Cardiopulmonary-renal complications are now the most common cause of mortality in sickle cell disease (SCD). Cardiovascular pathology is overshadowed by the effects of chronic anemia: presence of biventricular hypertrophy but normal ejection fractions. Left ventricular diastolic dysfunction and sudden unexplained deaths also occur commonly. Pulmonary artery hypertension (PAH) in SCD has been the focus of recent research and debate. Mildly elevated pulmonary arterial (PA) pressures, estimated by a tricuspid regurgitation jet velocity (TRV)>2.5m/s have been associated with high mortality in several studies. However, cardiac catheterization diagnosed PAH is only present in 25-33% of those with TRV>2.5m/s. Nevertheless, the number of adverse events in SCD patients with even very mild elevation in PA pressures is unexpectedly high and its mechanism/s is unknown. High TRV strongly associates with renal pathology in SCD. Based upon our preliminary data, we hypothesize that reactive oxygen species (ROS) and angiotensin 11 (AT)-AT1 receptor (AT1R) is activated in SCD to generate TGFP1, a profibrotic thrombo-lnflammatory cytokine that mediates SCD cardio-renal disease and sudden death, by causing a profibrotic state and a unique restrictive cardiomyopathy (RCM) with secondary PAH. We will {Aim 1) test whether the'increased ROS in SCD is derived via RAS-mediated G-protein signaling to worsen oxidative membrane damage and hemolysis using pharmacological, or genetic approaches and study the effects of ROS on cardio-renal pathologies;{Aim 2) examine the relative contribution of cardiac or renal AT1R signaling or TGF?1 production using mice deficient in AT1R or TGFbeta1 specifically in cardiac or renal tissues. We will also study the effects of TGF??1 derived from platelets, the largest source of circulating TGF??1 by using mice deficient in TGP??1 specifically in platelets and study the effect on cardio-renal pathology;
and (Aim 3) explore novel cardiac MR modalities to detect the unique restrictive cardiomyopathy and quantify diffuse myocardial fibrosis in patients with SCD with and without high TRV. The same novel CMR imaging will also be done in mice, where imaging can be correlated with anatomical and histopathological analysis. The diverse team of multidisciplinary investigators in hematology, cardiology and radiology, pharmacological and genetic approaches, and parallel human studies will allow a multifaceted analysis of the cardio-renal pathologies in SCD, to allow rapid translation of research discoveries into therapeutic targets and a future phase ll/lll trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL117709-01
Application #
8468307
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Hanspal, Manjit
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2013-08-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,796,772
Indirect Cost
$590,834
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Cohen, Robert M; Smith, Eric P; Arbabi, Shahriar et al. (2016) Do Red Blood Cell Indices Explain Racial Differences in the Relationship between Hemoglobin A1c and Blood Glucose? J Pediatr 176:7-9
Quinn, Charles T (2016) Minireview: Clinical severity in sickle cell disease: the challenges of definition and prognostication. Exp Biol Med (Maywood) 241:679-88
Quinn, Charles T; Smith, Eric P; Arbabi, Shahriar et al. (2016) Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia. Am J Hematol 91:1195-1201
Niss, Omar; Quinn, Charles T; Daily, Joshua et al. (2016) The Authors Reply. JACC Cardiovasc Imaging 9:1123-4
Bakeer, Nihal; James, Jeanne; Roy, Swarnava et al. (2016) Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology. Proc Natl Acad Sci U S A 113:E5182-91
Rai, Parul; Malik, Punam (2016) Gene therapy for hemoglobin disorders - a mini-review. J Rare Dis Res Treat 1:25-31
Niss, Omar; Quinn, Charles T; Lane, Adam et al. (2016) Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease. JACC Cardiovasc Imaging 9:243-52
Chang, Kyung Hee; Nayak, Ramesh C; Roy, Swarnava et al. (2015) Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial ATâ‚‚R and cytoskeletal dysregulation. Nat Commun 6:5914
Crosby, Lori E; Quinn, Charles T; Kalinyak, Karen A (2015) A biopsychosocial model for the management of patients with sickle-cell disease transitioning to adult medical care. Adv Ther 32:293-305
Quinn, Charles T (2013) Sickle cell disease in childhood: from newborn screening through transition to adult medical care. Pediatr Clin North Am 60:1363-81

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