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. Author manuscript; available in PMC: 2022 Nov 1.
Published in final edited form as: Am J Cardiol. 2021 Aug 31;158:59–65. doi: 10.1016/j.amjcard.2021.07.035

Clinical and Echocardiographic Characteristics of Patients Hospitalized with Acute versus Chronic Heart Failure with Preserved Ejection Fraction (From the ARIC Study)

Zainali S Chunawala 1, Marat Fudim 2, Sameer Arora 3, Arman Qamar 4, Muthiah Vaduganathan 5, Robert J Mentz 2, Ambarish Pandey 1, Melissa C Caughey 6
PMCID: PMC8577211  NIHMSID: NIHMS1737098  PMID: 34474908

Abstract

An expanding number of therapies are now indicated for comorbidity management in heart failure with preserved ejection fraction (HFpEF). Whether comorbidity burdens differ for patients with HFpEF who are hospitalized for acute decompensated heart failure (ADHF) vs. those with chronic stable heart failure (CSHF) who are hospitalized for other causes is uncertain. Since 2005, the Atherosclerosis Risk in Communities (ARIC) study has conducted adjudicated community surveillance of hospitalized heart failure. Hospitalized ADHF and CSHF were sampled identically, using prespecified discharge codes and demographic strata, but were differentiated by signs or symptoms of acute or worsening heart failure upon physician review of the medical record. HFpEF was defined by an ejection fraction ≥50%. All events were weighted by the inverse of the sampling probability for statistical analyses. From 2005–2014, 13,706 weighted (2,936 unweighted) hospitalizations (mean age 77 years, 64% women, 29% Black) were sampled among patients with HFpEF and adjudicated ADHF (86%) or CSHF (14%). Comorbidity prevalence was high both for ADHF and CSHF hospitalizations, irrespective of sex. Women hospitalized with ADHF vs. CSHF had greater prevalence of hypertension (89% vs. 84%) diabetes mellitus (48% vs 39%) and renal disease (85% vs 74%). Echocardiographic features such as left ventricular hypertrophy and valvular abnormalities were more common with ADHF than CSHF, for both sexes. However, the 28-day and 1-year mortality risk were comparable for ADHF and CSHF. In conclusion, hospitalized patients with HFpEF have a high comorbidity burden and risk of death, irrespective of the cause of hospitalization.

Keywords: HFpEF, comorbidities, echocardiography, diabetes mellitus, chronic kidney disease

Introduction

Heart failure (HF) is a complex syndrome associated with a large burden of cardiac and non-cardiac comorbidities such as hypertension, atrial fibrillation, chronic kidney disease (CKD), diabetes mellitus (DM) and obesity 1,2. Patients with HF with preserved ejection fraction (HFpEF) tend to have a heightened mortality risk with increasing comorbidity burden 3–6, particularly in association with non-cardiovascular comorbidities 7,8. A higher prevalence of comorbidities has consistently been reported for women with HFpEF relative to men, which may reflect the greater prevalence of comorbidities in the female general population 9,10. Less is known of the sex-specific comorbidity burden of patients hospitalized with acute decompensated heart failure (ADHF) relative to patients with chronic stable heart failure (CSHF) who are hospitalized for other causes. Although clinical practice guidelines identify opportunities for care optimization among patients hospitalized for ADHF (including HFpEF), 11 scarce data are available regarding the characteristics, post-discharge outcomes and readmission rates of patients with HFpEF hospitalized with CSHF, i.e., those admitted for non-HF reasons. In this investigation, we compare the sex-specific comorbidity burden and mortality outcomes of patients hospitalized with ADHF and CSHF, by examining community surveillance data captured by the Atherosclerosis Risk in Communities (ARIC) Study.

Methods

From 2005 – 2014, the ARIC study conducted population-based retrospective surveillance of hospitalized events in Forsyth County, North Carolina; Washington County, Maryland; Jackson, Mississippi; and 8 northwest suburbs of Minneapolis, Minnesota. Surveillance activities were approved by local institutional review boards from the 4 ARIC communities. Patient consent was not required for surveillance because all personal identifiers were redacted. Surveillance eligibility was restricted to residents 55 years of age or older, with a hospitalization ≥24 hours and a discharge date between January 1, 2005 – December 31, 2014. Hospitalizations with any discharge codes for congestive HF, rheumatic heart disease, hypertensive heart disease, acute cor pulmonale, chronic pulmonary heart disease, cardiomyopathies, acute edema of lung, or dyspnea were randomly sampled, using pre-specified sampling fractions within strata of ARIC communities, ICD-9 code (428.x or all other eligible codes), age (55–74, 75–84, or ≥85), sex, and race (black or white). Hospital medical records indicating signs or symptoms of HF were fully abstracted and reviewed by ARIC physicians, as previously described 12. Using standardized criteria, hospitalizations were classified as definite ADHF, probable ADHF, CSHF, not HF, or unclassifiable; based on diagnostic reports from the hospital record, physician notes, and discharge summaries.12 CSHF required evidence of compensated HF signs and symptoms controlled by therapy, with no increase in medications or worsening of symptoms during the hospitalization. ADHF was differentiated from CSHF by new onset or worsening signs or symptoms of HF.

Demographics, medical histories, echocardiographic data, laboratory values, and medications were obtained from the medical record by certified abstractors following a standardized protocol. History of coronary artery disease and myocardial infarction were recorded as separate variables, although classification of coronary artery disease included history of myocardial infarction. For the purposes of this analysis, obesity was defined by a body mass index ≥30 kg/m2, using the weight at hospital discharge. Anemia was defined by a hemoglobin value < 11 g/dL, using the last abstracted laboratory value to minimize the potential for hemodilution. Renal disease was defined by hemodialysis use or an estimated glomerular filtration rate < 60 mL/min/1.73 m2, using the last abstracted serum creatinine value from the hospital record and the CKD-Epi formula. Ejection fraction was abstracted from in-hospital echocardiography reports and considered indicative of HFpEF when ≥50%. Left ventricular hypertrophy, mitral regurgitation, aortic stenosis, aortic insufficiency, and pulmonary hypertension were considered present if classified as “moderate” or “severe” on the echocardiography report.

The first-listed ICD-9 code was considered the primary diagnosis at discharge for patients classified with CSHF. For the purposes of this analysis, diagnosis codes were categorized as infectious diseases (001–139), endocrine or metabolic diseases (240–279), cardiovascular (390–459), respiratory (460–519), gastrointestinal (520–579), genitourinary (580–629), symptoms, signs, and “ill-defined” conditions, (780–799), injury (800–999) or “miscellaneous”.

Length of hospital stay was calculated by subtracting the discharge date from the admission date, excluding any patients who were transferred to or from another hospital. Mortality outcomes within 28 days and 1 year of hospitalization were ascertained by the ARIC study, by linking hospital records with the National Death Index.

All analyses were performed using SAS Survey Procedures 9.4 (SAS Institute; Cary, NC). Statistical tests and models accounted for the stratified sampling design and were weighted by the inverse of the sampling probability 13. Demographic, clinical, and echocardiographic characteristics were compared between ADHF and CSHF in sex-stratified analyses. Continuous variables were assessed for normality and compared using the difference in least square means from weighted linear regression. Categorical variables were compared using Rao-Scott χ2 tests. Mortality outcomes at 28-days and 1-year of hospital admission were compared between patients with ADHF vs. CSHF by logistic and Cox regression, respectively, with adjustment for age, race, sex, year of admission, length of stay, and geographic region.

Results

From 2005–2014, a total of 23,409 hospitalized events were sampled. Of these, 11,889 were identified as ADHF (N=9,139) or CSHF (N= 2,750). After excluding 286 patients identified as race other than White or Black, 11,603 remained. Of these, 6786 (58%) had available in-hospital echocardiography data, with 3,085 (45%) classified as HFpEF based on the abstracted ejection fraction. After the exclusion of 149 patients with missing mortality data, a total of 2,936 remained (2,476 with ADHF, 460 with CSHF), corresponding to a weighted population of 13,706 hospitalized events (11,614 with ADHF, 2,093 with CSHF), Supplemental Figure 1. All subsequent results are presented with weighting by the sampling fraction.

In our overall study population, 64% were female, 29% were Black, and the mean age was 76 years. Demographic distributions were comparable by HF type; with similar proportions of female patients (64% vs. 60%; P = 0.09) and Black patients (32% vs. 29%; P = 0.1) among those with ADHF and CSHF. Diseases of the cardiovascular system were the most frequently listed primary discharge codes for patients with CSHF (27%), followed by respiratory conditions (21%), and infectious disease (12%); Figure 1. We relied upon the physician-adjudicated and standardized classification of ADHF and CSHF; however, a small percentage (3%) of CSHF patients had HF (ICD-9: 428.x) listed as the primary discharge code. When compared with ADHF, patients with CSHF more often had known history of HF documented in the medical record (90% vs. 63%; P <0.0001).Demographics and medical histories were largely comparable when stratified by sex and by HF type (Table 1 and Figure 2). However, women with ADHF had a significantly higher prevalence of cardiometabolic comorbidities such as hypertension (89% vs. 84%), DM (48% vs 39%) and renal disease (85% vs 74%) compared to women with CSHF. A differing comorbidity pattern was observed among male patients with ADHF relative to CSHF. Among male patients, ADHF was associated with a lower prevalence of coronary heart disease (55% vs. 63%), sleep apnea (17% vs. 24%) and depression (13% vs 19%). On echocardiography, women with ADHF had a significantly higher prevalence of left ventricular hypertrophy (29% vs 19%), aortic insufficiency (8% vs 3%), mitral regurgitation (30% vs 18%), and pulmonary hypertension (41% vs 24%), when compared to women with CSHF (Figure 3). Similar comparisons were observed in male patients, with a significantly higher prevalence of aortic insufficiency (8% vs. 3%), mitral regurgitation (23% vs. 10%) and pulmonary hypertension (33% vs. 25%) in those with ADHF compared to CSHF.

Figure 1:

Figure 1:

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Distribution of first-listed diagnosis codes for patients with concomitant chronic stable heart failure with preserved ejection fraction who were hospitalized for other causes. The Community Surveillance component of the Atherosclerosis Risk in Communities Study, 2005–2014.

Table 1:

Demographic, clinical, and echocardiographic characteristics of patients hospitalized with acute versus chronic heart failure with preserved ejection fraction, stratified by sex. The Community Surveillance component of the Atherosclerosis Risk in Communities Study, 2005–2014.

Women Men
Characteristic ADHF (N = 7469*) CSHF (N = 1248*) P-value ADHF ( N = 4145*) CSHF ( N = 844*) P-value
Demographics
Age (mean ± S.E.M) 77 ± 0.2 77 ± 0.5 0.7 75 ± 0.3 73 ± 0.6 0.09
Black 2181 (29%) 428 (34%) 0.1 1131 (27%) 249 (30%) 0.5
Health insurance 7288 (98%) 1221 (98%) 0.9 4009 (97%) 839 (99%) 0.003
Cardiovascular Comorbidities
Prior heart failure diagnosis 4584 (64%) 1104 (90%) <0.000 2467 (62%) 764 (92%) 0.0007
Myocardial infarction 1175 (16%) 180 (14%) 0.3 874 (21%) 235 (28%) 0.06
Coronary artery disease 3131 (42%) 562 (45%) 0.4 2273 (55%) 535 (63%) 0.05
Peripheral artery disease 713 (10%) 118 (9%) 0.9 541 (13%) 110 (13%) 1
Hypertension 6627 (89%) 1050 (84%) 0.05 3625 (87%) 764 (91%) 0.3
Atrial fibrillation 2769 (37%) 452 (36%) 0.8 1626 (39%) 322 (38%) 0.8
Stroke / transient ischemic attack 1464 (20%) 260 (21%) 0.7 795 (19%) 205 (24%) 0.1
Non-Cardiovascular Comorbidities
Obesity† 3209 (49%) 542 (50%) 0.7 1611 (43%) 340 (45%) 0.6
Diabetes mellitus 3613 (48%) 488 (39%) 0.009 1901 (46%) 418 (49%) 0.4
Renal disease‡ 4889 (85%) 639 (74%) 0.0003 2423 (78%) 427 (73%) 0.2
Chronic bronchitis / COPD 2708 (36%) 521 (42%) 0.1 1482 (36%) 366 (43%) 0.07
Sleep apnea 1051 (14%) 176 (14%) 1 707 (17%) 205 (24%) 0.04
Depression 1714 (23%) 297 (24%) 0.8 536 (13%) 163 (19%) 0.05
Anemia 4081 (55%) 676 (54%) 0.9 1995 (49%) 441 (52%) 0.4
Thyroid disease 2095 (28%) 346 (28%) 0.9 565 (14%) 149 (18%) 0.2
Echocardiography
Ejection fraction (%) 58 ± 0.2 59 ± 0.4 0.09 57 ± 0.2 58 ± 0.4 0.05
Left ventricular hypertrophy § 2128 (29%) 238 (19%) 0.003 1229 (30%) 217 (26%) 0.3
Left ventricular dilation 278 (4%) 41 (3%) 0.8 423 (10%) 54 (6%) 0.1
Aortic stenosis§ 942 (13%) 109 (9%) 0.1 460 (11%) 54 (6%) 0.1
Aortic insufficiency§ 565 (8%) 43 (3%) 0.03 346 (8%) 24 (3%) 0.003
Mitral regurgitation§ 2268 (30%) 226 (18%) 0.0001 946 (23%) 85 (10%) 0.0007
Right ventricular dilation 1635 (22%) 245 (20%) 0.5 919 (22%) 144 (17%) 0.2
Impaired right ventricular function 549 (6%) 86 (7%) 0.7 207 (5%) 36 (4%) 0.7
Pulmonary hypertension§ 3040 (41%) 297 (24%) <0.0001 1388 (33%) 211 (25%) 0.04
Medications
ACEi / ARBs 3430 (46%) 582 (47%) 0.0 1852 (45%) 429 (51%) 0.2
Beta Blockers 4715 (63%) 800 (64% ) 0.8 2749 (67%) 557 (66%) 0.9
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Abbreviations: ADHF = acute decompensated heart failure, ACEi / ARBs = angiotensin converting enzyme inhibitor / angiotensin receptor blockers, COPD = chronic obstructive pulmonary disease, CSHF = chronic stable heart failure.

*

Weighted sample sizes. Unweighted sample sizes for women = 1,499 with ADHF, 263 with CSHF. Unweighted sample sizes for men = 977 with ADHF, 197 with CSHF.

†

Obesity was defined by a body mass index ≥30 kg/m2, using the weight at hospital discharge

‡

Serum creatinine not abstracted in 2014, classification of renal disease missing for 3397

§

Echocardiographic abnormality classified by presence of moderate or severe lesion

Figure 2:

Figure 2:

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Distributions of non-cardiovascular and cardiovascular comorbidities among patients hospitalized with acute versus chronic heart failure with preserved ejection fraction, stratified by sex. The Community Surveillance component of the Atherosclerosis Risk in Communities Study, 2005–2014.

Footnote: Abbreviations: COPD = chronic obstructive pulmonary disease, MI = myocardial infarction, CAD = coronary artery disease, PAD = peripheral artery disease

Figure 3:

Figure 3:

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Distributions of echocardiographic abnormalities among patients hospitalized with acute versus chronic heart failure with preserved ejection fraction, stratified by sex. The Community Surveillance component of the Atherosclerosis Risk in Communities Study, 2005–2014.

Footnote: Abbreviations: HFrEF = heart failure with reduced ejection fraction, HFpEF = heart failure with preserved ejection fraction, LVH = left ventricular hypertrophy, RV = right ventricular

Transfers to or from another acute care hospital were uncommon (N=175, 1%). After excluding these patients, the overall mean length of hospital stay was 8 days, both for patients with ADHF and CSHF. When stratified by sex, the length of stay remained consistent for ADHF and CSHF, both among women (mean stay = 8 days, for both HF types) and among men (mean stay = 9 days for both HF types). A total of 1253 deaths occurred within 28 days of hospitalization, and 4043 within 1 year. ADHF and CSHF had comparable 28-day mortality rates, both among women (9% vs. 8%; P =0.4) and men (10% vs. 6%; P = 0.1). The 1-year mortality rates were also similar for ADHF and CSHF, both for women (29% vs. 27%; P = 0.5) and men (32% vs. 27%; P = 0.2). In multivariable models adjusted for age, race, sex, year of admission, length of stay, and geographic region, ADHF relative to CSHF yielded a 28-day mortality odds ratio of 1.28 (95% CI: 0.84 – 1.94) and a 1-year hazard ratio of 1.11 (95% CI: 0.86 – 1.43).

Discussion

In this community-based surveillance of 13,706 weighted hospitalizations classified as ADHF or CSHF with preserved ejection fraction, we make the following observations: 1) Hospitalized patients with HFpEF have a high burden of comorbidities, irrespective of the cause for admission. 2) Women hospitalized with ADHF have a higher prevalence of cardiometabolic comorbidities, compared to women with CSHF. 3) Echocardiographic abnormalities were more often observed with ADHF than CSHF, for both sexes. 4) The 28 day and 1-year mortality rates are similar for patients with HFpEF hospitalized with ADHF and CSHF.

We observed a higher prevalence of renal insufficiency among women with ADHF as compared with CSHF. Renal disease is an established risk factor for adverse events in patients with HF 14 and is common in those admitted for ADHF 15. Successful decongestion of patients with HF may be complicated by concomitant CKD and diuretic resistance, increasing the likelihood of both worsening renal failure 16 and recurrent acute decompensation. Although renal disease may necessitate an increased diuretic dose in patients with ADHF, angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ARBs) are frequently underused in patients with HF and coexisting renal disease, due to risk of worsening glomerular filtration rate and hyperkalemia 17. However, the PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARBs Global Outcomes in HF with Preserved Ejection Fraction) trial recently demonstrated efficacy of sacubitril/valsartan in the reduction of recurrent rehospitalizations for patients with HFpEF 18, and a 50% lower hazard of worsening renal disease compared with valsartan alone 19.

We also observed a higher prevalence of DM in women with HFpEF hospitalized with ADHF compared with CSHF. Previous studies from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry 20 and EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan) study 21 reported a longer length of hospital stay and a higher rate for hospital readmission in patients with ADHF and coexisting DM. Uncertainty exists; however, in the effective management of DM in patients with ADHF. In addition to increased mortality associated with insulin use in patients with HF22, several oral antidiabetic drugs have been shown to have harmful cardiovascular effects 23,24. Based on the recent SOLOIST-WHF (Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) and SCORED (Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) trials, there is sufficient evidence to treat DM in patients with HFpEF by SGLT-2 inhibitors 25,26. However, future studies are required to explore the optimal therapeutic approaches for patients admitted with ADHF.

Although a higher burden of cardiometabolic comorbidities for patients with ADHF compared with CSHF was observed only in the female patients, echocardiographic abnormalities were more prevalent with ADHF than CSHF, irrespective of sex. We observed an increased prevalence of left ventricular hypertrophy, pulmonary hypertension and valvular defects such as mitral regurgitation and aortic regurgitation in patients with ADHF as compared to CSHF, which may be attributable to volume overload, age and cardiac remodeling27. On the other hand, chronic and valvular disease can be a primary driver of detrimental hemodynamic loading, HF exacerbation, and precipitation of ADHF hospitalization 28. In previous reports of patients with HFpEF who were hospitalized with ADHF, a higher prevalence of mitral regurgitation was noted in women compared to men 29. Women with advanced mitral valve disease often receive delayed referral for interventions, resulting in less favorable outcomes 30, possibly increasing the risk of worsening pulmonary congestion and onset of ADHF.

Somewhat surprisingly, the all-cause 28-day and 1-year mortality were comparable for ADHF and CSHF, suggesting that patients hospitalized with ADHF vs. those with CSHF who are hospitalized for other causes are at an equivalently high risk of death. Importantly, a high comorbidity burden was observed for both types of admissions. As indicated therapies expand for HFpEF, effective comorbidity management should be emphasized, both for patients with ADHF, and patients admitted for non-HF reasons, a high-risk group that is under-appreciated by clinical practice guidelines.11

Our study has certain limitations that merit discussion. Longitudinal outcomes other than vital status were not available, and we were unable to consider subsequent clinical events such as rehospitalizations. Patients with CSHF were identified from hospitalizations sampled by a discharge listing (in any position) indicative of HF, and may not be generalizable to all patients with CSHF who were hospitalized for non-HF causes. Our analysis was limited to available data abstracted from the medical record, with echocardiography data abstracted from qualitative and unstandardized reports. On the other hand, the community surveillance component of the ARIC study also has several important strengths. These include the large sample of patients with clinically adjudicated ADHF and CSHF, standardized medical record abstractions, and ascertainment of mortality outcomes from the National Death Index.

In conclusion, patients with HFpEF who are hospitalized with ADHF have a higher prevalence of echocardiographic abnormalities than those hospitalized with CSHF, and among women, a greater burden of cardiometabolic comorbidities. Future studies should focus on understanding the sex-specific pathophysiology of HFpEF, especially in women, which could help develop effective therapeutic approaches in this population.

Supplementary Material

1

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 numbers (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I).

Disclosures

Dr Fudim was supported by NHLBI K23HL151744 from the National Heart, Lung, and Blood Institute (NHLBI), the American Heart Association grant No 20IPA35310955, Mario Family Award, Duke Chair’s Award, Translating Duke Health Award, Bayer and BTG Specialty Pharmaceuticals. He receives consulting fees from AxonTherapies, CVRx, Daxor, Edwards LifeSciences, NXT Biomedical, Zoll, Viscardia. Dr. Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals and Relypsa, and participates on clinical endpoint committees for studies sponsored by Galmed, Novartis, and the NIH. Dr. Mentz receives research support and honoraria from Amgen, AstraZeneca, Bayer, Merck, Novartis, American Regent, Abbott, Medtronic, Boston Scientific, Vifor, Sanofi and BI.

Footnotes

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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