Download Patients With Continuous-Flow Left Ventricular Assist

Patients With Continuous-Flow Left Ventricular Assist
Devices Provide Insight in Human Baroreflex Physiology
Jens Tank, Karsten Heusser, Doris Malehsa, Katrin Hegemann, Sven Haufe, Julia Brinkmann,
Uwe Tegtbur, André Diedrich, Christoph Bara, Jens Jordan, Martin Strüber
Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017
Abstract—The superior clinical outcome of new continuous-flow left ventricular assist devices (LVADs) challenges the
physiological dogma that cardiovascular autonomic homeostasis requires pulsatile blood flow and pressure. We tested
the hypothesis that continuous-flow LVADs impair baroreflex control of sympathetic nerve traffic, thus further
exacerbating sympathetic excitation. We included 9 male heart failure patients (26 – 61 years; 18.9 –28.3 kg/m2)
implanted with a continuous-flow LVAD. We recorded ECG, respiration, finger blood pressure, brachial blood pressure,
and muscle sympathetic nerve activity. After baseline measurements had been taken, patients underwent autonomic
function testing including deep breathing, a Valsalva maneuver, and 15° head-up tilt. Finally, we increased the LVAD
speed in 7 patients. Spontaneous sympathetic baroreflex sensitivity was analyzed. Brachial blood pressure was 99⫾4
mm Hg with 14⫾2 mm Hg finger pulse pressure. Muscle sympathetic nerve activity bursts showed a normal
morphology, were linked to the cardiac cycle, and were suppressed during blood pressure increases. Mean burst
frequency was lower compared with age- and body mass index–matched controls in 2 patients, slightly increased in 4
patients, and increased in 2 patients (P⫽0.11). Muscle sympathetic nerve activity burst latency and the median values
of the burst amplitude distribution were similar between groups. Muscle sympathetic nerve activity increased 4⫾1 bursts
per minute with head-up tilt (P⬍0.0003) and decreased 3⫾4 bursts per minute (P⬍0.031) when LVAD speed was
raised. The mean sympathetic baroreflex slope was ⫺3.75⫾0.79%/mm Hg in patients and ⫺3.80⫾0.55%/mm Hg in
controls. We conclude that low pulse pressure levels are sufficient to restrain sympathetic nervous system activity
through baroreflex mechanisms. (Hypertension. 2012;60:849-855.)
Key Words: left ventricular assist device 䡲 continuous flow device 䡲 pulse pressure
䡲 muscle sympathetic nerve activity 䡲 baroreflex sensitivity
M
ore than 5.8 million people in the United States
experience end stage systolic heart failure.1 Of those,
250 000 die each year despite improvements in pharmacotherapy and increasing implantable defibrillator use.2 Access to
cardiac transplantation, which improves symptoms and survival, is limited by donor organ shortage.2,3 Initially, left
ventricular assist devices (LVADs) served as a short-term
bridge to transplantation. Technology refinement and device
miniaturization allowed LVAD-treated patients to leave the
hospital for months or even years. End-stage heart failure
patients equipped with pulsatile LVADs showed 48% reductions in total mortality compared with patients on optimal
medical treatment.4 Earlier pulsatile flow LVADs were bulky
and associated with a high risk for infection, thromboembolism, and device failure.2,3 Recently developed LVADs produce continuous flow-through axial or centrifugal rotary
pumps. Compared with pulsatile devices, patients with
continuous-flow LVADs fared better in terms of cardiovas-
cular morbidity, reoperations for device repair or replacement, and total mortality.2,5–8 Thus, continuous-flow LVAD
use as a bridge to transplantation or as destination therapy is
likely to increase.2,4,7 The good clinical outcome challenges
the physiological dogma that cardiovascular homeostasis,
particularly baroreflex regulation, requires pulsatile blood
flow and pressure. Pulsatile pressure minimizes central baroreflex resetting and attenuates efferent sympathetic activity.9,10 Conversely, continuous, albeit reduced, baroreceptor
discharge with decreased pressure pulsatility could result in
sympathetic nervous system escape from baroreflex restraint.9 The issue is clinically relevant because sympathetic
activity is increased in heart failure patients and heralds a
poor prognosis.11 Therefore, we tested the hypothesis that
decreased cardiovascular pulsatility in patients with
continuous-flow LVADs is associated with profound abnormalities in baroreflex regulation of heart rate and sympathetic
nerve activity.
Received May 10, 2012; first decision May 23, 2012; revision accepted July 2, 2012.
From the Institute of Clinical Pharmacology (J.T., K.Heu., K.Heg., S.H., J.B., J.J.), Department of Cardiac, Thoracic, Transplantation, and Vascular
Surgery (D.M., C.B., M.S.), and Institute of Sports Medicine (S.H., U.T.), Hannover Medical School, Hannover, Germany; Division of Clinical
Pharmacology (A.D.), Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Correspondence to Jens Tank, Institute of Clinical Pharmacology, Hannover Medical School, Carl Neuberg Str 1, 30625 Hannover, Germany. E-mail
[email protected]
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.112.198630
849
850
Hypertension
Table 1.
September 2012
Patient Characteristics
Patient ID
1
2
3
4
5
6
7
8
9
Age, y
37
39
53
61
26
57
42
45
55
BMI, kg/m2
22.7
27.7
26.5
22.6
18.9
23.9
24.0
28.3
25.8
SBP, mm Hg
97
88
76
97
80
100
87
86
70
DBP, mm Hg
74
75
64
84
76
82
73
73
48
Pulse pressure, mm Hg
23
13
12
13
4
18
13
13
22
HR, bpm
62
75
61
73
69
62
62
62
76
MSNA, bursts per min
33
36
24
55
39
...
30
49
64
Time since implantation, mo
20
16
19
15
7
32
24
11
8
3060
2760
2740
2800
3000
2800
2800
2900
2840
23
24
36
24
16
18
21
23
21
LVAD speed, rpm
Vo2 max, mL/min per kg
BMI indicates body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; MSNA, muscle sympathetic nerve activity; LVAD, left
ventricular assist device; Vo2 max, maximum oxygen uptake during exercise.
Methods
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Patients
We included 9 male end-stage heart failure patients who had been
implanted with a continuous-flow LVADs (HeartWare International,
Framingham, MA). For each heart failure patient, we assessed
baseline recordings from 2 age- and body mass index–matched men.
The institutional review board approved the study, and written
informed consent was obtained before study entry.
Protocol
We conducted measurements after an overnight fast in the morning
hours. ECG, beat-by-beat blood pressure (Finometer Midi, Finapres
Medical Systems, Amsterdam, the Netherlands), brachial systolic
blood pressure (Doppler ultrasound), and respiration (Niccomo,
Medis GmbH, Ilmenau, Germany) were recorded. In addition, we
recorded muscle sympathetic nerve activity (MSNA) from the right
peroneal nerve (Nerve Traffic Analyzer 662C-3, Biomedical Engineering Department, University of Iowa, Iowa City, IA), as described
previously.12 Briefly, a unipolar tungsten electrode was inserted into
the muscle nerve fascicles in the popliteal space. Proper needle
positions were verified by the following criteria: (1) tapping on the
innervated muscle but not stroking the skin elicits afferent nerve
activity; (2) inspiratory breath hold increases the burst frequency; (3)
pulse synchrony of the bursts; (4) arousal does not evoke bursts; and
(5) internal nerve stimulation causes muscle twitches without any
paresthesias. Nerve activity was amplified with a total gain of
100 000, bandpass filtered (0.7–2.0 kHz), and integrated using a
0.1-second time constant.
After a ⱖ15-minute resting period, we obtained baseline measurements for 10 minutes followed by autonomic function testing
including deep breathing (respiratory rate of 6 per minute) and a
Valsalva maneuver. After connecting the remote control to the
LVAD, a second baseline was recorded. LVAD device speed was
then increased stepwise to a maximum of 3200 rpm to further reduce
pulse pressure. A third baseline was recorded after returning to the
baseline speed of the LVAD and disconnection of the remote control.
Finally, we tilted the bed to 15° (head up tilt) for 10 minutes to test
for an increase in sympathetic nerve traffic. Data were analog-todigital converted (sample rate, 500 Hz) and analyzed using a
program written by one of the authors (A.D.).
Data Analysis
Respiratory sinus arrhythmia was defined as the ratio between the
longest and shortest RR interval (distance between R peaks of the
ECG in ms) during one deep breathing cycle. The Valsalva ratio was
calculated as the ratio between the longest RR interval during phase
IV and the shortest RR interval during phase II. Heart rate and blood
pressure variabilities, as well as baroreflex heart rate regulation, were
assessed using spectral analysis, cross-spectral analysis, and the
transfer function between RR intervals and systolic blood pressure.12,13 We computed MSNA burst latency (in milliseconds), burst
frequency (bursts per minute), burst incidence (bursts per 100
heartbeats), and total activity (area under the bursts per minute as
Vs/min). The median value of the normalized burst amplitude
distribution was calculated in percentage to characterize possible
changes in fiber firing activity.14 We applied the threshold technique
to calculate sympathetic baroreflex slopes between burst incidence
and diastolic blood pressure.12,15 Diastolic blood pressure values for
each cardiac cycle (recorded during the baseline period) were
grouped into blood pressure bins (bin size, 1 mm Hg). The percentage of heartbeats associated with a burst in each of these blood
pressure bins was calculated. The slope of the relationship between
diastolic blood pressure and MSNA was calculated using linear
regression. The slope of this relationship has been shown previously
to agree with the baroreflex sensitivity calculated during a modified
Oxford baroreflex test.16
Statistics
All of the data are expressed as mean⫾SEM. Interindividual and
intraindividual differences were compared by Mann-Whitney and
Wilcoxon matched pairs tests, respectively. We also applied linear
regression analysis. P values ⬍0.05 were considered significant.
Results
Individual patient characteristics are given in Table 1. LVAD
had been implanted 7 to 32 months before the study. Mean
LVAD speed was 2860⫾37 rpm. All of the patients were on
heart failure medications, including angiotensin-converting
enzyme inhibitors (n⫽6) or angiotensin II type 1 receptor
blockers (n⫽1), ␤-1 adrenoreceptor blockers (n⫽6), loop
diuretics (n⫽3), and oral anticoagulants (n⫽9). End stage
heart failure resulted from dilated cardiomyopathy (n⫽5) or
coronary artery disease and myocardial infarction (n⫽4). Patients were in New York Heart Association classes II and III.
None showed signs or symptoms of left or right ventricular
decompensation. Resting left ventricular ejection fraction defined by transthoracic echocardiography increased from 16⫾1%
before implantation to 30⫾4% after implantation (P⬍0.03). We
obtained good quality sympathetic nerve recordings in 8 patients. The control group was composed of 16 healthy men
(24 – 62 years; body mass index, 21–28 kg/m2).
Systolic brachial blood pressure was 99⫾4 mm Hg. Finger
blood pressure recordings showed profoundly reduced pulsatility with large interindividual variability. Mean finger pulse
pressure was 14⫾2 mm Hg (range, 4 –23 mm Hg). Respira-
Tank et al
Baroreflex and Pulsatility
851
Table 2.
Anthropometric Data and Autonomic Regulation in
LVAD Patients and Matched Control Subjects
Parameter
Age, y
BMI, kg/m2
HR, bpm
Controls
LVAD
45⫾3
44⫾3
24.6⫾0.4
24.6⫾0.4
63⫾3
68⫾2
SBP, mm Hg
136⫾3
86⫾3*
DBP, mm Hg
73⫾3
73⫾3
PP, mm Hg
63⫾2
14⫾2*
MSNA, bursts per min
33⫾2
42⫾5
MSNA, bursts per 100 beats
55⫾4
63⫾6
MSNA, Vs/min
Burst latency, ms
Median burst amplitude, %
1.9⫾0.3
2.8⫾0.4
1320⫾35
1352⫾16
25⫾3
36⫾2
HRV
RMSSD, ms
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37⫾5
12⫾2*
1946⫾404
448⫾177*
2
LF, ms
763⫾152
128⫾65*
HF, ms2
362⫾111
30⫾9*
11⫾2
5⫾1*
Total power, ms2
Spontaneous baroreflex
BRS-LF, ms/mm Hg
BRS-symp, %/mm Hg
⫺3.8⫾0.5
⫺3.8⫾0.8
Data are mean values⫾SEM. BMI indicates body mass index; SBP, systolic
blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HR, heart
rate; LVAD, left ventricular assist device; MSNA, muscle sympathetic nerve
activity; HRV, heart rate variability; RMSSD, root mean square of successive
differences; LF, low-frequency power; HF, high-frequency power; BRS-LF,
baroreflex sensitivity in the low-frequency range calculated from the transfer
function between SBP and the RR intervals; BRS-symp, sympathetic baroreflex
sensitivity calculated as the slope between burst incidence and DBP.
*P⬍0.05, Wilcoxon signed-rank test.
tory sinus arrhythmia ranged between 1.02 and 1.20, and the
Valsalva ratio ranged between 1.05 and 1.56. Heart rate
variability total power ranged between 155 and 1730 ms2.
Spontaneous cardiac baroreflex sensitivity ranged between 2
and 13 ms/mm Hg and was ⬍3 ms/mm Hg in 3 patients. In
3 patients the Valsalva maneuver had to be aborted because of
ventricular arrhythmias. LVAD patients had lower systolic
blood pressure, lower pulse pressure, reduced heart rate
variability in the time and in the frequency domain, and
reduced baroreflex-mediated heart rate control compared
with matched control subjects (Table 2).
Figure 1 (top) shows representative finger blood pressure
and MSNA tracings in a 26-year– old patient. The patient
exhibited low pulse pressure and an MSNA burst frequency
of 33 bursts per minute. The recording also shows coupling
between blood pressure and sympathetic nerve traffic. Blood
pressure surges are associated with nerve silencing, whereas
pressure reductions elicit sympathetic activation. Coupling
becomes even more evident during and following premature
beats, as shown in Figure 1 (bottom) in another patient. A
profound drop in diastolic blood pressure during a compensatory pause after the premature beat induces a large sympathetic burst. In contrast, the increase in blood pressure after a
premature beat led to reflex-mediated sympathetic inhibition.
Mean MSNA burst latency, burst frequency, burst incidence,
Figure 1. ECG, finger blood pressure (FBP), and integrated
muscle sympathetic nerve activity (MSNA) for a patient with low
pulse pressure at baseline (top) and for another patient during
and after a premature beat (bottom).
the area under the burst, and the median value of the
normalized amplitude distribution in patients and in control
subjects are given in Table 2. None of these measurements
differed significantly between patients and control subjects.
Only the median value of normalized burst amplitude distribution tended to be higher in patients. Thus, in LVAD
patients, MSNA bursts show a normal morphology, are
linked to the cardiac cycle, and are suppressed as blood
pressure increases. MSNA burst frequency ranged from 27 to
65 bursts per minute, burst incidence ranged from 46 to 88
bursts/100 beats, and burst area ranged from 1.3 to 4.2
Vs/min in LVAD patients. Figure 2 illustrates individual
burst frequencies in patients and in control subjects. MSNA
was lower compared with age- and body mass index–matched
controls in 2 patients, slightly increased in 4 patients, and
increased in 2 patients (Figure 2, bottom).
In 6 of 8 patients, we observed a normal negative slope
between MSNA burst incidence and diastolic blood pressure
(Figure 3). Mean sympathetic baroreflex slope was similar
between groups (P⫽0.964; Table 2).
Figure 4 shows finger blood pressure and MSNA tracings
for 1 patient at baseline (top) and at highest LVAD speed of
3200 rpm (bottom). Pulse pressure decreased from 15 mm Hg
at baseline LVAD speed to 5 mm Hg at maximum speed in
this patient. Nevertheless, sympathetic nerve traffic was still
suppressed during blood pressure increases. The sympathetic
baroreflex slope was ⫺4.3%/mm Hg at baseline and
⫺3.5%/mm Hg at 3200 rpm in this patient. Mean sympathetic
baroreflex slope was similar in LVAD patients at increased
pump speed (⫺3.0⫾0.9%/mm Hg) compared with baseline
values.
With increased LVAD speed, a slight but statistically not
significant diastolic finger blood pressure increase was accompanied by MSNA reduction (⫺3⫾4 bursts per minute;
P⫽0.031), although pulse pressure decreased further. One
patient showed a different response (Figure 5, top). During
head-sup tilt, a comparable diastolic blood pressure rise was
852
Hypertension
patient ID
patient
1
matched controls
40
20
2
3
4
5
7
8
9
patient ID
0
150
200
SBP (mmHg)
80
MSNA (bursts/min)
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MSNA (bursts/min)
40
100
7
8
9
-10
patients
matched controls
Figure 3. Individual sympathetic baroreflex slopes vs age- and
body mass index (BMI)–matched healthy controls.
80
50
5
-5
0
1
2
0
60
BRS (%/mmHg)
MSNA (bursts/min)
80
September 2012
60
40
20
amplitude distribution, thought to be more informative than
burst frequency alone, was similar in LVAD patients compared with earlier reported values in healthy controls.14 Our
findings challenge the idea that normal pressure and flow
pulsatility are required to maintain cardiovascular homeostasis. Given the prognostic relevance of baroreflex dysfunction
and excessive sympathetic activity in heart failure patients,
our findings could translate into clinical outcomes.
In our LVAD-treated patients, pulse pressure was substantially reduced to values as low as 4 mm Hg. If normal pulse
pressures were required for baroreflexes to operate, one would
expect to observe profound abnormalities in heart rate and
MSNA regulation. Baroreceptor activation could be further
impeded by the fact that LVAD speed is adjusted such that the
aortic valve opens only intermittently.18 Baroreflex heart rate
regulation was intact at least in part in most of our patients, as
evidenced by the heart rate response during the Valsalva
maneuver and head-up tilt. However, the mean values of heart
0
40
60
80
100
DBP (mmHg)
Figure 2. Muscle sympathetic nerve activity (MSNA) in bursts
per minute) in individual patients compared with age- and body
mass index (BMI)–matched healthy controls (top), plotted
against systolic finger blood pressure (SBP; middle), and plotted against diastolic finger blood pressure (DBP; bottom).
accompanied by a 4⫾1-bursts per minute MSNA increase
(P⫽0.0003; Figure 5, bottom).
Discussion
The main finding of our study is that, in patients with
end-stage systolic heart failure implanted with continuousflow LVAD, baroreflex MSNA regulation is paradoxically
preserved. Moreover, sympathetic activity was surprisingly
low in our patients considering the severity of cardiac
contractile dysfunction. Only 2 of 8 patients exhibited resting
MSNA measurements close to values reported in the literature for patients with severe heart failure.14,17 Overall, we
only observed a tendency of a higher burst frequency and
higher median value of the normalized burst amplitude
distribution in LVAD patients compared with control subjects. Burst incidence and the area under the burst were
similar between groups. The median of the normalized burst
Figure 4. ECG, respiration (Resp), finger blood pressure (FBP),
and muscle sympathetic nerve activity (MSNA) tracings for 1
patient at baseline (top) and at 3200 rpm LVAD speed (bottom).
Reduction in pulse pressure with increased pump speed did not
compromise baroreflex-mediated sympathetic regulation.
MSNA (bursts/min)
00
32
l
Figure 5. Top, Diastolic finger blood pressure
(DBP; left), pulse pressure (middle), and muscle
sympathetic nerve activity (MSNA in bursts per
minute; right) at baseline (bsl) and at increased
LVAD speed (3200). Bottom, Diastolic finger
blood pressure (DBP; left), pulse pressure (PP;
middle), and muscle sympathetic nerve activity
(MSNA; in bursts per minute; right) at baseline
and during 15° head-up tilt (HUT).
50
rate variability and baroreflex sensitivity of heart rate control
were significantly reduced compared with healthy controls.
Nevertheless, we recorded abnormal spontaneous baroreflex
sensitivities in ⱕ3 of 8 patients. The observation is unexpected,
because parasympathetic heart rate control is severely impaired
in heart failure patients.10 Similar to an earlier study in patients
implanted with a HeartMate LVAD,19 our patients showed
reduced but preserved parasympathetic heart rate control assessed by autonomic reflex tests and spectral analysis. In fact,
heart rate variability may improve with LVAD treatment.19 This
conclusion remains speculative without measurements of heart
rate variability before and after LVAD treatment.
MSNA bursts are governed by baroreflex mechanisms.
Loss of afferent baroreceptor input elicits changes in MSNA
burst morphology while uncoupling MSNA activity from
blood pressure.20 Our patients showed similar MSNA burst
frequency, burst incidence, and area under the burst.21 Moreover, similar burst latency indicated that MSNA bursts were
properly linked to cardiac cycle and blood pressure.
In contrast to baroreflex heart rate control, baroreflex control
of sympathetic nerve activity appears to be maintained in heart
failure patients.10,22,23 We observed normal sympathetic baroreflex slopes in 6 of 8 LVAD-treated patients.
Increasing LVAD speed was crucial in studying pulse
pressure and baroreflex interactions. When we increased
LVAD speed, MSNA decreased together with pulse pressure.
The reduction in burst incidence as pump rate and diastolic
pressure increased is not surprising given that diastolic
pressure has a close correlation to sympathetic activity, which
is greater than that of either systolic or mean arterial pressures.24 Overall, our observations indicate that baroreflex
control of heart rate and MSNA is maintained in patients with
continuous-flow LVAD despite very low pulse pressure
values. The finding is important because baroreflexes restrain
sympathetic nervous system activity. Severely affected heart
failure patients show ⱕ50-fold increased cardiac norepineph-
T
U
H
H
U
T
l
l
20
bs
T
U
H
l
bs
l
bs
15
0
bs
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40
p=0.09
p=0.0003
bs
70
50
80
30
MSNA (bursts/min)
p=0.11
853
p=0.031
20
0
00
100
DBP (mmHg)
15
32
bs
l
40
p=0.09
00
70
Baroreflex and Pulsatility
80
30
32
p=0.11
pulse pressure (mmHg)
DBP (mmHg)
100
pulse pressure (mmHg)
Tank et al
rine spillover.10,25 Functional cardiac imaging studies with
different tracers suggested that increased global cardiac
uptake has a high negative predictive value in terms of
cardiac events.26 MSNA burst rates exceeding 49 bursts per
minute were associated with reduced 1-year survival rates in
122 heart failure patients.11 Our observation that resting
MSNA was not profoundly increased compared with matched
healthy controls is reassuring and indicates that continuousflow LVAD therapy might decrease sympathetic drive in
heart failure patients. In fact, an earlier study showed reductions in plasma catecholamine concentrations likely through
improved cardiac output and tissue perfusion.27
The minimal pulse pressure required to induce baroreflexmediated sympathetic inhibition in humans is unknown. The
pulmonary artery pulse pressure is preserved in continuousflow LVAD patients without right heart failure.28 Baroreceptors from other receptive fields like cardiopulmonary baroreceptors may compensate for the lack in carotid sinus
baroreceptor stimulation. Yet, cardiopulmonary baroreceptors are desensitized in heart failure patients.29 Increased
cardiopulmonary filling pressure can cause pathological sympathetic activation and baroreflex impairment.10,22 Relieving
the pulmonary circulation through continuous-flow LVAD
could elicit an opposite response. The increase in MSNA in
response to a mild orthostatic stimulus in our patients
supports this hypothesis. Improvements in physical exercise
capacity, reductions in myocardial ischemia, and normalized
breathing patterns reducing chemoreflex activation could
further improve cardiovascular autonomic control.17 Because
chronic continuous flow may cause aortic thinning, a reduced
pulse pressure may be sufficient to elicit baroreceptor excitation. Moreover, data obtained in sinoaortic denervated
animals during ganglionic blockade support the hypothesis
that cardiac-related bursting of sympathetic nerve activity is
not necessary for maintaining normal sympathetic vasoconstrictor tone.30,31 Nevertheless, the low pulse pressure accom-
854
Hypertension
September 2012
panied by normal MSNA burst morphology in LVAD patients may contradict experimental evidence from animal and
human studies.9,20,32
One limitation of our study is the relatively low number of
patients. Furthermore, because we did not include unstable
patients or patients with a complicated postoperative course,
our findings have to be interpreted with caution. Moreover,
cardiac sympathetic activity cannot be extrapolated from
MSNA recorded in peripheral nerves.
Perspectives
Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017
The low pulse pressure level in patients implanted with
continuous-flow LVAD is sufficient to maintain cardiovascular control through baroreflexes. Given the central role of
these mechanisms in adjusting heart rate and vascular tone to
the requirements of daily life, including standing, our findings are relevant for performance and quality of life in
chronically implanted patients. Neurohumoral mechanisms
engaged through baroreflex and nonbaroreflex mechanisms
have a bearing on long-term cardiovascular outcome. For
example, increased baroreceptor activation through electric
carotid sinus stimulation is beneficial in experimental heart
failure.33 Recent outcome studies showed improved survival
in patients with continuous-flow LVAD,8,34 together with
improved quality of life.35 The observation may be explained
in part by the fact that technical advantages of continuousflow LVAD, such as small size and reliability, are not offset
by impairments in baroreflex function or sympathetic activation. Our findings provide an impetus to revisit current
concepts of human baroreflex physiology in health and
disease, including arterial hypertension. Indeed, baroreflex
mechanisms contribute to the pathogenesis of arterial hypertension and have been recognized as an important treatment
target.12 The issue is relevant for patients with arterial
hypertension treated with electric carotid stimulators stimulating carotid baroreceptors in a nonpulsatile fashion. A
possible implication for the further clinical development of
electric carotid sinus stimulators is that continuous stimulation may be sufficient to reduce sympathetic activity and
blood pressure. Thus, linking electric discharges to the
cardiac cycle in a pulsatile fashion may not be warranted.
Acknowledgments
The time and cooperation of the patients are greatly appreciated.
Sources of Funding
J.T. and K.Heu. are supported by DLR (German Space Agency)
grants 50WB0917 and 50WB1117.
Disclosures
M.S. is a consultant to HeartWare.
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Novelty and Significance
What Is New?
●
●
●
Sympathetic baroreflex function has not been assessed in patients with
continuous-flow LVADs.
Very low pulse pressure in these patients was sufficient to maintain
sympathetic baroreflex function.
Sympathetic activity was surprisingly low.
What Is Relevant?
●
Impaired sympathetic baroreflex regulation predisposes to hypertension
and cardiovascular damage.
●
Our findings are particularly relevant for patients with reduced pulsatile
baroreceptor stimulation, including those with LVADs and hypertensive
patients treated with electrical carotid sinus stimulators.
Summary
Sympathetic baroreflex regulation is maintained in patients with
continuous-flow LVADs, suggesting that reduced pressure pulsatility is sufficient for human baroreflexes to operate.
Patients With Continuous-Flow Left Ventricular Assist Devices Provide Insight in Human
Baroreflex Physiology
Jens Tank, Karsten Heusser, Doris Malehsa, Katrin Hegemann, Sven Haufe, Julia Brinkmann,
Uwe Tegtbur, André Diedrich, Christoph Bara, Jens Jordan and Martin Strüber
Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017
Hypertension. 2012;60:849-855; originally published online July 23, 2012;
doi: 10.1161/HYPERTENSIONAHA.112.198630
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Copyright © 2012 American Heart Association, Inc. All rights reserved.
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