Download The CALF (Congenital Heart Disease in Adults Lower Extremity

Journal of the American College of Cardiology
© 2010 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 56, No. 2, 2010
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2010.02.048
Congenital Heart Disease
The CALF (Congenital Heart Disease
in Adults Lower Extremity Systemic
Venous Health in Fontan Patients) Study
Anne Marie Valente, MD,*† Ami B. Bhatt, MD,*† Stephen Cook, MD,‡ Michael G. Earing, MD,§
Deborah R. Gersony, MD,储 Jamil Aboulhosn, MD,¶ Alexander R. Opotowsky, MD, MPH,#
George Lui, MD,储 Michelle Gurvitz, MD, MS,** Dionne Graham, PHD,* Susan M. Fernandes, PA-C,*
Paul Khairy, MD, PHD,* Gary Webb, MD,# Marie Gerhard-Herman, MD,† Michael J. Landzberg, MD,*†
for the AARCC (Alliance for Adult Research in Congenital Cardiology) Investigators
Boston, Massachusetts; Columbus, Ohio; Milwaukee, Wisconsin; New York, New York; Los Angeles, California;
Philadelphia, Pennsylvania; and Seattle, Washington
Objectives
The objective of this study was to document the prevalence of chronic venous insufficiency (CVI) and its associated factors in adults with Fontan physiology.
Background
As the population of adults with complex congenital heart disease and Fontan physiology increases, so does the
occurrence of highly morbid and mortal outcomes, including heart failure and thromboembolism. The presence
of abnormal peripheral hemodynamic conditions in this population and their potential contribution to adverse
outcomes is not well known. The primary objective of this study was to document the prevalence of CVI in adults
with Fontan physiology.
Methods
A total of 159 adults with Fontan physiology from 7 adult congenital heart centers were prospectively assessed
for lower extremity CVI, with the assignment of clinical, etiological, anatomical, and pathophysiological classification grades, and compared with age-matched and sex-matched controls. Leg photographs were independently
reassessed to confirm interobserver reliability.
Results
The prevalence of CVI was significantly greater in the Fontan population (60%; 95% confidence interval [CI]: 52%
to 68%) compared with healthy controls (32%; 95% CI: 15% to 54%) (p ⫽ 0.008). Strikingly, the prevalence of
severe CVI (clinical, etiological, anatomical, and pathophysiological grade ⱖ4) was significantly higher in the
Fontan group (22%; 95% CI: 16% to 29%) versus the healthy controls (0%; 95% CI: 0% to 14%) (p ⫽ 0.005). In a
multivariate analysis, several factors were independently associated with severe CVI, including increased numbers of catheterizations with groin venous access, lower extremity itching, and deep venous thrombosis.
Conclusions
CVI is common in adult patients with congenital heart disease with Fontan physiology. The contribution of abnormal peripheral hemodynamic conditions to comorbidities, including thromboembolism and heart failure, and
interventions to improve peripheral hemodynamic conditions require further exploration. (J Am Coll Cardiol
2010;56:144–50) © 2010 by the American College of Cardiology Foundation
The Fontan operation has evolved over the past 4 decades from
palliation for tricuspid atresia to its wider current application
for many single-ventricle circulations (1). Gradual attrition in
survival in adults with Fontan physiology is related to thromboembolism, heart failure and sudden death (2), whereas loss
of functional ability has largely been correlated with central
hemodynamic status, alterations in neurohormonal activation,
and imbalance in ventilatory function (3–7).
More recently, there has been recognition of the potential
impact of changes in peripheral hemodynamic conditions,
From the *Department of Cardiology, Children’s Hospital Boston, Boston, Massachusetts; †Division of Cardiology, Brigham and Women’s Hospital and Harvard
Medical School, Boston, Massachusetts; ‡Ohio State University, Columbus, Ohio;
§Medical College of Wisconsin, Milwaukee, Wisconsin; 储Columbia University, New
York, New York; ¶University of California, Los Angeles, Los Angeles, California;
#University of Pennsylvania, Philadelphia, Pennsylvania; and the **University of
Washington, Seattle, Washington. This study was supported in part by the Dunlevie
Fund (Boston, Massachusetts). The Alliance for Adult Research in Congenital
Cardiology has received support from the Adult Congenital/Pediatric Cardiology
Section of the American College of Cardiology.
Manuscript received September 16, 2009; revised manuscript received February 5,
2010, accepted February 15, 2010.
Valente et al.
Venous Disease in Adult Fontan Patients
JACC Vol. 56, No. 2, 2010
July 6, 2010:144–50
skeletal muscle metabolism, and endothelial dysfunction on
the failing Fontan physiology. Endothelium-dependent circulating levels of von Willebrand factor, flow-mediated
dilation, and blood flow supply to skeletal muscle with
subsequent effect on exercise capacity have all been shown to
be abnormal in patients with Fontan palliation (8 –11).
See page 151
Chronic venous insufficiency (CVI) is a common clinical
problem. In the general population, CVI is associated with
a reduced quality of life, particularly in relation to pain,
depression, social isolation, mobility, and physical function
(12). Several pathophysiologic mechanisms appear common
to the occurrence of both CVI and Fontan failure, including
abnormalities in central and peripheral hemodynamic status.
However, to date, CVI has not been described in patients
who have undergone the Fontan procedure.
Risk factors for CVI in the general population (including
heredity, age [13–15], female sex, leg trauma, obesity,
history of phlebitis or deep vein thrombosis [16], pregnancy
[17], oral contraceptive use, and prolonged standing) and
symptoms referable to CVI (including aching, heaviness, a
sensation of swelling, and skin irritation) can be determined
by clinical history. Inspection and palpation define physical
findings to further classify CVI. CVI can be thereby
identified and graded according to a well-established scale
describing clinical, etiological, anatomical, and pathophysiological (CEAP) classifications (18,19).
The objective of this study was to document the prevalence of CVI and its associated factors in adults with Fontan
physiology. The hypothesis was that patients with Fontan
physiology have chronically elevated systemic venous pressure, and this finding in the setting of nonpulsatile pulmonary blood flow may place them at increased risk for CVI.
These results may further elucidate the complex relationships between central and peripheral hemodynamic conditions, as well as provide a foundation for future studies
aiming to improve functional outcomes in this population.
Methods
Study design. This multi-institutional, cross-sectional, observational study prospectively recruited successive subjects
age ⱖ18 years who had previously undergone Fontan
procedures and presented in stable condition for outpatient
evaluation at 1 of 7 U.S. adult congenital heart disease
centers for evaluation. The protocol was developed by the
core institution (Children’s Hospital Boston, Boston, Massachusetts) and was refined by the consensus of participating
centers within the Alliance for Adult Research in Congenital Cardiology framework (20). Subjects were excluded if
they had histories of cardiac transplantation or had major
surgery or traumatic injury within the previous 10 weeks.
Clinical, anatomical, and surgical data were collected at
enrollment (July 2007 to May 2009) by medical record
145
review and patient interview usAbbreviations
and Acronyms
ing standardized forms. Control
subjects consisting of hospital
CEAP ⴝ clinical,
employees without histories of
etiological, anatomical, and
congenital heart disease were
pathophysiological
identified and enrolled. A comCI ⴝ confidence interval
parison group of subjects cared
CVI ⴝ chronic venous
for by the core institution who
insufficiency
had previously undergone tetralTOF ⴝ tetralogy of Fallot
ogy of Fallot (TOF) surgical repair were also included. The protocol was approved by each center’s institutional review
board, and written informed consent was obtained.
Recruitment protocol. Standardized case report forms included basic demographic information, congenital cardiac
anatomical diagnosis as designated by the treating center
using standardized nomenclature (21), surgical procedures
including type of Fontan operation, current medications,
family history of venous disease, and symptoms. Laboratory
values and historical imaging data that were collected within
1 year of enrollment were included.
A directed physical examination was performed, including a thorough evaluation of the subjects’ lower extremities
with the assignment of CEAP classification grades by the
investigator at each center. The clinical signs in the affected
legs are categorized into 7 classes designated C0 to C6
(Table 1) (18). Patients with CEAP grades ⱖ4 are categorized as having severe CVI, given the presence of end-organ
changes from lipodermatosclerosis to ulceration (22).
Each center used a digital camera to photograph the
lower extremities according to a standardized protocol. The
photographs were taken at a distance of 1 to 2 feet from
the subject while he or she was standing in 4 distinct
positions. Additional photographs were taken at close range
of any ulcers, discoloration, or other skin changes.
Interobserver agreement. To test agreement of CEAP
classification by each center, a vascular medicine specialist
(M.G.H.) blinded to the subjects’ assigned CEAP classifications reviewed 50 randomly selected subjects and determined CEAP grades on the basis of visual inspection of the
photographs provided.
Statistical analysis. Continuous demographic and clinical
data are summarized as mean ⫾ SD or as medians and
CEAP
TableClassification
1
CEAP Classification
Class
Characteristics
0
No visible or palpable signs of venous disease
1
Telangiectasias or reticular veins
2
Varicose veins
3
Edema
4a
Skin changes ascribed to venous disease (pigmentation, eczema)
4b
Skin changes including lipodermatosclerosis and/or atrophie blanche
5
Skin changes as defined above with healed venous ulcer
6
Skin changes as defined above with active venous ulcer
CEAP ⫽ clinical, etiological, anatomical, and pathophysiological.
146
Valente et al.
Venous Disease in Adult Fontan Patients
JACC Vol. 56, No. 2, 2010
July 6, 2010:144–50
Baseline
of Fontan, TOF,
and Healthy
Control
Subjects
Table 2 Characteristics
Baseline Characteristics
of Fontan,
TOF, and
Healthy
Control Subjects
Fontan
(n ⴝ 159)
TOF
(n ⴝ 40)
p Value
Healthy
(n ⴝ 25)
p Value
30.6 ⫾ 9.1
35.6 ⫾ 10.7
0.003
32.1 ⫾ 7.6
0.43
Age at surgical repair* (yrs)
8.3 (4.3–15.2)
5.7 (1.5–10.0)
0.007
Male sex
73 (46%)
16 (40%)
0.50
10 (40%)
0.58
25.7 ⫾ 5.9
0.14
23.1 ⫾ 2.5
0.10
Characteristic
Age at enrollment (yrs)
Body mass index (kg/m2)
Cardiac catheterizations
Presence of leg symptoms
24.2 ⫾ 4.5
5 (3–7)
4 (2–6)
0.03
0 (0–0)
⬍0.0001
85 (54%)
16 (40%)
0.13
1 (4%)
⬍0.0001
Data are expressed as mean ⫾ SD, median (interquartile range), or n (%). *Age at surgical repair indicates age at Fontan completion surgery and
complete repair of tetralogy of Fallot (TOF).
interquartile ranges depending on normality. Categorical
data are reported as percents. Patient characteristics were
compared between the Fontan group and the control and
comparison groups using t tests, chi-square tests, and Fisher
exact tests, as appropriate. CVI was defined as CEAP grade
ⱖ1 and severe CVI as CEAP grade ⱖ4. The prevalence of
CVI in the Fontan group was compared with the control
and comparison groups using chi-square or Fisher exact
tests. The rates of severe venous insufficiency were similarly
compared.
Within the group of Fontan patients, univariate logistic
regression was used to identify demographic and clinical risk
factors of the binary outcome of severe CVI. Factors with
univariate p values ⬍0.05 were considered for inclusion in a
multivariate logistic regression model. To prevent overfitting, only models with at most 3 predictors were considered.
The final model was the one that maximized the likelihood
score statistic.
Interobserver agreement among the subset of patients
who were re-reviewed was quantified with the weighted
kappa coefficient. For all tests, statistical significance was
defined by a 2-sided p value ⬍0.05. Statistical analyses were
performed using SAS version 9.2 for Windows (SAS
Institute Inc., Cary, North Carolina).
cent of the repaired TOF group reported lower extremity
symptoms, compared with only 1 patient (4%) in the
healthy control group.
Table 3 summarizes the anatomical and clinical characteristics in the Fontan subjects. The 159 Fontan subjects
were 30.6 ⫾ 9.1 years of age at enrollment. The mean body
mass index of the cohort was 24.2 ⫾ 4.5 kg/m2, and the
mean resting oxygen saturation was 92.6 ⫾ 4.3%. The
distribution of ventricular morphologic subgroups was as
follows: left ventricle, 71%; right ventricle, 26%; and mixed,
3%. Eighty-three percent of subjects had undergone some
Anatomical
Fontan
Subjects
and
Clinical
Characteristics
Fontan
Subjects
Table 3
Anatomical and Clinical Characteristics
Characteristic
Fontan Patients
(n ⴝ 159)
Cardiac diagnosis
Tricuspid atresia
54 (34%)
Double-inlet LV
41 (26%)
Heterotaxy syndrome
21 (13%)
Hypoplastic left heart syndrome
4 (2%)
Unbalanced atrioventricular canal
4 (2.5%)
Pulmonary atresia, intact ventricular septum
Other single ventricle
3 (1.9%)
32 (20.6%)
Type of Fontan procedure
Results
Atriopulmonary
70 (44%)
Lateral tunnel
57 (36%)
Overall cohort. A total of 159 adults with Fontan physiology were enrolled at 7 U.S. adult congenital centers. The
control and comparison groups were enrolled at the core
center and consisted of 25 healthy subjects without heart
disease and 40 subjects with repaired TOF. The baseline
characteristics of this cohort are summarized in Table 2.
The mean age (32.1 ⫾ 7.6 years), sex distribution (40%
male), and body mass index (23.1 ⫾ 2.5 kg/m2) were
statistically comparable between the healthy control group
(p ⫽ NS) and the Fontan cohort. No subjects in the healthy
control group had undergone prior cardiac catheterization.
The repaired TOF group had a similar sex distribution (40%
male) and mean body mass index (25.7 ⫾ 5.9 kg/m2) (p ⫽
NS), but they were slightly older (mean age 35.6 ⫾ 10.7
years; p ⫽ 0.003) than the Fontan group. The repaired
TOF group had a median of 4 (interquartile range 2 to 6)
cardiac catheterizations with prior groin access. Forty per-
Atrioventricular
13 (8%)
Extracardiac conduit
Other
9 (6%)
10 (6%)
Vascular history
Deep venous thrombosis
10 (6.5%)
Fontan pathway thrombosis
24 (15.7%)
Pulmonary thrombus/embolism
10 (6.5%)
Medication use
Antiarrhythmic agents
54 (34.2%)
ACE inhibitors/ARBs
84 (53.2%)
Beta-blockers
39 (31%)
Diuretic agents
71 (44.9%)
Warfarin
91 (57.6%)
Aspirin
70 (44.3%)
Intracardiac devices
Pacemaker
Internal defibrillator
57 (35.8%)
2 (1.3%)
ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin II receptor blocker; LV ⫽ left ventricle.
Valente et al.
Venous Disease in Adult Fontan Patients
JACC Vol. 56, No. 2, 2010
July 6, 2010:144–50
147
prevalence of severe venous insufficiency (CEAP grade ⱖ4)
(Figs. 1 to 3) was significantly higher in the Fontan cohort
(22%; 95% CI: 16% to 29%) versus the healthy control
group (0%; 95% CI: 0% to 14%) (p ⫽ 0.005). There was no
difference in the prevalence of CVI between the Fontan
group (22%; 95% CI: 16% to 29%) and the subjects with
repaired TOF (12.5%; 95% CI: 4% to 27%) (p ⫽ 0.27).
Univariate and multivariate predictors of severe CVI in the
Fontan population are summarized in Table 4. The kappa
value was 0.76 for interobserver CEAP classification. Of
importance, 100% concordance was observed for patients
denoted as having severe disease (CEAP grade ⱖ4).
Discussion
Figure 1
35-Year-Old Woman, Status Post-Fontan Revision
to an Extracardiac Conduit 3 Years Before Enrollment
Clinical, etiological, anatomical, and pathophysiological (CEAP)
grade 4 with skin pigmentation and lipodermatosclerosis.
surgical palliation before Fontan completion. The mean
age at the initial Fontan procedure was 11.2 ⫾ 9.3 years,
and the most common types of Fontan procedures performed were atriopulmonary anastomosis and intracardiac
lateral tunnel. Twenty-eight patients had undergone subsequent Fontan revision, and 31 had undergone subsequent
Fontan fenestration closure. Subjects in the cohort had
undergone a median of 5 (interquartile range 3 to 7) cardiac
catheterizations with femoral intravenous access, and 10%
had documented femoral venous occlusion. Of the 147
patients who had imaging data within 1 year of enrollment,
over 40% of the cohort had at least mild systemic ventricular
dysfunction, and ⬎70% had at least mild atrial ventricular
valve regurgitation.
On direct questioning regarding symptoms relating to
systemic venous disease and health, 85 subjects (54%)
reported at least 1 of the following: burning, swelling, pain,
itching, or leg heaviness. Thirty-five percent of the cohort
was involved in activities that required long periods of
standing. Ten subjects had histories of deep venous thrombosis of the lower extremity, and 10 additional subjects had
received diagnoses of pulmonary emboli in the past. Additionally, 24 subjects had histories of thrombosis in the
Fontan pathway, and 9 had experienced cerebral vascular
accidents after Fontan completion. Forty percent reported
family histories of lower extremity venous disease. Twentythree percent had histories of tobacco abuse, 10% had
diabetes, and 27% of the women had completed at least 1
pregnancy.
Prevalence. The prevalence of CVI was significantly
greater in the Fontan population (60%; 95% confidence
interval [CI]: 52% to 68%) compared with healthy controls
(32%; 95% CI: 15% to 54%) (p ⫽ 0.008). Strikingly, the
This multi-institutional, prospective, cross-sectional assessment is the first to document the high prevalence of CVI in
adults with congenital heart disease and Fontan physiology;
strikingly, the point prevalence of severe CVI in the Fontan
population examined in this study approached 25%. This
appears to be more than 3 to 4 times higher than the point
prevalence of severe CVI reported in the general population,
although it approximates that seen in other groups (older
age, deep venous thrombosis) thought to be at high risk for
severe CVI (12,23). Of interest, this prevalence of severe
CVI in our cohort is similar to that reported for systemic
venous pathway thrombosis in a single-center study of adult
Fontan outpatients (24).
Several mechanisms contribute to the development and
maintenance of CVI, each of which is particularly relevant
to adult survivors with Fontan circulation. Pressure in lower
Figure 2
41-Year-Old Man Status Post-Right Atrial Appendage
to Pulmonary Artery Fontan at Age 18 Years
CEAP grade 5 with healed skin ulceration. Abbreviation as in Figure 1.
148
Figure 3
Valente et al.
Venous Disease in Adult Fontan Patients
43-Year-Old Man Status
Post-Atriopulmonary Fontan Procedure at Age 5 Years
CEAP grade 6 with extensive skin changes and area of active ulceration.
Abbreviation as in Figure 1.
extremity veins is determined by 2 components: hydrostatic
forces related to the weight of the column of blood from the
right atrium to the foot and a hydrodynamic determinant
related to pressures generated by contractions of the skeletal
muscles of the leg and the pressure in the capillary network
(25). Concomitant with the development of CVI, cellular
activation and cytokine release involving leukocyte interaction with the endothelium lead to an inflammatory and
potentially destructive process involving pathways similar to
those activated in chronic heart failure syndromes (26).
The hydrostatic component to the elevation of systemic
venous pressures may be increased in patients with Fontan
palliation because of several factors. This unique circulatory
model intricately ties the loading conditions of the central
pump to loading conditions in the systemic veins, in
contrast to the normal circulation, which has an intervening
pump in the subpulmonary position. By the very definition
of this physiology, right atrial pressure is greater than left
atrial pressure, leading to a reversal of the typical trend seen
in normal subjects, as well as to increased systemic venous
JACC Vol. 56, No. 2, 2010
July 6, 2010:144–50
pressure. Any additional resistance to flow, from the peripheral systemic veins through the right atrium and lungs,
leads to further elevation of hydrostatic pressure in the
systemic veins. With increasing heart rates, survivors with
Fontan circulation demonstrate limited inotropic response
and worsening of diastolic filling of the systemic arterial
pump, leading to elevation of left atrial pressure and,
because of direct coupling across the pulmonary vascular
bed, elevation in central venous pressure (4). Reduction of
normal respiratory changes in transhepatic systemic venous
flow and an increase in transhepatic venous resistance,
observed in adult survivors with Fontan physiology, may
further exacerbate distal systemic venous pressures (27).
Taken together, the elevation of distal and more proximal
systemic venous pressures leads to distention and engorgement of the veins, increased pressure on local tissue, and
ultimate induction of inflammation in the vascular wall,
venous valves (with development of valve remodeling, loss of
function, and reflux) (28 –30) and local tissues.
Additional hydrodynamic components leading to development of CVI in Fontan circulations have been less
examined. Inai et al. (8) recently demonstrated altered
skeletal muscle hemodynamic conditions in patients with
Fontan palliation, although calf pump function was not
specifically explored. Systemic venous valve dysfunction,
caused by high systemic venous pressures and inflammatory
microcirculation changes outlined previously, likely contribute to increased risk for venous thromboembolism and, as
well, are likely worsened by the heightened occurrence of
such venous thromboembolism in patients with Fontan
palliation (due in part to circulating prothrombotic factors
[31]) throughout the Fontan pathway (2).
The recognition and cataloguing of CVI in the population of adult congenital heart disease survivors is a new
finding and was aided by the collaborative efforts of a
multi-institutional research network. Multiple patient factors were identified as predictors of severe CVI, including
age, male sex, and prior occurrence of deep venous thrombosis. Adult survivors with Fontan palliation frequently
underwent catheterization using venous access at a much
younger age and smaller vessel size than the population of
other adults with CVI and associated coronary atherosclerosis (typically using arterial access), potentially leading to
greater degrees of venous obstruction and inflammation and
ultimately to increased occurrence of CVI.
Interestingly, cardiac findings traditionally considered to
be risk factors for adverse outcomes in adults with Fontan
physiology did not correlate with increased risk for CVI.
These include morphologic systemic ventricle type and
surgical type of Fontan procedure (atriopulmonary anastomosis vs. lateral tunnel procedure). Additionally, prescribed
patient use of anticoagulant agents did not predict the
severity of CVI.
One concerning, although important, finding in this
cohort is the lack of a significant difference between the
prevalence of CVI in the adult Fontan population compared
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149
Univariate
Multivariate
Predictors for
Severe CVI
Fontan
Patients
Table 4 and
Univariate
and Multivariate
Predictors
forinSevere
CVI
in Fontan Patients
Univariate
Multivariate
Odds Ratio
(95% CI)
p Value
Male sex
2.42 (1.12–5.25)
0.02
Age ⱖ31 yrs
6.54 (2.80–15.27)
⬍0.0001
Single right ventricle
0.41 (0.15–1.13)
0.07
Atriopulmonary Fontan
3.64 (1.36–9.79)
0.03
Atrioventricular Fontan
5.31 (1.31–21.57)
Extracardiac Fontan
2.43 (0.41–14.47)
Other Fontan type
0.95 (0.10–8.80)
Variable
Catheterizations ⱖ5
Odds Ratio
(95% CI)
p Value
5.68 (2.30–14.02)
0.0002
5.40 (1.92–15.18)
0.001
10.12 (4.30–23.82)
⬍0.0001
11.13 (4.25–29.11)
⬍0.0001
Diuretic agent use
5.01 (2.16–11.62)
⬍0.0001
Antiarrhythmic agent use
2.99 (1.38–6.46)
0.005
Heart failure diagnosis
2.46 (1.12–5.40)
0.03
History of DVT
6.15 (1.63–23.24)
0.007
5.80 (1.29–26.01)
0.02
History of venous surgery
3.78 (0.73–19.63)
0.12
Body mass index
1.11 (1.12–1.20)
0.01
Lower extremity itching
CI ⫽ confidence interval; CVI ⫽ chronic venous insufficiency; DVT ⫽ deep venous thrombosis.
with the comparison group of adults with repaired TOF.
The high prevalence of CVI in this slightly older latter
group suggests that these patients, as well, may have adverse
peripheral hemodynamic status, which remains to be explored. Patients with repaired TOF are a limited comparison population given the combination of potential confounding effects such as elevated systemic venous pressures
and subpulmonary ventricular dysfunction that may exist in
this group.
Adults with Fontan physiology are among the most
challenging groups followed in adult congenital clinics, with
high morbidity and mortality. Thromboembolism, exercise
incapacity, and heart failure appear common and increase
both in incidence and severity over time. The association
between peripheral hemodynamic status, CVI, and endothelial dysfunction may prove to both depend on, as well as
contribute to, the long-term consequences and decreased
functional capacity (32) associated with Fontan physiology.
As was shown by assessment of the comparison group
with TOF, examination of this unique patient population
underscores the importance of examining the peripheral
circulation in all adult patients with congenital heart disease,
to determine its contribution to mechanisms of heart failure
and exercise intolerance. Ultimately, recognition and determination of the mechanisms of CVI in survivors with
Fontan palliation may lead to the assessment of interventions with proven benefit in the general CVI population
(such as dedicated lower extremity muscle training exercises
and venous compression stockings) in the Fontan population. Pharmacological therapies to decrease systemic venous
pressure have not been shown to be effective in the general
population, but the benefit of such therapies on the occurrence of highly morbid and mortal outcomes in the Fontan
population remains unknown.
Study limitations. This study had several important limitations. This cross-sectional observational study was performed at 7 major adult congenital heart centers. The study
patient population may not be representative of all adults
with Fontan physiology in the general community, because
of a referral bias. However, it is recognized that the majority
of patients with Fontan palliation remain in care at such
institutions. Furthermore, this study was limited to measurements at a single physical assessment. Therefore,
changes in systemic venous health and disease over time
could not be assessed. However, this study lays the groundwork for the implementation of longitudinal examination of
the functional relationships and potential interventions in
this population. Given a possible association between CVI
and mortality, survivor bias is a concern. This would tend to
bias the findings toward a lower proportion of patients with
CVI, however, because those who died would likely have a
higher prevalence of CVI.
Finally, the lack of significant difference between the
prevalence of CVI in the adult Fontan population compared
with the comparison group of adults with repaired TOF
may reflect the age difference between the 2 groups or a lack
of power in the study due to inadequate sample size.
Conclusions
CVI is common in adult congenital heart patients with
Fontan physiology and is often severe. The occurrence of
CVI in other populations of adults with congenital heart
disease, as well as the contribution of abnormal peripheral
hemodynamic conditions in adult survivors with Fontan
palliation to comorbidities including thromboembolism and
heart failure, and interventions to improve peripheral hemodynamics require further exploration.
150
Valente et al.
Venous Disease in Adult Fontan Patients
JACC Vol. 56, No. 2, 2010
July 6, 2010:144–50
Acknowledgments
The authors thank the participants in this study, as well as
the numerous cardiologists and cardiothoracic surgeons who
have been involved in the care of these patients. The authors
also thank Elizabeth Rodriguez-Huertas, Terra Lafranchi,
NP, and Sarah Evans of the Boston Adult Congenital Heart
Research Team; Handan Titiz, EdM, of the Children’s
Hospital Boston Clinical Research Program; Deborah Shellenberger, PA-C, at the University of Pennsylvania; and
Mary Elizabeth Schlater, NP, at the University of Washington. The authors additionally thank Joseph Kay, MD,
Jennifer Ting, MD, Craig Broberg, MD, Michelle Nickolaus, NP, Carole Warnes, MD, and Karen Kuehl, MD, for
their collaboration through the Alliance for Adult Research
in Congenital Cardiology group.
Reprint requests and correspondence: Dr. Anne Marie Valente,
Boston Adult Congenital Heart Program, Department of Cardiology,
Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail: [email protected].
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Key Words: Fontan y venous insufficiency y adult congenital
heart disease.