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Pulmonary Arterial Hypertension, 25, and the Holy Grail

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Timothy Baillie, BBiomedSC, BMBS, FRACP
Toronto General Hospital
Toronto, ON, Canada

Arbitrary: based on random choice or personal whim, rather than any reason or system.

Undertaking a Fellowship should provide an opportunity to think and to ask questions. Moving to Toronto from Australia some months ago to continue training in my area of interest, pulmonary hypertension, I have been thinking: why is the sun so far away? Why aren't there more venomous creatures around? Why is Pulmonary Arterial Hypertension (PAH) only recognized as a 'problem' once hypertension arises, when it was noted that Primary Pulmonary Hypertension (now PAH) was best described as a "plexogenic pulmonary arteriopathy" back when gasoline (AKA Petrol) was 44c a gallon (AKA 3.785 litres) and you could pick up a new and improved version of the Ford Mustang (AKA Ford Mustang II) for $4105 (all USD of course) {Hatano S, 1975 #1273}? If PAH is a pulmonary arteriopathy, why is a mean pulmonary arterial pressure (mPAP) of 25mmHg a pre-requisite for diagnosis? How did 25 come about and what is wrong with, for instance, 24mmHg? Did a youthful Harrison Ford (HF) put himself through all that in search of a metallic drinking vessel, or was it an appetizer for the blockbuster "Indiana Jones and the Last Last Crusade," where a mature HF successfully navigates the bureaucratic minefield of medical research to realize the true Holy Grail, pre-clinical detection of PAH?

Before we address these questions, we need some background. Pulmonary hypertension (PH) is defined by an elevated resting mPAP (25mmHg) measured by right heart catheter (RHC). Pathophysiological conditions causing PH are pigeonholed into one of five categories based on common clinical, pathological and hemodynamic findings, and similar treatment strategies {Galie, 2016 #1068}. Pulmonary arterial hypertension represents Group 1 PH, and includes idiopathic and heritable PAH, PAH associated with underlying connective tissue diseases (CTD), such as systemic sclerosis and systemic lupus erythematosus, HIV, porto-pulmonary hypertension in the setting of liver cirrhosis, congenital heart disease and drug or toxin induced PAH. Idiopathic and CTD-associated PAH makeup much of the estimated 15-60 prevalent cases per million population {Peacock, 2007 #539}. Complex and incompletely understood metabolic, molecular, structural and functional changes drive the disease process, resulting in vasoconstriction, arterial wall remodeling and in situ thrombosis (histologically described as 'plexiform' lesions) which 'obliterate' small pulmonary arterioles. As the "plexogenic pulmonary arteriopathy" progresses, resistance to blood flow through the pulmonary vasculature rises, elevating pressures and placing undue strain on the right ventricle (RV) which, unchecked, results in RV failure and reduced life expectancy despite effective but non-curative medical therapies.

Now back to the questions. To knock the easy ones off, I have been told by unreliable sources that the faraway sun long ago drove nearly all venomous creatures to warmer continents - thank you on behalf of my fellow Australians. What is more ambiguous is the importance of a mPAP of 25mmHg in PAH. Different - but equally unreliable - sources have informed me this magical number was conjured in an idyllic chalet in the Swiss Alps by a small group of well-informed scientists enjoying delicate Trappist Ales [Note: I could not confirm this despite extensive PubMed searching]. The reality is that deranged hemodynamics at rest are a late consequence of the underlying pulmonary vascular disease. In fact, a majority (50-60%) of the pulmonary microcirculation are lost by the time the mPAP rises ≥ 25mmHg {Lau, 2011 #427} and close to a 40% deficit can be absorbed by one's reserve without any impact on their resting mPAP (upper limit normal being ~19mmHg {Kovacs, 2009 #533}. Why, therefore, do we define a disease that is first and foremost a pulmonary vasculopathy by arbitrary hemodynamic abnormalities that occur late in the disease process, particularly given certain populations at risk of developing the disease (e.g. systemic sclerosis) are readily identifiable and treatment is known to be most effective when instigated early {Lau, 2014 #956}? The unifying answer: the 'hypertension' component of PAH is readily measured whereas 'early disease' (vasculopathy without hemodynamic derangement) is not. Yet.

I had intentions of discussing some of the exciting progress being made by researchers around the globe in the search for the Holy Grail. Unfortunately, I used up my word count discussing animals and weather, and am also practicing the art of creating 'dramatic suspense' in the expectation I will be contracted by Lucasfilm soon. I will say that progress is being made via different approaches including standardized exercise protocols (observing for abnormal hemodynamic responses using invasive and non-invasive techniques), standardized magnetic resonance imaging protocols utilizing intravenous adenosine to detect reduced cardiopulmonary reserve, functional nuclear imaging to assess postural changes in lung perfusion, and metabolomics, whereby a certain 'metabolic signature' may suggest impending PAH. I should also note that this is not an easy research topic, largely due to the absence of a validated method against which results can be compared. Consequently, researchers necessarily extrapolate differences observed between healthy and PAH subjects, that is they assume that subjects with early disease will fit "somewhere in the middle." Only long-term trials with the capacity to quantify incident PAH cases will be definitive.

In summary, PAH is a late result of the underlying pulmonary vasculopathy with a mPAP of 25mmHg, reflecting an arbitrary 'line in the sand' that once crossed, simply confirms that the pulmonary vascular disease has progressed to a point that is readily measured. A paradigm shift towards early detection of this disease is possible in certain populations, but like HF, researchers will have to navigate a number of obstacles in order to realize their quest for the Holy Grail, although I am confident a similar ending will transpire. ■

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

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