C 2010, Wiley Periodicals, Inc.

Journal compilation 
DOI: 10.1111/j.1540-8175.2009.01011.x


C 2010, the Authors

Association between Endothelial Function and

Chronotropic Incompetence in Subjects with Chronic
Heart Failure Receiving Optimal Medical Therapy
Timothy J. Vittorio, M.S., M.D., Gregg Lanier, M.D., Ronald Zolty, M.D., Ph.D., Nitasha Sarswat, M.D.,
Chi-Hong Tseng, Ph.D., Paolo C. Colombo, M.D., and Ulrich P. Jorde, M.D.

Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY;
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Department of Medicine,
University of California Los Angeles, Los Angeles, CA; and Center for Advanced Cardiac Care, Columbia
University Medical Center, New York, NY

Objective: Impairment of flow-mediated, endothelium-dependent vasodilatation (FMD) of the brachial

artery identifies peripheral endothelial dysfunction in subjects with chronic congestive heart failure
(CHF) and is associated with increased morbidity and mortality. To further elucidate the interaction
of peripheral and central mechanisms in the syndrome of CHF, we examined the association between
endothelial function and chronotropic incompetence, an emerging prognostic marker in CHF. Methods:
Thirty subjects with stable New York Heart Association (NYHA) functional class IIIII CHF were studied.
A vascular ultrasound study was performed to measure brachial artery FMD. The percentage of ageadjusted maximal predicted heart rate (MPHR) reached during cardiopulmonary exercise tolerance
testing (CPETT) was used to assess the degree of chronotropic competence. All patients received ACE
inhibitors and -adrenoceptor blockers. Results: Brachial artery FMD averaged 1.3 2.4% and ageadjusted % MPHR 74.1 11.7%. FMD correlated with % MPHR among all patients (r = 0.60, P = 0.01).
FMD and resting heart rate (RHR) did not significantly correlate (r = 0.13, P = 0.55). Conclusions: FMD, a
measure of peripheral endothelial dysfunction, and % MPHR, a central determinant of cardiac output, are
moderately correlated in heart failure patients receiving optimal medical therapy. Whether a cause-effect
relationship underlies this association remains to be investigated. (Echocardiography 2010;27:294299)
Key words: brachial artery, dilated cardiomyopathy, heart failure, chronotropic incompetence, flowmediated dilatation

Impairment of endothelium-dependent vasodilatation has been demonstrated in hypertension,1 atherosclerosis,25 diabetes,6,7 and
congestive heart failure (CHF).810 Decreased
flow-mediated vasodilatation (FMD) in heart failure has been shown to be an independent predictor of adverse outcomes,1113 and is present even
in mild systolic dysfunction as compared with
healthy subjects.14,15 Nitric oxide (NO), the major
component of endothelium-derived relaxing factor, is central to the physiologic response to the
changes in oxygen demand and blood flow supply, both for coronary arteries and the peripheral
(skeletal and renal) vascular beds. Impairment of

Dr. Colombo and Dr. Jorde contributed equally to this study.

No financial support was received for the preparation of this
manuscript. We have no conflicts of interest to disclose.
Address for correspondence and reprint requests: Timothy J.
Vittorio, M.S., M.D., Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574. Fax:
+212-241-3546; E-mail: t_vittorio@hotmail.com

294

this mechanism results in chronic vascoconstriction and increased systemic vascular resistance,
which likely contributes to the pathophysiology
of systolic dysfunction.16 Consequently, therapies aimed at improving NO-mediated vasodilation, such as blockade of the renin-angiotensin
and sympathetic nervous systems,17,18 have been
shown to improve mortality.
In addition to having an impaired vasodilatory response in the periphery, many patients
with CHF are unable to appropriately augment their heart rate when cardiac demand increases.19 This condition, called chronotropic incompetence (CI), is defined as the inability to
achieve 80% of the maximum predicted heart
rate (MPHR) during exercise.20 The incidence of
CI in systolic heart failure has been shown to
be in the range of 3846%.18,21 The mechanism of CI is thought to be secondary to chronic
overactivation of the sympathetic nervous system and subsequent down-regulation of cardiac
-adrenoceptor densities.19 Additionally, cardiac
-adrenoceptor blockers, a cornerstone in the

Endothelial Function and Chronotropic Incompetence in CHF

treatment of CHF, further blunt the physiologic

response in heart rate to exercise. Although exercise has been shown to increase stroke volume in
some patients with CHF,22 heart rate response is a
significant determinant of cardiac output. In one
meta-analysis of 35 randomized studies, the mean
cardiac output increased after the peak heart rate
increased by an average of 4 beats/min or 2.5%
of the pretraining level.23 By limiting the heart
rate response and thus cardiac output, patients
with CHF and CI have a reduction in peak oxygen
consumption (VO2 ), and their exercise capacity is
decreased.
The present study aimed to further elucidate
the physiologic interdependence between peripheral vascular and central cardiac function.
Accordingly, we performed vascular ultrasound
studies and cardiopulmonary exercise tolerance
testing (CPETT) to examine the relationship between brachial artery FMD and % MPHR in a
group of stable ambulatory patients with CHF secondary to left ventricular (LV) systolic dysfunction,
in whom medical therapy had been optimized.
Methods:
Patient Population:
Thirty individuals with symptomatic, stable CHF
who agreed to participate were randomly recruited from the outpatient clinic over a 2-year
period. Subjects between the ages of 21 and 75
years with CHF for >3 month duration, symptoms compatible with New York Heart Association
(NYHA) functional class II or III, and LVEF <40%,
as determined by two-dimensional echocardiography using modified Simpsons method, were
eligible for the study. The criteria for exclusion
were systolic blood pressure <90 or >160 mmHg,
heart rate <50 or >100 beats/min, history of severe valvular disease, atrial fibrillation/flutter, intolerance to ACE inhibitors and -adrenoceptor
antagonists, acute coronary syndromes or open
heart surgery within the preceding 3 months,
any hospitalization within the past month, and
inability to perform exercise testing. All subjects
received stable doses of ACE inhibitors and adrenoceptor antagonists for at least 4 weeks before the study.
The protocol was approved by the Medical
Center Institutional Review Board on human research, and all subjects provided written informed
consent prior to the study. All procedures followed institutional guidelines.
Brachial Artery Ultrasound Imaging:
All subjects were studied following an 8-hour
fast, and all received their usual daily medications including their last dose of ACE inhibitor and
-adrenoceptor blocker 36 hours prior to assess-

ment of brachial artery FMD. All studies were performed in a quiet, temperature-controlled room.
The subjects were requested to lie in a supine position. The brachial artery in the nondominant arm
was visualized utilizing a high-resolution 11 MHz
linear array ultrasound transducer connected to
a standard ultrasound machine (Hewlett-Packard
Sonos 1500, Andover, MA, USA) adapted from
the previously published methods.2428 The machine used in the current study had a transducer
with an axial resolution of <0.1 mm.
Following 30 minutes of supine rest, heart rate
and blood pressure were measured. With the nondominant arm resting comfortably at the level
of the right atrium, a 5-cm wide blood pressure
cuff was placed around the upper forearm. Measurements were taken from the brachial artery
about 10 cm proximal to the antecubital fossa.
The vessel diameter was imaged in the longitudinal view. Using ultrasonic calipers, the arterial
diameter was taken as the widest distance between the superior and inferior intimal markings
of the vessel by the leading edge-to-leading edge
technique. The brachial artery diameter was measured at rest (baseline) and 6075 seconds after the release of transient arterial occlusion induced by rapid inflation of the forearm blood
pressure cuff to 50 mmHg above systolic blood
pressure for 5 minutes. Nitroglycerin was not
given prior to FMD measurement as it has been
shown previously that endothelium-independent
FMD is sometimes preserved in CHF,13,29 whereas
endothelial-dependent FMD has been shown to
be consistently decreased in CHF.11 The brachial
artery diameter was measured at end-diastole coincident with the R-wave on the electrocardiogram, and five consecutive diameter measurements were averaged. FMD was determined as
the percent change in the brachial artery diameter
after cuff release compared with the resting baseline brachial artery diameter. Figure 1 illustrates
the method of measuring FMD. Brachial artery
ultrasound imaging and FMD interpretation were
performed by the same technician. Intra- and interobserver variabilities for FMD measurements
were 1.3% and 2.7% respectively.3,27,28,30 Although lower and with less variability than FMD
in normal subjects,31 this range is consistent with
the impairment of endothelial function previously
reported in patients with CHF.29,32
Cardiopulmonary Exercise Tolerance Testing
(CPETT):
Peak oxygen consumption (peak VO2 [mL/kg per
minute]) was assessed during graded treadmill
exercise using a Sensor-Medics metabolic cart
(SensorMedics, Yorba Linda, CA, USA) as previously described.28,33 Expired gases were collected
throughout exercise, and oxygen consumption
295

Vittorio, et al.

Figure 1. Schematic diagram showing the method of measuring flow-mediated dilatation.

was recorded on a breath-by-breath basis. The

instruments were calibrated before every test and
were corrected for humidity, room temperature,
and barometric pressure according to the manufacturers protocol. The work-rate increased continuously as a ramp function by augmenting the
speed and grade of the treadmill according to
the Naughton protocol. Patients exercised to a
symptom-limited maximum. Heart rate and electrocardiogram were recorded continuously during exercise and blood pressure was measured at
rest, every 2 minutes during exercise and upon
completion of exercise. Peak VO2 was defined as
the highest value of oxygen uptake attained in the
final 20 seconds of exercise when the respiratory
exchange ratio was >1.0.
We employed a commonly applied definition
for CI, which is an inability to reach 80% of
maximal predicted heart rate (MPHR).20 MPHR
was calculated utilizing Astrands formula which
quantifies MPHR in the following manner: 220
age.34
Statistical Analysis:
The baseline clinical characteristics of the study
population are expressed as mean SD. Pearsons correlation coefficients were calculated to
evaluate the relationship between FMD and CI. Effect size (R2 ) was also calculated. A P-value <0.05
is considered statistically significant. All analysis
was performed using SAS software (SAS Institute
Inc., Cary, NC, USA).
Results:
Table I summarizes the baseline clinical characteristics of the study cohort. Thirty patients were
studied which were predominantly male. Ethnic groups were well represented. The etiology
296

of CHF consisted primarily of nonischemic idiopathic dilated cardiomyopathy (63%). The mean
LVEF was 25 9%. Patients were either NYHA
class II or III. All patients were receiving ACE inhibitors and -adrenoceptor antagonists. The patients in the present study were on optimal CHF
therapy, with a mean carvedilol dose of 40
16.1 mg and a mean metoprolol succinate dose
of 111.1 69.7 mg.
Brachial artery FMD averaged 1.3 2.4% and
age-adjusted % MPHR 74.1 11.7%. Although
there was no control group, the historical FMD
values of normal subjects ranged from 8.2 3.4%
to 15.9 4.1%.29,35 Overall, there was a moderate strength of a relationship between FMD and
% MPHR (r = 0.60, P = 0.01) with an effect size
(R2 ) of 0.36 (Fig. 2). FMD and RHR did not significantly correlate (r = 0.13, P = 0.55). There was
a low strength of a relationship between FMD
and peak VO2 ([r = 0.40, R2 = 0.16, P = 0.03],
Fig. 3). Subgroup analysis based on etiology of
CHF and type of -blocker did not show any significant differences (Table II).

TABLE I
Baseline Clinical Characteristics in CHF Patients (n = 30)
Mean
SD (%)
Age, years
Male, n (%)
Ethnicity, n (%)
Caucasian
AfricanAmerican
Hispanic
CHF etiology, n (%)
Ischemic
Nonischemic
NYHA class (%)
II
III
LVEF, %
Systolic blood pressure, mmHg
Heart rate, bpm
ACE inhibitors, (%)
-adrenoceptor blockers
Carvedilol
Metoprolol succinate
Diuretics, n (%)
Digoxin, n (%)
Aldactone, n (%)
Statin, n (%)
FMD, %
MPHR, %
Peak VO2 , mL/kg per minute

52 11
25 (83%)

Range
2172

11 (37%)
9 (30%)
10 (33%)
11 (37%)
19 (63%)
16 (53%)
14 (47%)
25 9
109 16
66 11
100
100
20 (67)
10 (33)
29 (97)
22 (73)
9 (30)
15 (50)
1.3 2.4
74.1 11.7
18.1 1.9

1040
90134
5088

4.86.5
44103
7.133.7

NYHA = New York Heart Association; ACE = angiotensin

converting enzyme; LVEF = left ventricular ejection fraction;
FMD = flow-mediated vasodilatation; MPHR = maximal predicted heart rate; Peak VO2 = maximal oxygen consumption.

Endothelial Function and Chronotropic Incompetence in CHF

r = 0.60
p = 0.01

10

TABLE II
Subgroup Analysis

FMD (%)

Group

0
0

50

100

150

-5

-10
MPHR (%)

Figure 2. Scatterplot and regression line comparing maximal predicted heart rate (MPHR) and brachial artery flowmediated vasodilatation (FMD) in patients with CHF (n = 30).

Discussion:
We assessed peripheral vascular and central cardiac function in 30 patients with stable CHF
on optimal medical therapy. Our study indicates
that endothelium NO-dependent FMD, as measured by high-resolution brachial artery ultrasound, moderately correlates with % MPHR, a
central determinant of cardiac output, measured
during graded treadmill exercise testing. To the
best of our knowledge, this is the first study to
show a correlation between % MPHR and FMD in
patients with CHF. Whether this identifies a common effect of the CHF syndrome or a potential
therapeutic target is unknown.
Only one other study has shown a similar correlation between % MPHR and FMD, but in patients with suspected coronary artery disease and
no evidence of heart failure. In the subset of patients with CI (20 patients in total), there was
a significant decrease in FMD as compared with
those patients demonstrating CI. The authors also
found a statistically significant elevation of NTproBNP, a marker of ventricular stretch and possibly early LV dysfunction.36 This may corroborate
the correlation found in the present study that
there is a relationship between central measures

r = 0.40
p < 0.05

10

FMD (%)

0
0

10

20

30

40

-5

-10

Peak VO2 (ml/kg/min)

Figure 3. Scatterplot and regression line comparing maximal

oxygen consumption (peak VO2 ) and brachial artery flowmediated vasodilatation (FMD) in patients with CHF (n = 30).

Etiology
Ischemic
Nonischemic
-blocker type
Carvedilol
Metoprolol XL

FMD vs.
MPHR

FMD vs.
Peak VO2

0.17 (0.60)
0.22 (0.40)

0.21 (0.51)
0.42 (0.18)

0.27 (0.26)
0.11 (0.76)

0.36 (0.12)
0.48 (0.16)

Pearson correlation coefficient (P-value).

of cardiac function (% MPHR and ventricular dysfunction) and peripheral FMD impairment.
A possible intermediary mechanism for developing both CI and impaired FMD in CHF
may be overstimulation of the sympathetic nervous system. It is has been shown that increased
sympathetic tone may lead to endothelial dysfunction.3739 Additionally, chronic sympathetic
stimulation of the sinus node and subsequent
down-regulation of the -adrenergic receptors
may result in CI.19 Since CHF results in many
cardiovascular derangements that lead to a persistently increased sympathetic outflow, it is logical that neurohormonal treatments such as adrenoceptor blockers and ACE inhibitors may
not only improve central determinants of cardiac
function like chronotropy, but also peripheral endothelial function. This has been validated in part
that ACE inhibitors, angiotensin-receptor blockers,17,40,41 and -adrenoceptor blockers42 have
been shown to improve FMD. Although it is clear
that -adrenoceptor blockers directly lower heart
rate and the response to exercise in the short
term, it is unknown whether chronic treatment
with neurohormonal blockers may paradoxically
improve CI through decreasing sympathetic tone.
One treatment strategy that has been shown
to improve both FMD and CI is exercise training, possibly through decreasing sympathetic
outflow, which has effects on both the central
chronotropic response to stress and the peripheral vasculature response to hyperemia. Physical
training has been shown in multiple trials to improve FMD in patients with CHF.17,4345 Exercise
also improves the heart rate response, VO2 , and
cardiac output in patients with CHF and CI.46
By improving baroreceptor response and possibly decreasing sympathetic outflow and plasma
catecholamines, exercise training may simultaneously improve both CI and FMD.47
Study Limitations:
Our study has several limitations: (1) the patient
cohort was small and there were very few females
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Vittorio, et al.

represented; (2) our investigation was observational and only supports that there might be a
causal relation between central cardiac function
(% MPHR) and peripheral (brachial artery endothelium [FMD]) vasculature; (3) patients with
NYHA functional class IV symptoms were excluded as they are often hospitalized and their
medical regimen more frequently altered; and (4)
there was no control group. Although the inclusion of patients was random, it was still dependent on the subjects willingness to participate,
which may have introduced selection bias.
Conclusion:
The modest correlation between FMD impairment and % MPHR found in the present study
of 30 patients with CHF may thus underscore the
possible interaction of the two, and suggest that
common treatments may improve both and ultimately the physiology in heart failure. Future
interventional studies investigating the response
to specific cardiac and peripheral vascular treatments on larger and more representative populations are still needed to confirm the observed
relationship and to establish a causal link between
cardiac and endothelial function.

10.

11.

12.

13.

14.
15.
16.
17.

18.

Acknowledgment: None.

19.

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