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Hiding in Plain Sight: Harvest of Pulmonary Artery Endothelial Cells from Discarded Swan-Ganz Catheter Balloons May Illuminate PAH-Specific Biological Processes

Michael J. Passineau, PhD
Allegheny Health Network
Pittsburgh, PA, USA

The diagnosis of pulmonary hypertension (PH) requires right heart catheterization (RHC), thus this diagnostic procedure becomes the gateway through which patients enter into management of PH, regardless of the etiology. While the hemodynamic information obtained by RHC is crucial to the management of PH, hemodynamics alone provide relatively little insight into the biological processes underlying pulmonary pressure changes, and thus a constellation of additional clinical observations are needed in order to properly assign a patient to the appropriate WHO Group classification.

In 2013, we reported in the Journal of Heart and Lung Transplantation that it was possible to recover Pulmonary Artery Endothelial Cells (PAECs) from the balloon tips of Swan-Ganz catheters after RHC. Our initial thoughts, which were shared by interested collaborators, were that culturing and expanding these cells would provide a new resource for determining patient-specific treatments, and possibly help to elucidate pathologic disease mechanisms, particularly in WHO Group I disease. The downside of this culture approach however, was twofold. First, it took several weeks to establish robust cultures, making it difficult to use these cells for diagnostic applications. Second, cultures probably favor a subset of harvested cells, possibly endothelial progenitor cells, that manifest a superior ability to survive and proliferate in culture. Thus, PAEC cultures probably do not reflect the in situ situation in the pulmonary artery with full fidelity.

To expand the versatility of this technique, we modified our protocol for harvest in order to perform direct analysis of PAECs without the need for an intermediate culture step. Several years of work have resulted in a reliable process that utilizes anti-CD45 affinity columns for leukocyte depletion followed by anti-CD146 columns for positive selection of PAECs yielding harvest that typically number in the 5000-20,000 live PAECs for downstream analysis. Importantly, we have shown that this process can be applied to catheter tips shipped overnight on wet ice, with cell viability remaining above 25% and overall numbers in the thousands of PAECs. This "clip and ship" protocol has become standard practice in our research group and we welcome receipt of catheter tips from centers throughout North America for collaborative projects.

Our interest has focused intently on biological markers potentially useful for differentiating WHO Group I pulmonary arterial hypertension (PAH), particularly its idiopathic form, from occult left-sided heart disease. Some patients with left heart failure with preserved ejection fraction (HFpEF) and those with combined pre and post capillary pulmonary hypertension (CPCPH) can present a vexing clinical entity which can be difficult to differentiate from PAH. Hemodynamic maneuvers, such as fluid or exercise challenges can be particularly useful in these instances, but are not completely reliable. Because the biology of PAH seems to have a unique disease process, we turned to earlier literature wherein histopathological and molecular studies of explanted lungs from PAH patients hinted at a role for bcl-2 in driving anti-apoptotic activity in PAECs [1-3]. Intriguingly, we have now been able to report single-center, unblinded data associating a flow cytometery-based index of bcl-2 in harvested PAECs with Group I PAH to the exclusion of HFpEF [4]. More work will be needed to confirm these findings with the current emphasis on obtaining a double-blind study carried out at multiple expert PAH centers. If independently validated, this new approach has great potential for increasing the precision of WHO Group I diagnosis.

Looking forward, it is important to remember that the regions of the pulmonary artery contacted by the Swan-Ganz catheter balloon are very proximal to the right ventricle. Yet, the pathophysiology of PAH, particularly the manifestations of anti-apoptotic phenotypes, presumably begins in the distal microvasculature, very remote from where a Swan-Ganz catheter would ever venture. So how do we reconcile the findings of Benza et al [4] from the standpoint of this presumed proximal/distal disconnect? Could the molecular pathophysiology of the distal vasculature in PAH be propagated distally to PAECs of the secondary and tertiary branches of the Pulmonary Artery? As implausible as this sounds, our observations suggest it may indeed be the case.

If so, what else could be learned about the distal microvasculature of a PAH patient from a Swan-Ganz catheter that would otherwise be discarded after RHC? Moreover, could it be that the emergence of an anti-apoptotic phenotype in the pulmonary vasculature heralds a disease process that is specifically responsive to PAH-specific medications? In complex disease, or so-called out-of-proportion PH, what will we observe with respect to this biological mechanism, and will it unlock a new approach to improved treatment outcomes by serving as a triggerpoint for deployment of PAH specific therapy?

These questions and more present an exciting new frontier for a more nuanced understanding of PAH pathophysiology, and possibly that of HFpEF as well. The past two decades have seen remarkable progress in PAH treatment. Indeed, it is worth reflecting on how the advent of not one, but four different classes of PAH-specific pharmacotherapies have transformed a grim, inevitably fatal prognosis into a serious condition in which a subset of patients respond and survive remarkably well. The advent of this technique, amounting to in essence a cellular biopsy of the pulmonary endothelium in situ, compels us to hone more precise treatment algorithms to use these powerful pharmacotherapies in biologically-targeted, patient-specific strategies.

The irony for the PAH physicians is that clinicians performing RHC have for decades been discarding Swan-Ganz catheters on which thousands of their patients' own PAECs have been hiding in plain sight. Sometimes the most exciting advancements are remarkably simple. Time will tell what the PAH community will make of this new frontier! ■

Disclosure Statement: The author has no conflicts of interest to disclose.


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