Research

JAMA Cardiology | Original Investigation

Characteristics and Outcomes of Adult Outpatients With

Heart Failure and Improved or Recovered Ejection Fraction
Andreas P. Kalogeropoulos, MD, MPH, PhD; Gregg C. Fonarow, MD; Vasiliki Georgiopoulou, MD, MPH, PhD;
Gregory Burkman, MD; Sarawut Siwamogsatham, MD; Akash Patel, MD; Song Li, MD;
Lampros Papadimitriou, MD, PhD; Javed Butler, MD, MPH, MBA

Editorial page 507

IMPORTANCE Heart failure (HF) guidelines recognize that a subset of patients with HF and Supplemental content at
preserved left ventricular ejection fraction (LVEF) previously had reduced LVEF but jamacardiology.com
experienced improvement or recovery in LVEF. However, data on these patients are limited.

OBJECTIVE To investigate the characteristics and outcomes of adult outpatients with HF and
improved or recovered ejection fraction (HFrecEF).

DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study (inception period, January 1,
2012, to April 30, 2012) with 3-year follow-up at cardiology clinics (including HF subspecialty)
in an academic institution. The dates of the analysis were May 21, 2015, to August 10, 2015.
Participants were all outpatients 18 years or older who received care for a verified diagnosis of
HF not attributed to specific cardiomyopathies or other special causes during the inception
period.

EXPOSURES Type of HF at baseline, classified as HF with reduced ejection fraction (HFrEF)

(defined as current LVEF 40%), HF with preserved ejection fraction (HFpEF) (defined as
current and all previous LVEF reports >40%), and HF with recovered ejection fraction
(HFrecEF) (defined as current LVEF >40% but any previously documented LVEF 40%).

MAIN OUTCOMES AND MEASURES Mortality, hospitalization rates, and composite end points.

RESULTS The study cohort comprised 2166 participants. Their median age was 65 years,
41.4% (896 of 2166) were female, 48.7% (1055 of 2166) were white and 45.2% (1368 of
2166) black, and 63.2% (1368 of 2166) had coronary artery disease. Preserved (>40%) LVEF
at inception was present in 816 of 2166 (37.7%) patients. Of these patients, 350 of 2166
(16.2%) had previously reduced (40%) LVEF and were classified as having HFrecEF,
whereas 466 of 2166 (21.5%) had no previous reduced LVEF and were classified as having
HFpEF. The remaining 1350 (62.3%) patients were classified as having HFrEF. After 3 years,
age and sexadjusted mortality was 16.3% in patients with HFrEF, 13.2% in patients with
HFpEF, and 4.8% in patients with HFrecEF (P < .001 vs HFrEF or HFpEF). Compared with
patients with HFpEF and patients with HFrEF, patients with HFrecEF had fewer all-cause
(adjusted rate ratio [RR] vs HFpEF, 0.71; 95% CI, 0.55-0.91; P = .007), cardiovascular (RR,
0.50; 95% CI, 0.35-0.71; P < .001), and HF-related (RR, 0.48; 95% CI, 0.30-0.76; P = .002)
hospitalizations and were less likely to experience composite end points commonly used in
clinical trials (death or cardiovascular hospitalization and death or HF hospitalization).

CONCLUSIONS AND RELEVANCE Outpatients with HFrecEF have a different clinical course than
patients with HFpEF and HFrEF, with lower mortality, less frequent hospitalizations, and
fewer composite end points. These patients may need to be investigated separately in
outcomes studies and clinical trials. Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Andreas P.
Kalogeropoulos, MD, MPH, PhD,
Division of Cardiology, Department of
Medicine, Emory University School of
Medicine, 1462 Clifton Rd NE,
JAMA Cardiol. 2016;1(5):510-518. doi:10.1001/jamacardio.2016.1325 Ste 535B, Atlanta, GA 30322
Published online July 6, 2016. (akaloge@emory.edu).

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 Heart Failure With Recovered vs Preserved Ejection Fraction
H
eart failure with preserved ejection fraction (HFpEF)
has been reported to account for almost half of all heart
failure (HF) cases.1-3 In most studies, the morbidity and
mortality of HFpEF were similar or comparable to those of HF
with reduced ejection fraction (HFrEF).1,2,4-7 Based on the epi-
demiological link of HFpEF to aging and age-related risk fac-
tors and comorbid conditions, the prevalence of HFpEF is pro-
jected to rise.1,7 There is also growing evidence that HFpEF is
a diverse entity encompassing a wide range of structural and
clinical phenotypes.8-10
It has been recently recognized that a subset of patients
with HFpEF previously had reduced left ventricular ejection
fraction (LVEF) but had improvement or recovery in LVEF
either by natural history or in response to therapy.11 Patients
with HF and recovered ejection fraction (HFrecEF) may be clini-
cally distinct from those with persistently preserved or re-
duced LVEF. However, there are few reports that describe the
characteristics and outcomes of patients with HFrecEF,12,13 with
these limited data suggesting that such patients may have im-
proved outcomes compared with patients with persistent
HFrEF or HFpEF,13 but further research is needed. Most im-
portant, data on hospitalizations have not been reported to
date.
To enhance our understanding regarding the characteris-
tics and outcomes of patients with HFrecEF, we reviewed the
medical records of approximately 2500 outpatients with HF
who received care in Emory Healthcare during a prespecified
window and collected 3-year follow-up data. Our primary hy-
pothesis was that patients having HFrecEF have lower mor-
tality compared with patients having HFpEF.
Methods
Study Population
We reviewed the medical records of 2507 adult (age 18 years)
outpatients who received care associated with International
Classification of Diseases, Ninth Revision, Clinical Modifica-
tion (ICD-9-CM) codes 402.X1, 404.X1, 404.X3, and 428.XX14
between January 1, 2012, and April 30, 2012, in Emory Health-
care by cardiologists. The inception time frame was selected
to allow for at least 3 years of follow-up. Medical records were
reviewed for symptoms, signs, and treatment of HF, as well as
the last reported LVEF, previous LVEF documentation, and spe-
cial causes of HF. The diagnosis of HF was verified in 2302 of
2507 patients (91.8%) based on physician documentation of
symptoms, signs, and guideline-based treatment for HF. We
excluded the following: (1) patients with specific cardiomy-
opathies (eg, hypertrophic, stress induced, infiltrative, restric-
tive, or chemotherapy induced), (2) patients with HF due to
adult congenital heart disease, (3) recipients of heart trans-
plant or mechanical circulatory support, (4) patients with pri-
mary right-sided disease (eg, right ventricular cardiomyo-
pathy or class I pulmonary arterial hypertension), and (5)
patients with primary valvular disease (eFigure in the Supple-
ment). We also excluded 7 patients who had no follow-up en-
counters and 7 patients who had no quantitative LVEF data.
Special causes of HF and all other exclusion criteria were ad-
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Original Investigation Research
Key Points
Question What are the outcomes of patients having heart failure
(HF) with recovered ejection fraction (ie, HF with initially reduced
ejection fraction that has partially or fully recovered over time)?
Findings In this cohort study of 2166 adult outpatients with HF,
16.2% of patients were seen with recovered ejection fraction.
After 3 years, these patients had significantly lower mortality
compared with patients having HF and permanently reduced or
preserved ejection fraction, as well as significantly fewer
hospitalizations.
Meaning Heart failure with recovered ejection fraction should be
treated as a distinct entity for clinical and research purposes.
judicated on the basis of individual review of medical rec-
ords. The ICD-9-CM codes were used for only cohort incep-
tion. Case verification for HF and all further classification were
done by individual medical record review. The final analysis
cohort consisted of 2166 patients. The Emory University In-
stitutional Review Board approved the study. Because this was
a retrospective study, no informed consent was required. The
institutional review board approved the use of data for the pur-
poses of this research.
Classification of HF Cases
We classified patients as having (1) HFrEF (defined as current
LVEF 40% regardless of previous LVEF assessments), (2)
HFpEF (defined as current and all previous LVEF reports
>40%), or (3) HFrecEF (defined as current LVEF >40% but any
previously documented LVEF 40%). Patients with current pre-
served LVEF (>40%) but no previous documentation of LVEF
were assigned to HFpEF. We opted for a cutoff of 40% or less
for HFrEF on the basis of the American guidelines suggesting
that this value is a reasonable definition of HFrEF.11 However,
recognizing that there is a subset of patients with borderline
LVEF, we classified cases using a greater than 50% cutoff in a
secondary analysis. For consistency, all LVEF assessments were
based on transthoracic echocardiography. When an LVEF range
was reported, the mean value was assigned for analysis pur-
poses (eg, for reported LVEF of 30%-35%, we assigned a value
of 32.5%).
Baseline Characteristics and Conditions
Baseline demographic, anthropometric, and vital signs data
were collected through the Emory Clinical Data Warehouse
from the index clinic visit record. Race was self-reported. For
laboratory values and medications, we extracted the last in-
formation available up to the index visit date. The presence
of baseline chronic conditions was adjudicated according to
the latest (2014) algorithm proposed by the Chronic Condi-
tions Data Warehouse,15 which is used to analyze Medicare
data.
Assessment and Classification of Outcomes
Outcomes data (death and hospitalizations) were collected
through the Emory Clinical Data Warehouse up to April 30,
2015, providing for a minimum of 3 years of follow-up for each
(Reprinted) JAMA Cardiology August 2016 Volume 1, Number 5 511
 Research Original Investigation
alive patient who continued to receive care in Emory Health-
care. For patients who were alive for the last encounter but did
not continue to receive care in the system throughout the study
period, the last encounter was considered the last date of fol-
low-up for analysis purposes.
We classified hospitalizations based on the primary ICD-
9-CM codes using the Clinical Classifications Software, 2015
version, as provided by the Healthcare Cost and Utilization Proj-
ect of the Agency for Healthcare Research and Quality.16 Hos-
pitalizations with primary ICD-9-CM diagnoses mapping to
Clinical Classifications Software category 7 (Diseases of the
circulatory system) were classified as cardiovascular. Hospi-
talizations with primary codes 402.X1, 404.X1, 404.X3, and
428.XX were classified as HF related.
End Points
We considered (1) time-to-event end points, including mor-
tality and composite end points (death or first hospitalization
for any cause, death or first hospitalization for cardiovascu-
lar causes, and death or first HF-related hospitalization), and
(2) hospitalization rates over the entire follow-up period (all-
cause, cardiovascular, and HF-related hospitalizations). We in-
cluded estimates of composite end points because these val-
ues are frequently used in clinical trials.
Statistical Analysis
Based on (1) an interim analysis for distribution of cases in
the first 400 eligible patients and (2) 1-year outcomes from
our cohort and previous mortality data,13 we calculated that
1900 eligible cases would provide 80% power to detect a
difference in mortality between the HFrecEF and HFpEF
groups at 2-sided = .05 (primary hypothesis), allowing for
5% early loss to follow-up. We opted to focus on these 2
groups because of similar LVEF at presentation and the
potential of contamination of HFpEF studies with HFre-
cEF cases, which may have a different prognosis. Therefore,
we opted to power the study for difference in mortality
between these 2 groups. Also, based on our preliminary
data, the mortality gradient was smaller between HFpEF
and HFrecEF (vs HFrEF and HFrecEF). Therefore, we pow-
ered the study to detect the smaller mortality gradient reli-
ably. Because data review was done in calendar month
increments, the final sample size exceeded the required
sample size. To compare characteristics between groups, we
used the Kruskal-Wallis test for continuous variables and
the Fisher 2 test for categorical variables. We used Cox pro-
portional hazards models for mortality and composite time-
to-event end points. Because we detected nonproportional
mortality between HF groups, we estimated hazard ratios
(HRs) separately for year 1 and years 2 to 3 based on an
analysis with flexible parametric models showing that a
knot at approximately 1 year best represented the time-
dependent component. There was no indication of nonpro-
portionality for other time-to-event end points. We used
negative binomial regression to estimate rate ratios of hos-
pitalizations between HF groups. The rationale for these
models for hospitalization rates has been described
previously. 17 We considered the following covariates in
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Heart Failure With Recovered vs Preserved Ejection Fraction
adjusted models based on associations with the exposure of
interest (HF group), associations with outcomes, clinical
interpretation, and previous work: age, sex, race (white,
black, and other), body mass index, coronary artery disease,
comorbid conditions (diabetes, depression, chronic lung
disease, chronic kidney disease, and atrial fibrillation),
blood pressure, renal function, hemoglobin level, serum
sodium and potassium levels, and therapy with -blockers,
angiotensin-converting enzyme inhibitors or angiotensin
receptor blockers, and loop diuretics. To evaluate for non-
linear effects of covariates, we used restricted cubic splines.
We performed 2 sensitivity analyses. First, we repeated
analyses using a greater than 50% cutoff for preserved
LVEF. Second, because outcomes in patients with HFrecEF
may reflect lead-time bias (ie, patients with HFrecEF had
survived long enough for LVEF to recover), 18 we left-
truncated follow-up at 1 year and repeated time-to-event
analyses. Finally, we investigated for interactions of sex and
race with HF groups for outcomes. We used a statistical
software program (Stata, version 14.0; StataCorp LP) for
analyses.
Results
Study Population and HF Classification
Among the 2166 eligible patients with HF, 816 (37.7%) were seen
with preserved LVEF (>40%) at the index visit. Of 816 pa-
tients, 350 (42.9%) were classified as having HFrecEF (16.2%;
95% CI, 14.6%-17.8% of the cohort), and 466 (57.1%) were clas-
sified as having HFpEF (21.5%; 95% CI, 19.8%-23.3% of the co-
hort). The remaining 1350 patients were classified as having
HFrEF (62.3%; 95% CI, 60.2%-64.4% of the cohort). The me-
dian time from the last reported LVEF was 182 days (25th to
75th percentile, 13-483 days) and did not differ between HF
groups (P = .14 for difference). The median LVEFs were 55%
(25th to 75th percentile, 50%-60%) among patients with
HFpEF, 50% (25th to 75th percentile, 45%-55%) among pa-
tients with HFrecEF (P < .001 vs HFpEF), and 25% (25th to 75th
percentile, 18%-33%) among patients with HFrEF. The me-
dian reduced LVEF among patients with HFrecEF before re-
covery was 25% (25th to 75th percentile, 18%-33%), and the
improvement in LVEF was observed over a median of 976 days
(25th to 75th percentile, 377-1797 days). Sixty-eight of 466
(14.6%) HFpEF cases with current preserved LVEF but no pre-
vious documentation of LVEF were categorized as HFpEF.
The baseline characteristics of patients are listed in Table 1.
Patients with HFrecEF were (1) younger, with male predomi-
nance compared with patients with HFpEF and with demo-
graphics closer to patients with HFrEF; (2) less likely to have
coronary artery disease, diabetes, and kidney disease and had
lower systolic blood pressure compared with patients with
HFpEF; (3) more likely to be receiving an angiotensin-
converting enzyme inhibitor or angiotensin receptor blocker
regimen and less likely to be taking loop diuretics, aspirin, or
digoxin compared with the other 2 groups; and (4) less likely
to be recipients of implantable cardioverter-defibrillator or car-
diac resynchronization therapy.
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 Heart Failure With Recovered vs Preserved Ejection Fraction Original Investigation Research

Table 1. Baseline Patient Characteristics

Overall HFrEF HFpEF HFrecEF
Variable (N = 2166) (n = 1350) (n = 466) (n = 350) P Value
Age, median (IQR), y 65 (54-75) 63 (51-72) 72 (62-82) 65 (55-74) <.001
Male sex, No. (%) 1270 (58.6) 887 (65.7) 201 (43.1) 182 (52.0) <.001
Race, No. (%)
White 1055 (48.7) 632 (46.8) 235 (50.4) 188 (53.7)
Black 979 (45.2) 619 (45.9) 208 (44.6) 152 (43.4) .006
Other 132 (6.1) 99 (7.3) 23 (4.9) 10 (2.9)
Body mass index, median (IQR)a 29 (25-35) 28 (25-34) 31 (26-38) 30 (25-34) <.001
Blood pressure, median (IQR), mm Hg
Systolic 124 (108-140) 119 (102-136) 135 (121-153) 129 (116-141) <.001
Diastolic 71 (63-80) 71 (63-79) 71 (62-80) 72 (64-80) .36
Current or former smoker, No. (%) 773 (35.7) 520 (38.5) 131 (28.1) 122 (34.9) <.001
History, No. (%)
Coronary artery disease 1368 (63.2) 883 (65.4) 290 (62.2) 195 (55.7) .004
Diabetes 716 (33.1) 414 (30.7) 196 (42.1) 106 (30.3) <.001
Hypertension 1556 (71.8) 902 (66.8) 400 (85.8) 254 (72.6) <.001
Cerebrovascular disease 167 (7.7) 104 (7.7) 39 (8.4) 24 (6.9) .74
Hyperlipidemia 1105 (51.0) 674 (49.9) 263 (56.4) 168 (48.0) .03
Atrial fibrillation 730 (33.7) 435 (32.2) 180 (38.6) 115 (32.9) .04
Chronic kidney disease 885 (40.9) 574 (42.5) 191 (41.0) 120 (34.3) .02
Chronic lung disease 352 (16.3) 208 (15.4) 99 (21.2) 45 (12.9) .003
Anemia 752 (34.7) 437 (32.4) 202 (43.3) 113 (32.3) <.001
Depression 348 (16.1) 200 (14.8) 98 (21.0) 50 (14.3) .005
Dementia 98 (4.3) 56 (4.2) 24 (5.2) 14 (4.0) .61
Laboratory values, median (IQR)
Hematocrit, % 37 (33-41) 38 (34-41) 36 (32-39) 37 (33-40) <.001
Hemoglobin level, g/dL 12 (11-14) 13 (11-14) 12 (11-13) 12 (11-14) <.001
White blood cell count, /L 6700 6700 6800 6700
.39
(5400-8400) (5300-8400) (5400-8700) (5400-8200)
Platelet count, /L 197 000 194 000 198 000 204 000
<.001
(158 000-242 000) (155 000-237 000) (163 000-245 000) (169 000-258 000)
Blood urea nitrogen level, mg/dL 20 (15-28) 20 (15-28) 21 (15-31) 17 (13-25) <.001
Creatinine level, mg/dL 1.2 (0.9-1.5) 1.2 (1.0-1.5) 1.2 (0.9-1.5) 1.1 (0.9-1.4) .001
Glucose level, mg/dL 104 (93-125) 104 (93-122) 107 (92-136) 103 (93-125) .13
Sodium level, mEq/L 138 (136-140) 138 (136-140) 139 (137-140) 139 (137-140) <.001
Potassium level, mEq/L 4.1 (3.9-4.5) 4.1 (3.9-4.5) 4.1 (3.8-4.5) 4.2 (3.9-4.5) .56
Therapy, No. (%)
Angiotensin-converting enzyme inhibitors 1584 (73.1) 1002 (74.2) 305 (65.5) 277 (79.1)
<.001
or angiotensin receptor blockers
-Blockers 1859 (85.8) 1180 (87.4) 369 (79.1) 310 (88.7) <.001
Loop diuretics 1545 (71.3) 973 (72.1) 357 (76.6) 215 (61.3) <.001
Thiazide diuretics 285 (13.2) 131 (9.7) 100 (21.4) 54 (15.4) <.001
Digoxin 293 (13.4) 212 (15.7) 41 (8.7) 40 (11.3) <.001
Nitrates 506 (23.3) 339 (25.1) 97 (20.9) 70 (20.1) .06
Hydralazine 516 (23.8) 348 (25.8) 89 (19.2) 79 (22.7) .02
Warfarin 643 (29.6) 435 (32.2) 118 (25.4) 90 (25.6) .005
Statins 1129 (52.1) 709 (52.5) 253 (54.3) 167 (47.7) .16
Aspirin 713 (32.9) 478 (35.4) 146 (31.4) 89 (25.3) .001
Implantable cardioverter-defibrillator 393 (18.1) 319 (23.6) 17 (3.6) 57 (16.3) <.001
Pacemaker 177 (8.2) 85 (6.3) 58 (12.4) 34 (9.7) <.001
Cardiac resynchronization therapy with 334 (15.4) 273 (20.2) 19 (4.1) 42 (12.0)
<.001
defibrillator capability
Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrecEF, proportion of 1.0, multiply by 0.01; hemoglobin level to grams per liter, multiply
heart failure with recovered ejection fraction; HFrEF, heart failure with reduced by 10.0; platelet count to 109/L, multiply by 1.0; potassium level to millimoles
ejection fraction; IQR, interquartile range. per liter, multiply by 1.0; sodium level to millimoles per liter, multiply by 1.0; and
SI conversion factors: To convert blood urea nitrogen level to millimoles per white blood cell count to 109/L, multiply by 0.001.
a
liter, multiply by 0.357; creatinine level to micromoles per liter, multiply by 88.4; Calculated as weight in kilograms divided by height in meters squared.
glucose level to millimoles per liter, multiply by 0.0555; hematocrit to

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 Research Original Investigation Heart Failure With Recovered vs Preserved Ejection Fraction

Figure. Kaplan-Meier Curves, Adjusted for Age and Sex, Across the 3 Heart Failure Groups

A Death B Death or all-cause hospitalization

20 60 58.8%
HFrEF
HFpEF 16.3%
50

Cumulative Event Rate, %

52.7%
Cumulative Mortality, %

15 HFrecEF
40
41.4%
13.2%
10 30

20
5
4.8% 10

0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Time, mo Time, mo
No. at risk No. at risk
HFpEF 466 444 412 385 349 310 243 HFpEF 466 360 293 247 212 176 122
HFrEf 1350 1224 1140 1057 962 869 678 HFrEf 1350 966 780 671 570 478 339
HFrecEF 350 331 312 298 289 277 211 HFrecEF 350 292 251 225 202 186 135

C Death or cardiovascular hospitalization D Death or heart failure hospitalization

60 60

Cumulative Event Rate, %

50 48.0% 50
Cumulative Event Rate, %

40.1%
40 40

37.2% 30 28.9%
30

20 20
17.4% 11.8%
10 10

0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Time, mo Time, mo
No. at risk No. at risk
HFpEF 466 405 349 312 275 230 170 HFpEF 466 423 368 337 298 256 193
HFrEf 1350 1038 893 793 685 590 429 HFrEf 1350 1086 962 867 764 670 493
HFrecEF 350 317 289 271 258 244 185 HFrecEF 350 326 303 288 276 262 197

The stratified log-rank 22 was 15.0 (P < .001) for difference in mortality between HFrecEF, heart failure with recovered ejection fraction; and HFrEF, heart failure
groups. HFpEF indicates heart failure with preserved ejection fraction; with reduced ejection fraction.

Table 2. Heart Failure Category and Mortality Risk

Hazard Ratio (95% CI)

Age and Sex Adjusted Fully Adjusteda
Variable Year 1 P Value Years 2-3 P Value Year 1 P Value Years 2-3 P Value
HFrEF 1 [Reference] NA 1 [Reference] NA 1 [Reference] NA 1 [Reference] NA
HFpEF 0.76 (0.47-1.22) .25 0.94 (0.66-1.33) .71 0.86 (0.52-1.42) .56 1.04 (0.72-1.52) .83
HFrecEF 0.71 (0.40-1.26) .24 0.27 (0.14-0.52) <.001 0.91 (0.50-1.64) .75 0.35 (0.18-0.70) .003
Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrecEF, disease, chronic kidney disease, and atrial fibrillation), blood pressure, renal
heart failure with recovered ejection fraction; HFrEF, heart failure with reduced function, hemoglobin level, serum sodium and potassium levels, and therapy
ejection fraction; NA, not applicable. with -blockers, angiotensin-converting enzyme inhibitors or angiotensin
a
Adjusted for age, sex, race, body mass index, presence of coronary artery receptor blockers, and loop diuretics.
disease and relevant comorbid conditions (diabetes, depression, chronic lung

Mortality
The median follow-up was 3.0 years (25th to 75th percentile,
1.9-3.2 years), with a total of 5367 patient-years. Death oc-
curred in 13.3% (288 of 2166) of the cohort. Age and sex
adjusted mortality at 1, 2, and 3 years was 5.0%, 9.4%, and
14.0%, respectively. Age and sexadjusted 3-year mortality was
4.8% in patients with HFrecEF vs 13.2% in patients with HFpEF
(log-rank 21 = 5.7, P = .02) and 16.3% in patients with HFrEF
(log-rank 21 = 13.3, P < .001) (Figure, A). Age and sex
adjusted mortality did not differ significantly between the
HFrEF and HFpEF groups.
Mortality in patients with HFrecEF decelerated after ap-
proximately 1 year. Table 2 lists HRs separately for year 1 and
years 2 to 3, with patients with HFrEF as the reference. Dur-
ing year 1, mortality was not different between the 3 groups,
but patients with HFrecEF had lower mortality in years 2 to 3

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 Heart Failure With Recovered vs Preserved Ejection Fraction Original Investigation Research

Table 3. Heart Failure Category and Risk for Death or Hospitalization

Abbreviations: HFpEF, heart failure
Hazard Ratio (95% CI)
with preserved ejection fraction;
Variable Age and Sex Adjusted P Value Fully Adjusteda P Value HFrecEF, heart failure with recovered
Death or all-cause hospitalization ejection fraction; HFrEF, heart failure
with reduced ejection fraction;
HFrEF 1 [Reference] NA 1 [Reference] NA
NA, not applicable.
HFpEF 0.89 (0.77-1.04) .14 0.80 (0.67-0.94) .007 a
Adjusted for age, sex, race, body
HFrecEF 0.63 (0.52-0.75) <.001 0.72 (0.59-0.88) .001 mass index, presence of coronary
Death or cardiovascular hospitalization artery disease and relevant
comorbid conditions (diabetes,
HFrEF 1 [Reference] NA 1 [Reference] NA
depression, chronic lung disease,
HFpEF 0.74 (0.62-0.88) .001 0.70 (0.57-0.85) <.001 chronic kidney disease, and atrial
HFrecEF 0.34 (0.26-0.44) <.001 0.40 (0.31-0.53) <.001 fibrillation), blood pressure, renal
function, hemoglobin level, serum
Death or heart failure hospitalization
sodium and potassium levels, and
HFrEF 1 [Reference] NA 1 [Reference] NA therapy with -blockers,
HFpEF 0.72 (0.59-0.88) .001 0.73 (0.59-0.90) .004 angiotensin-converting enzyme
inhibitors or angiotensin receptor
HFrecEF 0.29 (0.21-0.39) <.001 0.38 (0.28-0.52) <.001
blockers, and loop diuretics.

Table 4. Hospitalization Rates Across Heart Failure Groups

Abbreviations: HFpEF, heart failure
Rate Ratio (95% CI)
Rate (95% CI) with preserved ejection fraction;
Variable per 100 Patient-years Age and Sex Adjusted P Value Fully Adjusteda P Value HFrecEF, heart failure with recovered
All-cause hospitalization ejection fraction; HFrEF, heart failure
with reduced ejection fraction;
HFrEF 84.9 (76.1-93.9) 1 [Reference] NA 1 [Reference] NA
NA, not applicable.
HFpEF 67.7 (57.8-77.6) 0.82 (0.67-1.01) .07 0.88 (0.72-1.07) .20 a
Adjusted for age, sex, race, body
HFrecEF 39.5 (30.0-49.0) 0.47 (0.38-0.59) <.001 0.62 (0.50-0.77) <.001 mass index, presence of coronary
Cardiovascular hospitalization artery disease and relevant
comorbid conditions (diabetes,
HFrEF 49.8 (43.9-55.7) 1 [Reference] NA 1 [Reference] NA
depression, chronic lung disease,
HFpEF 27.9 (22.9-32.9) 0.59 (0.45-0.76) <.001 0.68 (0.53-0.88) .003 chronic kidney disease, and atrial
HFrecEF 11.4 (7.5-15.3) 0.22 (0.16-0.30) <.001 0.34 (0.25-0.46) <.001 fibrillation), blood pressure, renal
function, hemoglobin level, serum
Heart failure hospitalization
sodium and potassium levels, and
HFrEF 39.6 (34.0-45.1) 1 [Reference] NA 1 [Reference] NA therapy with -blockers,
HFpEF 17.1 (13.2-21.0) 0.45 (0.33-0.62) <.001 0.54 (0.39-0.74) <.001 angiotensin-converting enzyme
inhibitors or angiotensin receptor
HFrecEF 6.1 (2.9-9.3) 0.14 (0.10-0.21) <.001 0.26 (0.17-0.38) <.001
blockers, and loop diuretics.

compared with patients with HFrEF or HFpEF. This finding per-
sisted in fully adjusted models. The mean HR for mortality over
the 3-year period in the HFrecEF group was 0.56 (95% CI, 0.34-
0.92; P = .02) vs HFpEF and 0.55 (95% CI, 0.35-0.87; P = .01)
vs HFrEF in adjusted models. Mortality did not differ in pa-
tients with HFpEF vs HFrEF (HR, 0.98; 95% CI, 0.71-1.35;
P = .90) in adjusted models. There were no significant inter-
actions of HF group with sex or race for mortality.
Composite End Points
At 3 years, 55.2%, 41.1%, and 33.6% of patients met the com-
posite end points of death or all-cause hospitalization, death
or cardiovascular hospitalization, and death or HF hospital-
ization, respectively. Patients with HFrecEF were less likely to
meet a composite end point compared with patients with either
HFrEF or HFpEF, and patients with HFpEF were less likely to
meet a composite end point compared with patients with
HFrEF (Figure, B-D). These differences persisted in fully ad-
justed models (Table 3). We list 1-year, 2-year, and 3-year es-
timates for these end points in eTable 1 in the Supplement.
Patients having HFrecEF were less likely to experience
death or hospitalization compared with patients having HFpEF
(HR, 0.70; 95% CI, 0.57-0.87; P = .001), but this difference was
not significant in fully adjusted models (HR, 0.91; 95% CI, 0.72-
1.13; P = .38). However, death or cardiovascular hospitaliza-
tion (HR, 0.58; 95% CI, 0.43-0.78; P < .001) and death or HF
hospitalization (HR, 0.52; 95% CI, 0.37-0.74; P < .001) were less
likely in patients with HFrecEF vs HFpEF in adjusted models.
There were no significant interactions of HF group with sex
or race for these end points.
Hospitalization Rates
There were a total of 3813 hospitalizations (73.2 per 100 patient-
years). Of this total, 1996 (52.3%) were for cardiovascular causes
inclusive of HF (38.3 per 100 patient-years), and 1501 (39.4%)
had specifically HF as the primary diagnosis (28.8 per 100 pa-
tient-years). Compared with patients with HFrEF, hospitaliza-
tions for cardiovascular causes and HF were less frequent in
patients with either HFrecEF or HFpEF, and this difference per-
sisted in adjusted models (Table 4). However, all-cause hos-
pitalization rates did not differ significantly between pa-
tients with HFpEF and patients with HFrEF.
Patients having HFrecEF had less frequent hospitaliza-
tions compared with patients having HFpEF. In fully ad-
justed models, the rate ratios for hospitalization of patients with
HFrecEF vs HFpEF were 0.71 (95% CI, 0.55-0.91; P = .007) for

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 Research Original Investigation
all-cause hospitalizations, 0.50 (95% CI, 0.35-0.71; P < .001)
for cardiovascular hospitalizations, and 0.48 (95% CI, 0.30-
0.76; P = .002) for HF-related hospitalizations. There were no
significant interactions of HF group with sex or race for hos-
pitalization rates.
Alternative Definition of Preserved LVEF
When LVEF exceeding 50% was used to define preserved LVEF,
486 of 2166 patients (22.4%) had preserved LVEF at the index
visit. Of 486 patients, 153 (31.5%) were classified as having
HFrecEF (7.1%; 95% CI, 6.0%-8.2% of the cohort) and 333
(68.5%) as having HFpEF (15.4%; 95% CI, 13.9%-17.0% of the
cohort). The remaining 1680 patients (77.6%; 95% CI, 75.7%-
79.3% of the cohort) were classified as having HFrEF.
The mortality pattern across groups was similar to that ob-
served with the original definition (eTable 2 in the Supple-
ment). Patients with HFrecEF demonstrated lower rates of com-
posite end points and hospitalizations compared with the other
2 groups (eTable 3 and eTable 4 in the Supplement). The rela-
tive risk between patients with HFrEF and patients with HFpEF
for composite end points was not significant in adjusted mod-
els. Hospitalization rates for HF remained significantly lower
in patients with HFpEF vs HFrEF.
Analysis Excluding Year 1 Events
The HFrecEF outcomes may be differentially affected by
lead-time bias (ie, these patients survive long enough for
LVEF to recover before entering the study). Therefore, we
left-truncated follow-up at 1 year and repeated time-to-event
analyses.
The cohort now consisted of 1864 patients after exclud-
ing those who died in year 1 (n = 109) or had no follow-up af-
ter year 1 (n = 193). Excluded patients (n = 302) were older and
more likely to be white and smokers, had lower blood pres-
sure and body mass index, and were more likely to have coro-
nary artery disease and a worse comorbidity profile com-
pared with those with more than 1 year of follow-up (eTable 5
in the Supplement). Patients with HFrecEF still demon-
strated lower mortality compared with patients with HFpEF
or HFrEF, lower rates of death or hospitalization (all-cause, car-
diovascular, and HF-related hospitalizations) compared with
patients with HFrEF, and lower rates of death or hospitaliza-
tion (cardiovascular and HF-related hospitalizations) com-
pared with patients with HFpEF in adjusted models (eTable 6
in the Supplement).
Discussion
In this retrospective, single-center cohort study from an aca-
demic medical center, 42.9% (350 of 816) of outpatients with
HF who received cardiology care and had preserved LVEF
(>40%) at presentation were actually cases with recovered ejec-
tion fraction (HFrecEF). Patients with HFrecEF were younger,
predominantly male, and had lower prevalences of coronary
artery disease, hypertension, diabetes, chronic lung disease,
and atrial fibrillation compared with patients with HFpEF.
These patients with HFrecEF had distinctly better 3-year out-
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Heart Failure With Recovered vs Preserved Ejection Fraction
comes compared with patients with HFpEF or HFrEF, includ-
ing lower mortality and fewer all-cause, cardiovascular, and
HF-related hospitalizations.
Use of -blockers, medications targeting the renin-
angiotensin-aldosterone axis, and cardiac resynchronization
therapy led to improvement in LVEF in a substantial propor-
tion of patients with HFrEF.19-22 In the Improve the Use of Evi-
dence-Based Heart Failure Therapies in the Outpatient Setting22
registry, a performance improvement program aiming to in-
crease use of guideline-directed medical therapy among HF
outpatients, the mean LVEF among approximately 4000 pa-
tients increased from 25.8% at baseline to 32.3% at 24 months,
and 28.6% of patients had a greater than 10% improvement in
ejection fraction. These data indicate that LVEF recovery is pos-
sible with guideline-directed treatment in a substantial pro-
portion of patients with HFrEF. A previous study12 reported
that two-thirds of referral patients seen with preserved LVEF
were actually HFrecEF cases, associated with a more benign
clinical profile. In another referral cohort, 3 out of 5 patients
seen with LVEF of at least 50% were actually HFrecEF cases.13
Because of its referral nature, that cohort was heavily skewed
toward HFrEF (84% of patients). However, despite concerns
for survival bias in referral cohorts,18 the pattern of event rates
between HF groups reported in that study is similar to ours.13
Despite a more inclusive approach in our study (all cardiol-
ogy clinics vs HF specialist referrals),13 the academic medical
center setting still introduces bias toward younger patients with
more severe HF. However, in both studies, the mortality re-
ported for HFrecEF is comparable to that of patients without
HF or LVEF impairment.23 We extend those observations by
providing relative risk estimates for mortality, hospitaliza-
tions, and composite end points commonly used in clinical
trials in the largest cohort of patients with HFrecEF reported
to date. Notwithstanding the differences between these
cohorts, taken together these data indicate that patients with
HFrecEF should be distinguished from those with HFpEF.
There are several hypotheses regarding the more benign
course of HFrecEF, despite the ongoing presence of symp-
toms and signs of HF. One potential explanation is partial re-
verse remodeling with a more favorable neurohormonal
profile.13 In fact, some patients without scar may have achieved
near-normal left ventricular systolic function. In this aspect,
it is notable that our patients with HFrecEF had lower preva-
lence of coronary artery disease, consistent with previous
work.13,22 For example, the absence of prior myocardial in-
farction and nonischemic HF etiology were both associated
with a greater than 10% improvement in LVEF in the large
Improve Heart Failure Therapies in the Outpatient Setting
(IMPROVE HF) registry.22 Other comorbid conditions are also
less frequent in HFrecEF compared with HFrEF. In turn, bet-
ter response to guideline-based treatment might be the result
of a more favorable structural profile early in the disease
process or genetic variability. Both have been shown to be
the case in recipients of -blockers,24,25 renin-angiotensin-
aldosterone axis inhibitors,26,27 and cardiac resynchroniza-
tion therapy.28,29 Lead-time bias might partially explain the
more favorable outcomes in HFrecEF because these patients
may have survived long enough for LVEF to recover before
jamacardiology.com
 Heart Failure With Recovered vs Preserved Ejection Fraction Original Investigation Research

entering the study. In our study, the difference in outcomes
was still evident after excluding patients who died in year 1 or
had no follow-up after year 1.
However, the retrospective design of our study did not al-
low us to provide insights into potential predictors of LVEF re-
covery, including clinical and genetic characteristics. That
would require a different, longitudinal study design because
our present cross-sectional approach of HF group assign-
ment does not allow us to causally link characteristics to LVEF
recovery. In addition, lead-time, referral, and ascertainment
bias may have exaggerated the favorable outcomes among pa-
tients with HFrecEF. An ideal study on the topic would pro-
spectively enroll patients with newly diagnosed HFrEF within
a prespecified window of onset and regularly follow up these
patients with echocardiography for recovery after guideline-
directed medical and device therapy. A long-term extension
of that study for outcomes among groups defined, for ex-
ample, by LVEF recovery after 6 or 12 months would inform
us more definitively on the natural history and outcomes of
LVEF response groups.
Our study has several limitations. Classification of HF cases
was based on clinically available echocardiographic data; there-
fore, misclassification may have occurred. A number of HFpEF
cases did not have previous LVEF assessment. We opted to in-
clude these patients and classify them as HFpEF in the belief
that a patient is unlikely to have previous stage C HFrEF but
no documentation of LVEF. Although such latent HFrecEF
cases are theoretically possible, they should be uncommon in
practice. Similarly, not all patients with reduced LVEF had re-
peat LVEF assessments in prespecified time points. However,
the median time from the last LVEF assessment to cohort in-
ception was similar between the groups, indicating that more
recent echocardiographic assessments are a less likely expla-
nation for ascertainment bias toward HFrecEF. Referral bias to-
ward more advanced HF (and therefore HFrEF) is likely be-
cause of the tertiary nature of the institution. Considering also
the single-center nature of our study, the findings may not be
generalizable to other settings. Hospitalizations were ascer-
tained from the Emory Clinical Data Warehouse. Therefore,
hospitalization rates may have been underestimated because
outside hospitalizations may have occurred. However, we did
not observe any differential changes in hospitalization rates
across groups over time (eg, fewer hospitalizations in pa-
tients with HFrecEF because patients improve), implying that
the relative risk for hospitalization should be valid. We were
not able to comprehensively adjudicate causes of death; there-
fore, we could not provide cause-specific data for mortality.
The Emory Clinical Data Warehouse incorporates data on vi-
tal status from various sources (in-hospital death records, pa-
tient communication, financial services, etc). Considering that
we did not have institutional review board approval to con-
tact patients and families and obtain death certificates and
other information on mode of death, adjudication of cause of
death would be possible for only the fraction of deaths that oc-
curred in the hospital. Also, we did not measure neurohor-
monal markers; therefore, we could not provide these patho-
physiological insights. Residual measured and unmeasured
confounding may account for some of the findings. We did not
study patients with previous transition from preserved to re-
duced LVEF status as a separate entity.30 All patients who had
reduced LVEF at the time of inception were classified as hav-
ing HFrEF regardless of previous (reduced or preserved) LVEF.
We opted for this simple classification because pathophysiol-
ogy of HF converges once LVEF is reduced regardless of pre-
vious LVEF status. Also, there is no current evidence that these
patients should be treated differently depending on LVEF tra-
jectory. Finally, to facilitate communication, we opted not to
create a borderline LVEF category. Instead, we provide a sec-
ondary analysis using LVEF greater than 50% as the cutoff for
HFpEF. Moreover, we recognize that small improvements in
LVEF that still qualify as HFrecEF (eg, a change in LVEF from
35% to 45%) have probably different prognostic implications
than larger improvements.30 However, to quantify this ef-
fect, a prospective, serial echocardiographic study to ensure
consistent timing of LVEF measurements (because rate of im-
provement could be an important factor) would be needed.
Conclusions
In an outpatient HF cohort receiving cardiology care in an aca-
demic medical center, 42.9% (350 of 816) of patients seen with
LVEF exceeding 40% were patients with recovered rather than
persistently preserved LVEF. These patients had more favor-
able 3-year outcomes, including all-cause mortality, com-
pared with patients with persistent HFpEF or HFrEF, imply-
ing that patients with HFrecEF should be investigated
separately in future outcomes studies and clinical trials.

ARTICLE INFORMATION
Accepted for Publication: April 11, 2016.
Published Online: July 6, 2016.
doi:10.1001/jamacardio.2016.1325.
Author Affiliations: Division of Cardiology,
Department of Medicine, Emory University School
of Medicine, Atlanta, Georgia (Kalogeropoulos,
Georgiopoulou, Siwamogsatham, Papadimitriou,
Butler); AhmansonUCLA Cardiomyopathy Center,
Ronald ReaganUCLA Medical Center, University of
California, Los Angeles (Fonarow); Associate Editor
for Health Care Quality and Guidelines, JAMA
Cardiology (Fonarow, Patel, Li); Department of
Medicine, Emory University School of Medicine,
Atlanta, Georgia (Burkman); currently with
Department of Medicine, Faculty of Medicine,
Chulalongkorn University, Bangkok, Thailand
(Siwamogsatham); currently with Division of
Cardiology, Department of Medicine, Stony Brook
School of Medicine, Stony Brook, New York
(Papadimitriou, Butler).
Author Contributions: Dr Kalogeropoulos had full
access to all the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Kalogeropoulos,
Fonarow, Georgiopoulou, Siwamogsatham,
Papadimitriou, Butler.
Acquisition, analysis, or interpretation of data:
Kalogeropoulos, Burkman, Patel, Li, Papadimitriou,
Butler.
Drafting of the manuscript: Kalogeropoulos,
Georgiopoulou, Burkman, Papadimitriou, Butler.
Critical revision of the manuscript for important
intellectual content: Kalogeropoulos, Fonarow,
Georgiopoulou, Burkman, Siwamogsatham, Patel,
Li, Butler.
Statistical analysis: Kalogeropoulos.
Administrative, technical, or material support:
Butler.
Study supervision: Kalogeropoulos, Butler.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for

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 Research Original Investigation
Disclosure of Potential Conflicts of Interest, and
none were reported.
Disclaimer: Dr Fonarow is the Associate Editor for
Health Care Quality and Guidelines, JAMA
Cardiology, but was not involved in the editorial
review or decision to accept the manuscript for
publications.
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