (5.03%)
IR/1000 py 5.74 (4.68–7.03) 6.64 (4.00–11.01) 9.61 (6.49–14.22) 7.57 (4.08–14.08)
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Events presented as N (%) and crude IR as IR per 1000 person‐years (95% CI).

EF indicates ejection fraction; HF, heart failure; IR, incidence rate; and py, person‐year.

Figure 3. Prospective association of general and exertional fatigue in pre‐heart failure with risk of incident clinical heart failure events.

Figure 3

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Associations of fatigue categories with risk of incident clinical heart failure were determined using adjusted Cox proportional hazards regression. Estimates are reported as hazard ratios (95% CI) of incident clinical heart failure of any phenotype compared with the low/no fatigue category from adjusted Cox proportional hazards regression. Regressions were adjusted for age, race, education level, sex, smoking status, alcohol intake, body mass index, use of antihypertensive medications, systolic blood pressure, diabetes, coronary heart disease, atrial fibrillation, depressive symptoms, estimated glomerular filtration rate, triglycerides, and total cholesterol. HF indicates heart failure.

Of the 338 total incident clinical HF events, 173 were HFpEF, 143 were HFrEF, and 22 were undefined. Crude IRs of HFpEF per 1000 person‐years increased with higher levels and the co‐occurrence of general and exertional fatigue, with the high general and high exertional fatigue category having the highest IR of 18.2 per 1000 person‐years (95% CI 12.2–27.1). In contrast, IR of HFrEF did not increase with higher fatigue categories (Table 2). Similarly, compared with low/no general and exertional fatigue, all fatigue categories were independently associated with increased risk of incident HFpEF (Figure 4). Individuals with both high general and high exertional fatigue had the highest risk for incident HFpEF (HR, 2.59 [95% CI, 1.56–4.32]). There was no significant association of any fatigue category with the risk of incident HFrEF (Figure 4).

Figure 4. Prospective associaton of general and exertional fatigue in pre‐HF on risk of incident HFpEF and HFrEF.

Figure 4

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Associations of fatigue categories with risk of incident clinical HFpEF and HFrEF were determined using adjusted Cox proportional hazards regression. Estimates are reported as hazard ratios (95% CIs) of incident clinical HFpEF and HFrEF compared with the low/no fatigue category. Regressions are adjusted for age, race, education level, sex, smoking status, alcohol intake, body mass index, use of antihypertensive medications, systolic blood pressure, diabetes, coronary heart disease, atrial fibrillation, depressive symptoms, estimated glomerular filtration rate, triglycerides, and total cholesterol. HFpEF indicates heart failure with preserved ejection fraction; and HFrEF, heart failure with reduced ejection fraction.

In examining the association of general and exertional fatigue categories with HF risk, secondary analyses stratifying on sex (Table S5) and race (Table S6) demonstrated similar results across demographic groups with no statistically significant interactions (sex: P=0.69; race: P=0.73). Although lower levels of physical activity were more frequently present in those with greater severity and the co‐occurrence of general and exertional fatigue (Table S7), additionally adjusting for physical activity did not change the association of fatigue category with risk of incident clinical HF (Table S8). Associations also remained similar after excluding individuals with early incident clinical HF events within the first 3 years of follow‐up (Table S9), excluding individuals with an outpatient diagnosis of clinical HF at or before visit 5 by Centers for Medicare & Medicaid Services claims data (Table S10), and excluding individuals with an NT‐proBNP level ≥450 pg/mL, ≥ 300 pg/mL, and ≥125 pg/mL. (Table S11).

DISCUSSION

In this analysis of community dwelling adults with stage B HF, we found that greater severity and the co‐occurrence of general and exertional fatigue were associated with several sociodemographic characteristics and cardiometabolic risk factors including obesity, diabetes, and impaired kidney function. Both general and exertional fatigue, but more so their co‐occurrence, were associated with worse physical and mental QOL. Further, they were independently associated with greater risk of incident clinical HF events, with significant associations seen for HFpEF but not HFrEF. These findings suggest that individuals with stage B HF experiencing general or exertional fatigue may be at elevated HF risk, particularly for HFpEF, independent of traditional risk factors.

In clinical HF, studies have shown that greater severity of general and exertional fatigue is associated with adverse clinical outcomes and worse QOL. 3 In patients with clinical HF, symptoms like fatigue are known barriers to optimal HF self‐care, contributing to a greater risk for HF complications. 49 An understanding of the relationship between fatigue and lifestyle behaviors integral to HF risk in those with pre‐HF will be important to inform essential strategies for primary prevention. Additionally, in prior studies, impairment in functional capacity and cardiorespiratory fitness conferred increased risk of incident HF. 50 , 51 , 52 Our findings build upon prior work by showing that patient‐reported general and exertional fatigue in pre‐HF, and particularly their co‐occurrence, also have important risk implications for the development of clinical HF.

Participants in this analysis were classified as having pre‐HF (stage B HF) based on evidence of structural heart disease in the absence of a prior HF diagnosis, based on their local clinical care and as per current clinical guidelines. 14 However, there may be a concern that our analysis has included individuals who are in the early stages of clinical HF or mild HF that has not yet required hospitalization and thus is not captured in ARIC. To rule this out, we excluded incident cases of HF within the first few years of follow‐up; we excluded outpatient HF cases; and excluded individuals with NT‐proBNP ≥450 pg/mL, ≥ 300 pg/mL, and ≥125 pg/mL, again, with similar results.

Importantly, although the presence of fatigue symptoms demonstrates prognostic importance in this analysis, this alone is insufficient for the clinical diagnosis of HF. 53 Further, algorithms used in clinical practice and epidemiologic research consider a constellation of signs and symptoms that have varying degrees of specificity for the identification of HF. 14 , 53 , 54 Although general and exertional fatigue alone are insufficient for making a HF diagnosis, their higher prevalence in stage B HF, and their associations with worse QOL and greater HF risk, indicate that these symptoms may require greater clinical attention and reflect the need for early intervention for primary prevention of clinical HF.

A notable finding of our analysis is that high general fatigue only, high exertional fatigue only, and the co‐occurrence of the 2 are independently associated with increased risk of incident clinical HFpEF but not HFrEF. Cardiometabolic and sociodemographic risk factors, which are often preferentially associated with HFpEF, 55 , 56 , 57 were also associated with more severe general and exertional fatigue in this analysis. However, the associations of general and exertional fatigue with incident HFpEF seen here were notably independent of these covariates. Rather than being a challenge purely related to cardiac dysfunction, HFpEF is now appreciated as a multisystem syndrome with underlying cardiac and noncardiac pathophysiology that is still not completely understood. 55 , 58 The findings of this analysis highlight the need to characterize shared biological mechanisms linking fatigue symptomatology and HFpEF development.

Clinical Implications

These findings have significant clinical implications. First, general and exertional fatigue experienced in the setting of stage B HF appears to be a strong independent predictor of incident clinical HF, particularly HFpEF. In individuals with pre‐HF, fatigue is currently not routinely addressed clinically as a target for primary HF prevention. However, assessing these symptoms early in the disease trajectory may serve as an early screening tool and help highlight individuals at increased risk for HF development. Second, there may be common pathways shared by general and exertional fatigue and the mechanisms of HFpEF development. For example, skeletal muscle dysfunction is a key component of HFpEF pathophysiology, 59 with abnormal skeletal muscle metabolism associated with worse cardiorespiratory fitness, 60 which is in turn associated with adverse clinical outcomes. 61 Additionally, HFpEF is characterized by systemic inflammation thought to be driven by multiple comorbidities, metabolic stress, and dysfunctional adipose tissue. 62 In this study, greater severity of fatigue was associated with both higher body mass index and a greater prevalence of type 2 diabetes, suggesting that dysfunctional adiposity and metabolic disease may play a role in fatigue symptoms. With more study, these and other common pathways could elucidate modifiable targets for intervention.

Some promising interventional approaches may include pharmacologic and lifestyle optimization for the management of such comorbidities and HF risk reduction (eg, increasing physical activity, blood pressure management, weight loss, cardioprotective medications for those with diabetes or chronic kidney disease), as well as closer outpatient follow‐up for disease progression. Although these interventional approaches may reduce the risk of incident HF, 43 , 47 , 48 , 63 , 64 effects on alleviating fatigue symptoms are still unclear and require further study.

Limitations

This study has some limitations. This study is observational with the inherent risk of residual confounding. Additionally, the MRC Breathlessness Scale is a measure of exertional dyspnea and may not fully capture the construct of exertional fatigue. However, the subjective perception of exertion and dyspnea are related and are often used together in cardiopulmonary exercise testing protocols to determine fatigue with exertion. 20 , 21 It is also possible that we are capturing some individuals in our study population who already had clinical HF. However, sensitivity analyses excluding those with early incident HF events, those with an outpatient diagnosis of clinical HF, and those with NT‐proBNP levels ≥450 pg/mL, ≥ 300 pg/mL, and ≥ 125 pg/mL yielded similar results. Additionally, some variables associated with fatigue (eg, cardiorespiratory fitness, sleep apnea, thyroid disease, cancer, anemia, lung disease) are not well characterized in the ARIC study, potentially introducing unmeasured confounding. This analysis also has important strengths, including the use of a well‐characterized community‐based population with data on fatigue elements and incident cardiovascular events to provide novel insights about how general and exertional fatigue in pre‐HF relate to patient‐reported and clinical outcomes.

CONCLUSIONS

In a sample of community‐dwelling older adults with stage B HF at visit 5 of the ARIC study, greater severity and the co‐occurrence of general and exertional fatigue were associated with worse QOL and increased risk of incident clinical HF, particularly HFpEF. General and exertional fatigue demonstrate independent prognostic importance for those with pre‐HF and appear to be linked to worse QOL before the onset of clinical HF.

Sources of Funding

The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). Dr. Pavlovic has been funded with federal funds from National Institutes of Health National Heart, Lung, and Blood Institute 5T32HL007024‐49, National Institutes of Health National Institute of Nursing Research F31NR020136, NIH T32NR012704. Dr Ndumele is supported by R01 HL146907, National Institutes of Health, Bethesda, MD.

Disclosures

None.

Supporting information

Tables S1–S11

Figure S1

JAH3-15-e046789-s001.pdf (436.1KB, pdf)

STROBE Statement—Checklist

JAH3-15-e046789-s002.pdf (142.8KB, pdf)

Acknowledgments

The authors thank the staff and participants of the ARIC study for their important contributions.

This article was sent to Sula Mazimba, MD, MPH, Associate Editor, for review by expert referees, editorial decision, and final disposition

For Sources of Funding and Disclosures, see page 9 and 10.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Tables S1–S11

Figure S1

JAH3-15-e046789-s001.pdf (436.1KB, pdf)

STROBE Statement—Checklist

JAH3-15-e046789-s002.pdf (142.8KB, pdf)

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