the relationship of left heart hemodynamics, pulmonary hypertension, and clinical correlates in...

The Relationship of Left Heart Hemodynamics, Pulmonary Hypertension,

and Clinical Correlates in Children and Young Adults with Sickle Cell Disease

Josh Daily, MD

31th Annual Edward L. Pratt Lecture SeriesMay 16th, 2012

The Relationship of Left Heart Hemodynamics, PH, and Clinical Correlates in Children and Young Adults with SCD

Background

• 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.


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).

BackgroundThe Relationship of Left Heart Hemodynamics, PH, and Clinical Correlates in Children and Young Adults with SCD

Etiology Of PH in SCD• chronic hemolysis • dysregulated nitric oxide (NO) metabolism • chronic systemic vasculopathy• altered coagulation

Background

• chronic thromboembolic disease • chronic hypoxemia• iron overload

The most extensively studied contributor is chronic hemolysis and its effects on the metabolism of NO.


Etiology Of PH in SCDThe potential role of left sided heart disease

• Sickle Cell Disease is associated with left ventricular hypertrophy and diastolic dysfunction. Adult studies suggest this may be related to PH.

• Not previously studied in children.• Reduced bioavailability of NO may impair LV diastolic relaxation.

BackgroundThe Relationship of Left Heart Hemodynamics, PH, and Clinical Correlates in Children and Young Adults with SCD

PurposeTo determine correlates of Pulmonary Hypertension (PH) in children and young adults with Sickle Cell Disease (SCD).


HypothesisLeft sided heart disease, specifically LV geometry and diastolic dysfunction, is associated with PH in children and young adults with SCD.

Methods

• Study Population– Retrospective study of SCD patients at CCHMC – Ages 2-21– Only patients with echos obtained at baseline were

included (no sickle events +/- 3 weeks from echo date).

• Data Collection– Demographic data including age, gender, height, and

weight were taken– Laboratory data (baseline) and clinical variables were

obtained by reviewing all charts up until October 2010


• Echocardiography– Complete echocardiograms were performed– TRV was evaluated using pulsed-wave or continuous-flow Doppler and

used to estimate Pulmonary Artery Pressures. – LV Structure

• LVM (Left Ventricular Mass) Index was calculated using an accepted formula incorporating diameter, wall thickness, and height.

• LVH (Left Ventricular Hypertrophy): ≥ 95th percentile of LVM index.• Relative Wall Thickness: ratio of LV thickness to LV cavity size

MethodsThe Relationship of Left Heart Hemodynamics, PH, and Clinical Correlates 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.

Methods

Normal Concentric Hypertrophy Eccentric Hypertrophy


http://ccn.aacnjournals.org/content/24/6/14/F1.large.jpg

• Echo, continued– LV Diastolic Function

• Left Atrial diameter• MV annulus wall motion:

E’/A’ septum and E’/A’ lateral wall• Ratio of early transmitral blood flow velocity (E) to annulus wall

velocity (E’): E/E’ septum and E/E’ lateral wall


• Analysis– Pts were divided into 3 groups: PH (TRV≥2.5 m/s), NPH

(TRV<2.0 m/s), and High Normal Pulmonary Pressures (2.0m/s<TRV<2.5 m/s)

– Data were analyzed for significant differences and correlation and linear regression analyses were performed to identify associations between indices.


Study Population

NPH 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

Results

• 124 children and young adults (66 female, 58 male) diagnosed with SCD.

• Adequate readings of TRV in 96 patients.• 21 (22%) exhibited Pulmonary Hypertension (TRV ≥2.5 m/s), 26 (27%)

had No Pulmonary Hypertension (TRV<2.0 m/s), 49 (51%) had high-normal Pulmonary Artery Pressures (TRV ≥2.0 and <2.5 m/s).


Results

Left Ventricular Mass and Geometry NPH PH

N Mean N Mean p value

LVM Index 26 43.7 ± 14.8 21 47.7 ± 11.6 0.311

0%10%20%30%40%50%60%

ConcentricHypertrophy

ConcentricRemodeling

EccentricHypertrophy

Normal

No Pulmonary Hypertension Pulmonary Hypertension


No Pulmonary Hypertension Pulmonary HypertensionN Obs Mean N Obs Mean p value

LA Diameter 26 3.1 ± 0.7 20 3.7 ± 0.7 0.006E'/A' sept 23 2.7 ± 0.6 21 2.2 ± 0.6 0.009E'/A' lat 23 3.6 ± 1.0 21 3.0 ± 1.0 0.042E/E' sept 23 7.6 ± 1.3 21 8.1 ± 1.7 0.322E/E' lat 23 5.8 ± 1.0 21 6.6 ± 1.4 0.049

Results

LV Diastolic Function


Results

Laboratory Variables


N TRV<2.0 N TRV 2.0 to <2.5 N TRV>=2.5 P for Trend

Reticulocyte Percent 22 6.74 (5.03-8.45) 51 9.02 (5.93-12.1) 18 9.82 (7.09-12.5) 0.4909

HbF Percent If On Hydrox 13 17.6 (11.1-24.1) 17 23.2 (12.9-33.6) 12 14.8 (8.29-21.4) 0.3273

HbF Percent If Not on Hydrox 5 10.1(3.32-17) 19 12.7 (7.08-18.2) 2 4.05 (-35-42.8) 0.5282

WBC 22 9.63 (8.24-11) 49 10.3 (9.2-11.4) 17 10.7 (9.19-12.2) 0.6242

HgB 22 9.92 (9.26-10.6) 49 9.76 (9.29-10.2) 17 9.23 (8.55-9.9) 0.3609

PLT 22 404 (319-488) 48 392 (354-430) 17 450 (394-506) 0.3731

AST 13 50.2 (42.2-58.1) 21 61.1 (51.9-70.4) 11 63.4 (53.4-73.3) 0.1239

ALT 13 20.3 (14.7-25.9) 21 24.9 (19.3-30.5) 11 19.5 (14.7-24.2) 0.2811

GGT 13 32.4 (17.8-46.9) 21 28 (21.3-34.8) 11 33.7 (19-48.5) 0.6925

Bun 21 9.48 (7.68-11.3) 47 8.96 (8.07-9.84) 17 6.71 (5.39-8.03) 0.0205

Creatinine 21 0.6 (0.48-0.72) 47 0.5 (0.45-0.54) 17 0.46 (0.4-0.53) 0.0409

CRP 10 0.48 (0.37-0.59) 20 0.96 (0.61-1.3) 5 1.14 (0.18-2.1) 0.1003

IndirectBili 22 3.14 (1.05-5.23) 47 2.4 (1.8-3) 17 2.77 (1.95-3.59) 0.6069

LDH 13 1120 (941-1299) 30 1351 (1130-1572) 13 1355 (964-1746) 0.4205

Results

Clinical Variables


N TRV<2.0 N TRV 2.0 to <2.5 N TRV>=2.5 P for TrendTotal # of Admits, n 23 10.04 46 7.61 18 9.11 0.7283Total # of ER Visits, n 23 5.87 46 8 18 10.83 0.2311Patient On Hydroxyurea, n (%) 23 13 (57) 52 17 (33) 18 9 (67) 0.02Patient On Chronic Transfusion, n (%) 23 5 (22) 52 11 (21) 18 3 (17) 0.9058Hx of Acute Chest Syndrome, n (%) 23 13 (57) 52 22 (42) 18 14 (78) 0.0635Hx of Priapism, n (%) 23 1 (4) 52 4 (8) 18 1 (6) 0.8499Hx of Splenectomy, n (%) 23 2 (9) 52 4 (8) 18 1 (6) 0.9288Hx of Asthma, n (%) 23 6 (26) 52 16 (31) 18 5 (28) 0.9109Abnormal PFT, n (%) 12 5 (42) 23 7 (30) 10 5 (50) 0.4144Stone or Sludge on Abd U/S, n (%) 8 4 (50) 16 11 (69) 8 3 (38) 0.3203OSA on Sleep Study, n (%) 1 0 (0) 4 3 (75) 1 0 (0) 0.2231Proteinuria, n (%) 21 1 (5) 43 4 (9) 16 4 (25) 0.0614o2sat 22 97.9 (97.1-98.6) 45 97.8 (97-98.7) 18 97.5 (96.6-98.4) 0.8264

Results

Univariate Correlation with PH (TRV)LVM Index LA Diameter E'/A' sept E'/A' lat E/E' sept E/E' lat

Correlation Coefficient 0.135 0.323 -0.232 -0.133 0.163 0.24

p value 0.189 0.002 0.026 0.205 0.121 0.021

N obs 96 94 92 92 92 92


LV Diastolic Dysfunction is Associated with PH in Children and Young Adults with SCDResults

Stepwise Regression Analysis of TRV

ResultsPearson Correlation of Clinical and

Laboratory Variables with TRV


n r PWBC 90 0.13717 0.1973HgB 90 -0.19261 0.069Reticulocyte Percent 94 0.10209 0.3275PLT 89 0.17551 0.0999ALT 46 -0.00346 0.9818AST 46 0.27001 0.0696GGT 46 -0.01539 0.9192BUN 87 -0.24358 0.023Creatinine 87 -0.31491 0.003CRP 35 0.35778 0.0348IndirectBili 88 -0.06191 0.5667LDH 57 0.18641 0.165Number of Admits 89 -0.00805 0.9403Number of ER visits 89 0.13649 0.2022Age 95 -0.1167 0.2601BSA 95 -0.03489 0.7371

ResultsPearson Correlation of Clinical and Laboratory Variables with Markers of Diastolic Dysfunction


LA Diameter E'/A' sept E/A' lat E/E' sept E/E' lat

n r P n r P n r P n r P n r P

WBC 88 0.0336 0.756 88 -0.21259 0.0468 88 0.01666 0.8776 88 0.031 0.7743 88 -0.00257 0.9811

HgB 88 -0.2632 0.0132 88 0.00446 0.9671 88 0.08237 0.4455 88 -0.14907 0.1657 88 -0.25635 0.0159

Reticulocyte % 92 0.1534 0.1443 90 -0.24282 0.0211 90 -0.12203 0.2519 90 0.16937 0.1105 90 0.29952 0.0041

PLT 87 0.1216 0.2619 87 -0.01132 0.9172 87 0.06476 0.5512 87 0.05514 0.612 87 -0.03 0.7826

BUN 85 -0.18383 0.0922 85 0.03667 0.739 85 0.17944 0.1003 85 0.03379 0.7588 85 -0.01434 0.8964

Creatinine 85 0.18782 0.0852 85 -0.15337 0.1611 85 -0.02122 0.8472 85 0.06978 0.5257 85 -0.15312 0.1618

CRP 34 0.10624 0.5498 33 -0.19291 0.2821 33 0.01907 0.9161 33 0.07784 0.6668 33 0.00173 0.9924

Indirect Bili 86 0.37536 0.0004 86 -0.16484 0.1293 86 -0.04595 0.6744 86 -0.05749 0.599 86 0.00052 0.9962

LDH 56 0.20109 0.1373 55 -0.15446 0.2602 55 -0.11 0.424 55 0.11869 0.3881 55 0.15024 0.2736

Number of Admits 88 0.12583 0.2427 86 0.09576 0.3804 86 0.13624 0.211 86 0.05069 0.643 86 -0.00871 0.9366

Number of ER Visits 88 0.03931 0.7162 86 -0.04202 0.7009 86 0.00119 0.9913 86 0.14785 0.1743 86 0.03947 0.7182

LV Diastolic Function• LV Diastolic Dysfunction is associated with PH in

SCD.LV Geometry• LVM and LV geometry may be associated with PH,

but our study did not demonstrate a statistically significant relationship.

ConclusionThe Relationship of Left Heart Hemodynamics, PH, and Clinical Correlates in Children and Young Adults with SCD

Suggested Mechanism of Diastolic Dysfunction in SCD

• myocardial ischemia, fibrosis, iron deposition, relative systemic hypertension, and ventricular hypertrophy

• Sachdev, et al found significant correlation between LVDD and older age, worse anemia, higher systolic blood pressure, and elevated body mass index suggesting that hemolysis, increased afterload, and disease progression may play a role in the development of LVDD.

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.

Discussion

LV Diastolic Dysfunction and PH in SCD


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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.• Vicky Moore, ultrasonographer, Heart Institute• Charles Warden, student at Miami University


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