International Journal of Cardiology 203 (2016) 800–802
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International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Six-minute walk test in moderate to severe heart failure with preserved
ejection fraction: Useful for functional capacity assessment?☆
Patricia Palau a,⁎, Eloy Domínguez b, Eduardo Núñez c, Juan Sanchis c, Enrique Santas c, Julio Núñez c
a
Cardiology Department, Hospital de La Plana, Universitat Jaume I, Castellón, Spain
b
Cardiology Department, Hospital General de Castellón, Universitat Jaume I, Castellón, Spain
c
Cardiology Department, Hospital Clínico Universitario, INCLIVA, Universitat de València, Valencia, Spain
a r t i c l e i n f o
Article history:
Received 27 August 2015
Received in revised form 16 October 2015
Accepted 8 November 2015
Available online 10 November 2015
Keywords:
Heart failure with preserved ejection fraction
Functional capacity assessment
Peak VO2
Six-minute walk test
Despite improvements in medical treatment and prevention, heart
failure (HF) remains a major cause of morbidity and mortality world-
wide [1]. Currently, HF with preserved ejection fraction (HFpEF) has be-
come the most prevalent form of HF in elderly patients [2,3]. The
cardinal features in HF, aside from left ventricular systolic function,
are exertional dyspnea and reduced aerobic capacity. Although the
most accurate expression of exercise tolerance and severity in HF is
measured by peak oxygen uptake (peak VO2), its assessment is not
widely available in daily clinical practice. In patients with HF and re-
duced ejection fraction (HFrEF), numerous surrogates of exercise toler-
ance and HF severity such as New York Heart Association (NYHA) class,
Minnesota Living With Heart Failure Questionnaire (MLHF) and
distance-walked in 6 min (6-MWT) have shown to be well-correlated
with peak VO2 [4–7]. Nevertheless, this is not true for HFpEF, where
the clinical indicators of reduced peak VO2 have not been well-defined.
In this work, we sought to evaluate the clinical predictors for peak
VO2 in patients with stable moderate to severe HFpEF (NYHA II–IV).
With this purpose in mind, we included 26 outpatients with HFpEF
followed in the outpatient HF clinic of a single academic center. The
HFpEF diagnosis was performed by trained cardiologists according to
☆ Funding sources: This work was supported in part by grants from: Sociedad Española
de Cardiología: Investigación Clínica en Cardiología, Grant SEC 2015 and Red de
Investigación Cardiovascular; Programa 7 (RD12/0042/0010) FEDER.
⁎ Corresponding author at: Cardiology Department, Hospital de La Plana, Ctra de Vila-
real a Borriana, km. 0,5, 12540 Vila-real, Spain.
E-mail address: patri.palau@gmail.com (P. Palau).
http://dx.doi.org/10.1016/j.ijcard.2015.11.074
0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
the definition proposed by the European Society of Cardiology guide-
lines [8]. All of them met the following inclusion criteria: a) previous
history of symptomatic heart failure NYHA functional class ≥ II);
b) normal left ventricular ejection fraction (ejection fraction N 0.50
by the Simpson method and end-diastolic diameter b 60 mm);
c) structural heart disease (left ventricle hypertrophy/left atrial enlarge-
ment) and/or diastolic dysfunction estimated by 2D echocardiography;
d) previous admission for acute heart failure (AHF); and e) clinical sta-
bility, without hospital admissions in the past 3 months. Patients were
excluded if they could not perform a valid baseline exercise test or pre-
sented any medical condition such as: significant primary moderate to
severe valvular disease; acute coronary syndrome or cardiac surgery
within the previous three months; significant primary pulmonary dis-
ease (including pulmonary arterial hypertension, chronic thromboem-
bolic pulmonary disease or chronic obstructive pulmonary disease);
signs of ischemia during cardiopulmonary exercise testing (CPET);
and any other comorbidity with an expectancy of life less than one year.
This study was approved by an institutional review committee
conforming to the ethical guidelines of the 1975 Declaration of Helsinki
and all patients gave an informed consent. Patients included underwent
incremental and symptom-limited CPET on a bicycle ergometer, 6-
MWT, echocardiography, physician-perceived NYHA class, clinical ex-
amination, laboratory test, and assessment of quality of life (QoL) by
the MLHF.
Pearson correlation coefficient was used to assess the correlation be-
tween log-transformed peak VO2 and the different functional, echocar-
diographic and laboratory parameters. A multivariable linear regression
analysis was performed to identify clinical covariates associated with
the mean peak VO2. The linearity assumption for all continuous covari-
ates was simultaneously tested and, when appropriate, transformed
with fractional polynomials. A 2-sided p-value of p b 0.05 was consid-
ered to be statistically significant for all analyses. All analyses were per-
formed using Stata 13.1.
The median (interquartile range) of age was 73 (66–76) years;
half of patients were female and 70% displayed NYHA III. The mean
(SD) and median (IQR) for peak VO2 were 10.2 ± 3.2 and 10 (7.6–
12.5) mL/min/kg. Baseline characteristics of the sample are summa-
rized in Table 1. In a univariate setting, peak VO2 showed positive and
significant correlation with 6-MWT (r = 0.85, p b 0.01), right ventricu-
lar function (TAPSE) (r = 0.47, p = 0.01), hemoglobin (r = 0.64,
p b 0.01) and hematocrit (r = 0.57, p b 0.01) On the contrary, peak
 P. Palau et al. / International Journal of Cardiology 203 (2016) 800–802 801

Table 1 (r = − 0.38, p = 0.05). In a multivariate setting, and ranked in the

Baseline characteristics of study population. order of importance (drop in R2), distance in 6-MWT (79%), hemoglo-
Data are presented as the median ± interquartile range; categorical variables as percent-
ages.
bin (5%), creatinine (5%) and left atrial volume (3%) were the most im-
6-MWT; distance walked in 6 min; ACEI, angiotensin-converting enzyme inhibitor; ARB, portant covariates predicting the mean of peak VO2. A positive
angiotensin II receptor blocker; BMI, body mass index; Cr, creatinine; eGFR, estimated glo- relationship was found for distance in 6MWT and hemoglobin, whereas
merular filtration rate using the Modification of Diet in Renal Disease formula; LAVI, left for the rest of the covariates included in the final model a negative rela-
atrial volume index; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular
tionship was found. Plots depicting the direction and magnitude of
ejection fraction; LVMI, left ventricular mass index; METs, metabolic equivalents; MLHF,
Minnesota Living with Heart Failure questionnaire score; MR, mitral regurgitation grade; these relationships are presented in Fig. 1. The multivariate model
NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; accounted for 79.3% of the variability in peak VO2.
PASP, pulmonary artery systolic pressure; Peak VO2, peak oxygen uptake; QoL, quality of Evidence available to date has shown that patients with HFpEF have
life; RER, respiratory gas exchange ratio at termination; TAPSE, tricuspid annular plane markedly reduced functional capacity as objectively measured by peak
systolic excursion; TR, tricuspid regurgitation grade; VE/VCO2 slope, relationship between
minute ventilation and the rate of CO2 elimination; VO2 AT, oxygen uptake at anaerobic
VO2 [9]. Whereas 6-MWT has been widely used as a surrogate of peak
threshold. VO2 in HFrEF patients to evaluate exercise tolerance, little is known
about its utility in HFpEF. Our results suggest that 6-MWT is a simple
Variables
and reliable test to predict functional capacity in moderate to severe
Demographic and medical history HFpEF. Previous studies done in middle-aged patients with either mod-
Age, years 73 (66–76)
erate to advance HFrEF or mild diastolic HF (NYHA I–II) [4–7] have dem-
Female, n (%) 13 (50)
BMI, kg/m2 31 (28–36.3) onstrated a positive correlation between the 6-MWT and peak VO2 [7];
Hypertension, n (%) 25 (96) however, to our knowledge, this is the first study assessing the clinical
Dyslipidemia, n (%) 23 (88) determinants of peak VO2 in patients with moderate to severe HFpEF.
Diabetes mellitus, n (%) 15 (58) From all predictor tested, 6-MWT had the highest correlation (r =
Insulin-dependent diabetes mellitus, n (%) 9 (35)
0.85, p b 0.01). Moreover, our findings are in line with the concept
Ischemic heart disease, n (%) 12 (46)
Baseline NYHA Class III/IV, n (%) 18 (70) that these patients [10] exercise mainly on anaerobic metabolism and
Past smoker, n (%) 11 (42) reach near to or even maximal oxygen uptake during 6-MWT. We be-
Atrial fibrillation, n (%) 9 (35) lieve that our findings may have clinical impact since the availability
Pacemarker, n (%) 2 (8)
of CPET is limited in daily clinical practice. The main limitation to ac-
Laboratory knowledge is the small size of the study.
Hemoglobin, g/dL 13 (11.6–13.8) In conclusion, we found that 6-MWT is a valid and reliable test to
Cr, mg/dL 1.1 (0.84–1.69)
predict functional capacity in patients with moderate to severe HFpEF.
eGFR, ml/min/m2 58.5 (39–71)
NT-proBNP, pg/mL 1068 (289–1932)
Further studies are warranted to confirm these results and to explore
the clinical utility of this test for risk stratification.
Echocardiography
LVEFa, % 72 (65–77)
TAPSE, mm 21 (19–24) Conflict of interest
LAVI, mL/m2 47 (39–53.4)
LVEDD, mm 46.5 (43–53) The authors have no other funding, financial relationships, or con-
LVMI, g/m2 118 (98–149)
flicts of interest to disclose.
MR 1 (0–1)
TR 1 (0–3)
E/E′ ratio 16.2 (10.2–21.6) References
PASPb, mm Hg 45 (39–60)
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802 P. Palau et al. / International Journal of Cardiology 203 (2016) 800–802

Fig. 1. Functional form of the adjusted association among different clinical covariates and peak VO2. Variables modeled with fractional polynomials. Cr, creatinine; distance 6-MWT, dis-
tance walked in the 6-minute walk test; Hb, hemoglobin; peak VO2, peak oxygen uptake.