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