The vast majority of patients with pulmonary hypertension, regardless of the etiology, ultimately succumb to the disease by two main causes: sudden death or intractable right heart failure. While there has been great focus paid to the vascular abnormalities associated with pulmonary hypertension, there has been a relative paucity of attention given to the role of the right ventricle in this disease. An under-recognized potential factor that may play an important role in patients with pulmonary hypertension is ventricular- vascular uncoupling secondary to pulmonary vascular stiffening especially in patients with scleroderma- associated pulmonary hypertension. Preliminary data suggest that, while there is some degree of large artery vascular stiffening in idiopathic pulmonary arterial hypertension, this pathology is markedly worsened in patients with pulmonary hypertension related to scleroderma. Since stiffening means that even modest increases in cardiac ejection are associated with greater arterial after-load pressures, it can limit mechanisms of cardiovascular reserve. The guiding hypothesis of this proposal is that ventricular- vascular stiffening is enhanced in patients with pulmonary arterial hypertension, limiting cardiac reserve and contributing to exertional dyspnea, fatigue, and is directly related to mortality. This proposal employs many novel techniques to study RV-pulmonary vascular interactions in a way that may prove to be easily translated to clinical practice, as well to study molecular mechanisms that reinforce this hypothesis, and the effect on intervention on these pathways on symptoms, outcomes, and mortality in this patient population. Moreover, this proposal will attempt to tie molecular changes to RV failure and remodeling to the degree of RV-PA uncoupling and we will test the hypothesis that measurement of this uncoupling will be prognostic with regard to treatment success.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL084946-05
Application #
8212633
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
2013-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$381,992
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Yu, Bing; Pulit, Sara L; Hwang, Shih-Jen et al. (2016) Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. Circ Cardiovasc Genet 9:64-70
Gao, Li; Emond, Mary J; Louie, Tin et al. (2016) Identification of Rare Variants in ATP8B4 as a Risk Factor for Systemic Sclerosis by Whole-Exome Sequencing. Arthritis Rheumatol 68:191-200
Fan, Chunling; Meuchel, Lucas W; Su, Qingning et al. (2015) Resistin-Like Molecule ? in Allergen-Induced Pulmonary Vascular Remodeling. Am J Respir Cell Mol Biol 53:303-13
Ohyama, Yoshiaki; Ambale-Venkatesh, Bharath; Chamera, Elzbieta et al. (2015) Comparison of strain measurement from multimodality tissue tracking with strain-encoding MRI and harmonic phase MRI in pulmonary hypertension. Int J Cardiol 182:342-348
Hassoun, Paul M; Zamanian, Roham T; Damico, Rachel et al. (2015) Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 192:1102-10
Auer, Paul L; Nalls, Mike; Meschia, James F et al. (2015) Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JAMA Neurol 72:781-8
Parker, Sarah J; Raedschelders, Koen; Van Eyk, Jennifer E (2015) Emerging proteomic technologies for elucidating context-dependent cellular signaling events: A big challenge of tiny proportions. Proteomics 15:1486-502
Damico, Rachel; Kolb, Todd M; Valera, Lidenys et al. (2015) Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 191:208-18
Yamaji-Kegan, Kazuyo; Takimoto, Eiki; Zhang, Ailan et al. (2014) Hypoxia-induced mitogenic factor (FIZZ1/RELM?) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 306:L1090-103
Semba, Richard D; Huang, Hu; Lutty, Gerard A et al. (2014) The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy. Proteomics Clin Appl 8:218-31

Showing the most recent 10 out of 105 publications