Atrial Fibrillation in Heart Failure∗

Atrial Fibrillation in Heart Failure∗


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Atrial Fibrillation in Heart Failure* A Common and Deadly Combination Carolyn S.P. Lam, MBBS, PHD,a,b Bernadet T. Santema, MD,b Adriaan A. Voors MD, PHDb


trial fibrillation (AF) and heart failure (HF)

This analysis was accomplished using the nationwide

are global cardiovascular epidemics that are

Swedish HF Registry of 41,446 patients with clinician-

inextricably linked to each other and to pop-

judged HF, linked to the National Patient Registry for

ulation aging. Prior studies have established that AF

additional data on comorbidities, HF hospitalization,

is both a risk marker and risk factor in HF, resulting

and stroke or transient ischemic attack, as well as the

from, causing, and/or adversely impacting outcomes

National Population Registry for date of death and

in HF. Most prior studies focused on HF with reduced

Statistics Sweden for socioeconomic data. The most

ejection fraction (HFrEF), where the emphasis was on

striking finding was the very high prevalence of AF:

neurohormonal activation and hemodynamic mecha-

53% in HFrEF, 60% in HFmrEF, and 65% in HFpEF

nisms perpetuating the HFrEF–AF vicious cycle. In

(Table 1). The broad inclusion of AF, defined as having

contrast, in HF with preserved EF (HFpEF), at present

a history of AF (in either the Swedish HF or National

the dominant form of HF in the United States, the

Patient Registry) or AF on electrocardiography, may

focus is on systemic inflammation and shared risk

partially explain the high prevalence. Indeed, prior

factors for both AF and HFpEF (such as aging, hyper-

studies that similarly used International Classifica-

tension, and obesity) (1). Thus, given potential differ-

tion of Diseases-Ninth Revision-Clinical Modification

ences in pathogenesis, AF may relate differently to

codes to define their AF population reported higher

HFrEF versus HFpEF; however, few studies made

prevalence of AF compared with those that used the

this comparison within the same cohort (Table 1).

electrocardiographic diagnosis (Table 1). Another

Furthermore, no prior study has examined AF in HF

explanation may be the unselected population-wide

with midrange EF (HFmrEF).

approach used in the Swedish HF cohort, which

The paper by Sartipy et al. (2) in this issue of JACC:

included patients at an advanced age. In fact, age

Heart Failure is noteworthy for being one of the

above the median of 76 years old was the strongest

largest single population-based cohorts to systemat-

risk factor for AF, more than doubling the odds of AF

ically compare AF versus sinus rhythm across the

in HF regardless of EF.

entire EF spectrum of HF, including, for the first time,

The increasing prevalence of AF with increasing

patients with HFmrEF as a distinct category (Table 1).

EF deserves further consideration. Age may be the simplest explanation for the differences between EF groups, because HFpEF patients were oldest, HFrEF

*Editorials published in JACC: Heart Failure reflect the views of the au-


thors and do not necessarily represent the views of JACC: Heart Failure or

Figure 1 in Sartipy et al. (2) showed that at any

the American College of Cardiology.

given age the prevalence of AF was still higher in

From the aNational Heart Center Singapore, Singapore and Duke-National

HFpEF and, if anything, the difference in AF prev-

University of Singapore, Singapore; and the bDepartment of Cardiology, University of Groningen, University Medical Center Groningen, Gronin-






alence among HF groups widened with advancing

gen, the Netherlands. Dr. Lam has reported that she has received research

age. Beyond age, Sartipy et al. (2) also showed that

support from Boston Scientific, Bayer, Thermofisher, Medtronic, and

male sex, longer duration of HF, nonischemic eti-

Vifor Pharma; and served as a consultant for Bayer, Novartis, Takeda,

ology, and prior stroke independently increased the

Merck, Astra Zeneca, Janssen Research & Development, LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Stealth BioTherapeutics,

odds of AF. The commonality of these risk factors to

Covia, Roche, and Magen. All other authors have reported that they have

HFpEF, HFmrEF, and HFrEF suggests that the HF

no relationships relevant to the contents of this paper to disclose.

syndrome per se is most strongly related to AF risk,


Lam et al.


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Atrial Fibrillation in Heart Failure

T A B L E 1 Real-World Cohorts With Both HFpEF and HFrEF, Comparing AF vs. Sinus Rhythm or Non-AF


Sample Size


LVEF cutoff %

Swedish Heart Failure Registry



$50 vs.

SR 74.4  12.5 AF 79.1  9.0

SR 44 AF 46

40-49 vs.

SR 70.7  13.1 AF 76.8  9.9

SR 61 AF 60


SR 68.8  13.4 AF 74.3  10.7

SR 68 AF 73

$40 vs.

Non-AF 78.9  8.0 AF 80.8  7.4

Non-AF 33 AF 37


Non-AF 77.6  7.6 AF 78.8  7.3

Non-AF 55 AF 61

$50 vs.

SR 71.6  8.4 AF 73.8  8.9

SR 36 AF 21


SR 61.5  8.4 AF 63.0  7.1

SR 71 AF 63

Overall: Non-AF 71.6  13.1 Pre-existing AF 77.5  10.2

Overall: Non-AF 52 Pre-existing AF 52

First Author, Year (Ref. #)

Sartipy, 2017 (2)

Eapen, 2014 (3)

Retrospective, ADHERE-Core

Fung, 2007 (4)


Prospective, single center

McManus, 2013 (5)


Retrospective cohort




$50 vs.


#40 Santhanakrishnan, 2016 (6) Shamagian, 2006 (7)

Framingham Heart Study


Retrospective cohort


41/0/44 40/0/60

Age, mean  SD

Sex, % Male

$45 vs.

Overall 79  11

Overall 41


Overall 77  10

Overall 66

$50 vs.

Non-AF 72.7  10.6 AF 71.6  9.4

Non-AF 51 AF 46


Non-AF 67.4  12.5 AF 67.5  11.3

Non-AF 69 AF 71

T A B L E 1 Continued

First Author, Year (Ref. #)

Definition AF

Sartipy, 2017 (2)

History of AF or AF on any ECG

Eapen, 2014 (3)

History of AF or ICD-9-CM code at baseline

Fung, 2007 (4)

AF on baseline ECG

McManus, 2013 (5)

ICD-9-CM code

Control (SR or Non-AF)

Clinical Correlates of AF

Outcome in AF Compared With Control (95% CI)

HFpEF 65% HFmrEF 60% HFrEF 53%

Age, male, no prior MI, duration of HF, prior stroke/TIA

HF hospitalization or death HFpEF: HR 1.17 (1.09–1.26) HFmrEF: HR 1.29 (1.20–1.40) HFrEF: HR 1.15 (1.10–1.20)


HFpEF 47.6% HFrEF 44.2%

Age, male, no prior MI, no DM, prior stroke/TIA

30-day mortality HFpEF: HR 1.16 (1.08–1.25) HFrEF: HR 1.00 (0.94–1.08)


HFpEF 28.8% HFrEF 32.6%

Previous HF hospitalization, lower QoL

HF hospitalization or death HFpEF: HR 3.1 (1.6–5.2)


HFpEF 52.7% HFrEF 41.9%

Age, male, no prior MI, valvular disease

Mortality (pre-existing AF) HFpEF: HR 1.11 (1.03–1.20) HFrEF: HR 1.15 (1.05–1.26)

Santhanakrishnan, 2016 (6) Prevalent, concurrent or future AF on any ECG or hospital record


HFpEF 32% prevalent (18% concurrent, 12% future) HFrEF 23% prevalent (18% concurrent, 13% future)

No prior MI, no DM, preserved LVEF

Mortality (prevalent HF) New-onset AF HFpEF: HR 1.83 (1.41–2.37) HFrEF: HR 2.72 (2.12–3.48)

Shamagian, 2006 (7)


HFpEF 38.7% HFrEF 31.0%

No DM, nonischemic etiology, more peripheral edema, preserved LVEF

Mortality—HFpEF: no difference, Log rank 0.204 HFrEF: RR 1.83 (1.12–2.99)

AF on baseline ECG


Prevalence AF

ADHERE ¼ Acute Decompensated Heart Failure National Registry; AF ¼ atrial fibrillation; DM ¼ diabetes mellitus; ECG ¼ electrocardiogram; HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFmrEF ¼ heart failure with mid-range ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; HR ¼ hazard ratio; ICD-9-CM ¼ International Classification of DiseasesNinth Revision-Clinical Modification; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; RR ¼ relative risk; QoL ¼ quality of life score; SR ¼ sinus rhythm; TIA ¼ transient ischemic attack.

rather than potential different mechanisms among

Another potential explanation for the highest

the HF types. The greatest prevalence of AF in

prevalence of AF in the HFpEF group is misclassifi-

HFpEF would then imply that patients with HFpEF

cation of patients with symptomatic AF, but without

had the most severe HF, and indeed these patients

true HF, as HFpEF. The inclusion criterion of patients

had the worst outcomes, even when looking only at

with clinician-judged HF in the Swedish HF Registry

patients in sinus rhythm, compared with HFrEF and

is highly relevant, because clinical judgement of HF


depends on classic symptomatology (breathlessness,


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Lam et al.

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Atrial Fibrillation in Heart Failure

exertional intolerance), which overlaps with that of

biomarkers, or panels of biomarkers, may be useful

AF. Furthermore, diastolic function is challenging to

diagnostically, but require testing in cohorts of iso-

determine by echocardiography in the presence of

lated AF versus combined AF with HF (invasively

AF, and AF alone (without HF) is associated with

proven). The predisposition of men to AF in HF

increased N-terminal pro-B type natriuretic peptide

compared with women, and relative “protective”

(NT-proBNP) (1). However, one would expect better

effect of diabetes against AF in HFpEF (but not in

outcomes in patients with pure AF without HF, yet

HFrEF or HFmrEF), are intriguing observations.

outcomes in the group designated as HFpEF with AF

Additional mechanistic insights are needed, which

were dismal and worse than that of HFpEF with sinus

may be provided by investigating differential atrio-

rhythm, suggesting that the former were indeed

ventricular remodeling in men versus women, and in

patients with both diagnoses. Of note, median

diabetics versus nondiabetics. Finally, the heightened

NT-proBNP levels were >2.2 times higher in AF versus

risk of death, HF hospitalization, and stroke/transient

sinus rhythm in HFpEF, compared with 1.3 times in

ischemic attack in patients with AF and HF (regardless

HFrEF and 1.1 times in HFmrEF, and NT-proBNP was

of EF) underscores the importance of recognizing

independently related to AF in HFpEF but not HFrEF

and treating AF in HF. It is notable that patients

or HFmrEF. This suggests a greater contribution of AF

with missing data on AF or EF were older and had

to NT-proBNP elevation in HFpEF compared with

worse survival than in those whose AF status was

HFrEF or HFmrEF, implying a greater potential

known. Indeed, underdetection and undertreatment

for misdiagnosis of HFpEF based on increased

of AF in HF, especially among the elderly, remains a

NT-proBNP levels in the presence of AF, and impor-

key gap to address. Closer collaboration between HF

tantly supporting the use of higher NT-proBNP

and electrophysiology specialists may be needed for

cutoffs to establish the diagnosis of HFpEF when AF

optimal strategies to better understand, detect, and

is present.

manage the common and deadly combination of AF

The paper by Sartipy et al. (2) highlights numerous

in HF.

areas for future study. The relative contribution of AF versus HF to clinical symptomatology and increased


NT-proBNP in an individual patient remains a clinical

Lam, National Heart Center Singapore, 5 Hospital Drive,

conundrum, particularly in HFpEF. Novel circulating

Singapore 169609. E-mail: [email protected].

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lation 2016;133:484–92.

2. Sartipy U, Dahlström U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, midrange, and reduced ejection fraction. J Am Coll Cardiol HF 2017;5:XXX–XX. 3. Eapen ZJ, Greiner MA, Fonarow GC, et al. Associations between atrial fibrillation and early outcomes of patients with heart failure and reduced or preserved ejection fraction. Am Heart J 2014;167:375.e2.

5. McManus DD, Hsu G, Sung SH, et al. Atrial fibrillation and outcomes in heart failure with preserved versus reduced left ventricular ejection fraction. J Am Heart Assoc 2013;2:e005694.

7. Grigorian Shamagian L, Roman AV, Seara JG, Sande JLM, Veloso PR, Gonzalez-Juanatey JR. Atrial fibrillation in patients hospitalized for congestive heart failure: the same prognostic influence independently of left ventricular systolic function? Int J Cardiol 2006;110: 366–72.

6. Santhanakrishnan R, Wang N, Larson M, et al. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in

KEY WORDS atrial fibrillation, heart failure, preserved ejection fraction, outcomes