CONTROVERSIES IN PULMONARY HYPERTENSION AND SICKLE CELL DISEASE

1. CONTROVERSIES IN PULMONARY HYPERTENSION AND SICKLE CELL DISEASE Kristen Sanfilippo MD

2. No Financial Disclosures

3. http://www.newpittsburghcourieronline.com/ Perry NicholsPerry Nichols

4. Epidemiology: Sickle Cell Disease Adult Hemoglobin: Hemoglobin A Tetramer: 2 a and 2 �-globins Sickle Cell Hemoglobin: Hemoglobin S Point mutation in �-globin gene (?6 Glu ? Val) Autosomal Recessive Polymerizes to long fibers in deoxygenated state ? RBC deformability Glutamate to Valine Glutamate to Valine

5. Epidemiology: Sickle Cell Disease Prevalence 1 in 14 African heritage are heterozygous 1 in 700 African heritage newborns are homozygous 100,000 in the US Morbidity In 2004: 113,000 hospitalizations in US 75% were adults 488 million health care dollars 2 minutes 2 minutes

6. RBC Deformability: Sickle Cell Disease Sludging ? Vascular Obstruction & Ischemia Pain Crisis Acute Chest Syndrome Functional Asplenia Osteonecrosis

7. RBC Deformability: Sickle Cell Disease Shearing of RBC membrane Chronic extravascular hemolysis Chronic intravascular hemolysis Vascular Endothelium Damage/Adhesion Formation of Proliferative lesions/Thrombosis Vaso-Occlusion What is nitric oxideWhat is nitric oxide

8. RBC Deformability: Sickle Cell Disease Shearing/Damage of RBC membrane Chronic extravascular hemolysis Chronic intravascular hemolysis Vascular Endothelium Damage/Adhesion Formation of Proliferative lesions/Thrombosis Vaso-Occlusion What is nitric oxideWhat is nitric oxide

9. In the World of Sickle Cell Disease Pulmonary Hypertension

10. Pulmonary Hypertension Pulmonary HTN: Mean Pulmonary Artery Pressure = 25 mmHg Pulmonary Artery Hypertension Mean Pulmonary Artery Pressure = 25 mmHg PCWP/LVEDP = 15 mmHg Defined on cardiac catheterization PAH Pre-capillary absence of L sided HD, lung disease, or chronic thromboembolism Small pulmonary arteries � vascular endothelial and SM cell proliferationDefined on cardiac catheterization PAH Pre-capillary absence of L sided HD, lung disease, or chronic thromboembolism Small pulmonary arteries � vascular endothelial and SM cell proliferation

11. Approximating Pulmonary Hypertension Doppler Echocardiogram Tricuspid regurgitant jet velocity (TRV) =2.5m/s Peak velocity of retrograde flow from RV ? RA during systole 2SD of normal population Bernoulli Equation coverts this to PAP of ~30mmHg Berger M et al. J Am Coll Cardiol 1985 General population Scleroderma 4minutesGeneral population Scleroderma 4minutes

12. Trial that enrolled 195 patients with SCD (mostly HGB SS, some HGB SC, and some HGB BS) by community advertisement to determine the prevalence of PHTN as well as its prospective prognostic significance. They also enrolled 41 age/sex/race matched controls. Trial that enrolled 195 patients with SCD (mostly HGB SS, some HGB SC, and some HGB BS) by community advertisement to determine the prevalence of PHTN as well as its prospective prognostic significance. They also enrolled 41 age/sex/race matched controls.

13. A shows the values obtained for TRV in the sickle patients versus control. Screening prevalence was 32% in the population for sickle cell patients. C is a graph representing finding on RHC in 18 patients compare to their ECHO values and shows a significant correlation as estimated by Spearman�s correlation coefficient. They also found that in the 18 patients selected to undergo RHC (all of which had to have TRV > 2.5), 17 were found to have PAP on RHC of 25mmHg or greater which is the definition of PHTN as noted earlier. Mean PAP in this group was 34.5 +/- 2.7 mmHg A shows the values obtained for TRV in the sickle patients versus control. Screening prevalence was 32% in the population for sickle cell patients. C is a graph representing finding on RHC in 18 patients compare to their ECHO values and shows a significant correlation as estimated by Spearman�s correlation coefficient. They also found that in the 18 patients selected to undergo RHC (all of which had to have TRV > 2.5), 17 were found to have PAP on RHC of 25mmHg or greater which is the definition of PHTN as noted earlier. Mean PAP in this group was 34.5 +/- 2.7 mmHg

14. Using death certificates to confirm death of any patients, Gladwin et al. estimated survival changes between the two groups. Median f/u of 18.3 months for patients with TRV of < 2.5 and 17.3 months for those with TRV > 2.5. Using porportional hazards regression, they found a significant increase risk ratio of death of 10.1 (95% CI of 2.2-47) P < 0.001Using death certificates to confirm death of any patients, Gladwin et al. estimated survival changes between the two groups. Median f/u of 18.3 months for patients with TRV of < 2.5 and 17.3 months for those with TRV > 2.5. Using porportional hazards regression, they found a significant increase risk ratio of death of 10.1 (95% CI of 2.2-47) P < 0.001

15. Conclusion ECHO was an adequate SCREENING mechanism for detection of PH in SCD Mortality was significantly increased in patients with TRV = 2.5 m/s

16. Prospective multicenter study in France with the goal of determining the prevalence of PH as assessed on RHC in adults with SCD in who the disorder was suspected on the basis of Doppler ECHO. They excluded patients with severe renal, liver, or lung disease Prospective multicenter study in France with the goal of determining the prevalence of PH as assessed on RHC in adults with SCD in who the disorder was suspected on the basis of Doppler ECHO. They excluded patients with severe renal, liver, or lung disease

17. Design They screened 445 patients and excluded 45 for lung, liver, or kidney disease They screened 445 patients and excluded 45 for lung, liver, or kidney disease

18. What they found was����What they found was����

19. Conclusion Prevalence of Pulmonary Hypertension ECHO = 27% RHC = 6% ECHO Alone as Screening Test Positive Predictive Value 25% Leads to Unnecessary RHCs Those 13 patients� The probability that a positive test predicts those with the disease The probability that a positive test predicts those with the disease

20. Design

21. Conclusion Prevalence of Pulmonary Hypertension TRV = 2.5 m/s = 27% RHC = 6% ECHO Alone as Screening Test Positive Predictive Value 25% Leads to Unnecessary RHCs Those 13 patients� Those 47 patients� The probability that a positive test predicts those with the disease The probability that a positive test predicts those with the disease

22. Gladwin Letter To The Editor 533 SCD at NIH 86 RHCs performed 56 with PAP = 25 mmHg (10.5%) Median follow-up 4.4 years Mortality 20 of 56 patients vs. 50 of 477 patients, P<0.001

23. RBC Deformability: Sickle Cell Disease Shearing/Damage of RBC membrane Chronic extravascular hemolysis Chronic intravascular hemolysis Vascular Endothelium Damage/Adhesion Formation of Proliferative lesions/Thrombosis Vaso-Occlusive Disease What is nitric oxideWhat is nitric oxide

24. Pathogenesis: Pulmonary HTN

25. Pathogenesis: Pulmonary HTN

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29. Nitric Oxide Function INHIBITS Vasoconstriction Release of Procoagulant Factors Platelet Aggregation and Attachment to Endothelial Cells Release of Vascular Smooth Muscle and Endothelial Cell Growth Factors Inflammatory Cell Attachment to Endothelial Cells

30. Pathogenesis: Pulmonary HTN

31. Examined 213 patients and found the expected highly significant direct correlation of serum LDH with retic count, plasma hgb, unconjugatedbilirubin, and inversely correlated with blood HGB and serum haptoglobin Furthermore, those with the highest values of LDH had higher prevalence of PHTN, Leg ulcers, stroke, risk of death, and priapism Fractionation of LDH in a subgroup reveleased the majority of LDH to be LDH1isoenzyme c/w LDH from red cell lysisExamined 213 patients and found the expected highly significant direct correlation of serum LDH with retic count, plasma hgb, unconjugatedbilirubin, and inversely correlated with blood HGB and serum haptoglobin Furthermore, those with the highest values of LDH had higher prevalence of PHTN, Leg ulcers, stroke, risk of death, and priapism Fractionation of LDH in a subgroup reveleased the majority of LDH to be LDH1isoenzyme c/w LDH from red cell lysis

32. Guilt by Association? No one doubts that plasma HGB leads to depletion of NO. Largest argument is that all studies showing a correlation between degree of hemolysis have performed measures indirectly (LDH, AST) etc. These may be elevated due to other causes. They call for a need for direct measurement of plasma HGB levels in larger studies. No one doubts that plasma HGB leads to depletion of NO. Largest argument is that all studies showing a correlation between degree of hemolysis have performed measures indirectly (LDH, AST) etc. These may be elevated due to other causes. They call for a need for direct measurement of plasma HGB levels in larger studies.

33. RBC Deformability: Sickle Cell Disease Shearing/Damage of RBC membrane Chronic extravascular hemolysis Chronic intravascular hemolysis Vascular Endothelium Damage/Adhesion Formation of Proliferative lesions/Thrombosis Vaso-Occlusive Disease

34. Alternate Hypothesis Sickle Cell Deformability ? Endothelial Damage ? Acute and Chronic Inflammation ? Hypercoagulation ? Vaso-Occlusive Disease One example they use to counter this is that PNH has much higher levels of intra-vascular hemolysis and does not have complications such as stroke and priapism which are hypothesized to be related to NO deficiency One example they use to counter this is that PNH has much higher levels of intra-vascular hemolysis and does not have complications such as stroke and priapism which are hypothesized to be related to NO deficiency

35. What Caused Perry�s PH? Bets?

36. References Lorey FW, Arnopp J, Cunningham GC. Distribution of hemoglobinopathy variants by ethnicity in a multiethnic state. Genet Epidemiol 1996;13:501-512 Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med 1994;330:1639-1644 Steiner CA, Miller JL. Sickle cell disease patients in U.S. hospitals, 2004. Statistical brief. No. 21. Rockville, Md: Agency for Healthcare Research and Quality, December 2006. Schechter AN, Gladwin MT. Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 2003;348:1483-1485 Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350:886-895 Castro O, Hoque M, Brown BD. Pulmonary Hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2003; 101:1257-61 Simmons BE, Santhanam V, Castaner A et al. Sickle cell heart disease: two-dimensional echo and Doppler ultrasonographic findings in the hearts of adult patients with sickle cell anemia. Arch Intern Med 1988;148:1526-8. Sutton LL, Castro O, Cross DJ et al. Pulmonary hypertension in sickle cell disease. Am J Cardiol 199 Castro OL, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2002;101:1257-61.4;74: 626-8. Berger M, Haimowitz A, Van Tosh A et al. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol 1985;6:359-65. Hsu LL, Champion HC, Campbell-Lee SA, et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 2007;109:3088-98