Abstract 17011: Loss-of-function SIRT3 Single Nucleotide Polymorphisms in Patients With Pulmonary Arterial Hypertension (PAH): Insights into the Metabolic Basis of PAH
PAH is characterized by a proliferative vascular remodeling, in part due to apoptosis-resistance secondary to suppressed mitochondrial function in vascular cells. Recently PAH patients have been shown to have evidence of insulin resistance. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase, the absence of which leads to a global suppression of mitochondrial function. A loss-of-function SNP in humans (rs11246020) has been linked to metabolic syndrome. In a parallel abstract submission (Paulin et al) we show that SIRT3 knockout mice develop spontaneous PAH and that inhaled gene therapy replenishing SIRT3 levels in a rat model, reverses established PAH.
We hypothesized that the SIRT3 SNP may be over-represented in PAH patients.
METHODS: We studied 78 consecutive patients referred for potential PAH (based on history or echocardiogram). Following complete workup including right heart catheterization and cardiac MRI, 21 had idiopathic PAH (iPAH), 40 had PAH associated with scleroderma (aPAH) and 17 did not have PAH (noPAH). Blood was prospectively collected upon referral, DNA was extracted from buffy coat samples and genotyped.
RESULTS: The frequency of SNP homozygosity and heterozygosity in the noPAH group was for both 4%, the normal genotype being predominant (92%). SNP heterozygosity was increased in aPAH (33%). In iPAH, SNP homozygosity and heterozygosity reached 12% and 48% respectively. A Pearson Chi Square test showed an association between PAH and the SNP (p<0.001). Although there was a trend, the mean pulmonary artery pressure was not higher in PAH patients with the SNP compared to PAH patients without it. Interestingly, there was an increase in the RV mass index in the former group (p=0.01).
CONCLUSIONS: A loss-of-function SIRT3 SNP is prevalent in PAH. Along with our animal work, this suggests that loss of SIRT3 activity may predispose to PAH. While the presence of the SNP does not correlate with hemodynamics, the association with RV remodeling is intriguing, but difficult to interpret because of potential direct effects of the loss-of-function of SIRT3 in the RV myocardium (it is known to promote cardiac hypertrophy) and the small sample size. If confirmed in larger cohorts, SIRT3 may become the basis of biomarker and therapeutic discovery programs in PAH.
- © 2013 by American Heart Association, Inc.