Download Josh Daily, MD, Tom Kimball, MD, Punam Malik, MD. Left Ventricular

LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
Left Ventricular Diastolic Dysfunction
is Associated with Pulmonary
Hypertension in Children and Young
Adults with Sickle Cell Disease
Josh Daily, MD
30th Annual Edward L. Pratt Lecture Series
May 18th, 2011
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
Purpose
To determine if left sided heart disease, specifically
diastolic dysfunction, is associated with PH in SCD
children and young adults.
Background
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
• Pulmonary Hypertension (PH) has long been known to
be a complication of Sickle Cell Disease (SCD).
• Several recent pediatric SCD studies demonstrated
prevalence of PH in children and adolescents to be
between 10 and 40%.
• PH has been established as a leading cause of
morbidity and mortality in patients with SCD.
Background
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
Definition
•
•
•
The actual diagnosis of PH is made by cardiac catheterization.
A widely-accepted indirect estimation of Pulmonary Hypertension (PH) is
elevated tricuspid regurgitation jet velocity (TRV) ≥ 2.5 m/s on transthoracic
echocardiography.
The Bernoulli equation allows the estimation of a pressure gradient across
any obstruction based on velocity of flow (ΔPRV-RA = 4VTR^2).
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
Background
Etiology Of PH in SCD
• The etiology of PH in SCD is thought to be due to an interaction of
multiple factors, including chronic hemolysis, dysregulated nitric oxide
(NO) metabolism, chronic systemic vasculopathy, altered coagulation and
chronic thromboembolic disease, chronic hypoxemia, and iron overload.
• The most extensively studied contributor is chronic hemolysis and its
effects on the metabolism of NO.
Background
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
Etiology Of PH in SCD
The potential role of left sided heart disease
•
•
•
Multiple studies have demonstrated that Sickle Cell Disease is associated with
left ventricular hypertrophy and diastolic dysfunction. Some adult studies have
suggested that this may be related to PH.
However this relationship and its potential contribution to PH has not been
previously studied in children.
Given our understanding of impaired NO metabolism in SCD, it is reasonable
to suggest that the reduced bioavailability of NO may also impair LV diastolic
relaxation.
Methods
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
• Study Population
– Retrospective study of SCD patients at CCHMC
– Ages 2-21
– Only patients with echos obtained at baseline were
included (no sickle events +/- 2 months from echo
date).
• Data Collection
– Demographic data including age, gender, height, and
weight were taken
Methods
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
• Echocardiography
– Complete echocardiograms were performed
– Pulmonary Hypertension (PH)
• TRV was evaluated using pulsed-wave or continuous-flow Doppler
• PH = TRV ≥ 2.5 m/s
– No Pulmonary Hypertension (NPH)
• TRV<2.0 m/s was considered to be the upper limit of normal based
on the 95th percentile for normal teenage males.
– LV Structure
• LVM (Left Ventricular Mass) Index was calculated using an accepted
formula incorporating diameter, wall thickness, and height.
• LVH (Left Ventricular Hypertrophy) was determined based on the
≥95th percentile of LVM index using equations developed at
CCHMC's Heart Institute.
• Relative Wall Thickness
Methods
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
• Echo, continued
• Geometry
– Geometry type was calculated using LVM index and relative wall
thickness, with division into the following groups: Eccentric
Hypertrophy, Concentric Hypertrophy, Concentric Remodeling, or
Normal.
Normal
Concentric Hypertrophy
Eccentric Hypertrophy
Methods
• Echo, continued
– LV Diastolic Function
• Left Atrial diameter
• MV annulus wall motion
E’/A’ septum
E’/A’ lateral wall
• E/E’ septum
• E/E’ lateral wall
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
Methods
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
• Analysis
– Pts were divided into 2 groups: PH (TRV≥2.5 m/s) and
NPH (TRV<2.0 m/s)
– Data were analyzed for significant differences and
correlation and linear regression analyses were performed
to identify associations between indices.
Results
Demographics
NPH
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
PH
N
Mean
N
Mean
P value
Age
26
12.23 ± 5.57
21
12.19 ± 4.79
0.9792
Gender
26
13 female (50%)
21
11 female (52%)
0.8710
Height
26
144.98 ± 23.86
21
147.58 ± 22.74
0.7076
Weight
26
43.96 ± 21.39
21
43.85 ± 17.29
0.9849
Left Ventricular Mass
NPH
LVM Index
PH
N
Mean
N
Mean
P value
26
43.65 ± 14.81
21
47.70 ± 11.59
0.3107
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
Results
LV Geometry
Concentric Hypertrophy
Concentric Remodeling
Eccentric Hypertrophy
Normal
NPH
38.46% (10/26)
38.46% (10/26)
11.54% (3/26)
11.54% (3/26)
PH
P value
57.14% (12/21) 0.283
14.29% (3/21)
9.52% (2/21)
19.05% (4/21)
60.00%
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
Concentric
Hypertrophy
Concentric
Remodeling
No Pulmonary Hypertension
Eccentric
Hypertrophy
Normal
Pulmonary Hypertension
Results
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
LV Diastolic Function
LA Diameter
E'/A' sept
E'/A' lat
E/E' sept
E/E' lat
No Pulmonary Hypertension
Pulmonary Hypertension
N Obs
Mean
N Obs
Mean
P value
26
20
3.11 ± 0.73
3.70 ± 0.65 0.0061
23
21
2.70 ± 0.59
2.20 ± 0.64 0.0092
23
21
3.61 ± 1.01
2.99 ± 0.95 0.0423
23
21
7.66 ± 1.32
8.12 ± 1.69 0.3221
23
21
5.78 ± 1.05
6.55 ± 1.44 0.0491
Correlation
Correlation with TRV using Spearman Correlation Coefficients
L V Mass Index LA Diameter E'/A' sept
Correlation Coefficiant
0.135
0.323
-0.232
P value
0.189
0.002
0.026
N obs
96
94
92
E'/A' lat
-0.133
0.205
92
E/E' sept
0.163
0.121
92
E/E' lat
0.24
0.021
92
Conclusion
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
LV Geometry
• LVM and LV geometry may be associated with PH,
but our study did not have sufficient numbers to be
powered to demonstrate a statistically significant
difference.
LV Diastolic Function
• LV Diastolic Dysfunction is associated with PH in
SCD.
Discussion
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
LV Diastolic Dysfunction and PH in SCD
Suggested Mechanism of Diastolic Dysfunction
in SCD
• Dysregulated NO metabolism may directly
contribute to impaired relaxation of the LV and
indirectly contribute by impairing vasodilation of
the coronary vasculature contributing to ischemia
which is a known cause of diastolic dysfunction.
• LV hypertrophy which is a known complication of
SCD likely contributes to impaired relaxation of
the LV.
Diastolic Dysfunction as an Etiology of PH
• Diastolic Dysfunction of the LV causes elevated
LV filling pressures, elevated left atrial pressures,
pulmonary venous hypertension, and finally
pulmonary artery hypertension.
Future Directions
LV Diastolic Dysfunction is
Associated with PH in Children
and Young Adults with SCD
• The clinical significance of both PH and Diastolic Dysfunction in
children with SCD has not been previously studied.
• A second phase of the study is currently underway. All patients
included in this study have had the following data extracted from their
charts: episodes of acute chest, sickle crisis, strokes, hospitalizations,
and deaths. The following laboratory values are also being collected:
baseline hemoglobin, reticulocyte count, LDH, and other markers of
intravascular hemolysis.
• Statistical analyses are beginning.
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LV Diastolic Dysfunction is
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and Young Adults with SCD
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LV Diastolic Dysfunction is
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and Young Adults with SCD
Acknowledgements
• Thomas R. Kimball, MD, Professor of Pediatrics, University of Cincinnati College of
Medicine, Medical Director of the Heart Institute, Director of Cardiac Ultrasound, Director of
Cardiovascular Imaging Core Research Laboratory.
• Punam Malik, MD, Associate Professor of Pediatrics, Program Leader of Molecular and
Gene Therapy Program, Director of the Translational Core Laboratory, Division of
Experimental Hematology & Cancer Biology.
• Phil Khoury, MS, statistician, Heart Institute
• Ellen Skalski, BS, research nurse, Division of Experimental Hematology & Cancer Biology.
• Charles Warden, student