Imatinib and Carvedilol for High Blood Pressure in the Lungs in Adults With Sickle Cell Disease

* Eligibility Criteria * Subjects 18 years of age or older * Must be able to provide written informed consent * Subjects with SCD and prior RHC documenting mPAP greater than or equal to 25 mmHg * Suspicion of Pulmonary Hypertension based on any of the below criterion: \<TAB\>- exertional breathlessness \<TAB\>- echocardiographic evidence of tricuspid insufficiency (TRVgreater than or equal to 2.7 m/s) \<TAB\>- oxy-hemoglobin desaturation during six minute walking test \<TAB\>- hypoxia requiring supplemental oxygen \<TAB\>- pedal edema \<TAB\>- ascites \<TAB\>- elevated BNP \<TAB\>- or history of acute chest syndrome, stroke, or other serious complication of vaso-occlusive disease \<TAB\>- history of chest pain, syncopal events or thromboembolic events \<TAB\>- The referring physician may refer the subject for other suspicious symptoms or findings of SCD-PH INCLUSION CRITERIA: Arm A (Imatinib) 1. Satisfaction of screening criteria 2. Subjects 18 years of age or older 3. Women of childbearing potential and male subjects must agree to use reliable methods of birth control (oral contraceptives, other hormonal contraceptives including vaginal contraceptive rings and contraceptive patches, barrier contraceptives such as condoms, an intra uterine device (IUD) or abstinence). This is because the effects of imatinib mesylate on the developing human fetus are not fully known. 4. Diagnosis of sickle cell disease (electrophoresis or HPLC) 5. Documentation of SS, SC, S-Beta thalassemia or other major sickling phenotypes) 6. Diagnosis of sickle cell disease associated pulmonary hypertension by right heart catheterization (mean PAP greater than or equal to 25 mmHg AND PCWP less than or equal to 15 mmHg with PVR greater than or equal to 3.0 Wood s Units) 7. WHO functional class II or III symptoms Arm B (Carvedilol) 1. Satisfaction of screening criteria 2. Right heart catheterization (mean PAP greater than or equal to 25 mmHg AND PCWP \> 15 mmHg 3. Clinically stable for at least 6 weeks prior to enrollment. PAH treatments must be stable for three months prior to study drug initiation. Prostacyclin analogs, type 5 phosphodiesterase inhibitors and endothelin-1 receptor antagonists are all allowed, alone or in combinations 4. Diagnosis of sickle cell disease (electrophoresis or HPLC documentation of SS, SC, S-Beta thalassemia or other major sickling phenotypes) 5. Women of childbearing potential and male subjects must agree to use reliable methods of birth control (oral contraceptives, other hormonal contraceptives including vaginal contraceptive rings and contraceptive patches, barrier contraceptives such as condoms, an intra uterine device (IUD) or abstinence). This is because the effects of Carvedilol in pregnancy is unknown (pregnancy risk factor C). 6. Subjects 18 years of age or older 7. WHO functional class II or III symptoms Arm C (Hyperdynamic) 1. Sickle cell disease 2. Diagnosis of sickle cell disease associated pulmonary hypertension by right heart catheterization (mean PAP greater than or equal to 25 mmHg AND PCWP less than or equal to 15 mmHg with PVR \< 3.0 Wood s Units) 3. Subjects 18 years of age or older Arm D 1\) Don t qualify for Arm A, B, or C after completing the baseline assessments. EXCLUSION CRITERIA Arm A (Imatinib): 1. Current pregnancy and lactation. 2. Life expectancy less than 6 months. 3. WHO functional class IV symptoms or NYHA-IV dyspnea. 4. Presence of any of the medical conditions that are considered to be the cause of subject s pulmonary hypertension by subject s physician, including but not limited to: \<TAB\>- Scleroderma. \<TAB\>- Known significant obstructive or restrictive respiratory disease with FEV1, FVC or TLC below 60 percent of predicted normal. \<TAB\>- Known diagnosis of Obesity-Hypoventilation Syndrome. \<TAB\>- Portal hypertension or Child Class B or C cirrhosis. \<TAB\>- Significant left ventricular dysfunction (LVEF below 50 percent), significant ischemic, valvular, constrictive or restrictive heart disease. 5. Persistently uncontrolled severe systemic hypertension (SBP above 160 mmHg or DBP above 100 mmHg) 6. Clinical diagnosis of decompensated congestive heart failure 7. Any initiation of new therapeutic intervention within the last 90 days or a dose change within 30 days, that is expected to have an impact on pulmonary hypertension, including but not limited to: 1. \<TAB\>Specific pulmonary hypertension medication (e.g. prostacyclin analogues, endothelin receptor antagonists or phosphodiestrase-5 inhibitors) 2. \<TAB\>Hydroxyurea 3. \<TAB\>Scheduled blood transfusions or exchange transfusions 8. Any acute or chronic, physical or psychiatric impairment, likely to limit subject s ability to comply with study requirements as determined by investigators. 9. Subjects having inadequate organ function or hematopoeisis as defined below: 1. Absolute Neutrophil Count (ANC) \< 1200/mcL 2. Platelets Count \< 50, 000 / mcL 3. ALT (SGPT) \> 3 times upper limit of normal 4. Creatinine greater than or equal to 2.0 mg/dl 5. Creatinine Clearance \< 60 mL/min/1.73 m sq 10. Subjects enrolled in any other interventional drug trial. 11. History of allergic reaction to compounds with similar chemical or biologic composition to imatinib. 12. Any know concurrent condition that is likely to confound investigators ability to monitor drug related adverse events. 13. Any previous treatment with any Tyrosine Kinase Inhibitor within last 90 days. 14. Any SCD related acute illness requiring hospitalization within two weeks. This will include but is not limited to: 1. \<TAB\>Acute vaso-occlusive pain crisis. 2. \<TAB\>Acute chest syndrome 3. \<TAB\>Significant upper or lower respiratory tract infection 15. Significant upper or lower respiratory tract infection requiring hospitalization or emergency department visit within 2 weeks. 16. HIV positive subjects on Highly Active Anti-retroviral therapy (due to potential for drug interaction as well as severe immunosuppression). 17. Acute pulmonary embolism within the previous 90 days. Subjects enrolled on this protocol who are excluded due to above criteria may proceed when their circumstances change to satisfy the exclusion criteria requirements. Arm B (Carvedilol) 1. Current pregnancy and lactation 2. Life expectancy less than 6 months. 3. WHO functional class IV symptoms or NYHA-IV dyspnea. 4. Presence of the following medical conditions that are considered to be the cause of subject s pulmonary hypertension: 1. \<TAB\>Scleroderma 2. \<TAB\>Known significant obstructive or restrictive respiratory disease with FEV1, FVC or TLC below 60 percent of predicted normal. 3. \<TAB\>Known diagnosis of Obesity-Hypoventilation Syndrome. 4. \<TAB\>Portal hypertension or any form of severe liver dysfunction. 5. \<TAB\>Structural or congenital heart disease felt to be causing the pulmonary hypertension 5. Decompensated left ventricular failure requiring intravenous inotropic therapy 6. Persistent hypotension (SBP below 90 mmHg or DBP below 50 mmHg). 7. Any subject with baseline heart rate less than or equal to 60 bpm, sick sinus syndrome, or second or third degree AV block. 8. Any initiation of new therapeutic intervention within the last 90 days or a dose change within 30 days, that is expected to have an impact on pulmonary hypertension, including but not limited to: 1. \<TAB\>Specific pulmonary hypertension medication (e.g. prostacyclin analogues, endothelin receptor antagonists or phosphodiestrase-5 inhibitors) 2. \<TAB\>Hydroxyurea 3. \<TAB\>Scheduled blood transfusions or exchange transfusions 9. Any acute or chronic, physical or psychiatric impairment, likely to limit subject s ability to comply with study requirements as determined by investigators. 10. Subjects enrolled in any other interventional trial. 11. History of allergic reaction to compounds with similar chemical or biologic composition to carvedilol 12. Any know concurrent condition that is likely to confound investigators ability to monitor drug related adverse events 13. Use of beta-blockers within previous 90 days. 14. Cardiac index \< 1.8 l/ min (2) 15. Severe renal insufficiency (creatinine clearance \<30 ml/min/m(2)) 16. Any SCD related acute illness requiring hospitalization within two weeks. This will include but is not limited to: 1. \<TAB\>Acute vaso-occlusive pain crisis. 2. \<TAB\>Acute chest syndrome 3. \<TAB\>Significant upper or lower respiratory tract infection requiring hospitalization or emergency department visit 17. Significant upper or lower respiratory tract infection requiring hospitalization or emergency department visit within 2 weeks. 18. HIV positive subjects on Highly Active Anti-retroviral therapy due to potential for drug interaction. 19. Subjects with active hepatitis infection as the monitoring of drug related liver toxicity will be confounded. 20. Acute pulmonary embolism within the previous 90 days. 21. Liver function abnormalities (screening serum ALT\>5 times upper limit) 22. Subjects with severe asthma as defined by presence of one or more of the following: \<TAB\>- Presence of asthma symptoms throughout the day \<TAB\>- Nocturnal symptoms every night \<TAB\>- Need for rescue medications several times per day \<TAB\>- Two or more acute exacerbations of asthma requiring systemic steroids therapy within the preceding year \<TAB\>- A reduced FEV1/FVC ratio or FEV1 below 60 percent of predicted normal. Subjects enrolled on this protocol that are excluded due to above criteria may proceed when their circumstances change to satisfy the exclusion criteria requirements. Arm C (Hyperdynamic) 1\) There are no exclusion criteria. Arm D 1\) There are no exclusion criteria.