JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
5, 2016
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VOL. 68, NO.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.05.043
High-Output Heart Failure
A 15-Year Experience
Yogesh N.V. Reddy, MD, Vojtech Melenovsky, MD, PHD, Margaret M. Redfield, MD,
Rick A. Nishimura, MD, Barry A. Borlaug, MD
ABSTRACT
BACKGROUND High-output heart failure (HF) is an unusual cause of cardiac failure that has not been
well-characterized.
OBJECTIVES This study sought to characterize the etiologies, pathophysiology, clinical and hemodynamic
characteristics, and outcomes of high-output HF in the modern era.
METHODS We performed a retrospective analysis of all consecutive patients referred to the Mayo Clinic catheterization
laboratory for hemodynamic assessment between 2000 and 2014. Subjects with definite HF, as defined by the
Framingham criteria, were compared to controls of similar age and sex.
RESULTS The most common etiologies of high-output HF (n ¼ 120) were obesity (31%), liver disease (23%), arterio-
venous shunts (23%), lung disease (16%), and myeloproliferative disorders (8%). Compared with controls (n ¼ 24),
subjects with high-output HF displayed eccentric left ventricular remodeling, greater natriuretic peptide activation,
higher filling pressures, pulmonary hypertension, and increased cardiac output, despite similar ejection fraction. Elevated
cardiac output in high-output HF patients was related to both lower arterial afterload (decreased systemic vascular
resistance) and higher metabolic rate. Mortality was increased in high-output HF as compared with controls (hazard ratio:
3.4; 95% confidence interval: 1.6 to 7.6). Hemodynamics and outcomes were poorest amongst patients with the lowest
systemic vascular resistance.
CONCLUSIONS High-output HF is an important cause of clinical HF in the modern era that is related to excessive
vasodilation, and most frequently caused by obesity, arteriovenous shunts, and liver disease. Given the high
mortality and increasing prevalence of these comorbidities in Western countries, high-output HF must be considered
in the differential diagnosis of patients presenting with dyspnea, congestion, and a normal ejection fraction.
(J Am Coll Cardiol 2016;68:473–82) © 2016 by the American College of Cardiology Foundation.
C ardiac output is usually normal or low in
patients with heart failure (HF), but a minor-
ity of patients present in a high-output state,
which has historically been referred to as high-output
important unmet clinical need, forming the basis for
the current study.
METHODS
HF (1,2). The pathophysiology is believed to be
related to decreased systemic vascular resistance Consecutive patients with elevated cardiac index
(1–3), but this understanding is based upon reviews ($4 l/min/m 2) referred to the Mayo Clinic for right
and limited case reports. Standard therapies for HF, heart catheterization between January 1, 2000, and
such as vasodilators and inotropes, are potentially August 20, 2014, were identified. A cardiologist
detrimental in high-output HF, and there is no evaluated all patients before and after catheteriza-
proven treatment. This makes improved understand- tion. Patients were identified based upon cardiologist
ing of the pathophysiology, causes, and clinical diagnosis of congestive HF, and demonstrated
course of high-output HF in the modern era an elevated cardiac filling pressures and/or pulmonary
From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. The authors have reported that they have no
relationships relevant to the contents of this paper to disclose.
Manuscript received March 3, 2016; revised manuscript received April 18, 2016, accepted May 3, 2016.
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474 Reddy et al.
High-Output Heart Failure
ABBREVIATIONS hypertension by direct invasive assessment.
AND ACRONYMS High-output HF cases were adjudicated using
the Framingham criteria to confirm the
CI = confidence interval
diagnosis (Online Table 1) (4). Patients were
EF = ejection fraction
categorized as having left-sided HF if an
HF = heart failure
elevation in pulmonary capillary wedge
HFpEF = heart failure with pressure was identified at the time of cathe-
preserved ejection fraction
terization ($15 mm Hg). Patients with clinical
HF, elevated mean pulmonary artery pressure
($25 mm Hg), but normal pulmonary wedge pressure
(<15 mm Hg) were defined as having right-sided HF.
SEE PAGE 483
Subjects with alternative causes of high cardiac
output, either physiological (pregnancy, fever, infec-
tion), congenital, or iatrogenic (pulmonary vasodila-
tors, inotropes) were excluded, as were patients with
severe anemia (hemoglobin <8 mg/dl), thyrotoxicosis,
valvular heart disease (> mild stenosis, > moderate
regurgitation), constrictive pericarditis, left ventricu-
lar systolic dysfunction (ejection fraction [EF] <45%),
cardiomyopathies, and heart transplantation.
Control subjects free of HF enrolled in a separate
prospective study were included as the comparator
population (5,6). Control subjects displayed no evi-
dence of cardiac pathology after detailed noninvasive
and invasive assessment, including history, physical,
imaging, and normal rest and exercise pulmonary
wedge pressures and mean pulmonary artery pres-
sures (5,6).
CLINICAL ASSESSMENT. The etiology of high-output
HF was determined from detailed chart review with
patients categorized into the following 5 cohorts:
1) systemic arteriovenous shunts (including congen-
ital, traumatic, or hemodialysis fistulas); 2) cirrhotic
liver disease; 3) pulmonary disease; 4) myeloprolif-
erative hematologic disorders; and 5) obesity (body
2
mass index >35 kg/m ). Obesity was only considered
as the etiology if no other identifiable cause of HF or a
high-output state could be identified. Mortality was
assessed from the medical records, the Mayo Clinic
registration database, the Rochester Epidemiology
Project death database, and the Social Security Death
Index to obtain 100% verification of vital status.
INVASIVE HEMODYNAMIC ASSESSMENT. Subjects
were studied on their chronic medications in the fasted
state and supine position after minimal sedation, as
described previously (5–7). Pressures in the right
atrium, pulmonary artery, and pulmonary capillary
wedge position were measured at end-expiration from
electronically stored continuous recordings of pres-
sure tracings digitized at 240 Hz. Systemic and mixed
venous oxygen contents were determined by blood
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JACC VOL. 68, NO. 5, 2016
AUGUST 2, 2016:473–82
sampling (¼ saturation  hemoglobin  1.34) to
determine the arterial-venous oxygen content differ-
ence. Cardiac output was determined by the direct Fick
method (oxygen consumption/[arterial-venous oxy-
gen difference]) (n ¼ 53) or by thermodilution (n ¼ 91).
Oxygen consumption was measured directly by
expired gas analysis (MedGraphics, St. Paul, Minne-
sota), or calculated indirectly by multiplying the
thermodilution cardiac output by the directly
measured arterial-venous oxygen content difference
according to the Fick principle.
Stroke volume was calculated as cardiac output
divided by heart rate. Systemic vascular resistance
was calculated from the pressure drop across the
systemic circulations (mean arterial pressure-right
atrial pressure) multiplied by 80, divided by cardiac
output (5–7). Plasma volume at the time of catheter-
ization was estimated by: (1  hematocrit)  (a þ [b 
weight in kg]), where a ¼ 1,530 in men and 864 in
women, and b ¼ 41 in men and 47.9 in women (8).
ECHOCARDIOGRAPHIC ASSESSMENT. Experienced
sonographers and echocardiologists performed 2-
dimensional and Doppler echocardiography within 4
weeks of catheterization according to American
Society of Echocardiography guidelines (9).
STATISTICAL ANALYSIS. Data are reported as
mean  standard deviation or median (25th to 75th
interquartile range). Between-group differences for
categorical variables were compared by chi-square or
Wilcoxon rank-sum tests, as appropriate. Analysis of
variance or Student t tests were used to examine
differences between the groups for continuous vari-
ables. To correct for multiple comparisons between
groups, the Tukey test or Steel-Dwass test were used.
Survival was assessed by the Kaplan-Meier method,
with adjustment for baseline differences by Cox
regression analysis. Receiver operating characteristic
curve analysis was performed to determine optimal
cutoff points according to the maximum Youden in-
dex to noninvasively diagnose high-output failure.
Linear regression was used to determine the correla-
tion between continuous variables of interest. All
tests were 2-sided, with a p value <0.05 considered
significant. Analyses were performed using JMP
version 10.0.0 (SAS Institute, Cary, North Carolina).
RESULTS
Of 16,462 consecutive patients undergoing right heart
catheterization between January 1, 2000, and August
20, 2014, 525 displayed an elevated cardiac index.
From this group, 120 cases of definite high-output HF
were identified (Figure 1A). Compared with controls,
patients with high-output HF displayed higher body
JACC VOL. 68, NO. 5, 2016 Reddy et al. 475
AUGUST 2, 2016:473–82 High-Output Heart Failure

F I G U R E 1 High-Output Heart Failure Patient Identification and Causes

A B
Patients screened
undergoing RHC between
Jan 2000 and August 2014
(n=16462) Myelo
8%

Patients excluded with Shunt

normal cardiac index 22%
(n=15937)

Liver
Patients with high cardiac 23%
index (n=525)

Patients excluded based on

exclusion criteria; or the
absence of clinical heart
failure (n=395)

Patients with heart failure Lung Obesity

and high cardiac output
16% 31%
(n=130)

Patients excluded with a

reversible cause of high
caridiac output such as
anemia (n=9) or
thyrotoxicosis (n=1)

Patients with non-reversible

cause of high output heart
failure (n=120)

(A) Consort diagram. (B) Etiologies of high-output heart failure. Myelo ¼ myeloproliferative; RHC ¼ right heart catheterization.

mass index, more natriuretic peptide activation,
greater estimated plasma volume, and a higher like-
lihood of being treated with diuretic agents (Table 1).
Age, sex, comorbid conditions, and body surface area
were similar in high-output HF cases and controls.
Most of the high-output patients presented with
left-sided HF (n ¼ 91, 76%), although a minority pre-
sented with right HF (n ¼ 29, 24%). The clinical,
echocardiographic, and hemodynamic differences
between left- and right-sided high-output HF are
provided in Online Table 2. Left-sided HF patients
demonstrated more systemic vasodilation, with a
resultant higher plasma volume and wedge pressure.
Right-sided HF patients had higher pulmonary
vascular resistance at baseline, but their degree of
natriuretic peptide activation was similar.
VENTRICULAR STRUCTURE-FUNCTION,
HEMODYNAMICS, AND METABOLISM
Compared to controls, high-output HF patients dis-
played hyperdynamic hearts with higher EF, and
eccentric ventricular remodeling with increased
ventricular chamber size and mass (Table 1). High-
output HF subjects also displayed higher echocar-
diographic estimates of ventricular filling pressures
(E/e’ ratio), greater estimated right ventricular sys-
tolic pressures, and higher estimated cardiac indexes
on echocardiography.
At cardiac catheterization, patients with high-
output HF displayed 2-fold higher cardiac filling
pressures (right atrial and pulmonary wedge pres-
sures), coupled with markedly higher pulmonary
artery pressures (all p <0.0001) (Table 1). Elevated
cardiac output was related to both a greater stroke
volume and heart rate in patients compared with
controls. A higher ventricular preload (increased left
ventricular diastolic dimension), more complete
emptying (higher EF), and lower arterial afterload
(decreased systemic vascular resistance) drove the
increased stroke volume.
A high cardiac output can be caused by an
increased metabolic demand (reflected by higher
oxygen consumption). Compared with controls, total

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476 Reddy et al. JACC VOL. 68, NO. 5, 2016

High-Output Heart Failure AUGUST 2, 2016:473–82

and body massindexed oxygen consumption were

T A B L E 1 Baseline Characteristics
higher in high-output HF, indicating a relatively
Control (n ¼ 24) HOHF (n ¼ 120) p Value hypermetabolic state. Oxygen carrying capacity was
Age, yrs 61  12 59  12 0.40 lower in high-output HF (lower hemoglobin), with
Female 46 53 0.60
resultant decreased oxygen content of arterial and
Body surface area, m2 1.9  0.2 2.0  0.3 0.20
2
mixed venous blood samples. However, arterial-
Body mass index, kg/m 26.6 (24.1–30.1) 32.5 (25.5–39.1) 0.003
Estimated plasma volume, ml 2,831 (2,493–3,060) 3,561 (2,946–4,132) <0.0001
venous oxygen content difference (reflecting tissue
Comorbidities oxygen extraction) was lower in high-output HF
Atrial fibrillation 8 16 0.30 compared with controls, suggesting that, on average,
Coronary artery disease 25 20 0.60 this increased tissue perfusion was in excess of
Hypertension 63 56 0.60 metabolic demand in patients with high-output HF.
Medications
Cardiac output remained higher in high-output HF
Beta-blocker 46 54 0.50
after adjusting for oxygen consumption (p < 0.0001),
ACEI/ARB 42 50 0.50
but not after adjusting for systemic vascular resis-
Diuretic 4 62 <0.0001
Laboratories
tance (p ¼ 0.10), suggesting that excessive vasodila-
Hemoglobin, g/dl 13.9  1.2 11.1  1.8 <0.0001 tion was the stronger pathophysiologic contributor to
eGFR, ml/min/1.73 m2 87  29 81  56 0.60 the high-output state. The pathophysiologic impor-
NT-proBNP, pg/ml 76 (38–228) 734 (327–2,253) <0.0001 tance of excessive vasodilation was further supported
Radiographic cardiomegaly, % 0 53 <0.0001 by greater elevation in filling pressures with lower
Echocardiography
systemic vascular resistance, as well as with
Ejection fraction, % 60  9 64  8 0.03
increasing cardiac output (Figure 2).
LV end-diastolic dimension, mm 48  6 51  5 0.005
LV mass index, g/m2 88  20 110  32 0.002 CAUSES OF HIGH-OUTPUT HF. Morbid obesity was
E/A ratio 1.0  0.6 1.5  0.7 0.005 the most common cause of high-output HF (n ¼ 37,
E/e’ ratio 10  3 16  6 <0.0001 31%), followed by arteriovenous shunts and liver
Estimated RVSP, mm Hg 30  7 60  15 <0.0001
disease (Figure 1B). Within the shunt group (n ¼ 27,
Estimated cardiac index, l/min/m2 2.8  0.6 3.9  0.9 <0.0001
22%), 18 patients had systemic arteriovenous fistula,
Vital signs
of which 17 were hemodialysis fistulas, and 8 had
Heart rate, min-1 68  13 81  15 0.0002
Systolic blood pressure, mm Hg 139  24 133  25 0.30
hereditary hemorrhagic telangiectasia. All patients
Mean blood pressure, mm Hg 91  13 88  18 0.50 with liver diseaseassociated high-output HF (n ¼ 27,
Central hemodynamics 23%) displayed advanced hepatic cirrhosis.
Right atrial pressure mm Hg 42 11  5 <0.0001 Lung diseaseassociated high-output HF (n ¼ 19,
PA systolic pressure, mm Hg 27  6 57  15 <0.0001 16%) included patients with chronic obstructive pul-
PA mean pressure, mm Hg 16  4 37  9 <0.0001
monary disease (n ¼ 7), connective tissue disorders
PA wedge pressure, mm Hg 73 18  6 <0.0001
(n ¼ 5), bronchiolitis obliterans (n ¼ 1), interstitial
Flow measures
lung disease (n ¼ 5), and bronchiectasis (n ¼ 1).
Cardiac output, l/min 5.2  1.8 9.5  2.1 <0.0001
Cardiac index, l/min/m2 2.68  0.80 4.72  0.75 <0.0001 Hematologic disorders were the only identifiable
Stroke volume, ml 77  23 122  33 <0.0001 cause in 8% of cases (n ¼ 10). Each of these were
Stroke volume index, ml/m2 40  9 60  14 <0.0001 myeloproliferative disorders characterized by hep-
Metabolic and vascular measures atosplenomegaly and extramedullary hematopoiesis,
O2 consumption, ml/min 210  61 333  111 <0.0001 including primary and secondary myelofibrosis
O2 consumption, ml/min$kg 2.60  0.49 3.65  1.19 <0.0001
(n ¼ 8), and chronic myelomonocytic leukemia (n ¼ 2).
Arterial O2 content, ml/dl 18.0  1.7 13.8  2.3 <0.0001
Mixed venous O2 content, ml/dl 13.5  1.8 10.3  2.4 <0.0001
CHARACTERISTICS OF HIGH-OUTPUT HF ETIOLOGIES.
Arterial-venous O2 difference, ml/dl 4.4  0.9 3.5  1.1 0.0005
Most hemodynamic and ventricular function findings
SVR, dyne/s$cm5 1,460  475 682  241 <0.0001
were fairly uniform among the different etiologies of
SVRI, dyne$m2/s$cm5 2,782  846 1,336  399 <0.0001
PVR, dyne/s$cm 5
150  64 170  94 0.30 high-output HF, although there were some notable
PVRI, dyne/s$cm5 287  118 331  165 0.20 differences (Table 2). Obesity and liver-associated pa-
tients had greater body size, weight, and higher esti-
Values are mean  SD, %, or median (25th–75th interquartile range).
mated plasma volume. The hematologic and liver
ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin-receptor blocker; E/A ¼ ratio of mitral
inflow velocity between early diastole and atrial contraction; E/e’ ¼ ratio of early diastolic mitral inflow velocity diseaseassociated high-output HF groups had
and early diastolic tissue relaxation velocity at the ventricular septum (a noninvasive estimate of LV filling
pressure); eGFR ¼ estimated glomerular filtration rate; HOHF ¼ high-output heart failure; LV ¼ left ventricle; NT-
marginally lower hemoglobin levels than the remain-
proBNP ¼ N-terminal pro-B-type natriuretic peptide; O2 ¼ oxygen; PA ¼ pulmonary artery; PVR ¼ pulmonary ing groups. As expected, the shunt group had worse
vascular resistance; PVRI ¼ pulmonary vascular resistance index; RVSP ¼ right ventricular systolic pressure;
SVR ¼ systemic vascular resistance; SVRI ¼ systemic vascular resistance index. renal function, given that 67% had arteriovenous fis-
tulas for the purpose of hemodialysis access.

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JACC VOL. 68, NO. 5, 2016 Reddy et al. 477
AUGUST 2, 2016:473–82 High-Output Heart Failure

F I G U R E 2 Relationships Between Filling Pressures, Flow, Load, and Volume Expansion

A 40
B
r= 0.5, p<0.0001 40 r= -0.6, p<0.0001

PA Wedge Pressure (mm Hg)

PA Wedge Pressure (mm Hg)

30 30

20 20

10 10

0 0
0 5 10 15 20 0 1000 2000 3000
Cardiac Output (I/min) Systemic Vascular Resistance (DSC)

C D
10000 r= -0.5, p<0.0001 40 r= 0.5, p<0.0001
PA Wedge Pressure (mm Hg)
Plasma Volume (ml)

8000
30
6000
20
4000

10
2000

0 0
0 1000 2000 3000 0 2000 4000 6000 8000 10000
Systemic Vascular Resistance (DSC) Plasma Volume (ml)

High output heart failure

Control

Correlations between the severity of left heart congestion, as measured by pulmonary artery (PA) wedge pressure with (A) cardiac output and
(B) systemic vascular resistance in patients with high-output heart failure. Decreasing vascular resistance was associated with greater elevation
in estimated plasma volume (C), which was in turn associated with increasing PA wedge pressure (D). DSC ¼ dyne$s/cm5.

Absolute oxygen consumption was highest in interval [CI]: 1.6 to 7.6; p ¼ 0.002) (Figure 3A). Among
obesity-related high-output HF, but this was explained the individual causes, obesity-related high-output HF
solely by greater body mass, as the difference was had the lowest 5-year mortality (19%), whereas liver
eliminated after adjustment for weight (Table 2). Ox- disease (59%) and shunt-associated high-output HF
ygen consumption corrected to weight was highest and (58%) had the highest 5-year mortality (p ¼ 0.01)
mixed venous oxygen content was the lowest in the (Figure 3B).
myeloproliferative disorder group, suggesting a hy- Among all high-output HF etiologies, excessive
permetabolic state with relatively inadequate tissue vasodilation was associated with the poorest prog-
perfusion relative to demand. Low arterial-venous nosis: patients with a very low systemic vascular
oxygen content difference and depressed systemic resistance (bottom quartile, <1,030 dyne$m 2/s$cm 5)
vascular resistance were common to all of the different displayed increased mortality compared to the
etiologies, but tended to be lowest in the liver- remainder of patients with mildly depressed or
associated high-output HF group. Patients with normal systemic vascular resistance (61% vs. 36%;
shunt-related high-output HF had the most ventricular HR: 2.5; 95% CI: 1.2 to 5.1; p ¼ 0.01) (Figure 3C).
remodeling whereas ventricular dimensions were NONINVASIVE IDENTIFICATION OF HIGH-OUTPUT
smallest in lung diseaseassociated high-output HF. HF. A cardiac index, estimated by echocardiography,
SURVIVAL. Patients with high-output HF displayed of 3.54 l/min/m 2 or greater identified high-output
increased 3-year mortality compared with controls HF with 62% sensitivity and 96% specificity (area
(38% vs. 0%; hazard ratio [HR]: 3.4; 95% confidence under the curve: 0.85, p < 0.0001). Most patients

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478 Reddy et al. JACC VOL. 68, NO. 5, 2016

High-Output Heart Failure AUGUST 2, 2016:473–82

T A B L E 2 Comparison of Different High-Output Heart Failure Etiologies

Myeloproliferative Liver Disease Lung Disease Obesity Shunt

(n ¼ 10) (n ¼ 27) (n ¼ 19) (n ¼ 37) (n ¼ 27) p Value

Demographics
Age, yrs 67  8 56  10 56  15 61  12 59  14 0.10
Female 50 44 68 51 52 0.60
Body surface area, m2 1.90  0.20 2.07  0.26*†‡ 1.80  0.32 2.25  0.27§ 1.85  0.27 <0.0001
Body mass index, kg/m2 25.4 (21.5-32.8) 33.5 (30.1-39.7)§ 26.6 (22.8-32.6) 40 (35.6-46.5)§ 25.8 (24-30.8) <0.0001
Comorbidities
Coronary artery disease 10 15 11 30 22 0.40
Hypertension 60 30 37 63 63 0.001
Laboratory values
Hemoglobin, g/dl 10  1.5*‡ 10.4  1.7*‡ 11.6  1.9 11.2  1.8 11.5  1.7 0.04
eGFR, ml/min/1.73 m2 57 (41-80) 82 (65-132) 72 (44-92) 111 (77-146) 15 (15-51)§ <0.0001
NT-proBNP, pg/ml 1,439 (633-3,475) 416 (181-645) 819 (159-2,494) 1,009 (266-1,827) 2,556 (444-29,856) 0.04
Estimated plasma volume, l 3.3  0.7 3.8  0.7§ 2.9  0.6 4.3  0.9§ 3.0  0.6 <0.0001
Echocardiography
Ejection fraction, % 61  7 67  7 64  8 63  7 64  7 0.20
LV end-diastolic dimension, mm 51  4 51  4 46  4§ 53  5 51  5 <0.0001
LV mass index, g/m2 109  18 99  23 90  18 111  28*‡ 134  43§ <0.0001
E/e’ 14  6‡ 16  5 12  4†‡k 16  7 19  6 0.006
Vital Signs
Heart rate, min-1 85  14 79  14 88  15 80  16 77  12 0.10
Systolic blood pressure, mm Hg 139  33 121  18†‡¶ 127  20 140  25 136  29 0.02
Mean blood pressure, mm Hg 89  24 81  12†‡ 84  14 93  17 93  21 0.03
Central hemodynamics
Right atrial pressure, mm Hg 10  5 12  5 8  5†‡k 12  5 13  5 0.02
PA systolic pressure, mm Hg 60  14 55  13 54  18 59  15 59  18 0.60
PA mean pressure, mm Hg 39  8 35  7 37  11 39  10 38  9 0.70
Pulmonary wedge pressure, mm Hg 16  6 19  6 16  7 20  6 18  6 0.10
Right-sided heart failure, % 30 22 42 14 26 0.20
Flow measures
Cardiac output, l/min 8.8  1.5 10.6  2.4*ঠ8.3  2.1 10.3  1.8*ঠ8.6  1.7 <0.0001
Cardiac index, l/min/m2 4.6  0.5 5.1  0.9*†‡ 4.6  0.6 4.6  0.4 4.7  1 0.04
Stroke volume, ml 103  14 138  37*‡# 95  22‡ 133  29*‡¶ 115  31 <0.0001
Stroke volume index, ml/m2 55.9  8.3 65.8  13.6 52.8  10.9‡k 59.2  11.2 63.7  16.5 0.003
Determinants of cardiac output
Oxygen consumption, ml/min 370 (224-463) 277 (233-337) 278 (244-327) 358 (283-451)*‡k 295 (217-333) 0.002
Oxygen consumption, ml/min$kg 4.4 (3.7-5.8)†k 3.3 (2.5-3.9) 3.8 (3.6-4) 3.1 (2.7-3.9) 3.6 (3.0-4.5) 0.001
Arterial O2 content, ml/dl 12.2  1.7 13.3  2 14.3  2.4 14  2.5 14.5  2.3 0.08
Mixed venous O2 content, ml/dl 8  1.8§ 10.3  2 10.6  2.4 10.2  2.5 11  2.4 0.02
A-V O2 difference, ml/dl 4.6  1§ 2.9  1†¶ 3.4  0.9 3.8  1 3.4  1.1 0.0008
SVR, dyne/s$cm5 660 (520-750) 500 (420-730)*‡ 810 (570-900) 620 (530-830) 780 (540-990) 0.025
SVRI dyne$m2/s$cm5 1,331 (916-1,462) 1,088 (893-1,359)† 1,399 (1,121-1,576) 1,444 (1,203-1,722) 1,454 (1,009-1,776) 0.008

Values are mean  SD, %, or median (25th to 75th interquartile range). *p < 0.05 vs. lung, Tukey’s HSD, or Steel-Dwass test. †p < 0.05 vs. obesity, Tukey’s HSD, or Steel-Dwass test.
‡p < 0.05 vs. shunt, Tukey’s HSD, or Steel-Dwass test. §p < 0.05 vs. all other groups, Tukey’s HSD, or Steel-Dwass test. kp < 0.05 vs. liver, Tukey’s HSD, or Steel-Dwass test. ¶p < 0.05 vs.
heme, Tukey’s HSD, or Steel-Dwass test. #p < 0.05 vs. myeloproliferative, Tukey’s HSD, or Steel-Dwass test.
A-V ¼ arteriovenous; other abbreviations as in Table 1.

with high-output HF also displayed an elevated
Doppler-estimated right ventricular systolic pressure
($42 mm Hg; 92% sensitivity; 100% specificity [area
under the curve: 0.97; p < 0.0001]).
DISCUSSION
This study represents the first large-scale, systematic
characterization of patients with invasively proven
high-output HF. We show that compared to controls
without HF, patients with high-output HF demon-
strate a hyperdynamic state characterized by natri-
uretic peptide activation, plasma volume expansion,
elevated cardiac filling pressures, and pulmonary
hypertension. Although ventricular dimensions were
higher in cases than controls, marked eccentric
remodeling was not present. The most common cau-
ses of high-output HF in this contemporary series

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JACC VOL. 68, NO. 5, 2016 Reddy et al. 479
AUGUST 2, 2016:473–82 High-Output Heart Failure

were obesity, cirrhosis, and arteriovenous shunts,

F I G U R E 3 Outcomes in High-Output Heart Failure
although pulmonary and myeloproliferative disorders
were also important, previously under-recognized
causes of this syndrome (Central Illustration). Exces-
A 100
Control
sive vasodilation and, to a lesser extent, an increased 90

Patients Alive (%)

metabolic rate, were common to all etiologies and
were associated with more deranged hemodynamics. 80 High Output Failure
Survival was depressed in high-output HF patients as
70
compared with controls, emphasizing the clinical
importance of this disorder, and patients with more 60
Hazard ratio, 3.4 (95% CI, 1.6-7.6), p=0.002
dramatic vasodilation displayed the highest mortal-
50
ity, supporting the pathophysiologic importance of 0 1 2 3
excessive afterload reduction in this cause of HF. Years
No at risk
Given the increasing prevalence of obesity and liver HOHF 120 94 76 58
and kidney disease in Western countries, high-output Control 24 24 21 4

HF must be considered in the differential diagnosis of

patients presenting with the clinical syndrome of B 100

cardiac failure with preserved EF. Obesity

80
Patients Alive (%)

PATHOPHYSIOLOGY OF HIGH-OUTPUT HF. All other 60 Lung

Myelo
things being equal, cardiac output increases with
40 Liver
isolated reductions in vascular resistance (cardiac Shunt
load), increases in oxygen consumption (cardiac 20
log rank test p=0.01
demand), or both. Excessive systemic vasodilation
has been considered to be a unifying mechanism of 0
0 1 2 3 4 5
high-output HF (1–3), and this study confirms this Years
hypothesis in a large series of patients with varying No at risk
Obesity 37 32 29 27 23 15
etiologies. Reduction in arterial afterload may be Liver 27 19 14 12 10 9
Myeloproliferative 10 8 5 4 4 2
related to shunting from macrovascular causes, such Shunt 27 20 18 10 6 5
as arteriovenous fistulas, or secondary to a systemic Lung 19 19 14 10 9 7

process producing peripheral vasodilation, such as

cirrhosis, hypercapnia from advanced lung disease, or C 100

morbid obesity.
80 Low normal SVRI
Patients Alive (%)

We further show for the first time that resting ox-

ygen consumption is increased in high-output HF, 60
contributing to the high-output state. Increases in
40 Very low SVRI
flow due to physiological causes, such as exercise or
fever, are considered to be normal, but we show that 20
pathological conditions, such as obesity and myelo- Hazard ratio, 2.5 (95% CI, 1.2-5.1), p=0.01

fibrosis, may be associated with increased metabolic 0

0 1 2 3 4 5
demand for tissue perfusion. This may be caused by Survival Time (Years)
excess quantity of tissue to perfuse (obesity) or No at risk
Very low 29 22 17 13 8 7
potentially by qualitative changes in tissue meta- Low or normal 89 71 59 46 39 32
bolism related to underlying noncardiac diseases
(extramedullary hematopoiesis). Survival curves in (A) high-output heart failure (HOHF) versus controls, (B)
Importantly, cardiac output was much higher in different etiologies of HOHF, and (C) bottom quartile of systemic vascular
high-output HF patients even after adjusting for VO2 resistance index (SVRI) (<1,030 dyne$m2/s$cm5) compared to top 3 quartiles.
(p < 0.0001), indicating that heightened metabolic CI ¼ confidence interval; Myelo ¼ myeloproliferative.

demand alone does not explain the elevated flow.

Adjusting for systemic vascular resistance eliminated
group differences in output. This indicates that
excessive reduction in afterload indeed plays the
dominant role in the pathophysiology of high-output
HF. The pathophysiologic importance of excessive
afterload reduction is underscored by the correlations
between lower systemic vascular resistance (arterial
underfilling), plasma volume expansion, and higher
filling pressures (Figure 2), and by the greater

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480 Reddy et al. JACC VOL. 68, NO. 5, 2016

High-Output Heart Failure AUGUST 2, 2016:473–82

study design). We also excluded patients with severe

C E NT R AL IL L U STR AT IO N Pathophysiology of anemia, as this is a well-described and more easily
High-Output Heart Failure
reversible cause of high-outputrelated congestion
(11). Although this may, in part, be related to the
referral bias of a cardiac catheterization laboratory
population, it appears that in the modern era, obesity,
cirrhosis, and arteriovenous shunts may be the most
Obesity Liver Arteriovenous Lung Myeloproliferative common causes of this form of HF.
disease fistula disease disorders
OBESITY-RELATED HIGH-OUTPUT HF. Two-thirds of
American adults are currently overweight or obese,
Vasodilation and the prevalence is growing (12). As such, the
Metabolism problem of obesity-related heart diseases will only be
Microvascular density
Body mass expected to increase in the coming years (13). Obesity
Arteriovenous shunting
was the most common cause of high-output HF in this
contemporary series. Reductions in arterial resistance
Low systemic vascular resistance Elevated oxygen consumption are well-described in obesity (13–15), caused by
increased capillary perfusion to adipose tissue and
elaboration in fat cells of vasoactive adipokines (16).
Arterial underfilling The resultant renal hypoperfusion caused by low
Renal perfusion vascular resistance is believed to promote sodium
retention and increase cardiac work (1–3). Total
body oxygen consumption was increased in obesity,
Plasma volume
expansion
Cardiac output but this was driven largely by higher total body
mass, in comparison to the other etiologies of high-
output HF.
High output heart failure In addition to peripheral effects on vascular resis-
tance and metabolism, obesity affects the heart
Reddy, Y.N.V. et al. J Am Coll Cardiol. 2016;68(5):473–82. directly. Left ventricular efficiency is 50% lower when
the heart utilizes fatty acids as opposed to glucose as
Comorbid conditions leading to vasodilation and arteriovenous shunting decrease sys- its primary substrate (17). In obese women without
temic vascular resistance, which lowers left ventricular afterload to increase cardiac HF, myocardial oxygen consumption, fatty acid up-
output. The reduction in systemic vascular resistance also leads to decreases in arterial take, and stroke work vary directly with body mass,
volume and renal hypoperfusion causing neurohormonal activation and plasma volume
whereas ventricular efficiency varies inversely with
expansion. Comorbid conditions may also increase tissue oxygen consumption, increasing
demand for blood flow and contributing to the high-output state. Together, the combi- body mass (18). In patients without HF, weight loss
nation of high output and plasma volume expansion causes the clinical syndrome of high- decreases blood volume, cardiac work, ventricular
output heart failure. size, mass, and filling pressures, while improving
diastolic and systolic ventricular function, insulin
sensitivity, and glucose uptake (19). Further study is
mortality observed in patients with the greatest required to evaluate the effects of weight loss in
reduction in systemic vascular resistance (Figure 3C). obesity-related high-output HF.
The fluid retention and congestion in patients OTHER ETIOLOGIES OF HIGH-OUTPUT HF. Arterio-
with high-output failure is similar to what has previ- venous shunts and cirrhosis were the next most
ously been described in elegant pathophysiologic common causes of high-output HF. Shunts are
studies of low-output HF (10) and severe anemia (11). important to consider because surgical modification
Further study is needed to determine whether or banding may improve or even eliminate congestive
interventions to mitigate excessive vasodilation may symptoms in this cohort, although data is limited
be effective in treating the various forms of high- in this regard. Patients with cirrhosis develop
output failure. splanchnic vasodilation, decreasing systemic vas-
SPECIFIC ETIOLOGIES. Traditionally described cau- cular resistance (20). This is believed to be caused by
ses of high-output HF, such as thiamine deficiency bacterial translocation from the intestinal lumen
(beriberi) and Paget’s disease were not observed in causing cytokine release, as well as increased con-
this series, and only 1 case of thyrotoxicosis was centrations of vasoactive substances that are not
identified (not included in the analysis according to cleared by the failing liver (21). The liver-induced

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JACC VOL. 68, NO. 5, 2016
AUGUST 2, 2016:473–82
high-output HF group had the lowest arterial resis-
tance and highest mortality, although it is likely that
the poor survival was related, in part, to the impact of
hepatic dysfunction.
Two other major causes of high-output HF that are
less well-described in published reports were identi-
fied: chronic pulmonary and myeloproliferative dis-
eases. Hypoxia and hypercapnia are associated with a
high output, reduced arterial resistance, salt and
water retention, and impaired renal blood flow in
patients with chronic obstructive pulmonary disease
(22,23). One-half of the patients in this series with
lung diseaseassociated high-output HF presented
with isolated right HF in the absence of high left heart
filling pressures. This is likely explained by the
combination of a high-flow state from systemic
vasodilation in the setting of vascular remodeling and
hypoxic pulmonary vasoconstriction.
Patients with hematologic disorders presented
with some form of myeloproliferative disease char-
acterized by extramedullary hematopoiesis, which
may contribute to both an increase in oxygen
consumption and reduction in arterial resistance.
One-third of myelofibrotic patients presented with
isolated right HF, which may be related to the adverse
effects of high circulating progenitor cells on right
ventricular and pulmonary vascular function, super-
imposed on a high-flow state (24).
CLINICAL IMPLICATIONS. Gross indicators of sys-
tolic performance, including EF, were normal in the
patients studied, indicating that significant cardiac
pump failure was not present; yet all patients fulfilled
rigorous clinical and hemodynamic definitions of HF,
as applied in practice. This emphasizes that the clin-
ical syndrome of HF does not necessarily require
significant abnormalities in pump function, and may
be caused by abnormalities external to the heart
affecting vascular load and metabolism.
Patients in the high-output group displayed an
elevated E/e’ ratio (often used as a noninvasive
measure of diastolic dysfunction) and normal EF,
suggesting that many of these patients might have
been erroneously diagnosed as having HF with pre-
served EF (HFpEF) if there had been no direct
assessment of cardiac output. This observation
emphasizes the importance of considering high-
output HF in the differential diagnosis. There is
increasing evidence that patients with HFpEF are a
heterogeneous group comprising many phenotypes
(25). The current data show that high-output HF must
also be considered in the differential diagnosis, and
probably should be categorized separately from more
garden-variety patients with HFpEF. The current data
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Reddy et al. 481
High-Output Heart Failure
show that the presence of an increased echocardio-
graphic Doppler-derived cardiac index >3.5 l/min/m 2
should prompt clinicians to consider further evalua-
tion to clarify the diagnosis.
STUDY LIMITATIONS. This study was performed in a
catheterization laboratory referral population, thus
some causes of high-output HF might have been
underrepresented if patients were less likely to be
referred for invasive study. Data were not acquired
prospectively, but from chart review. Very few
patients received specific treatments directed toward
high-output HF, other than diuretic agents, so we
cannot make any conclusions regarding treatment
from these data. Cause of death was not available.
Oxygen consumption was not directly measured in all
subjects, but rather solved for by using the Fick
equation in patients where thermodilution outputs
were obtained.
CONCLUSIONS
High-output HF is an important cause of cardiac
failure that is associated with increased mortality.
Despite the wide variety of underlying etiologies, the
causes share a common pathophysiology of exces-
sively depressed arterial resistance and heightened
metabolic demand that causes congestion, despite a
hyperdynamic circulation. Given the high mortality in
high-output HF, and the increasing prevalence of
obesity and liver and kidney disease worldwide, this
disease must be considered in the differential diag-
nosis of patients presenting with clinical HF in the
setting of a normal EF.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Barry A. Borlaug, Mayo Clinic and Foundation, 200
First Street SW, Rochester, Minnesota 55905. E-mail:
borlaug.barry@mayo.edu.
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: The most
frequent causes of high-output HF have changed over time, and
today include obesity, liver disease, and arteriovenous fistulas,
although pulmonary and myeloproliferative diseases are addi-
tional, underappreciated causes. Outcomes differ little from
those in patients with low-output HF due to systolic dysfunction.
TRANSLATIONAL OUTLOOK: Further studies are needed to
develop criteria that clinicians can use to distinguish patients
with high-output HF from those with HFpEF.
482 Reddy et al.
High-Output Heart Failure
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KEY WORDS cirrhosis, hemodynamics,
obesity
A PPE NDI X For supplemental tables, please
see the online version of this article.