reduced EF (HFrEF) and 42 HF preserved EF (HFpEF)], after which HRR was measured. HRR was defined as the
difference between heart rate at peak exercise and 1 min following test termination. Patients were assessed for
major cardiac events during a mean follow-up period of 22.8+22.1 months. There were 50 major cardiac events
during the tracking period. Univariate Cox regression analysis results identified HRR after both the 6MWT and
CPX as a significant (P , 0.001) predictor of adverse events. Multivariate Cox regression analysis revealed that
dichotomized HRR after the 6MWT and CPX was the strongest predictor of survival (x261.1 and 53.8, respectively;
P , 0.001), with LVEF (residual x26.1, P , 0.05) adding significant prognostic value to the 6MWT model and ven-
tilatory efficiency (the VE/VCO2slope) (residual x26.6, P , 0 .05) adding significant prognostic value to the CPX
HRR after the 6MWT is a powerful prognosticator that performs similarly to HRR after maximal exercise. If con-
firmed in subsequent studies, 6MWT HRR should replace 6MWT distance as the reference criterion 6MWT
measure to consider when grading cardiovascular risk in HF patients.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Heart failure † Heart rate recovery † 6 Min walk test † Cardiopulmonary exercise test
Heart rate recovery after the 6 min walk test
rather than distance ambulated is a powerful
prognostic indicator in heart failure with reduced
and preserved ejection fraction: a comparison
with cardiopulmonary exercise testing
Lawrence P. Cahalin1, Ross Arena2, Valentina Labate3, Francesco Bandera3,
Carl J. Lavie4, and Marco Guazzi3*
1Department of Physical Therapy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA;2Division of Physical Therapy, Department of Orthopaedics and
Rehabilitation, and Division of Cardiology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA;3Cardiology, IRCCS Policlinico
San Donato, University of Milano, San Donato Milanese, Italy; and4Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School,
The University of Queensland School of Medicine, New Orleans, LA, and Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
Received 27 August 2012; revised 15 November 2012; accepted 23 November 2012; online publish-ahead-of-print 8 February 2013
Heart rate recovery (HRR) appears to be a robust prognostic marker in heart failure (HF). When using the 6 min
walk test (6MWT) in HF, distance ambulated is generally the reference prognostic variable. We hypothesized that
HRR after the 6MWT would be a better prognostic measure than distance ambulated.
A 6MWT and cardiopulmonary exercise testing (CPX) were randomly performed in 258 HF patients [216 HF with
The 6 min walk test (6MWT) is a functional performance measure
that has received substantial attention as a tool to examine the
functional status of patients with heart and lung disease.1–3The
distance ambulated during the 6MWT has been most studied,
with a distance of 300 m being a threshold below which a
patient with heart failure (HF) appears to have poorer prognosis.2,3
A 6MWT distance of 300 m was also recently found to be a signifi-
cant predictor of all-cause mortality in a multivariate model
*Corresponding author. Tel:/Fax: +39 02 52774966, Email: firstname.lastname@example.org
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: email@example.com.
European Journal of Heart Failure (2013) 15, 519–527
examining predictors of clinical outcome in elderly patients with
advanced HF.4Even so, cardiopulmonary exercise testing (CPX)
is considered the clinical gold standard for the functional assess-
ment of patients with systolic HF.5,6A variety of CPX measure-
ments have been found to provide substantial prognostic value in
the assessment of patients with HF, and include peak VO2, the
minute ventilation/carbon dioxide production (VE/VCO2) slope,
and exercise oscillatory ventilation (EOV).
An additional measurement which appears to have substantial
prognostic value in patients with and without HF is the trajectory
of heart rate (HR) decline after test termination, commonly re-
ferred to as heart rate recovery (HRR).7–13A low HRR value
has consistently been observed to be a marker of increased mor-
tality.7–13The rapid deceleration of the HR after exercise appears
to reflect parasympathetic reactivation, providing a unique per-
spective regarding the health and function of the autonomic
nervous system.7–13A HRR ≤12 beats at 1 min post-exercise
has been proposed as a threshold to define an abnormal
response,12,13which is supported by other investigators.10,11
The clinical utility of HRR does not appear to be dependent on
maximal exercise since two previous large studies administering
symptom-limited exercise tests (terminating exercise at 85–90%
of age-predicted peak HR) found that an abnormal HRR remained
a prognostic index despite achieving less than age-predicted
maximal HR values.14,15Because of previous findings, we believed
it important to examine the prognostic utility of HRR after an
accepted submaximal functional assessment such as the 6MWT,
testing the hypothesis that it may become a valuable submaximal
variable in the prognostic work-up of HF patients.
This was a prospective study of patients with HF referred for functional
assessment at San Paolo Hospital, Milan, Italy. Two hundred and
fifty-eight patients diagnosed with HF who underwent a 6MWT and
CPX between June 1999 and December 2008 were included in the
study. Patients who were unable to perform either exercise assess-
ment were excluded from the study. All patients were in NYHA func-
tional classes II and III. Patients with both HF with reduced EF (HFrEF)
and HF with preserved EF (HFpEF) were enrolled. HFpEF was defined
using the following criteria: (i) signs and symptoms of HF; (ii) presence
of preserved LV systolic function (LVEF ≥50%) as assessed by two-
dimensional echocardiography;16and (iii) documentation of mitral
inflow early (E) velocity to mitral annulus early velocity (E′) ≥ 8.17Ap-
proval by the institutional review board was obtained before the study
was initiated, and all patients provided written informed consent to
participate in the study. The investigation conforms with the principles
outlined in the Declaration of Helsinki.
6 min walk test procedures
The 6MWT was performed on a level surface by a physician who was
unaware of echocardiographic, CPX, and clinical results. Each subject
underwent two 6MWTs performed on separate days. The first test
was performed to familiarize the patient with the 6MWT and the
second test was performed to obtain true functional performance. In
80 patients, a third 6MWT was performed to test day-to-day reprodu-
cibility. Patients were instructed to cover the greatest distance possible
during the allotted time, at a self-determined walking speed, and were
allowed to pause and rest when needed. The distance covered was
measured by a body-borne pedometer with which the total number
of steps taken during the 6MWT were used to calculate the 6MWT
distance using the equation reported by Roul et al. (d ¼ y × 10 m/x;
where d ¼ distance ambulated in m; y ¼ total number of steps during
6MWT; and x ¼ number of steps for each subject to cover 10 m).3
The distance ambulated in 6 min was also dichotomized using the com-
monly accepted threshold (6MWT distance ≤ / . 300 m).2,3The HR
was obtained while standing via electrocardiographic telemetry at rest
before the 6MWT, at the end of the 6MWT, and 1 min after
the 6MWT. The 6MWT HR reserve was calculated as the difference
between the HR at the end of the 6MWT and the resting HR. The
6MWT HRR was defined as the difference between the HR at the end
the 6MWT was passive and consisted of stationary standing.
Cardiopulmonary exercise testing
Symptom-limited CPX was performed on a bicycle ergometer for all
subjects. Pharmacological therapy was maintained during CPX. Indivi-
dualized ramp protocols were designed to obtain a duration
between 8 and 10 min. Ventilatory expired gas analysis was performed
using a Sensormedics metabolic cart (Vmax, Yorba Linda, CA, USA).
Before each test, the equipment was calibrated according to the man-
ufacturer’s specifications using reference gases.
Standard 12-lead ECGs were obtained at rest, each minute during
exercise, and for at least 5 min during the recovery phase; blood pres-
sure was measured using a standard cuff sphygmomanometer. The HR
was determined at rest, peak exercise, and at 1 min of recovery. The
percentage age-predicted maximal HR achieved was determined by
the following equation: [peak HR/(220 – age)] × 100. The CPX HR
reserve was calculated as the difference between the peak HR and
resting HR. The CPX HRR was defined as the difference between
peak HR and HR at 1 min following test termination. An active cool-
down period of at least 1 min was employed for all tests. In addition,
minute ventilation [VE; body temperature, pressure, and saturated
(BTPS)], oxygen uptake [VO2; standard temperature, pressure, and
dry (STPD)], and carbon dioxide output (VCO2; STPD) were acquired
breath-by-breath, averaged over 30 s, and printed using rolling averages
every 10 s. The V-slope method was used to measure the anaerobic
threshold.18Peak VO2 and the peak respiratory exchange ratio
(RER) were expressed as the highest 10 s averaged sample obtained
during the last 20 s of testing. VE and VCO2values, acquired from
the initiation of exercise to peak, were input into spreadsheet software
(Microsoft Excel, Microsoft Corp., Bellevue, WA, USA) to calculate the
VE/VCO2slope via least squares linear regression (y ¼ mx + b, where
m ¼ slope). Exercise oscillatory ventilation (EOV) during CPX was
defined as previously described in detail.19,20Briefly, criteria for EOV
included the presence of ≥3 regular oscillatory fluctuations in VE
with a minimal average amplitude of 5 L/min persisting for at least
60% of the entire exercise test. The Modified Borg Rating of Perceived
Exertion (RPE) was also obtained throughout the CPX.21
Test termination criteria consisted of symptoms (i.e. dyspnoea and/
or fatigue), ventricular tachycardia, ≥2 mm of horizontal or downslop-
ing ST-segment depression, or a drop of systolic blood pressure
≥20 mmHg during progressive exercise. A qualified exercise physiolo-
gist with physician supervision conducted each exercise test.
The LV chamber dimensions were evaluated using standard proce-
dures. The LVEF was calculated from two-dimensional apical images
according to Simpson’s method.
L.P. Cahalin et al.
Subjects were followed for major cardiac-related events (i.e. cardiac
death or urgent transplantation) by hospital and outpatient medical
chart review to obtain the high likelihood that all major events were
captured. Any death with a cardiac-related discharge diagnosis was
considered an event. Clinicians conducting the study measurements
were not involved in decisions regarding cause of death or heart
A statistical software package (SPSS 19.0, Chicago, IL, USA) was used
to perform all analyses. Continuous and categorical data are reported
as mean+standard deviation and percentages, respectively. Independ-
ent t-tests and x2tests were used to assess differences in patient char-
acteristics, 6MWT variables, and CPX variables between subjects who
remained event free or suffered a major cardiac event during the track-
ing period and between patients with HFrEF and HFpEF. The area
under the receiver operating characteristic (ROC) curve was com-
pared between the 6MWT distance ambulated and 6MWT HRR,
and between 6MWT HRR and CPX HRR. Additional diagnostic
testing of HRR after the 6MWT and CPX was performed, and included
the calculation of sensitivity, specificity, positive predictive value,
negative predictive value, and accuracy. Univariate Cox regression ana-
lysis was used to assess the prognostic value of key patient character-
istics, 6MWT, and CPX variables. Multivariate Cox regression analysis
(forward stepwise method; entry and removal value 0.05 and 0.10, re-
spectively) was used to assess the prognostic value of the 6MWT vs.
CPX by using two patient characteristics (age and LVEF), four
6MWT variables (6MWT distance, peak HR, 6MWT HR reserve,
and dichotomous 6MWT HRR), and four CPX variables (peak VO2,
the VE/VCO2slope, EOV, and dichotomous CPX HRR) in two separ-
ate models using the 6MWT variables and CPX variables. Hazard
ratios were also determined according to the established dichotomous
classification of HRR (≤ / . 12 beats)9–12as well as 6MWT (6MWT
distance ≤ / . 300 m).2,3Kaplan–Meier analysis was used to assess
the differences in survival among subjects according to dichotomous
variate Cox regression analyses of survival in patients with HFrEF and
HFpEF using the same 6MWT and CPX variables as above were per-
formed. Separate multivariate Cox regression analyses of survival in
patients with HFrEF using the same 6MWT and CPX variables as
above were also performed. In patients with HFpEF, separate multivari-
ate Cox regression analyses of survival using two 6MWT variables
Height (cm) 169.7+7.4
Weight (kg) 76.4 +14.6
COPD (%) 24
6MWT distance (m)357+95
6MWT resting HR (b.p.m.) 70.9+8.3
6MWT peak HR (b.p.m.) 123+16.6
6MWT HRR (beats)12.9+3.0
6MWT HR reserve (beats)52.0+18.2
CPX resting HR (b.p.m.)73.2+9.2
CPX peak HR (b.pm.) 130.6+17.1
CPX HRR (beats) 18.5+3.2
CPX HR reserve (beats)57.5+19.4
CPX Borg RPE (0–10)5.8+1.1
CPX peak RER1.06+0.13
CPX peak VO2(mL O2/kg/min)15.4+4.8
CPX VO2AT (mL O2/kg/min)11.3+3.6
CPX EOV (%) 36.5
ACE inhibitors (%) 82
Beta-blockade (%) 60
Anti-aldosterone (%) 36
Table 1 Differences in patient characteristics, 6 min walk test, and cardiopulmonary exercise testing variables according
to major cardiac event status
Event free (n 5 208) Major cardiac
event (n 5 50)
AT, anaerobic threshold; CPX, cardiopulmonary exercise testing; EOV, exercise oscillatory ventilation; HR, heart rate; HRR, heart rate recovery; 6MWT, 6 min walk test; RER,
respiratory exchange ratio; RPE, rating of perceived exertion; VE/VCO2, minute ventilation/carbon dioxide production; VO2, oxygen consumption.
Heart rate recovery after 6MWT is a powerful prognostic indicator in HF
Figure 1 Receiver operating characteristic curve comparing (A) 6MWT HRR and 6MWT distance and (B) 6MWT HRR and CPX HRR.
6MWT, 6 min walk test; HRR, heart rate recovery; CPX, cardiopulmonary exercise testing.
L.P. Cahalin et al.
(VE/VCO2slope and CPX dichotomous HRR) were also performed.
A P-value ,0.05 was considered statistically significant for all tests.
Follow-up on survival
No patients were lost to follow-up during the mean follow-up
period of 22.8+22.1 months. There were 50 cardiac-related
events (48 deaths and 2 urgent transplantations) during the track-
ing period, yielding an annual event rate of 9.3%. None of the sub-
jects in the study experienced a non-cardiac-related death. The
mortality rate of patients diagnosed with non-ischaemic vs ischae-
mic aetiology of HF was not significantly different between survi-
vors and non-survivors (65%, 82/126 vs. 60%, 18/30; P ¼ 0.81).
The mortality rate of patients diagnosed with HFrEF (19.1%, 41
of 215) and HFpEF (17.1%, 7 of 41) was similar (P ¼ 0.76).
Table 1 lists patient characteristics as well as 6MWT and CPX vari-
ables between subjects who were event free and those who suf-
fered a major cardiac event. Based on the patient characteristics
and CPX results presented in Table 1, the patient population
represents a mixed group with advanced and intermediate levels
of HF. There were significant differences for all variables, with
the exception of height, weight, 6MWT distance ambulated, and
peak RER. Subjects who suffered a major cardiac event were sig-
nificantly older, had poorer cardiac performance, and had a
higher resting HR and lower peak HR (yielding a lower HR
reserve). Moreover, subjects suffering a major cardiac event had
significantly higher Borg RPE scores, a lower peak VO2, and a
greater VE/VCO2slope. A greater percentage of subjects suffering
an event also presented with EOV. Although not statistically signifi-
cant (P ¼ 0.75), a greater number of patients with ischaemic HF
(n ¼ 32) experienced a major cardiac event compared with
patients with non-ischaemic HF (n ¼ 18).
The characteristics of patients with HFrEF (n ¼ 216) and HFpEF
(n ¼ 42) were relatively similar except for significant differences in
the LVEF (32.8+8.3% vs. 55.2+4.3%, respectively; P , 0.001)
and peak RER (1.05+0.13 vs. 1.10+0.13, respectively; P ,
0.01). No significant differences in the provision of medical therap-
ies to patients with HFrEF and HFpEF were observed.
Receiver operating characteristic curves
and related diagnostic analyses
Figure 1 presents the ROC curves comparing 6MWT HRR with
6MWT distance ambulated and the 6MWT HRR with CPX HRR.
The area under the ROC curve for 6MWT HRR was 0.813 com-
pared to 0.600 for the 6MWT distance. The area under the ROC
curve for HRR after CPX was slightly greater (0.827) than that for
HRR after the 6MWT (0.813). The sensitivity and specificity of
6MWT HRR were 0.94 and 0.55, respectively. The sensitivity
and specificity of CPX HRR were 0.88 and 0.74, respectively.
The positive and negative predictive values of 6MWT HRR were
0.33 and 0.97, respectively. The positive and negative predictive
values of CPX HRR were 0.44 and 0.96, respectively. The accuracy
of 6MWT HRR was 0.62 compared with 0.76 for CPX HRR.
Univariate Cox regression analyses
Table 2 lists the univariate Cox regression analyses for key 6MWT
and CPX variables. With the exception of 6MWT resting HR and
dichotomized 6MWT (6MWT distance ≤ / . 300 m), all other
variables were prognostically significant. The dichotomized HRR
during the 6MWT (HRR at 1 min ≤ / . 12 beats) was the
strongest significant univariate predictor of major cardiac events
(x260.9, P , 0.001) and the 6MWT distance was the least signifi-
cant predictor of major cardiac events (x26.80, P , 0.01). Kaplan–
Meier analysis for the HRR threshold of ≤ / . 12 beats after the
6MWT is illustrated in Figure 2A.
Univariate Cox regression analysis results for key CPX variables
are also listed in Table 2. With the exception of CPX resting HR, all
other variables were prognostically significant. The dichotomized
HRR during CPX (HRR at 1 min ≤ / . 12 beats) was the strongest
significant univariate predictor of major cardiac events (x266.6,
P , 0.001). The Borg RPE at peak exercise was also a significant
predictor of major cardiac events (x263.0, P , 0.001). Exercise
oscillatory ventilation and the VE/VCO2slope were also highly
significant predictors of major cardiac events (x235.9 and 21.3,
respectively; P , 0.001). Kaplan–Meier analysis for the HRR
threshold of ≤ / . 12 beats after CPX is illustrated in Figure 2B.
Resting HR 1.37
HR reserve 22.6
Borg RPE 63.0
Table 2 Univariate prognostic analysis for key 6 min
walk test and cardiopulmonary exercise testing
AT, anaerobic threshold; CI, confidence interval; CPX, cardiopulmonary exercise
testing; Distance*, dichotomized 6MWT distance (,300 m vs. ≥300 m); EOV,
exercise oscillatory ventilation; HR, heart rate; HRR, heart rate recovery; HRR*,
dichotomized HRR (≤12beatsvs. .12beats);6MWT,6 minwalk test;RPE, rating
of perceived exertion; VE/VCO2, minute ventilation/carbon dioxide production;
VO2, oxygen consumption.
Heart rate recovery after 6MWT is a powerful prognostic indicator in HF
Figure 2 Kaplan–Meier analysis for (A) 6MWT HRR and (B) CPX HRR. 6MWT, 6 min walk test; HRR, heart rate recovery; CPX, cardiopul-
monary exercise testing. A ¼ HRR . 12 beats; B =HRR , 12 beats.
L.P. Cahalin et al.
Multivariate Cox regression analysis
Table 3 lists the univariate and multivariate Cox regression analyses
for key resting and exercise variables. Age and LVEF were signifi-
cant univariate predictors of major cardiac events (x27.11 and
5.99, respectively; P , 0.001 and P , 0.05, respectively). Multivari-
ate analysis of the 6MWT variables revealed that the dichotomous
6MWT HRR was the most robust prognostic marker (x261.07,
P , 0.001), while LVEF added significant predictive value (residual
x26.12, P , 0.05) and was retained in the regression, whereas HF
aetiology and all other key 6MWT variables were not significant
univariate or multivariate prognostic markers.
Multivariate analysis of the CPX variables revealed that the
dichotomous CPX HRR was the most robust prognostic marker
(x253.82, P , 0.001), while the VE/VCO2slope added significant
predictive value (residual x26.65, P , 0.05) and was retained in
the regression. HF aetiology and all other key CPX variables
were not significant multivariate predictors of major cardiac
Univariate and multivariate Cox
regression subanalyses of major cardiac
events by heart failure type
Separate univariate and multivariate Cox regression analyses of
major cardiac events in patients with HFrEF and HFpEF using
6MWT variables as well as CPX variables were performed and
found many similar significant predictors of major cardiac events
in patients with HFrEF and HFpEF (Table 4). Univariate Cox regres-
sion analyses of only patients with HFrEF found all previous 6MWT
and CPX variables to be significant predictors of major cardiac
events, but with lower x2values. The HFrEF univariate Cox regres-
sion analysis results identified the dichotomized 6MWT HRR and
CPX HRR as the most powerful predictors (x256.25 and 59.59,
respectively; P , 0.001). Univariate Cox regression analyses of
only patients with HFpEF found all previous 6MWT and CPX vari-
ables to be significant predictors of major cardiac events, except
for 6MWT distance and CPX non-dichotomized HRR. Further-
more, the x2values of all significant HFpEF 6MWT and CPX vari-
ables were lower than the x2values of the HFrEF 6MWT and CPX
variables. The most robust HFpEF 6MWT and CPX predictors of
major cardiac events were peak HR and the VE/VCO2slope, re-
spectively (x213.51, P , 0.001 and 10.52, P , 0.01, respectively).
Age and LVEF were both significant univariate predictors of
major cardiac events in patients with HFrEF, but only age was a
significant univariate predictor of major cardiac events in patients
with HFpEF (Table 4).
Multivariate Cox regression analysis of patients with HFrEF
found identical multivariate predictors of major cardiac events
for the 6MWT and CPX, with dichotomous HRR being the stron-
gest predictor (x256.25 and 51.51, respectively; P , 0.001) and
Table 3 Prognostic analysis for key patient characteristics, 6 min walk test, and cardiopulmonary exercise testing
Hazard ratio (95% CI)
6MWT variables Multivariate analysis
CPX variablesMultivariate analysis
CI, confidence interval; CPX, cardiopulmonary exercise testing; EOV, exercise oscillatory ventilation; HF, heart failure; HR, heart rate; HRR*, dichotomized heart rate recovery
(≤12 beats vs. .12 beats); 6MWT, 6 min walk test; VE/VCO2, minute ventilation/carbon dioxide production; VO2, oxygen consumption.
Heart rate recovery after 6MWT is a powerful prognostic indicator in HF
LVEF adding significant predictive value (residual x212.22 and 6.17,
respectively; P , 0.05), which was retained in both the 6MWT and
CPX regressions. Multivariate Cox regression analysis of patients
with HFpEF using 6MWT distance and dichotomous 6MWT
HRR as predictors found the dichotomous 6MWT HRR to be
the only significant predictor of major cardiac events (x26.11,
P , 0.05). Multivariate Cox regression analysis of patients with
HFpEF using the CPX variables dichotomous CPX HRR and the
VE/VCO2slope as predictors found the VE/VCO2slope to be
the only significant predictor of major cardiac events (x210.52,
P , 0.01).
Our study provides new information by expanding the clinical and
prognostic applicability of the 6MWT in a cohort of HF patients
with both HFrEF and HFpEF. Specifically, this is the first study
aimed at identifying whether the HR response during and after
the 6MWT provides significant prognostic insights, challenging
the distance ambulated as the reference measure in the assessment
of cardiac-related functional limitation. Importantly, HRR after the
6MWT is a powerful prognosticator that performs better than dis-
tance ambulated and similarly to HRR after maximal exercise.
Initial studies examining the prognostic value of the 6MWT in
patients with HF found that a distance ≤300 m was associated
with poorer survival.1–3However, more recent investigations have
formation unlesspatients haveadvanced HF.22–25This has beenpri-
marily interpreted as a consequence of beta-blocker therapy which
was not standard therapy during earlier investigations,25but add-
itional reasons may be advocated. Interestingly, in the current
study, 6MWT distance was a significant univariate predictor of
major cardiac events, but only as a continuous variable, and the
threshold of 300 m was a near significant (P ¼ 0.05) univariate pre-
dictor of major cardiac events. Furthermore, 6MWT distance was
not retained as a significant predictor in multivariate analyses.
A previous study of the 6MWT in patients with HFrEF who were
and not receiving cardiac transplantation.26This previous study of
only patients with HFrEF did not extend their analyses to other
HR measures.26Our study examined the prognostic value of
6MWT HRR being the strongest predictor.
Overall, the 6MWT seems to elicit a cardiac response that is
similar to that observed during a maximal effort from CPX and
is able to identify a greater percentage of patients with an abnormal
HRR. In fact, the mean peak HR of the 6MWT was 122+16 b.p.m.
and the mean peak HR during CPX was 129+17 b.p.m. In view of
these findings, it is possible that beta-blocker therapy, which may
be responsible for the decreased prognostic value of 6MWT dis-
tance, may also be responsible for the increased sensitivity of the
6MWT HRR.25It is also possible that the autonomic nervous
system response during the 6MWT provides a more balanced sym-
pathetic/parasympathetic drive that possibly better reflects para-
sympathetic reactivation in patients with HF.6–14At the very
least, it appears that the 6MWT provides a sufficient stimulus to
capture chronotropic incompetence, parasympathetic reactivation,
and related symptoms in patients with HF.27
It is important to note that beta-blockade was included in the
Cox regression models for both CPX and the 6MWT, and it
was not observed to be a significant predictor of major cardiac
events in either model. Furthermore, separate Cox regression
models were analysed for patients with and without beta-blockade
and there was no difference in the results for the separate models
compared with the full models of the 6MWT and CPX. Thus, beta-
blockade does not appear to influence the prognostic ability of
Age 4.051.04 (1.00–1.07)
LVEF 14.77 0.001 (0.000–0.025)
HRR*56.25 30.19 (7.22–126.31)
Peak HR13.750.96 (0.94–0.98)
HR reserve13.67 0.97 (0.95–0.98)
HRR56.40 0.65 (0.58–0.74)
HRR*59.59 16.88 (6.59–43.18)
EOV 28.61 5.87 (2.87–12.03)
Age4.46 1.09 (1.00–1.18)
HRR* 6.118.87 (1.05–74.94)
Distance 5.450.99 (0.98–0.99)
Distance* 5.240.18 (0.04–0.89)
Peak HR 13.510.91 (0.85–0.97)
HR reserve11.02 0.93 (0.89–0.98)
VE/VCO2slope 10.521.16 (1.05–1.27)
Table 4 Prognostic analysis for key patient
characteristics, 6 min walk test variables, and
cardiopulmonary exercise testing variables in patients
with reduced and preserved ejection fraction
Hazard ratio (95% CI)
CI, confidence interval; CPX, cardiopulmonary exercise testing; Distance*,
dichotomized 6MWT distance (,300 m vs. ≥300 m); EOV, exercise oscillatory
ventilation; HR, heart rate; HRR, heart rate recovery; HRR*, dichotomized HRR
(≤12 beats vs. .12 beats); 6MWT, 6 min walk test; VE/VCO2, minute ventilation/
carbon dioxide production; VO2, oxygen consumption.
L.P. Cahalin et al.
HRR in patients with HF as has been shown previously.28This Download full-text
study has expanded the clinical utility of HRR not only after
CPX, but also after the 6MWT in patients with and without beta-
blockade. However, due to the relatively small sample size, we are
unable to make conclusive decisions regarding the effects of beta-
blocker treatment on the major adverse events of the study.
Assessment of HRR during the 6MWT emerged as comparably
valuable in patients with HFrEF and HFpEF. This finding is particu-
larity relevant since HFpEF patients are more likely to be elderly
and less prone to undergo a maximal symptom-limited evaluation.
Also, elderly patients seem to be less tolerant of the mouthpiece
and noseclip required for respiratory gas analysis during CPX. Add-
itionally, the 6MWT is universally available, whereas CPX may only
be available in more specialized centres.
A potential limitation to this study is that only 16% of the
patients studied were patients with HFpEF. Despite our subana-
lyses finding almost identical univariate and multivariate prognostic
indices in patients with HFpEF and HFrEF, further investigation of
HRR in a larger population of patients with HFpEF is warranted.
Also, although the methods we employed to measure 6MWT dis-
tance have been previously reported and found to be clinically
useful and prognostic in patients with HF,3further examination
of 6MWT distance using such methods is in need of investigation.
To our knowledge, this is the first study that identifies HRR,
rather than distance ambulated, as the strongest prognostic vari-
able derived from the 6MWT, thus making the 6MWT a relatively
simple, but comprehensive functional performance measure that is
readily available to most patients with HF. The predictive accuracy
of HRR after the 6MWT is robust and comparable with HRR after
maximal exertion during CPX and is equally applicable to the
broad spectrum of HFpEF and HFrEF patients.
The Monzino Foundation, Milano, Italy.
Conflict of interest: none declared.
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Heart rate recovery after 6MWT is a powerful prognostic indicator in HF