Corsica, France, July 29-31, 1997:  A first-ever symposium of many of the world’s leading experts on Primary Pulmonary Hypertension (PPH) was convened by the to honor the memory of Francois Brenot, a French doctor-scientist who specialized in PPH, cared for many patients, and unfortunately passed last year from a heart attack. He was barely 40 years old, and an extraordinary warm, caring and diligent individual. The symposium was expertly chaired and organized by Dr. Lewis Rubin, M.D., of the University of Maryland School of Medicine.

Thanks to the initiative of Dr. Rubin, the leading medical journal CHEST will publish the proceedings of the symposium in a special issue due to come out in late 1997 or early 1998. The cost of the special issue will be underwritten by the PPH Cure , assisted by grants from Glaxo Wellcome U.S. ($10,000), Knoll Pharmaceuticals, Schering AG, and Glaxo Wellcome France ($20,000). This publication will enable researchers throughout the world to benefit from the insights of three days of expert "shirtsleeve" discussions and brainstorming on the causes of and ways to cure PPH.

The symposium was attended by Dr. Galie of Italy, Dr. Simmoneau of France, Dr. Higenbottam and Prof. Moncada of the UK, Drs. Rabinovich and Gaiad of Canada and Drs. Rubin, Fishman, Rich, Barst, Crow, Loyd, Christman, Voelkel of the U.S. Major discussion topics were the causes and pathways of endothelial and smooth muscle cell dysfunction, the role of diet suppressants, the mechanisms of action of prostacyclin, the impact of genetics and the need for cooperative lung tissue banking.

Typical comments of the sense of the meeting was Dr. Stuart Rich’s (of the Rush Heart Institute’s Center for Pulmonary Heart Disease) opinion that "I came away with a lot of very new ideas and perspectives. I think you can look to it as an extraordinarily worthwhile meeting." Similarly, Dr. Adel Giaid (of the Montreal General Hospital and McGill University) opined "I enjoyed the heated discussions which were extremely useful in setting our plans for the future." This was the purpose of the symposium – to trigger new ideas and conceptual breakthroughs in treating and curing pulmonary hypertension.

A frequently heard theme was that PPH is probably caused by some sort of infection that settles into the pulmonary vascular bed in genetically susceptible individuals. A period of time passes – ranging from months to decades – until the infection has caused enough damage to pulmonary vascular bed cells to commence a self-reinforcing spiral hypertension. The hypertension results both from excessive vasoconstriction and from obliteration of the smallest blood vessels in the lungs, both of which increase the resistance against which the right side of the heart must pump blood. A very complex chain of intercellular and intracellular signals is probably involved is probably involved in triggering and maintaining the vasoconstriction and proliferation of malformed endothelial cells into the blood vessel which typify pulmonary hypertension.

Another frequently heard theme is that pulmonary hypertension is a condition that can result from several different causes, and may always or at least usually have both a genetic and an environmental component. In this regard, the differentiation of "primary" and "secondary" pulmonary hypertension may have limited utility. Primary pulmonary hypertension means pulmonary hypertension of no known cause. But in a multi-causal model, this distinction begins to lose significance. For example, there is considerable ambiguity as to whether diet suppressant induced pulmonary hypertension or HIV-related pulmonary hypertension is "primary" or "secondary." They are usually called "primary" because we do not understand why and how diet suppressants and HIV trigger pulmonary hypertension in some individuals, but not others. Apparently, there must be some degree of genetic predisposition in the affected individuals. On the other hand, pulmonary hypertension as a result of liver cirrhosis or portal hypertension is always called secondary primary hypertension because we believe we understand how the underlying liver disorder gives rise to the pulmonary hypertension. However, only a small percentage of patients with such liver disorders do, in fact, get pulmonary hypertension. Once again, there appears to be a genetic predisposition as well as a secondary cause, and there appears to be as much doubt about the precise pathogenesis of such "secondary" pulmonary hypertension as there is in a case of "primary" pulmonary hypertension.

A final theme heard frequently at the symposium is that it is necessary to uncover each and all of the causes of pulmonary hypertension, and to develop treatments specific to each set of causes. It is most unlikely that any one drug will fully cure all types of pulmonary hypertension (although compounds such as prostacyclin can alleviate the symptoms of most kinds of pulmonary hypertension, much as aspirin alleviates the symptoms of headaches that result from many different causes). Indeed, combination drug therapy will likely be necessary for any one kind of pulmonary hypertension due to the multiple intersecting causal factors that always exist. Any of several different genetic mutations might be found to create a predisposition for pulmonary hypertension if certain environmental factors are present, and those environmental factors (e.g. diet suppressant, HIV, hypoxia, etc.) may be different for different genetic mutations. Hence it is important to learn all of the different genetic mutations that can give rise to pulmonary hypertension, so that we can understand which proteins they instruct to be or not be produced, and how those proteins end up interacting with other molecules in the complex biochemistry of the pulmonary vascular bed. The genetic mutation which causes familial primary pulmonary hypertension is especially important to uncover since it may cause PPH even in the absence of an environmental stimuli. This simplifies the task of understanding how a protein produced in a cell, under DNA-RNA instructions, ends up causing vasoconstriction and endothelial proliferation because at least there are no confounding environmental stimuli to factor in as well.

One encouraging point made at the symposium is that pulmonary hypertension is probably not systemic in origin, because it has never recurred in a person who received a lung transplant. This gives rise to hope that the causes of PPH are localized to the pulmonary vascular bed, and that if we can both halt the cause(s), and reverse the damage previously done by the cause(s), we can in fact cure the disease. A number of drug compounds are being developed to reverse the damage done by pulmonary hypertension. Even if we don’t soon find the cause(s), normal lives can be lived by pharmaceutical prevention of the damage. But every cause found and identified makes our pharmaceutical treatment strategy more directed, specific and effective. Hence, the pulmonary hypertension research community is simultaneously trying to both identify the pathogenesis of PPH and to reverse its effects. The Francois Brenot Symposium gave many researchers renewed energy and insights in carrying out these tasks.