Download Factors Influencing the Rate of Flow Through Continuous

JACC: HEART FAILURE
VOL. 2, NO. 4, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2014.03.007
EDITORIAL COMMENT
Factors Influencing the Rate of
Flow Through Continuous-Flow
Left Ventricular Assist Devices
at Rest and With Exercise*
Benjamin D. Levine, MD,yz William K. Cornwell III, MD,yz Mark H. Drazner, MD, MSCz
T
he heart failure (HF) community has wit-
set at a fixed pump speed for optimal unloading of the
nessed a rapid evolution in mechanical cir-
LV. Although pump speed is the primary determinant
culatory support over the past decade.
of pump flow rate (independent of any regulatory
Following publication of the pivotal HeartMate II tri-
signals from the body), changes in the head pressure,
als, continuous-flow left ventricular assist devices
or differential pressure across the pump (aortic pres-
(cfLVADs) with an axial rotor (e.g., HeartMate II)
sure minus ventricular pressure) brought on by
quickly replaced the first-generation, pulsatile de-
changes in pre-load and/or afterload, influence
vices as both a bridge to transplant and as destina-
overall pump output (5,6). As the head pressure in-
tion therapy for patients with advanced HF (1,2).
creases, flow through the LVAD decreases (5,7). This
The centrifugal-flow LVADs (e.g., HeartWare) have
physiology underscores the importance of blood
recently been approved as a bridge to transplant
pressure control because elevated arterial pressures
and are another alternative for patients with ad-
increase the head pressure, leading to greater
vanced HF (3). Major advancements with these newer
impedance of flow and a reduction in pump output
cfLVADs include a smaller design and long-term dura-
(8). In a similar fashion, a reduction in pre-load
bility compared with the larger, pulsatile LVADs (4).
translates into a wider pressure differential across
However, questions remain over the effects of long-
the pump, which in turn leads to reductions in flow
term exposure to nonpulsatile or minimally pulsatile
through the device (5).
flow on the human body. Moreover, it is uncertain
In this context, there is great interest in further
how these devices respond to changes in loading
examining the effect of changes in loading conditions,
conditions that occur during exercise to match perfu-
such as those that occur during exercise, on LVAD
sion with metabolic demand.
flow. The ability to augment flow (i.e., cardiac output)
The cfLVAD consists of inlet and outlet cannulae,
during increases in metabolic demand is one of the
as well as a rotor, which is responsible for propelling
key factors regulating the cardiovascular response to
blood throughout the body (5). Currently, the rotor is
exercise and, in normal individuals, is remarkably
independent of age, sex, or fitness (9–11). The signals
to augment cardiac output come primarily from skel-
*Editorials published in JACC: Heart Failure reflect the views of the
authors and do not necessarily represent the views of JACC: Heart Failure
or the American College of Cardiology.
From the yInstitute for Exercise and Environmental Medicine, Texas
Health Presbyterian Hospital, Dallas, Texas; and the zDepartment of In-
etal muscle; when such signals are deranged, cardiac
output may increase out of proportion to metabolic
demand (12,13). Conversely, patients with severe HF
may not be able to augment cardiac output adequately
ternal Medicine, Division of Cardiology, University of Texas South-
due to impaired myocardial contractility, which is a
western Medical Center, Dallas, Texas. Thoratec Corporation has
harbinger of a poor outcome (14).
provided some funding for ongoing studies performed at the Institute of
Exercise and Environmental Medicine under the direction of Dr. Levine.
How cardiac output may be regulated during
Drs. Cornwell and Drazner have reported that they have no relationships
exercise in patients in whom these metabolic and
relevant to the contents of this paper to disclose.
mechanical afferent signals are divorced from the
332
Levine et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014
AUGUST 2014:331–4
LVAD Flow at Rest and Exercise
ultimate response (blood flow delivery), such as in
tilt (HUT). The change in body position from su-
patients with LVADs, has not been well studied.
pine to 30 led to a reduction in flow (baseline flow
Moreover, the importance of nonpulsatile flow,
4.9 0.6 l/min; flow at 30 HUT 4.5 0.5 l/min; p <
which greatly alters baroreflex function at rest (15),
0.01), but no further reductions were observed at
has rarely been considered during exercise. Several
60 or 80 HUT. After 3 min in each position, pa-
previous analyses have demonstrated that flow in-
tients were asked to perform active ankle flexion
creases during aerobic exercise in LVAD patients
exercises to increase venous return to the heart,
with a treadmill (16) and cycle ergometry (17–20). In
which increased flow back to the baseline value. It
this issue of JACC: Heart Failure, Muthiah et al. (21)
is important to emphasize 2 things about this pro-
hypothesized that the mechanism by which in-
tocol. First is that the head-to-foot gravitational
creased LVAD flow occurs is likely related to either an
gradient (Gz) is proportional to the sine of the tilt
increase in venous return or intrinsic heart rate (HR)
angle. Therefore 50% of this gradient is achieved at
and sought to determine the relative extent to which
an angle of 30 , 87% at 60 , and 98% at 80 ; there-
these 2 factors influenced LVAD flow.
fore, there is about half as much blood pooling
below the heart at 30 compared with 80 . The de-
SEE PAGE 323
gree to which right ventricular (RV) stroke volume
To accomplish these objectives, 11 patients with
is affected depends on the Starling curve of the RV,
HeartWare centrifugal-flow LVADs and pacemakers
RV compliance, venous compliance, and the pres-
were enrolled in 2 separate studies. First, HR was
ence of pericardial restraint; thus, the reader should
changed by either increasing (approximately 40
be cautious before assuming that the majority of
beats/min) or decreasing (approximately 30 beats/
venous pooling occurs at 30 upright tilt as stated by
min) the pacemaker rate. Despite these large changes
the authors. The fact that 20 head-down tilt had
in intrinsic HR, LVAD flow was minimally affected
minimal effect on flow through the LVAD suggests
(baseline flow rate 5.21 1.3 l/min; flow rate at
that RV and consequent LV filling were already
maximum HR 5.17 1.2 l/min; p ¼ 1.0). Such an
maximized in the supine position and is not surpris-
outcome would be expected if there was little
ing. Second, because of the increased Gz gradient
contribution of the intrinsic LV to forward cardiac
with increasing tilt angle, the patients had to lift
output, although it is possible that increasing HR
twice as much weight during toe raises at the higher
could improve right-sided cardiac output and thereby
compared with the lower tilt angles. Although the
improve LVAD filling.
muscle pump is maximally activated at lower con-
In a second study, the effect of pre-load on pump
traction intensities, the stimulation of both metabolic
flow was assessed in 10 patients by a tilt-table
and mechanical afferents is increased with the in-
assessment at supine, 30 , 60 , and 80
head-up
tensity of muscle contraction (22). That is the likely
explanation for why blood pressure was elevated by
nearly 10 mm Hg when toe raises were performed at
80 compared with 30 , which may well have influenced the flow outcomes.
Although these results do shed some light on the
mechanism by which exercise increases the LVAD
flow rate (Fig. 1), there are several considerations and
potential confounders that must be addressed. First,
pacing-induced increases in HR under resting conditions
may
not
elicit
the
same
physiological
response as exercise-induced increases in HR. In
healthy individuals, increases in cardiac output with
exercise result from a reduction in peripheral resistance, along with increases in contractility, venous
return (thereby increasing stroke volume), and HR.
F I G U R E 1 Factors That May Influence LVAD Flow Rate
Although venous return has been shown to affect flow, the contribution of
heart rate, contractility, right ventricular (RV) function and peripheral
Recent studies in healthy individuals failed to show
a relationship between pacing-induced increases in
HR and augmentation of cardiac output during ex-
resistance to exercise-induced changes in left ventricular assist device (LVAD)
ercise (23,24). Almost a century ago, Bainbridge (25)
flow remains unanswered.
described exercise-induced increases in HR as a
response to increased venous return, stating that
Levine et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014
AUGUST 2014:331–4
LVAD Flow at Rest and Exercise
“when venous filling is increased, the circulation can
Finally, it is worth mentioning that this study
be maintained by the more rapid transference of
evaluated patients with centrifugal-flow HeartWare
blood from the venous to the arterial system.” Thus,
LVADs. Differences in intrinsic properties of axial and
the lack of a relationship between increases in paced
centrifugal-flow pumps lead to profound differences
HR and LVAD flow under resting conditions in the
in response to changes in head pressure (8). An
study by Muthiah et al. (21) did not sufficiently
analysis of the pressure-flow curve of these devices
replicate the physiological response to exercise.
reveals that the centrifugal-flow LVADs are more
Second, the potential role for other aforemen-
sensitive to changes in head pressure than axial-flow
tioned responses to exercise (i.e., reduced peripheral
devices. This results in greater changes in flow for any
resistance and increased contractility) on LVAD flow
given change in pressure across the pump. In this
was not fully explored in the current study. Specif-
regard, conclusions from this study should not be
ically, neither stable ventricular dimensions nor
generalized to patients with axial-flow
unchanged frequency of aortic valve opening are
without first acknowledging the fundamental differ-
adequate surrogates for more subtle changes in
ences in flow characteristics between the different
contractility. Increased contractility of either the RV,
devices. A follow-up study comparing the response of
by delivering more blood to the LV, or the LV, by
axial-flow and centrifugal-flow LVADs to exercise
propelling blood faster through the LVAD, could
would be of great interest.
devices
theoretically increase LVAD flow. We recognize that
Muthiah et al. (21) are to be congratulated for
in HF, exercise-related increases in contractility are
advancing the field. Their study has effectively
less pronounced than those in healthy individuals;
demonstrated that hydrostatic gradients induced by
however, it may be that contractile reserve improves
position changes under resting conditions influence
following months of unloading by an LVAD (16). As
LVAD flow rate. This is likely one mechanism by
an example, Jakovljevic et al. (16) showed that stroke
which exercise leads to increases in pump flow rate,
volume during exercise was greater in patients with
by augmenting venous return to the RV via the
cfLVADs than those with advanced HF without
muscle pump. Secondly, they convincingly demon-
LVADs.
strated that manipulations of intrinsic HR under
RV function can have a major impact on LVAD flow
resting conditions had no significant impact on LVAD
rate (26) because a severely dysfunctional RV may not
flow rate in this study, with the caveat that a pacing
be able to adequately fill the LV, which would limit
model does not fully mimic the effect of increased HR
increases in flow during exercise. In the current
(through vagal withdrawal and sympathetic activa-
study, 6 of the 11 patients evaluated had imaging
tion) during exercise in patients with cfLVADs. This
evidence of RV systolic dysfunction and there were
study sets the stage for additional investigation into
no differences between those with preserved or
other potential factors that increase cfLVAD flow
impaired RV function when the impact of changes in
under exercise, with the most obvious being con-
HR on the LVAD flow rate were examined. However,
tractile reserve of either or both ventricles.
given that the severity of RV dysfunction in the
study by Muthiah et al. (21) was not provided (RV
REPRINT REQUESTS AND CORRESPONDENCE : Dr.
dysfunction was defined as mild dysfunction or
Benjamin D. Levine, Institute for Exercise and
greater) and the small sample size of patients evalu-
Environmental Medicine, Texas Health Presbyterian
ated, it is difficult to draw any firm conclusions on the
Hospital Dallas, 7232 Greenville Avenue, Suite 435,
contribution of the RV, or lack thereof, to exercise-
Dallas, Texas 75231-5129. E-mail: benjaminlevine@
induced increases in flow.
texashealth.org.
REFERENCES
1. Miller LW, Pagani FD, Russell SD, et al. Use
of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;
357:885–96.
2. Slaughter MS, Rogers JG, Milano CA, et al.
Advanced heart failure treated with continuousflow left ventricular assist device. N Engl J Med
flow, centrifugal pump in patients awaiting
heart transplantation. Circulation 2012;125:
3191–200.
4. Garbade J, Bittner HB, Barten MJ, Mohr FW.
Current trends in implantable left ventricular
assist devices. Cardiol Res Pract 2011;2011:
290561.
clinical practice. J Heart Lung Transplant 2013;
32:1–11.
6. Akimoto T, Yamazaki K, Litwak P, et al. Rotary
blood pump flow spontaneously increases during
exercise under constant pump speed: results of a
chronic study. Artif Organs 1999;23:797–801.
3. Aaronson KD, Slaughter MS, Miller LW,
5. Moazami N, Fukamachi K, Kobayashi M, et al.
Axial and centrifugal continuous-flow rotary
7. Pennings KA, Martina JR, Rodermans BF, et al.
Pump flow estimation from pressure head and
power uptake for the HeartAssist5, HeartMate II,
et al. Use of an intrapericardial, continuous-
pumps: a translation from pump mechanics to
and HeartWare VADs. ASAIO J 2013;59:420–6.
2009;361:2241–51.
333
334
Levine et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014
AUGUST 2014:331–4
LVAD Flow at Rest and Exercise
8. Pagani FD. Continuous-flow rotary left ventricular assist devices with “3rd generation”
design. Semin Thorac Cardiovasc Surg 2008;20:
255–63.
9. McGuire DK, Levine BD, Williamson JW, et al.
A 30-year follow-up of the Dallas Bed Rest and
Training Study: I. Effect of age on the cardiovascular response to exercise. Circulation 2001;104:
1350–7.
nonpulsatile left ventricular assist devices. Circ
Heart Fail 2013;6:293–9.
16. Jakovljevic DG, George RS, Donovan G, et al.
Comparison of cardiac power output and exercise
performance in patients with left ventricular assist
devices, explanted (recovered) patients, and those
with moderate to severe heart failure. Am J Cardiol 2010;105:1780–5.
flows in patients with continuous-flow left ventricular assist devices. J Am Coll Cardiol HF 2014;
2:323–30.
22. Mitchell JH, Victor RG. Neural control of the
cardiovascular system: insights from muscle sympathetic nerve recordings in humans. Med Sci
Sports Exerc 1996;28:60–9.
10. Carrick-Ranson G, Hastings JL, Bhella PS, et al.
The effect of lifelong exercise dose on cardiovascular function during exercise. J Appl Physiol
(1985) 2014;116:736–45.
17. Brassard P, Jensen AS, Nordsborg N, et al.
Central and peripheral blood flow during exercise
with a continuous-flow left ventricular assist
device: constant versus increasing pump speed: a
pilot study. Circ Heart Fail 2011;4:554–60.
23. Munch GD, Svendsen JH, Damsgaard R,
Secher NH, Gonzalez-Alonso J, Mortensen SP.
Maximal heart rate does not limit cardiovascular
capacity in healthy humans: insight from right
atrial pacing during maximal exercise. J Physiol
2014;592:377–90.
11. Fu Q, Levine BD. Cardiovascular response to
exercise in women. Med Sci Sports Exerc 2005;37:
1433–5.
18. Andersen M, Gustafsson F, Madsen PL, et al.
Hemodynamic stress echocardiography in patients supported with a continuous-flow left
24. Mortensen SP, Svendsen JH, Ersboll M,
Hellsten Y, Secher NH, Saltin B. Skeletal muscle
signaling and the heart rate and blood pressure
12. Bhella PS, Prasad A, Heinicke K, et al.
ventricular assist device. J Am Coll Cardiol Img
2010;3:854–9.
response to exercise: insight from heart rate
pacing during exercise with a trained and a
deconditioned muscle group. Hypertension 2013;
61:1126–33.
Abnormal haemodynamic response to exercise in
heart failure with preserved ejection fraction. Eur J
Heart Fail 2011;13:1296–304.
13. Taivassalo T, Jensen TD, Kennaway N,
DiMauro S, Vissing J, Haller RG. The spectrum of
exercise tolerance in mitochondrial myopathies—a
study of 40 patients. Brain 2003;126:413–23.
19. Martina J, de Jonge N, Rutten M, et al. Exercise hemodynamics during extended continuous flow left ventricular assist device support:
the response of systemic cardiovascular parameters and pump performance. Artif Organs 2013;
37:754–62.
14. Chomsky DB, Lang CC, Rayos GH, et al. Hemodynamic exercise testing: a valuable tool in the
selection of cardiac transplantation candidates.
20. Salamonsen RF, Pellegrino V, Fraser JF, et al.
Exercise studies in patients with rotary blood
pumps: cause, effects, and implications for
Circulation 1996;94:3176–83.
starling-like control of changes in pump flow. Artif
Organs 2013;37:695–703.
15. Markham DW, Fu Q, Palmer MD, et al. Sympathetic neural and hemodynamic responses to
upright tilt in patients with pulsatile and
21. Muthiah K, Gupta S, Otton J, et al. Body position and activity, but not heart rate, affect pump
25. Bainbridge FA. The influence of venous
filling upon the rate of the heart. J Physiol 1915;
50:65–84.
26. Slaughter MS, Pagani FD, Rogers JG, et al.
Clinical management of continuous-flow left
ventricular assist devices in advanced heart failure.
J Heart Lung Transplant 2010;29:S1–39.
KEY WORDS exercise, heart rate, LVAD,
posture, tilt-table