A Peripheral Blood Signature of Vasodilator-Responsive Pulmonary Arterial Hypertension
Editor's Note: Commentary based on Hemnes AR, Trammell AW, Archer SL et al.A Peripeheral Blood Signature of Vasodilator-Responsive Pulmonary Arterial Hypertension. Circulation 2014;.114.013317. [Epub ahead of print].
It has long been noted that there is a small group of patients with idiopathic pulmonary arterial hypertension who have a marked improvement in their hemodynamics when given vasodilators acutely such as nitric oxide. These so-called vasodilator responders can often be successfully treated with calcium channel blocker therapy, as opposed to the great majority of idiopathic pulmonary arterial hypertension patients who do not have such an improvement and are generally treated with standard pulmonary arterial hypertension medications, e.g. phosphodiesterase 5 inhibitors, endothelin receptor antagonists and prostaglandins. We hypothesized that there is a different molecular etiology of idiopathic pulmonary arterial hypertension in patients who have this vasodilator response compared with those that do not have a response. We performed microarray studies on cultured lymphocytes from the two groups and found that they are, indeed, different by mRNA expression patterns. We confirmed our findings in whole blood mRNA that was not from cultured lymphocytes and created decision trees based on the mRNA expression levels to identify the responsive idiopathic pulmonary arterial hypertension patients. We then recruited a cohort of idiopathic pulmonary arterial hypertension from another center and were able to confirm our findings in this second, independent cohort. So, in summary, we found that there is a different molecular etiology of vasodilator responsive idiopathic pulmonary arterial hypertension than in non-responsive idiopathic pulmonary arterial hypertension that can be found in peripheral blood mRNA patterns.
There several implications of these findings. First, it is possible to use blood mRNA patterns to identify sub-phenotypes within pulmonary arterial hypertension that might point to different molecular causes of pulmonary hypertension. This suggests that we can move from a phenotypic classification to a molecular classification of pulmonary hypertension one day. Transcriptomics is one way to molecularly phenotype, but there are other potential technologies to do this such as metabolomics or genomics. Second, these data show that we can identify patients with pulmonary arterial hypertension a priori who are likely to respond to one class of drug or another. The data need to be replicated in other cohorts and with response to other drug classes, and underlying pharmacogenomics studied, but our data suggest that we may be able to move beyond a "one size fits most" approach to pulmonary arterial hypertension therapy and develop a more precision-medicine based therapeutic algorithm. Finally, these data suggest that in future drug trials in pulmonary vascular disease we need to be collecting genomic and transcriptomic data at a minimum at trial entry to potentially match patients with a strong effect size to genomic or transcriptomic patterns that can be used clinically or to better design future trials.
It is a major step forward to realize that we can characterize PAH phenotypes by molecular means. This small subset of vasodilator responsive PAH patients was particularly well-suited to study first because they were so different clinically from other forms of PAH. So, the next studies need to have a similarly distinct patient phenotype. For the exact molecular studies, each center and scientist will certainly have their own opinions about how best to do this, but we favored our approach because it 1) used lymphocytes cultured outside of the body to remove medication and environmental effects and 2) validated the lymphocyte data in more readily available whole blood mRNA expression patterns. Because we were able to enroll patients with prevalent disease, we were able to rapidly enroll which was a major strength of this approach also. I would add that it's also possible that we can use the same methodology to identify molecular characteristics of non-Group 1 pulmonary hypertension. Moving forward, we as a community need to advocate for collecting biospecimens, e.g. DNA, mRNA, lymphocytes, on all well-phenotyped pulmonary hypertension patients and we need to collaborate with other pulmonary hypertension centers to increase our strength through numbers and cross-validation of findings. The end result of these efforts will be, ideally, a better molecular understanding of pulmonary hypertension and better care for this hetereogeneous yet all to commonly devastating condition.
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