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Pulmonary Vascular Disease in SCD: Impact of Hypoxia,
Hemolysis and Thrombosis Elizabeth S Klings, MD
Director, Center for Excellence in Sickle Cell Disease
The Pulmonary Center
Boston University School of Medicine, Boston, MA, USA
History - 2009
50 year old female with HbSS disease presents in July 2009 with 1 month of worsening DOE
June 2008 – Presented with an acute PE
Oct. 2008 – Referred to BMC, minimal DOE noted
July 2009 – Notes increased DOE on 1-2 blocks x few weeks, using supplemental O2 more
Denies SOB at rest, PND, orthopnea, chest pain, syncope, LE edema
Physical Exam – Exertional hypoxemia, elevated JVP
Echocardiogram
Normal biventricular size and systolic function.
Estimated LVEF 55-60%.
Normal biatrial size. Trace AI. Trace MR. Trace TR.
Trace PI.
Estimated RV systolic pressure 32 mm Hg
assuming an RA pressure of 5 mm Hg (TRV= 2.7
m/sec) .
Normal IVC size. No significant pericardial effusion.
Pulmonary HTN in SCD - Non-invasive Testing
• Echo – non-invasive assessment of cardiac function
• Elevated tricuspid regurgitant jet velocity (TRV) suggestive of PH. Occurs in:
• 32% HbSS and 10-28% HbSC adults
• 10-20% of HbSS children and adolescents
• Elevated NT-pro-BNP and reduced 6 minute walk distance – associated with PH too
Gladwin MT, et al. NEJM 2004;350(9):886-95. Gordeuk VR, et al. Haematologica. 2011;96(1):33-40. Klings ES, et al. Am J Respir Crit Care Med. 2014;189(6):727-40
Definitions
Mean Pulmonary Artery Pressure > 25 mmHg
Pulmonary Arterial Hypertension/Pre-Capillary PH: PCWP or left ventricular end-diastolic pressure < 15 mm Hg, and a PVR > 160 dynes sec/cm5
Pulmonary Venous Hypertension/Post-Capillary PH: PCWP or LVEDP > 15 mmHg and a PVR < 160 dynes sec/cm5
Klings ES, et al. AJRCCM 2014; 189:727-740.
Restrictive Cardiomyopathy of SCD
Meta-analysis of 4 studies where RHC and echo were performed 53/173 (31%) of those with a TRV > 2.5 m/sec had PH confirmed by RHC 60% of those with PH had a PAWP > 15 mmHg In review of 134 SCD patients (3-22 years old, median age 11) – LAD and increased LV mass were the most common echo abnormalities
Niss O, et al. JACC: Cardiovasc Imaging 2016;9:243-252.
Cardiac Fibrosis and Ischemia in Transgenic Sickle Mice
Bakeer N, et al. Proc Natl Acad Sci 2016; ES182-ES191.
Right Heart Cath
Normal (SCD) 2009
RA pressure (mmHg) 2-8 7
RV pressure (mmHg) 15/5 54/0
PA pressure (mmHg) 20-25/8-12 58/14
mPAP (mmHg) < 20 35
PAWP (mmHg) 8-12 11
CO (L/min) 7-9 7.0
PVR (dynes-sec/cm5) 60-80 274
Pulmonary Hypertension Increases Mortality in SCD
Mehari A, et al. Amer J Resp Crit Care Med 2013; 187: 840-847.
40% 6 year mortality
PH of SCD in 2016: What we know now
• Elevated PASP by echo ≠ PH – 25-31% positive predictive value
• 6-11% of SCD adults have PH
• 40 % 6 yr mortality
• But an elevated PASP by echo is a risk factor for mortality - systemic vasculopathy
Parent F, et al. NEJM 2011; 365:44-53. Mehari A, et al. JAMA 2012; 307:1254-1256. Klings ES, et al. AJRCCM 2014; 189:727-740.
Treatment Strategies
• General Measures – O2 and diuretics
• Evaluate and treat co-morbidities: SDB/OSA, VTE
• Maximize treatment of SCD
• Pulmonary arterial hypertension therapy
2016: No specific treatment for PH in SCD
Klings ES, et al. AJRCCM 2014; 189:727-740.
MRI visualization of RV dysfunction in PH of SCD
Nguyen K-L, et al. Haematologica 2016 101: e40-e43. Harjola VP, et al. Eur J Heart Fail 2016;18:226-241.
Right Ventricular Dysfunction Increases Mortality in PH of SCD
Nguyen K-L, et al. Haematologica 2016 101: e40-e43
Pathology of Pulmonary Hypertension
Dasgupta A, et al. Clin Pharmacol Ther 2015;97(1):88-102. Gordeuk VR, et al. Blood 2016;127(7):820-8.
What makes PH of SCD Different from PAH?
• Co-existent left-sided heart disease in many patients
• Hemolysis
• Increased thromboembolic disease risk
• Increased tissue hypoxia
Rother RR, JAMA 2005;293:1653-1662.
Direct impact of heme on the vasculature
• Binds to endothelial TLR4 to increase adhesion molecule expression via NF-κB translocation
• Increased intracellular ROS
• Reduced NOS activity and gene expression
• Increased HO-1 expression and Fe deposition
Vinchi F et al. Circulation 2013; 127: 1317-1329 Belcher JD, et al., Blood 2014; 123(3):377-90 Ghosh S, et al. J Clin Invest 2013; 123(11):4809-20.
Irwin DC, et al. Free Rad Biol and Med 2015; 82: 50-62
Haptoglobin repletion counteracts vascular remodeling of Hb + hypoxia
VTE Risk Factors in SCD Non-SCD Specific
SCD specific
Naik RP, et al. J Thromb Haemost 2014; 12: 2010-2016. Mehari A and Klings ES. Chest 2016; 149(5):1313-24.
CSSCD – 1523 patients (1978-1998): 11.3% of SCD patients had a VTE by 40 yrs of age
The Link Between VTE and PH
2-4% of patients with PE will develop CTEPH
Autopsy studies of IPAH patients – in situ thrombosis
Patients with PH of SCD – thrombotic arteriopathy of small PA’s
Cross-sectional study of 414 SCD patients – non-catheter related VTE in 18.8%, RR 1.65 (95% CI, 1.12-2.45) in patients with TRV > 2.5 m/sec
Haque AK, et al.Hum Pathol 2002; 33(10):1037-1043.
Graham JK, et al. Am J Forensic Med Pathol 2007; 28(2):168-172. Naik RP, et al. Am J Hematology 2013; 443-449. Ataga KI, et al. Haematologica 2008; 93(1):20-26. Wilkins H, et al. Int J Cardiol 2011; 154S1: S54-S60.
Hypoxia in SCD
• Under-recognized and historically, under-treated
• Frequent de-saturations with exercise and sleep
• Impaired diffusion capacity, rightward shift of Hb-O2 dissociation curve, hypoventilation
Klings ES et al. Amer J Resp Crit Care Med 2006; 173:1264-1269 Mehari A and Klings ES Chest 2016 pii: S0012-3692(15)00182-8.
Sleep-Disordered Breathing and SCD
Multiple small studies in kids and adolescents – nocturnal desats in up to 79%
Most retrospective, referred cohorts
Two distinct entities – OSA and nocturnal hypoxemia
Historically - upper airway obstruction related to lymphoid hyperplasia
Adenoidectomy/tonsillectomy- curative in some, but not all
32 HbSS adults irrespective of symptoms – 44% had SDB, average AHI 17/hour
Sharma S, et al. J Clin Sleep Med 2015; 11(3):219-23.
Nocturnal Hypoxemia in SCD
• Occurs in up to 40% of children and adolescents
• Nearly half of them do not have OSA
• May be associated with daytime hypoxemia
• Associations with frequency of vasoocclusive crises
• But also linked to priapism and enuresis
OSA, Hypoxia and Pulmonary Hypertension
Kholdani, C, et al. Pulm Circ 2015; 5(2): 220–227
Hypotheses 1) SDB is common in SCD adolescents and adults
2) SDB has adverse impacts on endothelial function and cardiopulmonary outcomes
3) Screening for SDB can identify a modifiable risk factor for morbidity and mortality across the lifespan of SCD patients
Retrospective chart review of BMC patients
Prospective study at Howard University
Sleep-Disordered Breathing in Adults
• Two studies – 1 prospective, 1 retrospective
• BMC – 46 SCD patients (23 pediatric, 23 adult) sent for sleep studies – 41% abnormal
• OSA - Not associated with obesity, but increased with age
• % of sleep time with hypoxemia inversely correlated with daytime resting O2 sat and Hb, directly correlated with WBC and retic count
• Prospective study –Howard – 20 non-obese adults regardless of sxs – 10/20 had AHI > 5, associated with priapism.
• NH in some associated with worsening anemia
Whitesell P, et al. Sleep Med 2016; 22:47-9.
61% 11%
21%
7%
Study Population (n=46)
Normal
NH
OSA
NH+OSA
44%
4%
39%
13%
Adults (n=23)
Normal
NH
OSA
NH+OSA
74%
17%
9%
Pediatric (n=23)
Normal
NH
OSA
Worsham C, Martin S, et al. 2016 (manuscript in preparation)
Let’s go back to my patient….
• 2009 – Started on bosentan 125 mg BID, on lifelong warfarin, sleep study negative
• 2010 – Inhaled treprostinil added to regimen
• 2013 – Prolonged ICU stay – RHC – consistent with diastolic dysfunction/PH. Developed VOC post-cath. Went to OSH – IVF – Came to BMC – acute hypoxemic respiratory failure/ACS/shock. In ICU x 1 month, but eventually better and d/c’ed home
• 2013 – 2015 – Did well clinically, rare admissions
2015
• Over the course of the year, worsening progressive dyspnea
• Now dyspneic on walking <25 feet
• No orthopnea, PND or LE edema
• But is having chest pain and dizziness with exertion
• And is requiring 2 liters O2 continuously
Right Heart Cath
Normal (SCD) 2009 2015
RA pressure (mmHg) 2-8 7 2
RV pressure (mmHg) 15/5 54/0 86/1
PA pressure (mmHg) 20-25/8-12 58/14 89/25
mPAP (mmHg) < 20 35 49
PAWP (mmHg) 8-12 11 4
CO (L/min) 7-9 7.0 5.2
PVR (dynes-sec/cm5) 60-80 274 699
What happened to this patient?
Summary
• Pulmonary hypertension occurs in 6-11% of adults with SCD
• RV failure is a risk factor for mortality
• Those with pre-capillary PH may benefit from pulmonary vasodilators but need to consider SCD-specific and non-specific disease modulators
• Need a greater understanding of the interplay of hypoxia, hemolysis and thrombosis in disease pathogenesis
Acknowledgements
Boston University
• Martin Steinberg
• Robyn Cohen
• Susan Perrine
• Christopher Worsham
• Stephon Martin
• Hugo Carmona
• BU/BMC Sickle Cell Center
Howard University Peter Whitesell
Alem Mehari
Thomas Mellman
University of Pittsburgh
Greg Kato
Syed-Mehdi Nouraie
Emory University
Claudia Morris
Lakshmanan Krishnamurti
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