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CHASING ZEBRAS: PULMONARY HYPERTENSION WORLD SYMPOSIUMS

Veronica Franco, MD
Ohio State University

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veronica francoThe 5th Pulmonary Hypertension (PH) World Symposium will take place in Nice next year. This is a key meeting for our council as important scientific publications are reviewed and task forces' conclusions traditionally result in changes in the nomenclature and classification of PH, which pave the way for further advancements.

The 1st World Symposium took place in Geneva, Switzerland in 1973 after the World Health Organization convened a group of experts to standardize clinical and pathological definitions of PH. It was also the first attempt for a classification of PH: primary (a diagnosis of exclusion) vs. secondary (with other medical conditions). This gathering was prompted by the outbreak of aminorex-induced PH in the late 1960s, as its incidence increased by 10-fold. Aminorex fumarate was an appetite suppressant sold over-the-counter to promote weight loss. It resembled epinephrine and amphetamine in chemical structure, and its toxic effects have been attributed predominantly to the release of catecholamines and norepinephrine. The drug was withdrawn from the market in October 1968, as it was thought responsible for the PH epidemic. Autopsies of these patients showed that they had pulmonary plexiform vascular lesions, similar to those with primary PH.

The aminorex epidemic raised several important questions: why didn't everyone who took it develop PH? (only 2% of those who ingested aminorex developed primary PH, suggesting genetic predisposition). Are there any specific triggers that determine when the symptoms of PH start?

The 2nd World Symposium took place 25 years later in Evian, France in 1998 with the goal of proposing a clinical classification for all types of PH. Notably, Epoprostenol (Flolan) was approved by the FDA in 1995, revolutionizing the treatment of primary PH. The aim of the "Evian classification" was to individualize different categories sharing similarities in pathophysiological mechanisms, clinical presentation, and therapeutic options, particularly focusing on patients that would benefit from IV prostacyclin therapy. Thus, such a clinical classification was essential to standardizing diagnosis and treatment and to conducting trials with a homogeneous group of patients. PH diseases were grouped according to specific therapeutic interventions directed at dealing with the cause of: 1) PAH (which included primary and related conditions), 2) pulmonary venous hypertension, 3) PH associated with disorders of the respiratory system or hypoxemia, 4) PH caused by thrombotic or embolic diseases, and 5) PH caused by diseases affecting the pulmonary vasculature.

Subsequently, the world symposiums have been held every 5 years. Remarkably, another selective vasodilator, Bosentan, was approved by the FDA in 2001. The 3rd World Symposium in PH was prompted by a remarkable surge in the understanding of the mechanisms involved in the pathogenesis of PH. Held in 2003 in Venice, Italy, it provided the opportunity to assess the impact and the usefulness of the Evian classification and to propose some modifications. Thus, the term "secondary PH" was abandoned because it was found confusing and without value for diagnosis and treatment. The term "primary PH" was replaced with "idiopathic pulmonary arterial hypertension."

By the time the 4th World Symposium took place in Dana Point, California in 2008, the scientific knowledge about PH was burgeoning. This was a 4-day summit of international experts highlighting the findings of 11 scientific working groups in areas of basic science, clinical science, and future perspectives. The purpose of this symposium was to review the progress made in diagnosing and treating PH and PAH, resulting in a new classification for PH with more etiologies added to WHO group 1 (PAH). Interestingly, more diverse participation occurred at the 4th World Symposium, in contrast with the previous 3rd World Symposium which seemed somewhat more "exclusive," with a relatively limited number of global experts meeting in small groups. With the advent of widely available, effective therapy for PAH, it was no longer considered a rarefied condition treated in a handful of institutions by high-level experts.

The 5th World Symposium in PH promises to be a historical event. There will be a collective dedication of a group of experts to reach that elusive, yet definite, goal: finding the cure for PAH, a "medical zebra" considered-until recently-uniformly fatal. Thirty years ago, adults diagnosed with PAH could expect to live less than 3 years, with the therapeutic armamentarium limited to nonselective vasodilators. Today, our selection of therapeutic modalities is broader with 8-FDA approved therapies resulting in better outcomes. Yet, there is much more to do and new therapeutic modalities are urgently needed. We expect the upcoming symposium to focus on genetic variations in PAH, RV remodeling and function including understanding fundamental components of the RV-PA coupling, as well as creative, thoughtful approaches targeting novel pathways in PAH. Stay tuned!

Disclosure Statement: The author has received research support from Actelion and United Therapeutics and consultant and speaker bureau for Gilead.