Download Basal Pulmonary Vascular Resistance and Nitric Oxide

Basal Pulmonary Vascular Resistance and Nitric Oxide
Responsiveness Late After Fontan-Type Operation
S. Khambadkone, MD, MRCP; J. Li, MBBS; M.R. de Leval, MD, FRCS;
S. Cullen, MB, BCh, BaO, FRCPI; J.E. Deanfield, FRCP; A.N. Redington, FRCP
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
Background—The pulsatile nature of pulmonary blood flow is important for shear stress–mediated release of
endothelium-derived nitric oxide (NO) and lowering pulmonary vascular resistance (PVR) by passive recruitment of
capillaries. Normal pulsatile flow is lost or markedly attenuated after Fontan-type operations, but to date, there are no
data on basal pulmonary vascular resistance and its responsiveness to exogenous NO at late follow-up in these patients.
Methods and Results—We measured indexed PVR (PVRI) using Fick principle to calculate pulmonary blood flow, with
respiratory mass spectrometry to measure oxygen consumption, in 15 patients (median age, 12 years; range, 7 to 17
years; 12 male, 3 female) at a median of 9 years after a Fontan-type operation (6 atriopulmonary connections, 7 lateral
tunnels, 2 extracardiac conduits). The basal PVRI was 2.11⫾0.79 Wood unit (WU) times m2 (mean⫾SD) and showed
a significant reduction to 1.61⫾0.48 (P⫽0.016) after 20 ppm of NO for 10 minutes. The patients with nonpulsatile group
in the pulmonary circulation dropped the PVRI from 2.18⫾0.34 to 1.82⫾0.55 (P⬍0.05) after NO inhalation.
Conclusions—PVR falls with exogenous NO late after Fontan-type operation. These data suggest pulmonary endothelial
dysfunction, related in some part to lack of pulsatility in the pulmonary circulation because of altered flow
characteristics. Therapeutic strategies to enhance pulmonary endothelial NO release may have a role in these patients.
(Circulation. 2003;107:3204-3208.)
Key Words: Fontan procedure 䡲 pulmonary vascular resistance 䡲 endothelial dysfunction
T
he Fontan circulation is unique in exposing the pulmonary
vascular bed to flow without a hydraulic pump as the
driving force. In the absence of driving force from a ventricle, a
low pulmonary vascular resistance is essential for the optimum
functioning of the Fontan circulation.1,2 The Fontan operation
leads to loss or severe attenuation of pulsatile pulmonary blood
flow. Pulsatile flow is important for shear stress–mediated
release of endothelium-derived nitric oxide (NO) and lowering
of pulmonary vascular resistance by passive recruitment of
capillaries.3 Even though exogenous NO has been used therapeutically to reduce pulmonary vascular resistance and improve
cardiac output in early postoperative states after Fontan operation,2,4 –7 to our knowledge, there are no data on the basal
pulmonary vascular resistance and its responsiveness to NO late
after Fontan operation.
In this study, we measured the basal pulmonary vascular
resistance (PVR) and its responsiveness to exogenous NO in
patients with Fontan operation late after repair to investigate the
integrity of pulmonary vascular endothelium in these patients.
cardiac catheterization under general anesthesia. The study protocol
received approval of the ethics committee of Great Ormond Street
Hospital and Institute of Child Health. Informed consent was
obtained from all participating patients and parents. The study
protocol was carried out at the end of cardiac catheterization
performed as a routine diagnostic study or for specific purposes such
as occlusion of fenestration or collaterals.
Cardiac catheterization and angiography were performed under
general anesthesia with muscle paralysis in inspired oxygen concentration less than 0.3, which then remained constant throughout the
study. All patients were intubated with a cuffed endotracheal tube
and ventilated with a Servo 900B ventilator, and the exhaled gas was
collected in a mixing chamber and analyzed using a mass spectrometer (Amis 2000, Innovision) to measure oxygen consumption. A
transesophageal echocardiogram was performed. Routine diagnostic
cardiac catheterization and angiography was performed to obtain
basic hemodynamic data and rule out any shunt, obstruction, or
significant atrioventricular or semilunar valve regurgitation. All
pressure measurements were done with cessation of ventilation.
Study Protocol
After routine hemodynamic and angiographic assessment and in the
absence of significant shunts or branch pulmonary artery stenosis,
we measured the oxygen consumption (V̇O2) and calculated pulmonary blood flow by using the Fick principle with arteriovenous
oxygen difference obtained from a constant site in a branch pulmonary artery and left atrium or left ventricle in absence of right to left
shunt. After baseline measurements, 20 ppm NO was administered
Methods
Study Population
We studied 15 patients with Fontan circulation to assess basal
pulmonary vascular resistance and its response to inhaled NO during
Received October 1, 2002; revision received April 1, 2003; accepted April 4, 2003.
From Cardiothoracic Unit, Great Ormond Street Hospital for Children NHS Trust and Grown Up Congenital Heart Unit (S.C.), Heart Hospital, London,
UK.
Correspondence to Dr Sachin Khambadkone, MD, MRCP, Cardiology Department, Great Ormond Street Hospital, Great Ormond St, London WC1N
3JH, UK. E mail [email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000074210.49434.40
3204
Khambadkone et al
Pulmonary Vascular Resistance After Fontan
3205
Demographic and Clinical Information of Study Group
Patient
No.
1
Age,
y
17
Duration After
Surgery, y
15
7.5
Diagnosis
Type of
Operation
NYHA
Class
3
TA
LAT
NRGA
TUNN
DILV PA
APC
1
2
15
3
15
14
PA IVS
APC
1
4
8
4
DILV,DO
ECC
2
ECC
3
RV
5
11
9
DILV
DORV
6
10
9
PA IVS
LAT
1
TUNN
7
12
8
7
10
TA
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
9
13
11
10
7
5
1
DILV
LAT
1
TGA
TUNN
PA IVS
APC
1
TA
APC
1
LAT
3
NRGA
11
9
8
TA
TUNN
12
13
14
12
9
14
11
7
10
DILV
LAT
TGA
TUNN
DILV
LAT
TGA
TUNN
CCTGA
LAT
1
1
2
TUNN
15
16
14
TA
APC
exogenous NO and 2-tailed unpaired t tests when comparing 2
groups. Statistical significance was defined as P⬍0.05.
Results
APC
NRGA
0.08
Figure 1. Age (in years) plotted against PVRI shows no correlation between increasing age and PVRI.
1
CCTGA indicates congenitally corrected transposition of great arteries; DILV,
double-inlet left ventricle; DORV, double-outlet right ventricle; IVS, intact
ventricular septum; NRGA, normally related great arteries; PA, pulmonary
atresia; TA, tricuspid atresia; APC, atriopulmonary connection; LAT TUNN,
lateral tunnel Fontan operation; and ECC, extracardiac conduit.
through the ventilator circuit with continuous analysis of the dose
delivered and monitoring of NO2 levels. After 10 minutes of NO,
V̇O2 was measured and pulmonary blood flow was calculated again.
These measurements were repeated after a washout period of 10
minutes.
The pulmonary vascular resistance was calculated as follows:
PVR ⫽ (mPAP⫺mPCWP)/Qp,
where mPAP indicates mean pulmonary artery pressure, mPCWP
indicates mean pulmonary capillary wedge pressure, which was
taken as a measure of mean left atrial pressure, and Qp indicates
pulmonary blood flow.
Pressure measurements were done in apnea and after blood
sampling to avoid fluctuations in V̇O2 and blood gases. The PVR
index (PVRI, WU 䡠 m2) was calculated by using cardiac index
(Qp/body surface area) in the denominator.
Data are described as median and range for continuous variables
and mean and standard deviations for discrete variables. We studied
the relationship of age, NYHA functional class, and duration after
Fontan operation to the baseline PVRI and assessed the effect of NO
on PVRI of the group as a whole, on the subgroup with PVRI
⬎WU 䡠 m2, and on groups with different palliations before their
Fontan operation and different pulmonary artery flow patterns after
their Fontan operations. Statistical analysis was done by 2-tailed,
paired t tests for parameters before and after intervention with
The demographic and clinical information of the study group
is described in the Table. The median age of the patients was
12 years (range, 7 to 17 years), and the median duration after
operation was 9 years (range, 0.08 to 15 years). The diagnosis
was tricuspid atresia in 5, with concordant ventriculoarterial
connections in 3 and discordant in 2, double-inlet left ventricle in 6, pulmonary atresia with intact ventricular septum in 3,
and atrioventricular and ventriculoarterial discordance in 1.
The Fontan operation involved atriopulmonary connection in
6, lateral tunnel in 7, and extracardiac conduits in 2. Three
patients were in NYHA class 3, 2 were in class 2, and the rest
were in class 1.
The mean cardiac index and mean pulmonary vascular
resistance index was 2.48⫾0.57 L/min per m2 and 2.11⫾0.79
WU 䡠 m2, respectively, in the study group.
Thus, the mean pulmonary vascular resistance index was
elevated in our study group (normal values ⬍2 WU 䡠 m2).8 To
our knowledge, this is the first documentation of elevated
PVRI late after Fontan operation. The age of the patients and
duration of follow-up after the operation had no correlation
with PVRI (Figures 1 and 2, respectively). When the patients
were divided into 2 groups on the basis of NYHA functional
class, group A (NYHA 1) had a significantly lower mean
PVRI (1.72⫾0.38 WU 䡠 m2) compared with group B (NYHA
2 and 3) (2.82⫾0.88) (P⬍0.05) (Figure 3).
After 20 ppm of inhaled NO for a period of 10 minutes, the
mean cardiac index dropped marginally from 2.48⫾0.57 to
2.38⫾0.83 L/min per m2 (P⫽0.489); however, the mean
PVRI dropped from 2.11⫾0.79 to 1.61⫾0.48 WU 䡠 m2
(P⫽0.016, paired t test) (Figure 4). The NO inhalation
produced no significant change in the mean left ventricular
Figure 2. PVRI plotted against time after operation shows no
correlation.
3206
Circulation
July 1, 2003
Figure 3. NYHA class and PVRI. Patients with higher PVRI were
in NYHA classes 2 and 3. *P⬍0.05.
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
end-diastolic pressure (7.8⫾2.6 to 7.4⫾3.1 mm Hg, P⫽0.32)
and the V̇O2 (3.6⫾0.8 to 3.5⫾0.8 mL/kg per min, P⫽0.37).
Interestingly, of the patients in the study group who had
elevated PVRI (⬎2 WU 䡠 m2), 6 of the 7 showed a dramatic
response to exogenous NO (2.64⫾0.77 to 1.75⫾0.54,
P⬍0.05, paired t test) compared those with PVRI ⬍2, who
showed no significant change (1.59⫾0.33 to 1.47⫾0.4,
P⫽0.2) (Figure 5).
The basal PVRI did not show any important differences
between patients who had a pulmonary band as an initial
palliation (n⫽5) compared with those who had systemic to
pulmonary artery shunts (n⫽9). The response to NO was,
however, more significant in those with a band (2⫾0.22 to
1.47⫾0.22, P⫽0.006, paired t test) (Figure 6).
We found different pressure tracings in pulmonary arteries
of patients with atriopulmonary and some lateral tunnel
connections and extracardiac conduits. On the basis of pulse
pressures (difference between peak and nadir), we divided
patients into groups with pulsatile flow (mainly seen with
atriopulmonary [6] and 1 lateral tunnel connection; n⫽7) and
nonpulsatile flow (2 extracardiac conduits, 6 lateral tunnels).
The mean pulse pressure in pulsatile group was 3.7 and in the
nonpulsatile group 0.3.
There was no significant difference between the basal
PVRI in the 2 groups; however, the nonpulsatile group
dropped the PVRI from 2.18⫾0.34 to 1.82⫾0.55, P⬍0.05
(Figure 7). This may indicate that the pulmonary endothelial
dysfunction is related, at least in some part, to lack of
pulsatility in the pulmonary circulation because of altered
flow characteristics after Fontan operation.
Figure 5. Effect of exogenous NO on patients with PVRI ⬎2
(*P⫽0.023).
report severe functional decline, congestive heart failure, and
late death with increasing follow-up.1,9 –11 The reasons for
deterioration are multifactorial, but a low pulmonary vascular
resistance remains an important prognostic factor for a good
functional result after the Fontan operation.12
NO has been used to treat pulmonary endothelial dysfunction resulting from cardiopulmonary bypass after Fontan
operation.5,13 However, to our knowledge, there are no
studies examining the effect of inhaled NO on pulmonary
vascular resistance late after Fontan-type operations.
NO plays an important role in regulation of basal pulmonary vascular tone.14 –16 Supplemental inhaled NO has no
effect on basal pulmonary vascular tone or pulmonary blood
flow,17 but blockade of NO production leads to pulmonary
vasoconstriction and reduced pulmonary blood flow in the
normal lung.18 –20
In our study, the mean PVRI was elevated in patients late
after Fontan-type operation. There was no correlation between the age at follow-up and duration after surgery and
elevated PVRI. This probably suggests that the elevated
PVRI is not a consequence of the Fontan state in patients
deemed as “good Fontans” but may reflect the preparation
during their initial staging operations.
Supplemental inhaled NO led to a fall in PVR, suggesting
that basal PVR is increased, presumably as a result of
endothelial dysfunction. There are many possible reasons for
Discussion
The Fontan operation has evolved over the last 3 decades,
with many changes in the selection criteria and preoperative
preparation leading to a significant reduction in early mortality and morbidity.1,2 Although the long-term outlook for
contemporary series remains uncertain, historical cohorts
Figure 4. Effect of exogenous NO on PVRI late after Fontan
operation. NO caused a significant drop of mean PVRI in the
study group (*P⫽0.016).
Figure 6. Effect of NO on PVRI of patients with pulmonary
artery band as initial palliation showed a significant response
(*P⫽0.006) compared with the shunt group (P⫽0.04).
Khambadkone et al
Figure 7. Effect of exogenous NO on PVRI of patients with nonpulsatile flow in the pulmonary arteries. Significant drop of mean
PVRI (*P⬍0.05).
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
pulmonary endothelial dysfunction after Fontan operation.
The Fontan circulation leads to alterations in the flow patterns
in the pulmonary vascular bed.21 There is a phasic dependence of pulmonary blood flow with changes in intrathoracic
pressure but a loss or severe attenuation of cardiac pulsatility
in the pulmonary vascular bed. The pulsatile flow is important for maintaining a low resistance in the pulmonary
vasculature by the passive recruitment of capillaries and shear
stress–mediated release of NO causing endothelial relaxation.
Indeed, pulsatile flow has been shown to be a more potent
stimulus for release of NO to the same volume of laminar
flow.22 Pulsatile shear stress acts on the endothelium via
diverse mechanisms.23 Experimentally, induction of hyperpolarization of endothelial cell causes elevation of cGMP via an
NO-dependent mechanism, redistribution of the endothelial
cytoskeletal protein, actin, and upregulation of NO synthase
gene transcription, which may be caused by pulsatile shear
stress. Reduced pulsatile shear stress in the Fontan pulmonary
circulation, thus, may downregulate the endothelial NO
synthase expression and attenuate endothelial-dependent
vasodilatation.
On this basis, the degree of elevation of PVR or NO
responsiveness might be expected to correlate with the
residual pulsatility in the pulmonary circulation in our patients. Although some pulsatility was preserved in those with
atriopulmonary connection and lateral tunnel Fontan with
dilated right atrium, pulsatility was essentially absent in those
with an extracardiac conduit. Although there was no difference in the basal PVRI between the 2 groups, we found that
the nonpulsatile group responded to exogenous NO with a
significant drop in their PVRI compared with those with
pulsatile flow. This may reflect the altered pulmonary endothelial function attributable to important changes in flow
characteristics after some types of Fontan operations. However, it is difficult to rule out the impact of pre-Fontan
hemodynamics and flow patterns in the pulmonary circulation of this cohort of patients and attribute these changes
solely to pulsatility or the lack of it.
Recent data are somewhat counterintuitive with regards to
the magnitude of shear stress and type of Fontan circulation.
Using 3D phase-contrast MRI, increasing shear stress was
detected at the anastomosis in Fontan circuits with total
cavopulmonary connection compared with atriopulmonary
connections.24 This is attributable to circular swirling vortices
in the laminar flow and increase in circumferential stress.
Pulmonary Vascular Resistance After Fontan
3207
However, this study did not attempt to measure shear stress in
the more peripheral pulmonary arteriolar bed, the major
resistance vessels responsible for modulation of PVR.
Therefore, the issues surrounding pulmonary endothelial
dysfunction in Fontan circulation are complex and remain
fully to be explored. Furthermore, we cannot exclude an
entirely separate mechanism for the effect of NO in our
patients. Inhaled NO is a potent pulmonary vasodilator in the
presence of alveolar hypercapnia, hypoxia, pulmonary parenchymal disease, and circulating vasoconstrictors such as
endothelins. Although we can exclude ventilatory and parenchymal abnormalities, the role of spontaneous respiration and
gravity on pulmonary blood flow could not be assessed in our
patients.25 Also, inhaled NO may be effecting pulmonary
vasodilatation by antagonizing a constrictor. No matter what
the mechanism, our findings suggest that some patients may
benefit from treatment to enhance or replace pulmonary NO
production or release. There are no specific data regarding
such agents, but it is known that angiotensin-converting
enzyme inhibitors (known to increase NO effects and decrease oxidants) fail to improve functional capacity in unselected patients after Fontan operations.26
Limitations
This cohort study investigates a small nonselective group of
patients after Fontan operation; hence, interpretation of comparison between smaller subgroups should be cautious. Also,
all patients were studied under general anesthesia; therefore,
the effect of spontaneous respiration and gravity could not be
taken into account. However, any influence of ventilation
problems on PVR could safely be excluded.
In summary, pulmonary vascular resistance is elevated and
falls in response to exogenous NO, late after Fontan operation. There is no difference in the basal PVR and its response
to exogenous NO between different Fontan-type operations.
Elevated PVR correlates with poor functional performance
late after Fontan operations. Pharmacological manipulation of
pulmonary vascular tone may have a therapeutic role in
selected patients late after Fontan-type operations.
Acknowledgments
Dr Khambadkone was supported by a British Heart Foundation
Research Grant. Research at Institute of Child Health and Great
Ormond Street Hospital for Children NHS Trust benefits from
Research and Development funding received from the NHS
Executive.
References
1. Gentles TL, Mayer JE Jr, Gauvreau K, et al. Fontan operation in five
hundred consecutive patients: factors influencing early and late outcome.
J Thorac Cardiovasc Surg. 1997;114:376 –391.
2. Knott-Craig CJ, Danielson GK, Schaff HV, et al. The modified Fontan
operation: an analysis of risk factors for early postoperative death or
takedown in 702 consecutive patients from one institution. J Thorac
Cardiovasc Surg. 1995;109:1237–1243.
3. Hakim TS. Flow-induced release of EDRF in the pulmonary vasculature:
site of release and action. Am J Physiol. 1994;267(1 pt 2):H363–H369.
4. Goldman AP, Delius RE, Deanfield JE, et al. Pharmacological control of
pulmonary blood flow with inhaled nitric oxide after the fenestrated
Fontan operation. Circulation. 1996;94(9 suppl):II44 –II48.
5. Ishizaka T, Kumon K, Yahagi N, et al. Inhaled nitric oxide after Fontan
type operation [in Japanese]. Rinsho Kyobu Geka. 1994;14:323–326.
3208
Circulation
July 1, 2003
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
6. Yahagi N, Kumon K, Tanigami H, et al. Inhaled nitric oxide for the
postoperative management of Fontan-type operations. Ann Thorac Surg.
1994;57:1371–1373.
7. Gamillscheg A, Zobel G, Urlesberger B, et al. Inhaled nitric oxide in
patients with critical pulmonary perfusion after Fontan-type procedures
and bidirectional Glenn anastomosis. J Thorac Cardiovasc Surg. 1997;
113:435– 442.
8. Vargo TA. Cardiac catheterisation measurements. In: Garson A, Bricker
TJ, Fisher DJ, et al, eds. The Science and Practice of Pediatric Cardiology. 2nd ed. Baltimore: Williams & Wilkins; 1998:981–1024.
9. Mair DD, Puga FJ, Danielson GK. The Fontan procedure for tricuspid
atresia: early and late results of a 25-year experience with 216 patients.
J Am Coll Cardiol. 2001;37:933–939.
10. Cohen AJ, Cleveland DC, Dyck J, et al. Results of the Fontan procedure
for patients with univentricular heart. Ann Thorac Surg. 1991;52:
1266 –1270.
11. Fontan F, Kirklin JW, Fernandez G, et al. Outcome after a “perfect”
Fontan operation. Circulation. 1990;81:1520 –1536.
12. Kaulitz R, Ziemer G, Luhmer I, et al. Modified Fontan operation in
functionally univentricular hearts: preoperative risk factors and intermediate results. J Thorac Cardiovasc Surg. 1996;112:658 – 664.
13. Goldman AP, Delius RE, Deanfield JE, et al. Pharmacological control of
pulmonary blood flow with inhaled nitric oxide after the fenestrated
Fontan operation. Circulation. 1996;94(9 suppl):II44 –II48.
14. Kiely DG, Lee AF, Struthers AD, et al. Nitric oxide: an important role in
the maintenance of systemic and pulmonary vascular tone in man. Br J
Clin Pharmacol. 1998;46:263–266.
15. Chen YF, Oparil S. Endothelial dysfunction in the pulmonary vascular
bed. Am J Med Sci. 2000;320:223–232.
16. Rossi GP, Seccia TM, Nussdorfer GG. Reciprocal regulation of
endothelin-1 and nitric oxide: relevance in the physiology and pathology
of the cardiovascular system. Int Rev Cytol. 2001;209:241–272.
17. Brett SJ, Chambers J, Bush A, et al. Pulmonary response of normal
human subjects to inhaled vasodilator substances. Clin Sci (Lond). 1998;
95:621– 627.
18. Celermajer DS, Dollery C, Burch M, et al. Role of endothelium in the
maintenance of low pulmonary vascular tone in normal children. Circulation. 1994;89:2041–2044.
19. Kiely DG, Lee AF, Struthers AD, et al. Nitric oxide: an important role in
the maintenance of systemic and pulmonary vascular tone in man. Br J
Clin Pharmacol. 1998;46:263–266.
20. Van Camp JR, Yian C, Lupinetti FM. Regulation of pulmonary vascular
resistance by endogenous and exogenous nitric oxide. Ann Thorac Surg.
1994;58:1025–1029.
21. Penny DJ, Redington AN. Doppler echocardiographic evaluation of pulmonary blood flow after the Fontan operation: the role of the lungs. Br
Heart J. 1991;66:372–374.
22. Raj JU, Kaapa P, Anderson J. Effect of pulsatile flow on microvascular
resistance in adult rabbit lungs. J Appl Physiol. 1992;72:73– 81.
23. Busse R, Fleming I. Pulsatile stretch and shear stress: physical stimuli
determining the production of endothelium-derived relaxing factors. J
Vasc Res. 1998;35:73– 84.
24. Morgan VL, Graham TP Jr, Roselli RJ, et al. Alterations in pulmonary
artery flow patterns and shear stress determined with three-dimensional
phase-contrast magnetic resonance imaging in Fontan patients. J Thorac
Cardiovasc Surg. 1998;116:294 –304.
25. Hsia TY, Khambadkone S, Redington AN, et al. Effects of respiration and
gravity on infradiaphragmatic venous flow in normal and Fontan patients.
Circulation. 2000;19(suppl 3):III148 –III153.
26. Kouatli AA, Garcia JA, Zellers TM, et al. Enalapril does not enhance
exercise capacity in patients after Fontan procedure. Circulation. 1997;
96:1507–1512.
Basal Pulmonary Vascular Resistance and Nitric Oxide Responsiveness Late After
Fontan-Type Operation
S. Khambadkone, J. Li, M.R. de Leval, S. Cullen, J.E. Deanfield and A.N. Redington
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
Circulation. 2003;107:3204-3208; originally published online June 23, 2003;
doi: 10.1161/01.CIR.0000074210.49434.40
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2003 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/107/25/3204
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/