Circulation Topic Review

Circulation: Heart Failure

2013 Editors’ Picks
The Editors
The following articles are being highlighted as part of Circulation’s Topic Review series. This series summarizes the most important
manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this
article represent Editors’ Picks for each Circulation: Heart Failure issue published in 2013.  (Circulation. 2014;129:e14-e19.)

Diagnosis, Treatment, and Outcome variables were associated with the likelihood of dyspnea improve-
ment. The likelihood of achieving dyspnea relief was particularly
of Giant-Cell Myocarditis in the Era of high when both pulmonary capillary wedge pressure and mean pul-
Combined Immunosuppression monary artery pressure were effectively reduced. These results sug-
gest that the failure to achieve early dyspnea relief in clinical practice
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Summary—Giant-cell myocarditis is often rapidly progressive myo-

cardial disease of unknown pathogenesis. The diagnosis is based on
endomyocardial biopsy. To select appropriate treatment strategy, dif-
ferential diagnosis from viral myocarditis and cardiac sarcoidosis is
essential. We found that the sensitivity of the first endomyocardial
biopsy was 68% and sensitivity was increased to 93% with up to 3
biopsies. Thus repeat endomyocardial biopsies are frequently needed
to diagnose giant-cell myocarditis. Earlier reports have shown that
if left untreated, giant-cell myocarditis is often fatal. On contempo-
rary immunosuppression, two thirds of patients reach a partial clini-
cal remission characterized by freedom from severe heart failure and
need of transplantation.
Conclusions—Repeat endomyocardial biopsies are frequently
needed to diagnose giant-cell myocarditis. On contemporary immu-
nosuppession, two thirds of patients reach a partial clinical remission
characterized by freedom from severe heart failure and need of trans-
plantation but continuing proneness to ventricular tachyarrhythmias.1
Hemodynamic Determinants of
Dyspnea Improvement in Acute
Decompensated Heart Failure
Summary—Relief of dyspnea constitutes a major treatment goal
in acute heart failure and an important end point in clinical trials.
However, recent studies have shown that rapid relief of dyspnea is
frequently not achieved in patients with decompensated heart failure.
Previous studies failed to identify clinical characteristics or labora-
tory tests that reliably predict dyspnea relief. In the present study
we examined the relationship between hemodynamic changes and
dyspnea relief (defined as moderate or marked improvement) using
frequent measurements of hemodynamic parameters and simulta-
neous dyspnea assessments in patients with acute heart failure who
were treated with vasodilators and diuretics. We observed a clear
time dependency of dyspnea relief that was strongly related to the
improvement in hemodynamic parameters. Specifically, dyspnea
relief depended on 2 hemodynamic variables, pulmonary capillary
wedge pressure and mean pulmonary artery pressure. Both the abso-
lute level and the magnitude of reductions of these hemodynamic
and in clinical trials is likely related, at least in part, to the failure to
achieve a rapid reduction in these hemodynamic parameters.
Conclusions—A clinically significant improvement in dyspnea is
associated with a reduction in both PCWP and mean pulmonary
artery pressure.2
Genetic and Pharmacological Inhibition of
Galectin-3 Prevents Cardiac Remodeling by
Interfering With Myocardial Fibrogenesis
Summary—Cardiac remodeling is the heart’s general response to
injury and is characterized by the development of myocyte hyper-
trophy and fibrosis formation. Progressive cardiac remodeling is
the main predictor of heart failure development. Despite extensive
research and advances in drug development, there is still a strong need
for novel pharmacological agents that attenuate cardiac remodeling
and prevent heart failure. Galectin-3 is a β-galactosidase–binding lec-
tin and has been shown to enhance cardiac remodeling. Galectin-3 is
secreted by macrophages and fibroblasts, and is important in fibrosis
formation. Galectin-3 is also secreted into the circulation, where lev-
els of ­galectin-3 reflect disease severity and prognosis, and as such,
­galectin-3 is currently being used as a biomarker. Because galectin-3
has an established causative role in tissue fibrosis, we hypothesized that
disruption or inhibition of galectin-3 would inhibit myocardial fibrosis
and afford cardioprotection. Using mouse and rat models of cardiac
remodeling and fibrosis, we show that genetic disruption and phar-
macological inhibition (with the oligosaccharide N-acetyllactosamine,
N-Lac) of galectin-3 effectively attenuates myocardial fibrosis, which
is accompanied with less myofibroblast activation, less collagen pro-
duction, and lower collagen stiffness. This was associated with pre-
served cardiac function. Our results identify galectin-3 as a feasible
target for therapy to prevent cardiac remodeling and heart failure.
Conclusions—Genetic disruption and pharmacological inhibition
of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subse-
quent heart failure development. Drugs binding to galectin-3 may be
potential therapeutic candidates for the prevention or reversal of heart
failure with extensive fibrosis.3

Correspondence to The Editors, 560 Harrison Avenue, Suite 502, Boston, MA 02118. E-mail circ@circulationjournal.org
© 2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.008229

e14
 The Editors   Circ Heart Failure 2013 Editor's Picks    e15
Impact of Mineralocorticoid Receptor
Antagonists on Changes in Cardiac Structure
and Function of Left Ventricular Dysfunction: A
Meta-analysis of Randomized Controlled Trials
Summary—As a major agonist for mineralocorticoid receptors,
aldosterone is regarded as a potent mediator of cardiac remodeling,
a core pathogenetic feature of left ventricular dysfunction and heart
failure progression. Strong evidence indicates that administration
of mineralocorticoid receptor antagonists (MRAs) in patients with
left ventricular dysfunction results in a reduction in morbidity and
mortality; however, a comprehensive evaluation of M ­ RA-induced
changes in cardiac structure and function is lacking. To address this
issue, we conducted a meta-analysis of 19 randomized controlled
trials that reported effects of MRAs on cardiac structure and func-
tion. Most indexes exhibited improvement during treatment with
MRAs, especially in patients with heart failure with reduced ejec-
tion fraction. Treatment with MRAs also significantly reduced
serum amino-terminal peptide of procollagen type-III and B-type
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natriuretic peptide. MRA treatment was associated with increased
risk of developing hyperkalemia and elevated serum creatinine, call-
ing for careful monitoring of serum electrolytes and renal function
in clinical practice. These meta-analytic data provide evidence that
treatment with MRAs in patients with left ventricular dysfunction
results in favorable effects on left ventricular structure and function,
which can in part explain the favorable clinical effects seen in ran-
domized trials.
Conclusions—Our findings demonstrate that mineralocorticoid
receptor antagonist treatment may exert beneficial effects on the
reversal of cardiac remodeling and improvement of left ventricular
function.4
Treating Anemia in Older Adults With Heart
Failure With a Preserved Ejection Fraction
With Epoetin Alfa: Single-blind Randomized
Clinical Trial of Safety and Efficacy
Summary—Among more than half of patients with heart failure
who have a preserved ejection fraction, treatment is largely empiri-
cal and predominately focused on the cardiovascular phenotype. A
majority of patients with heart failure who have a preserved ejection
fraction are older adult women with hypertension and several other
comorbidities, including obesity, renal dysfunction, diabetes melli-
tus, and anemia, among others. Whether treating these comorbidi-
ties will have clinical benefits has been suggested but as yet has not
been subject to rigorous study. Accordingly, we conducted a prospec-
tive, randomized, single-blind clinical trial of treating anemia with
epoetin alfa in older adults with heart failure who have a preserved
ejection fraction. The trial recruited an older adult cohort (mean age,
>75 years), predominately women (67%) with multiple comorbidi-
ties (including chronic pain and depression), which mimics what is
seen in community-based studies of heart failure, but has, until now,
not been replicated in a prospective clinical trial. Despite increasing
hemoglobin in a safe manner using a prespecified dosing algorithm,
epoetin alfa was not associated with ventricular remodeling nor was
it associated with improvements in submaximal exercise capacity or
quality of life compared with placebo. These data suggest that for
the rapidly rising population of heart failure who have a preserved
ejection fraction, treatment with erythropoietin as prescribed in this
trial is not associated with meaningful clinical benefits. Furthermore,
these data demonstrate that randomized clinical trials can be carried
out in the population by using novel approaches (eg, nonprinciple
visits being conducted in the subject’s home) and provide an evidence
base for informing clinicians caring for this vulnerable population.
Conclusions—Administration of epoetin alfa to older adult patients
with heart failure and a preserved ejection fraction compared with
placebo did not change left ventricular end-diastolic volume and left
ventricular mass nor did it improve submaximal exercise capacity or
quality of life.5
AAV9.I-1c Delivered via Direct Coronary
Infusion in a Porcine Model of Heart
Failure Improves Contractility and
Mitigates Adverse Remodeling
Summary—Congestive heart failure is a major cause of morbidity
and mortality in the United States. Although progress in conventional
treatments is making steady and incremental gains to reduce heart
failure mortality, there is a critical need to explore new therapeutic
approaches. Gene therapy was initially applied in the clinical setting
for inherited monogenic disorders. It is now apparent that gene ther-
apy has broader potential in diseases such as congestive heart failure.
Improvement in our understanding of the molecular mechanisms of
heart failure, along with the development of novel and safer vectors
for gene delivery, has led to the identification of novel targets that are
difficult to manipulate pharmacologically but may be more amenable
to gene therapy. Over the past few years, calcium cycling abnormali-
ties and specifically deficiencies in sarcoplasmic reticulum calcium
uptake have been hallmarks of advanced heart failure. The complex
of SERCA2a-phospholamban-protein phosphatase 1 has been diffi-
cult to target pharmacologically. However, the encouraging results
from the CUPID Trial in which AAV1.SERCA2a gene transfer was
found to be safe and demonstrated benefit in clinical outcomes, symp-
toms, functional status, NT-proBNP, and cardiac structure in a phase
2 study have once again validated calcium cycling as being an impor-
tant target for heart failure treatment. For this reason, I-1c with its
additional benefits is emerging as an important and valid target for the
treatment of heart failure. In this research report, we describe positive
impacts of I-1c delivery using the AAV9 vector to a clinically relevant
large animal model of heart failure.
Conclusions—In this preclinical model of heart failure, overexpres-
sion of I-1c by intracoronary in vivo gene transfer preserved cardiac
function and reduced the scar size.6
Echocardiography-Guided Left
Ventricular Lead Placement for Cardiac
Resynchronization Therapy: Results of the
Speckle Tracking Assisted Resynchronization
Therapy for Electrode Region Trial
Summary—Cardiac resynchronization therapy (CRT) improves
mortality and morbidity in patients with heart failure with wide QRS
complex and diminished left ventricular (LV) function, but many
patients do not respond to this therapy. The reasons for the lack of
response to CRT remain ill-defined. The Speckle Tracking Assisted
Resynchronization Therapy for Electrode Region (STARTER) was
a prospective, double-blind, randomized controlled trial that tested
the hypothesis that an incremental benefit to CRT would be gained
by echo-guided (EG) transvenous LV lead placement versus a rou-
tine fluoroscopic approach. EG LV lead placement was attempted at
the site of latest time-to-peak radial strain by speckle tracking echo-
cardiography. STARTER enrolled 187 class II to IV heart failure
patients: 110 were randomized to EG and 77 to routine strategies.
 e16  Circulation  January 14, 2014
Primary events included 30 deaths and 37 heart failure hospitaliza-
tions over 1.8 years. Using intention-to-treat, patients randomized to
an EG strategy had a significantly more favorable event-free survival
(hazard ratio, 0.48; 95% confidence interval, 0.28–0.82; P=0.006).
Exact or adjacent concordance of LV lead with latest site could be
achieved in 85% of the EG group and occurred fortuitously in 66%
of controls (P=0.010) and was associated with an improvement in
event-free survival (hazard ratio, 0.40, 95% confidence interval,
­ when analyzed by intention to treat.9
0.22–0.71; P=0.002). STARTER demonstrated that a strategy of EG
LV lead placement for CRT improves patient outcomes by reducing
the combined risk of death or heart failure hospitalizations. These
data have direct implications on the approach to implant CRT devices.
Conclusions—A strategy of EG LV lead placement for cardiac resyn-
chronization therapy improved patient outcomes by reducing the
combined risk of death or HF hospitalizations and has implications
for delivery of cardiac resynchronization therapy.7
Right Ventricular Function, Pulmonary
Pressure Estimation, and Clinical Outcomes
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in Cardiac Resynchronization Therapy
Summary—Right ventricular function (RVF) is a known predictor of
adverse outcome in patients with heart failure. We assessed RVF at
baseline and follow-up in patients being randomized to cardiac resyn-
chronization therapy or implantable cardioverter defibrillator only in
the Multicenter Automatic Defibrillator Implantation Trial-Cardiac
Resynchronization Therapy Trial. Although baseline RVF was well
preserved in this relatively low-risk New York Heart Association class
I and II population and was not itself a predictor of outcome, RVF did
improve with cardiac resynchronization therapy and those patients
with the best right ventricular function at 1 year had the best subse-
quent outcomes. These data suggest that right ventricular function
may be a marker for cardiac resynchronization therapy response, and
improvement in RVF may identify a group of patients who will have
lowest subsequent event rates after cardiac resynchronization therapy.
Conclusions—In this population with mild heart failure symptoms,
CRT was associated with improvement in RVF, which improved
in parallel with improvement in left ventricular function. Patients
with the best RVF at 1 year demonstrated the lowest subsequent
event rates.8
Influence of Crossover on Mortality in a
Randomized Study of Revascularization
in Patients With Systolic Heart Failure
and Coronary Artery Disease
Summary—The international, multicenter Surgical Treatment for
Ischemic Heart Failure (STICH) trial had identified a 14% relative
risk reduction in mortality of coronary artery bypass graft versus
medical therapy alone. However, this risk reduction was not statis-
tically significant. We illustrate in this article that crossover events
within the first year of randomization diluted the difference between
the 2 treatment options because all medical therapy alone patients had
higher 5-year mortality than all coronary artery bypass graft patients.
Importantly, we analyzed the reasons for such crossover events and
were unable to identify predictable patterns or risk profiles that char-
acterized the crossover patients. In other words, we provide strong
support for the conclusion that crossover events were random and not
associated with the patients perceived risk at the time of randomiza-
tion or thereafter. This information should, therefore, be helpful for
advising all patients with systolic heart failure and coronary artery
disease amenable for bypass surgery with respect to treatment options
until definitive information on all-cause mortality is available by the
STICH Extension Study.
Conclusions—CABG reduced mortality in both the per-protocol and
crossover STICH patient populations. Crossover from assigned ther-
apy, therefore, diminished the impact of CABG on survival in STICH
Physical Fitness and Risk for Heart
Failure and Coronary Artery Disease
Summary—Physical activity and cardiorespiratory fitness are
important determinants of long-term cardiovascular disease mortal-
ity. Multiple studies have shown a strong and consistent association
between a single measurement of fitness in midlife and risk of car-
diovascular disease mortality decades later. However, limited data
exist on the association between midlife fitness and nonfatal car-
diovascular disease events, such as hospitalization for heart failure
and myocardial infarction at a later age. The aim of this study was
to determine the association between midlife physical fitness levels
and the long-term risk for heart failure and acute myocardial infarc-
tion using data from Cooper Center Longitudinal Study participants
linked to Medicare utilization data. We found that low midlife fit-
ness was associated with a significantly higher risk for heart fail-
ure hospitalization and acute myocardial infarction at a later age.
Moreover, the magnitude of the association between low fitness and
heart failure hospitalization was nearly twice that observed for the
association between fitness and acute myocardial infarction. These
findings highlight the importance of heart failure risk in the path-
way from low fitness to cardiovascular disease mortality. Further
research is warranted to determine the biological mechanisms
through which fitness in middle-age might influence heart failure
risk in the elderly.
Conclusions—Fitness in healthy, middle-aged adults is more strongly
associated with heart failure hospitalization than acute myocardial
infarction outcomes decades later in older age.10
Do Countries or Hospitals With Longer
Hospital Stays for Acute Heart Failure
Have Lower Readmission Rates?:
Findings From ASCEND-HF
Summary—Heart failure (HF) is the leading cause of early readmis-
sions in the United States and is a focus of payers and policy makers.
Currently, there are few interventions and processes of care associ-
ated with reductions in 30-day readmission rates. In this analysis of
data from the largest multinational trial to date among patients with
acute decompensated heart failure, we found that patients treated in
countries with longer lengths of stay for heart failure hospitalizations
had significantly lower rates of early readmission. Among US sites,
we found that each 1-day increase in the mean length of stay was
independently associated with a lower risk of all-cause and heart
failure readmission. Consistent with observations in other disease
states, our findings provide evidence that shorter lengths of stay for
HF patients are associated with less favorable outcomes in terms of
this metric. Identifying the appropriate length of stay for patients and
efficient transitions of care to ambulatory settings are critical compo-
nents of providing not only patient-centered care but also more cost-
effective care.
Conclusions—Countries with longer length of stay for heart failure
hospitalizations had significantly lower rates of readmission within
 The Editors   Circ Heart Failure 2013 Editor's Picks    e17
30 days of randomization. These findings may have implications for
developing strategies to prevent readmission, defining quality mea-
sures, and designing clinical trials in acute heart failure.11
Risk Stratification and Transplant
Benefit in Children Listed for Heart
Transplant in the United States
Summary—The sickest children among those listed for heart trans-
plant (HT) are also at a higher risk of post-transplant mortality.
Although it may be assumed that the sicker child waiting for HT is
more likely to benefit from transplant, the actual relationship between
heart failure severity and transplant benefit is unknown. We defined
transplant benefit as percentage reduction in risk of 1-year mortality
on receiving HT and analyzed all 2979 children aged <18 years listed
for first HT in the United States between July 2004 and December
2010. We stratified study children into 10 groups (deciles) based on
increasing risk of death or becoming too sick to transplant within
90 days of listing. The groups were followed up for 1 year to assess
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cumulative 1-year wait-list mortality. We estimated the risk of 1-year
post-transplant mortality (or graft loss) on receiving HT close to list-
ing in each of the 10 risk groups. Overall, 18% of listed children died
or became too sick to transplant within 1 year. Of 2034 children who
received HT, 10.8% died within 1 year. The risk of 90-day wait-list
mortality increased from 2.4% to 51.6% from the first to the tenth
risk group. Transplant benefit increased progressively among the 10
risk groups. However, transplant benefit for children in the top 5%
of risk was lower than estimated benefit for children in the 91st to
95th percentile of risk. We conclude that the sicker children on the
wait-list benefit more from HT unless the post-transplant mortality is
predicted to be very high.
Conclusions—Sicker children on the wait-list benefit more from
HT unless the post-transplant mortality is predicted to be very high.
Whether consideration of transplant benefit in allocation policy
can improve overall survival among listed children requires further
analysis.12
Risk Prediction Models for Mortality
in Ambulatory Patients With Heart
Failure: A Systematic Review
Summary—Many models are available to predict adverse outcomes
in patients with heart failure. Clinicians and researchers wishing to
use prognostic models would benefit from knowledge of their char-
acteristics and performance. Therefore, we performed a systematic
review to identify studies evaluating risk prediction models for mor-
tality in ambulatory patients with HF, to describe their performance
and clinical applicability. This systematic review included 34 studies
testing 20 models. Only 5 models were validated in an independent
cohort: the Heart Failure Survival Score, the Seattle Heart Failure
Model, the PACE risk score, a model by Frankenstein et al,12 and
the SHOCKED predictors. The Heart Failure Survival Score, vali-
dated in 8 cohorts, showed poor-to-modest discrimination (c-statistic,
0.56–0.79), being lower in the more recent validation studies pos-
sibly because of greater use of β-blockers and implantable cardiac
defibrillators. The Seattle Heart Failure Model was validated in 14
cohorts describing poor-to-acceptable discrimination (0.63–0.81),
remaining relatively stable over time. Both models reported adequate
calibration, although overestimating survival in some specific pop-
ulations. The other 3 models were validated in a cohort each, with
­poor-to-modest discrimination (0.66–0.74). There were no studies
reporting the clinical impact of medical decision-making guided
by the use of these models. In conclusion, externally validated HF
models showed inconsistent performance. The Heart Failure Survival
Score and Seattle Heart Failure Model demonstrated modest discrim-
ination and questionable calibration. A new model derived from con-
temporary patient cohorts may be required for improved prognostic
performance.
Conclusions—Externally validated heart failure models showed
inconsistent performance. The Heart Failure Survival Score and
Seattle Heart Failure Model demonstrated modest discrimination
and questionable calibration. A new model derived from contem-
porary patient cohorts may be required for improved prognostic
performance.13
Race Influences the Safety and Efficacy of
Spironolactone in Severe Heart Failure
Summary—In this post hoc analysis of the Randomized Aldactone
Evalulation Study (RALES), we assessed hyperkalemia and clini-
cal outcomes among African American (AA) participants (n=120)
versus non-AA participants (n=1543) randomized to spironolactone
or placebo for the treatment of moderate to severe heart failure.
Baseline potassium was similar between AA and non-AA groups.
After 1 month, potassium levels rose significantly in non-AA partici-
pants randomized to spironolactone but not in AA individuals, and
levels remained elevated among non-AA throughout the trial, with
a significant race by treatment interaction for change in potassium
levels (P=0.03). Compared with AA, non-AA had higher rates of
hyperkalemia and lower rates of hypokalemia. Moreover, in non-AA
participants, spironolactone was associated with a 30% reduction in
the risk for all-cause mortality and a 36% reduction in the risk for
the composite outcome of death or hospitalization for heart failure.
By contrast, in AA participants, spironolactone use was associated
with no effect on mortality or death or hospitalizations for heart fail-
ure, with a significant race by treatment interaction for the combined
outcome of death or hospitalizations for heart failure (P=0.038).
These hypothesis-generating findings suggest that while AA exhibit
less hyperkalemia when taking spironolactone, they may also derive
less clinical benefit. Future prospective studies should assess the role
of mineralocorticoid receptor antagonists in AA patients with heart
failure.
Conclusions—AAs with HF exhibited less hyperkalemia and more
hypokalemia with spironolactone compared with non-AAs and
seemed to derive less clinical benefit. These hypothesis-generating
findings suggest that safety and efficacy of mineralocorticoid receptor
antagonists may differ by race.14
Validity and Reliability of a Novel Slow
Cuff-Deflation System for Noninvasive
Blood Pressure Monitoring in Patients With
Continuous-Flow Left Ventricular Assist Device
Summary—This study prospectively analyzes invasive and
noninvasive blood pressure (BP) measurements in patients on
­continuous-flow left ventricular assist device support. Due to the
reduced pulse pressure, noninvasive BP measurements are challeng-
ing in c­ ontinuous-flow left ventricular assist device patients; hence,
Doppler ultrasound is frequently used. However, the relationship of
Doppler BP to systolic BP and mean arterial pressure remains uncer-
tain. In addition, Doppler BP measurement cannot be performed by
patients at home, requiring trained personnel in the hospital setting.
Our results indicate that (1) contrary to previous reports, Doppler
BP better reflects systolic BP rather than mean arterial pressure; (2)
 e18  Circulation  January 14, 2014
Terumo Elemano (an automated BP device with a slow cuff-deflation
setting to enhance sensitivity) has a high rate of measurement suc-
cess, particularly in comparison to traditional automated BP devices;
and (3) Terumo Elemano BP monitor provides an accurate and reli-
able measurement of systolic BP and of mean arterial pressure. The
data from this study may allow physicians to more accurately opti-
mize medical treatment both in the inpatient and outpatient setting.
Further studies are warranted to test whether home BP monitoring
may translate into fewer hypo- and hypertension-related events and,
potentially, into a higher rate of myocardial recovery by enabling
faster uptitration of neurohormonal blockade.
Conclusions—Doppler BP more closely approximates SBP than
MAP. Terumo Elemano was successful, reliable, and valid when
compared with A-line and Doppler.15
Incidence and Predictors of ­End-
Stage Renal Disease in Outpatients
With Systolic Heart Failure
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Summary—Renal dysfunction is the most frequent comorbidity in
systolic heart failure (HF). For years it has been known that renal
dysfunction is associated with an increased risk of death and risk of
a HF admission. It is also known that therapy that improves survival
in systolic HF has renal side effects and that monitoring of plasma
creatinine and plasma potassium is necessary. Despite several pub-
lications of the role of the kidneys in HF it is still unknown if the
proportion of patients with HF and renal dysfunction progress to
end-stage renal disease (ESRD) requiring renal replacement therapy.
In the present study, we investigated whether renal dysfunction pro-
gresses to ESRD in a large cohort of outpatients with systolic HF and
identified predictors for ESRD. We observed that the incidence of
ESRD is low and that the risk of death is substantially increased on
progression. A low estimated glomerular filtration rate, young age,
need of diuretics, and hypertension were associated with progression
to ESRD. Our analyses suggest that despite improved survival in sys-
tolic HF, risk of death is still a much larger clinical problem than risk
of ESRD, and that in patients with stable HF, fear of ESRD in patients
with moderate renal dysfunction should not discourage uptitration of
guideline-based therapy in HF clinics where renal function is closely
monitored. Overall, the need of renal replacement therapy in outpa-
tients with systolic HF is low.
Conclusions—ESRD is rare in outpatients with systolic HF and is
mainly observed in patients with an eGFR <30 mL/min per 1.73
m2. A low eGFR, age <60 years, need of diuretics, and uncontrolled
hypertension identify patients with an increased risk for ESRD.16
Comparable Performance of the Kansas
City Cardiomyopathy Questionnaire in
Patients With Heart Failure With Preserved
and Reduced Ejection Fraction
Summary—Heart failure with preserved ejection fraction (HFpEF)
is a growing epidemic in the United States and comprises approxi-
mately half of heart failure hospitalizations annually. Beyond its
effect on mortality, HFpEF can also have a profound impact on
patients’ quality of life. Yet, there have been no established meth-
ods for quantifying health status in patients with HFpEF. Although
it may be tempting to use previously tested disease-specific health
status measures from the studies done with HF with reduced EF,
patients with HFpEF have distinct demographics and comorbidi-
ties. Hence, such an extrapolation might be inapplicable. In this
article, we evaluated the Kansas City Cardiomyopathy Questionnaire
(KCCQ), a validated measure of heart failure in HF with reduced
EF, in patients with HFpEF using a prospectively collected insti-
tutional heart failure registry. We found that the predictive validity
of the KCCQ overall summary scores was no different in HFpEF
compared with HF with reduced EF. The association between New
York Heart Association class was strongly associated with KCCQ
summary scores as well, regardless of ejection fraction. Finally, in
HFpEF, the KCCQ domains demonstrated high internal consistency.
Together, these findings demonstrate that the KCCQ seems to be a
valid and reliable tool to assess health status in heart failure, includ-
ing in HFpEF. Future studies are needed to assess responsiveness of
the questionnaire to clinical change in these patients.
Conclusions—Among patients with HFpEF, the KCCQ seems to be a
valid and reliable measure of health status and offers excellent prog-
nostic ability. Future studies should extend and replicate our findings,
including the establishment of its responsiveness to clinical change.17
Low-Sodium DASH Diet Improves
Diastolic Function and Ventricular–Arterial
Coupling in Hypertensive Heart Failure
With Preserved Ejection Fraction
Summary—Heart failure with preserved ejection fraction (HFPEF)
is associated with failure of cardiovascular reserve in multiple
domains, including ventricular diastolic function and ventric-
ular–vascular coupling. Several salt-sensitive animal models
develop hypertension and HFPEF during high sodium intake. In
­salt-sensitive humans without heart failure, the sodium-restricted
dietary approaches to stop hypertension (DASH/SRD) eating
pattern reduces blood pressure and improves vascular function.
Observational cohorts suggest that a similar phenotype exists in
human HFPEF, but the effects of dietary modification on cardio-
vascular function in patients with HFPEF are largely unknown. In
a proof-of-concept pilot study, 13 patients with stable hyperten-
sive HFPEF consumed the DASH/SRD (50 mmol sodium/2100
kcal target) for 21 days. We previously demonstrated reductions in
ambulatory blood pressure and oxidative stress in this cohort and
hypothesized that the DASH/SRD would also improve diastolic
function and ventricular–vascular coupling. Diastolic function was
assessed using the parametrized diastolic formalism that uses mitral
inflow profiles to quantify diastolic function in terms of relaxation
(c) and stiffness (k) constants. Arterial elastance (Ea), ventricular
end-systolic elastance (Ees), and the ventricular–arterial coupling
ratio (Ees/Ea) were determined using previously published methods.
The DASH/SRD was associated with significant reductions in c and
k, indicating improved diastolic function, as well as Ea, signifying
reduced ventricular afterload. Ventricular–vascular coupling also
improved, as evidenced by increases in the Ees/Ea ratio, the maxi-
mum rate of change of pressure-normalized stress and the left ven-
tricular mechanical energetic efficiency. These preliminary findings
support further dietary modification studies to clarify links between
the salt-sensitive phenotype and hypertensive HFPEF.
Conclusions—In patients with hypertensive HFPEF, the
s­ odium-restricted DASH diet was associated with favorable changes
in ventricular diastolic function, arterial elastance, and ventricular–
arterial coupling.18
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 Circulation: Heart Failure: 2013 Editors' Picks
The Editors

Circulation. 2014;129:e14-e19
doi: 10.1161/CIRCULATIONAHA.113.008229
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