The Prins lab will work to define the molecular mechanisms that underlie right ventricular (RV) failure in pulmonary arterial hypertension (PAH). Although rare, PAH is a devastating disease with a median survival of only 5 years after diagnosis. The strongest predictor of long-term outcomes in PAH is RV function, but the molecular and cellular determinants of RV dysfunction are poorly understood. Our goal is to help define these mechanisms using rodent models of PAH and human samples from our Pulmonary Hypertension Clinic.
Understanding the role of junctophilin-2 in RV failure:
In this project, we are building on our previous publication (Prins et al., JAHA) showing junctophilin-2 is downregulated in the RV and associated with t-tubule disruptions and RV dysfunction in rodent PAH. Now, we are looking to define epigenetic regulators of junctophilin-2 and how inhibition of those regulators alters junctophilin-2 protein levels, t-tubule morphology, calcium handling, and RV function in rodent models of PAH.
Investigating the contribution of metabolic derangements to RV failure:
Here, we are investigating a novel protein-protein interaction that likely controls RV metabolism through mitochondrial regulation. In this project, we will analyze mitochondrial function and RV metabolism and how altering each modulates RV function in vivo.
Determine the role of inflammation in RV dysfunction:
In this project, we are aiming to understand how inflammation may promote impaired RV function. In a clinical study (Prins et al., JHLT), we showed the inflammatory cytokine interleukin-6 was associated with RV failure in PAH patients. The goal of this project is to define the molecular mechanism of this observation in isolated cardiomyocytes and rodent PAH models.
Understand the right ventricle in pulmonary hypertension due to lung disease:
In this project, we are building on our previous publication (Prins et al., AJRCCM) showing patients with pulmonary hypertension due to chronic lung disease have worse RV function than PAH patients despite having less severe pulmonary vascular disease. We will employ imaging and hemodynamic measures of RV function to gain insight into our observation.
Database analysis to gain insights into PAH pathophysiology:
Using the MEASURE database, which has a comprehensive review of over 800 pulmonary hypertension patients, we can perform studies to compare different pulmonary hypertension subgroups or investigate one particular type of pulmonary hypertension.
Full list of publications at Experts@Minnesota.
- K.W. Prins, L. Rose, S.L. Archer, M. Pritzker, E.K. Weir, F. Kamirczak, J.R. Misialek, T. Thenappan. 2018. Disproportionate right ventricular dysfunction and poor survival in group 3 pulmonary hypertension. Am. J. Respir. Crit. Care Med., accepted
- Prins K.W., Archer SL, Weir EK, Rose L, Pritzker MR, and Thenappan T, 2017. Interleukin-6 is Independently Associated with Right Ventricular Dysfunction in Pulmonary Arterial Hypertension. JHLT. 37(3):376-384.
- Prins, K.W., L. Tian, D. Wu, T. Thenappan, J. Metzger, and S.L., Archer, 2017. Colchicine Depolymerizes Microtubules, Increases Junctophilin-2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension. JAHA. 6: 1-13
- Prins, K.W., S. Duval, J. Markowitz, M. Pritzker, and T. Thennappan. 2017. Chronic Effects of PAH-Specific Therapy in World Health Organization Group III Pulmonary Hypertension: A Systematic Review and Meta-Analysis. Pulm Circ. 1: 145-155
- Prins, K.W., E.K. Weir, S.L. Archer, J. Markowitz, L. Rose, M. Pritzker, R. Madlon-Kay, and T. Thennappan. 2016. Pulmonary Pulse-wave Transit Time is Associated with Right Ventricular-Pulmonary Artery Coupling in Pulmonary Arterial Hypertension. Pulm Circ. 6: 576-585
- Prins, K.W., and T. Thenappan. 2016. WHO Group 1 Pulmonary Hypertension: Epidemiology and Pathophysiology. Cardiology Clinics. 34: 363-374
- Prins, K.W., M. Asp, H. Zhang, W. Wang, and J. Metzger. 2016. Microtubule-mediated Misregulation of Junctophilin-2 Underlies T-tubule Disruptions and Calcium Mishandling in Mdx Mice. JACC Basic to Trans Science. 3: 122-130
- Thenappan, T., K.W. Prins, M. Pritzker, J. Scandurra, K. Volmers, and E. Weir. 2016. The Critical Role of Pulmonary Arterial Compliance in Pulmonary Hypertension. Annals ATS. 2: 276-284
- Prins, K.W., T, Thenappan, J. Markowitz, and M. Pritzker. 2015. Cardiorenal Syndrome Type 1: Renal Dysfunction in Acute Decompensated Heart Failure, J. Clin Outcomes Mange. 22: 443-454
- Prins, K.W., J.O. Neill, J.O. Tyler, P.M. Eckman, and S. Duval. 2015. Effects of -blocker withdrawal in acute decompensated heart failure: A systematic review and meta-analysis. JACC Heart Fail. 3: 647-653
- Thenappan, T, K.W. Prins, R. Cogswell, and S. Shah. 2015. Pulmonary Hypertension Secondary to Heart Failure with Preserved Ejection Fraction. Can. J. Cardiol. 4:430-439
Full list of publications at Experts@Minnesota.