Download Effects of Continuous Flow Left Ventricular Assist Device Support on

Effects of Continuous Flow Left Ventricular
Assist Device Support on Microvascular
Endothelial Function
Xiaoying Lou, Danielle L. Templeton,
Ranjit John & Donald R. Dengel
Journal of Cardiovascular
Translational Research
ISSN 1937-5387
Volume 5
Number 3
J. of Cardiovasc. Trans. Res. (2012)
5:345-350
DOI 10.1007/s12265-011-9321-z
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Author's personal copy
J. of Cardiovasc. Trans. Res. (2012) 5:345–350
DOI 10.1007/s12265-011-9321-z
Effects of Continuous Flow Left Ventricular Assist Device
Support on Microvascular Endothelial Function
Xiaoying Lou & Danielle L. Templeton & Ranjit John &
Donald R. Dengel
Received: 9 June 2011 / Accepted: 9 September 2011 / Published online: 20 September 2011
# Springer Science+Business Media, LLC 2011
Abstract The effects of continuous flow left ventricular
assist device (CF-LVAD) support on microvascular endothelial function in New York Heart Association (NYHA) class IV
heart failure (HF) patients are currently unknown. Microvascular endothelial function was assessed by beat-to-beat
plethysmographic measurement of finger arterial pulse wave
signal changes for 5 min following reactive hyperemia. A
group of seven NYHA class IV HF patients was evaluated
before CF-LVAD placement (HF), and a second group of six
NYHA class IV HF patients was evaluated 1–4 months
following CF-LVAD placement (CF-LVAD). Additionally, a
third group of seven age-matched healthy subjects served as
controls (control). There was no significant (P>0.05) difference among the three groups in age, weight, or height.
Systolic blood pressure (BP) was significantly higher in the
control group (120±2 mmHg) as compared to that in the HF
(97±8 mmHg, P=0.005) and CF-LVAD (106±4 mmHg, P=
0.003) groups. Diastolic BP was significantly lower in the
HF group (57±5 mmHg) as compared to that in the control
(71±2 mmHg, P=0.012) and CF-LVAD (80±7 mmHg, P=
0.008) groups. The reactive hyperemic index (RHI), a
measure of endothelial function, was significantly higher in
the control group (2.373±0.274) than in both the HF
(1.543±0.173, P=0.013) and CF-LVAD (1.355±0.163, P=
0.004) groups; however, there was no significant (P=0.223)
difference in RHI between the HF and CF-LVAD groups.
The results of the present study demonstrate that while 1–
4 months of CF-LVAD support do not negatively affect
microvascular endothelial function, 1–4 months of CFLVAD support do not significantly improve vascular
function in resistance vessels.
X. Lou
College of Biological Sciences, University of Minnesota,
Minneapolis, MN, USA
Endothelial dysfunction is a systemic disorder and a wellestablished marker in the pathogenesis of atherosclerosis and
its complications [1]. A number of studies have established a
relationship between endothelial dysfunction and heart
failure (HF) severity or prognosis [2–5]. Teerlink et al. [6]
demonstrated impairment in endothelium-dependent vasodilation in chronic HF rats, which increased in severity as HF
progressed. Recently, Shechter et al. [7] demonstrated that
vascular endothelial dysfunction predicts risk for adverse
cardiovascular events and mortality in New York Heart
Association (NYHA) class IV ischemic HF patients; Katz et
al. [8] reported similar findings in NYHA class II–III
ischemic and nonischemic HF patients. However, these and
other studies have relied on ultrasound imaging during flowmediated dilation of conduit vessels. It may well be that
D. L. Templeton
School of Kinesiology, University of Minnesota,
Minneapolis, MN, USA
R. John
Veterans Affairs Medical Center, Division of Cardiothoracic
Surgery, University of Minnesota Medical School,
Minneapolis, MN, USA
D. R. Dengel (*)
Veterans Affairs Medical Center, School of Kinesiology,
University of Minnesota,
1900 University Avenue S.E., 110 Cooke Hall,
Minneapolis, MN 55455, USA
e-mail: [email protected]
Keywords Endothelial function . Reactive hyperemia
index . Heart failure . Continuous flow left ventricular assist
device . Resistance vessels . Microvascular . Endothelium .
Vascular
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endothelial dysfunction also occurs in microvascular resistance vessels during HF.
Left ventricular assist devices (LVADs) have been
introduced as a bridge to heart transplantation, providing
improved survival time [9] and functional independence
[10] for those awaiting transplantation. Although the firstgeneration pulsatile flow LVADs (PF-LVAD) have been
shown to improve arterial function [11, 12], the secondgeneration continuous flow LVADs (CF-LVAD) are
currently being used with greater frequency due to their
smaller size, lack of valves, and fewer moving parts,
which improve mechanical reliability [13, 14]. The
purpose of the present study sought to examine the effects
of HF and CF-LVAD support on endothelial function in
microvascular resistance vessels.
Methods
Patients
Thirteen NYHA class IV HF patients were tested during
two different treatment phases: seven patients were measured prior to LVAD surgery (HF), and another six HF
patients were measured 1–4 months following CF-LVAD
placement (CF-LVAD). All surgical patients received a
HeartMate II (Thoratec Corporation, Pleasanton, CA) CFLVAD as a bridge to transplantation due to chronic endstage HF. All HF patients were recruited prospectively from
the University of Minnesota Medical Center–Fairview
(Minneapolis, MN). Study inclusion criteria were patients
aged >18 years with NYHA class IV HF. In addition, seven
healthy subjects were tested as age-matched controls
(control). These subjects had no history of HF. The study
protocol was reviewed and approved by the University of
Minnesota Institutional Review Board. Written informed
consent was given by all participants.
Study Protocol
All subjects were asked to fast for 8 h prior to testing,
withhold morning medications until after the vascular
studies, and refrain from strenuous physical activity for
12 h prior to testing. Height and weight were measured
using a stadiometer (Ayrton Stadiometer, Model S100, Prior
Lake, MN) and an electronic scale (ST Scale-Tronix, White
Plains, NY), respectively. Body mass index (BMI) was
calculated as weight (kilograms) divided by height2
(meters). Supine blood pressure (BP) on the right arm was
obtained after 5 min of quiet rest using an automatic
sphygmomanometer (Colin Press-Mate, Model BP-8800C,
San Antonio, TX). Medication profile, medical history, and
HF etiology were obtained from patient medical files.
J. of Cardiovasc. Trans. Res. (2012) 5:345–350
Measurement of Endothelial Function
All vascular testing was performed at the University of
Minnesota Clinical and Translational Science Institute in a
quiet room of constant temperature (22–23°C). Finger
plethysmography (Endo-PAT2000, Itamar Medical, Caesarea,
Israel) was used to non-invasively evaluate microvascular
endothelial function following reactive hyperemia of the
brachial artery. After 10 min of quiet rest in the supine
position, finger probes were placed on the index fingers of
both hands to measure baseline and reactive hyperemic pulse
amplitude. The probes were inflated to apply a uniform
pressure (10 mmHg less than diastolic BP) on the fingers and
detect small pulse volume changes throughout the cardiac
cycle. Following the collection of 5 min of baseline data, a BP
cuff on the upper forearm (just below the elbow) was inflated
to a suprasystolic level for 5 min. After cuff release, the
change in pulse amplitude during reactive hyperemia was
measured for 5 min. The ratio of the hyperemic and the
baseline pulse amplitude (corrected for the same ratio on the
control finger) was calculated using a computerized automated algorithm and expressed as the reactive hyperemic index
(RHI). RHI is defined as the ratio of the average pulse wave
amplitude during the 1-min period following the release of a
BP cuff to the average pulse wave amplitude during a 210-s
baseline period. Lower values of RHI indicate higher levels of
endothelial dysfunction [15] and correlate with vascular
abnormality [16]. The reliability of Endo-PAT2000 in
assessing endothelial function has been previously validated
[17, 18].
Statistical Analysis
Data were analyzed by SPSS statistical package version
17.0 (2010 SPSS Inc., Chicago, IL), and graphical
representations were performed using GraphPad Prism 5®
(2007 GraphPad Software, Inc., La Jolla, CA). Analysis of
variance was used to determine differences in descriptive
characteristics and measures of endothelial function. An
unpaired independent t test was used to compare ischemic
and nonischemic HF etiologies between the HF and CFLVAD groups. A chi-square test for trend was used to
compare medication profiles, disease conditions, and
ethnicity between the groups. All data were expressed as
mean ± standard error of the mean, and differences were
considered significant when P<0.05.
Results
A summary of subject characteristics is presented in Table 1.
There was no significant (P>0.05) difference among the
three groups in age, weight, height, or BMI. Moreover,
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347
there was no significant difference in years with HF
between the HF and CF-LVAD groups. Systolic BP was
significantly higher in the control group as compared to that
in the HF (P=0.005) and CF-LVAD (P=0.003) groups.
There was no significant difference in diastolic BP between
the control and CF-LVAD groups (P=0.108). However, the
diastolic BP was significantly lower in the HF group as
compared to that in both the control (P=0.012) and CFLVAD (P=0.008) groups. Pulse pressure was significantly
higher in the control group as compared to that in both the
HF (P=0.025) and CF-LVAD (P<0.001) groups; additionally, pulse pressure was significantly (P=0.029) higher in
the HF as compared to that in the CF-LVAD group.
The HF and CF-LVAD groups were on an array of
medications; only two control subjects were on mild
hypertension medication (Table 2). The breakdown for
ischemic and nonischemic HF is evenly distributed among
the HF and CF-LVAD groups, with a majority of subjects
having ischemic etiologies. There was no significant
difference between HF and CF-LVAD groups for peak
oxygen uptake (P=0.222) or ejection fraction (P=0.631)
(Table 1).
The RHI was significantly greater in the control
group (2.373 ±0.274) than in both the HF (1.543±
0.173, P=0.013) and CF-LVAD (1.355± 0.163, P= 0.004)
groups; however, there was no significant (P= 0.223)
difference in RHI between the HF and CF-LVAD groups
(Fig. 1).
Discussion
To our knowledge, the present study is the first to
demonstrate decreased microvascular endothelial function
in a group of NYHA class IV HF patients as compared to
age-matched healthy controls. Moreover, it is the first to
report that microvascular endothelial function is not
improved in HF patients who have undergone CF-LVAD
implantation as compared to those who have not.
Impaired endothelium-dependent vasodilation and relaxation have been well established in virtually all cardiovascular diseases [19, 20] including severe HF [21, 22].
However, whereas previous studies were performed in
peripheral conduit vessels such as the brachial artery [23–
25], the present study is the first to use RHI to noninvasively assess microvascular endothelial function in
severe HF patients. In a study by Houben et al. [26], the
microvascular density, diameters, and morphology of
vessels in the bulbar conjunctiva and skin nailfold of 14
NYHA class III–IV HF patients were examined using
intravital microscopy. An increase in abnormal capillary
morphologic features and a decrease in microvascular
density and recruitment capacity were observed, suggesting
the presence of structural and functional changes to the
microcirculation. The results of the present study confirm
the findings of Houben et al. [26], but whereas their study
was performed on the static microvessels of the bulbar
conjunctiva and skin nailfold, ours demonstrates the
Table 1 Mean (±SE) descriptive characteristics of the age-matched control group (control), NYHA class IV heart failure group (HF), and
continuous flow left ventricular assist device group (CF-LVAD)
Control
N
Age (years)
Gender (M/F)
Ethnicity
Caucasian
African–American
Asian
Weight (kg)
Height (cm)
Body mass index (kg/m2)
Years with HF
Ejection fraction (%)
Peak oxygen uptake (mL/kg/min)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Pulse pressure (mmHg)
*
CF-LVAD
7
50.7±3.3
6/1
7
49.8±3.3
6/1
6
43.2±3.6
6/0
6
0
1
89.9±7.6
179.1±3.8
28.0±1.6
–
–
–
120±5
71±4
52±4
6
1
0
94.5±7.6
176.9±3.8
30.2±1.6
7.1±1.6
14.7±2.4
11.7±1.1
96±5*
57±5*,**
38±4*,**
4
2
0
101.2±8.2
180.2±4.1
30.8±1.8
8.3±1.3
13.3±1.0
14.1±1.3
106±5*
80±5
24±5*
P<0.05 (significantly different than the control value);
P<0.05 (significantly different than the CF-LVAD value)
**
HF
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Control
Number
HF
CF-LVAD
7
7
6
28
0
86
86*
67
67*
Angio II antagonists
0
29
17
Digitalis
Anti-arrhythmias
Ca+ channel blockers
0
0
0
29
29
0
17
17
0
Vasodilators
Diuretics
0
0
29
86*
17
83*
Other medications
Laxatives
0
29*
67*
Cholesterol
Anti-coagulates
0
0
0
29*
33
50*
Anti-bacterials
Pain medications
Ulcer/GERD medications
0
0
0
0
43*
43*
33
50*
50*
0
0
43*
71
83*
17
0
0
0
43*
57*
100*
50*
83*
66*
0
0
57*
43
67*
33
CV medications
Beta-blockers
ACE inhibitors
Disease conditions
Diabetes
Smoking
Kidney disease
Asthma
Anxiety/depression
HF etiology
Ischemic
Nonischemic
*P<0.05 (significantly different than the control group)
impairment of microvascular endothelial vasoreactivity in
dynamic microvessels of a different vessel bed, thus
contributing to the growing body of evidence indicating
that endothelial function of microvascular resistant vessels
is compromised in HF patients.
To date, few studies have examined the effects of LVAD
support on endothelial function. Khan et al. [12] reported
that PF-LVAD implantation did not improve vascular
conductance in severe HF patients until late (8 to 12 weeks)
postoperative recovery phase; moreover, no improvement
in vascular conductance was observed in the early
(<4 weeks) postoperative recovery phase after PF-LVAD
implantation. Amir et al. [27] compared the effects of
LVAD type (CF-LVAD versus PF-LVAD) on endothelial
function in conduit arteries. HF patients supported with CFLVADs had significantly lower endothelial function than
HF patients supported with PF-LVADs, indicating that the
pulsatile blood flow characteristics of PF-LVADs offer
significant vascular benefits over the continuous blood flow
characteristics of CF-LVADs. Bittner et al. [28] compared
microvascular forearm responses to reactive hyperemia in
healthy controls versus end-stage HF patients treated with
the Berlin heart biventricular assist device system (BVAD).
The time taken to reach peak post-occlusive reactive
hyperemia values was lower in BVAD patients than in
healthy controls, indicating the presence of microvascular
dysfunction in these patients. Drakos et al. [28] examined
myocardial tissue obtained from the LV apical core in HF
patients prior to LVAD implantation and cardiac transplantation. LVAD implantation resulted in increased microvascular density and decreased microvascular luminal area,
suggesting an improvement in microvascular function. It
should be noted that Drakos et al. [28] examined HF
patients implanted with a PF-LVAD and not a CF-LVAD as
used in the present study. The results of the present study
support previous research that endothelial function in HF
patients is not improved after implantation with a CFLVAD. Moreover, our data suggest that the lack of
improvement in endothelial function is extended to resistance blood vessels and is not exclusive to conduit blood
vessels.
Current clinical evidence indicates that CF-LVADs have
been successful in managing end-organ perfusion and
function for extended durations but may not markedly
improve vascular flow and pulsatility [29–33]. Although
vascular pulsatility appears to decrease immediately postoperatively, it chronically increases after prolonged CF-LVAD
support, likely due to vascular stiffening [30]. It is thought
that the attenuated cushioning effect of stiff arteries amplifies
pressure pulsatility and increases transmission of potentially
harmful pulsatile energy to the peripheral vessels. Because of
the relatively small diameters of these vessels (∼300 μm),
pressure pulsatility damage is further compounded in the
microcirculation and by microvascular remodeling, resulting
Control
Heart Failure
Reactive Hyperemic Index (RHI)
Table 2 Medication profiles, disease conditions, and heart failure
etiologies of the age-matched control group (control), NYHA class IV
heart failure group (HF), and continuous flow left ventricular assist
device group (CF-LVAD), expressed as a percentage of total number
of subjects in each group
3
2
CF-LVAD
*
*
1
0
Fig. 1 RHI in the control (closed bar), NYHA class IV heart failure
(open bar), and continuous flow left ventricular assist device (striped
bar) patients. *P<0.05, significantly different than the control subjects
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J. of Cardiovasc. Trans. Res. (2012) 5:345–350
349
in target organ damage to high blood flow low-impedance
organs like the brain and the kidneys [31]. Moreover,
decreased peripheral microvascular distensibility and compliance result in increased end-systolic pressure in the left
ventricle, leading to increased ventricular pressure, cardiac
hypertrophy, and ventricular workload.
The long-term implications of decreased RHI in this study's
patient population even 1–4 months after LVAD surgery
indicate the need for increased surveillance and further
intervention post-LVAD placement. The observed changes in
RHI may be involved in increasing the hemodynamic load
on LVAD function and may be relevant to the medical
management of LVAD patients and the longevity of the
device itself. There is evidence for the preoperative use of
medications such as statins and highly selective β-1 receptor
antagonists in improving microvascular endothelial function
[32]. Consideration of these factors will be especially
important as CF-LVADs become increasingly utilized as
destination therapy for severe HF patients.
vessels is impaired in NYHA class IV HF and is not
improved 1–4 months following CF-LVAD surgery. To our
knowledge, this is the first study to investigate the effects of
severe HF and CF-LVAD support on endothelial function in
the microvasculature. These studies confirm previous
research that CF-LVAD does not improve endothelial
function, and this work has now been extended to
resistance vessels. Future studies are needed to examine
the longitudinal changes in endothelial function following
LVAD placement in HF patients.
Limitations
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dysfunction a marker of atherosclerotic risk. Arteriosclerosis,
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dysfunction in patients with heart failure: relationship to disease
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Circulation, 84, 1589–1596.
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endothelium-mediated vasodilation in the peripheral vasculature
of patients with congestive heart failure. Journal of the American
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5. Drexler, H., Hayoz, D., Münzer, T., et al. (1992). Endothelial
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evolution of endothelial dysfunction in a rat model of chronic
heart failure. Journal of the American College of Cardiology, 22,
615–620.
7. Shechter, M., Matetzky, S., Arad, M., et al. (2009). Vascular
endothelial function predicts mortality risk in patients with
advanced ischaemic chronic heart failure. European Journal of
Heart Failure, 11, 588–593.
8. Katz, S. D., Hryniewicz, K., Hriljac, I., et al. (2005). Vascular
endothelial dysfunction and mortality risk in patients with chronic
heart failure. Circulation, 111, 310–314.
9. Radovancevic, B., Vrtovec, B., de Kort, E., et al. (2007). Endorgan function in patients on long-term circulatory support with
continuous- or pulsatile-flow assist devices. The Journal of Heart
and Lung Transplantation, 26, 815–818.
10. Nguyen, T., Pham, L., Vinh, P., et al. (2007). Heart failure. In T.
Nguyen, D. Hu, M. Kim, & C. Grines (Eds.), Management of
complex cardiovascular problems: the evidence-based medicine
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of impaired metabolic vasodilation in patients with end-stage heart
There are several important limitations of the present study.
First, due to its cross-sectional design, there is an inherent
possibility that genetic and/or other lifestyle behaviors,
independent of cardiovascular disease, influenced our
results. It also remains a possibility that the decreased
reactive hyperemic indices of these patients were related to
co-morbid conditions associated with endothelial dysfunction. Second, there was a range of HF etiologies and
physiological variation among subjects and between
groups. Moreover, a large percentage of study participants
were on an intensive regimen of cardiovascular drugs such
as beta-blockers, ACE inhibitors, and diuretics, which were
withheld for only 12 h prior to study measurements. Due to
post-surgical complications and illness, post-implantation
measures were done between 1 and 4 months. A number of
alterations are occurring during this time period that may
affect the results. Finally, the relatively small sample size
and the short 1–4-month duration of the study postimplantation prevent widespread and longitudinal extrapolation of our results. It is possible that longer (>1 year)
durations of CF-LVAD use could alter our findings;
longitudinal testing of a larger number of advanced NYHA
class IV HF patients is indicated in future studies.
Conclusion
The purpose of the present study was to determine the
effects of chronic HF and CF-LVAD support on the
endothelial function of microvascular resistance vessels.
Major findings indicate that endothelial function of these
Conflict of Interest and Funding Sources The authors of this
manuscript do not have any relationships with companies or relevant
entities that make products pertinent to this manuscript.
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