Primary pulmonary arterial hypertension
A look back
Alfred P. Fishman, MD*,*
* University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Manuscript received November 26, 2003;
revised manuscript received March 2, 2004,
accepted March 8, 2004.
*
Reprint requests and correspondence: Dr. Alfred P. Fishman, Senior Associate Dean, University of Pennsylvania School of Medicine, 423 Guardian Drive, 1320 Blockley Hall, Philadelphia, Pennsylvania 19102, USA.
fishmana{at}mail.med.upenn.edu
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Abstract
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For the first half of the twentieth century, the published reports on primary pulmonary hypertension (PPH) were confined to clinical pathological correlations. In the 1950s the physiological aspects began to be reported followed by epidemiologic studies triggered by an epidemic of PPH due to the ingestion of an appetite suppressant, aminorex fumarate. The epidemic prompted a series of meetings of the World Health Organization, which led, in turn, to the creation of the U.S. Registry of Primary Pulmonary Hypertension, standardization of nomenclature, and an etiologic classification of all types of pulmonary hypertension.
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Abbreviations and Acronyms
| | PAH | = pulmonary arterial hypertension | | PPH | = primary pulmonary hypertension | | WHO | = World Health Organization |
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For more than a century before pulmonary arterial pressures could be measured directly in humans, pulmonary arteriosclerosis was widely accepted as the morphologic signature of chronic pulmonary arterial hypertension (PAH) (1,2). In 1891, Ernst von Romberg, a German physician, was puzzled by his inability to discover at autopsy the etiology of the pulmonary vascular lesions, which he designated as "pulmonary vascular sclerosis." Light began to be shed on the corresponding clinical syndrome in 1901, when Dr. Abel Ayerza, Professor of Medicine at the University of Buenos Aires, Argentina, lectured on the syndrome of chronic cyanosis, dyspnea, and polycythemia, which was associated with sclerosis of the pulmonary artery. This syndrome was subsequently designated as Ayerza's disease by one of his students, Dr. F.C. Arrillaga.
The first reports of the disease now know as "primary pulmonary hypertension" (PPH) were clinical-pathological correlations (1–7). These were followed by speculations concerning etiology. They began in 1913 with Dr. Arrillaga, who attributed the disease to syphilitic pulmonary endarteritis. This misconception spurred a controversy about the etiologic role of the spirochete, which lasted for two decades when the theory of a syphilitic etiology was laid to rest by Oscar Brenner, a British physician who searched the literature and the Pathology Department of the Massachusetts General Hospital for clues to etiology (8). Based on published accounts of Ayerza's disease, coupled with his own observations, Dr. Brenner concluded that so-called Ayerza's disease was neither a clinical nor a pathological entity. Instead, he concluded accurately that the clinical manifestations of so-called Ayerza's disease were those of heart failure secondary to pulmonary disease, and he interpreted the pathological findings as morphologic evidence of chronic pulmonary disease, moderate pulmonary atherosclerosis, and right ventricular hypertrophy. He saw no reason for the term "Ayerza's disease." However, he did fail to see the connection between the pulmonary vascular disease and the right ventricular hypertrophy, picturing each as a separate entity due to "an unknown cause." Another half-century was to go by before histopathology of the disease was clarified and the relationships between the pulmonary vascular lesions and the right ventricular hypertrophy were clearly understood (9).
Postmortem studies of the pulmonary vasculature in the 1930s could provide little insight into the functional behavior of the pulmonary resistance vessels (i.e., the small muscular pulmonary arteries and arterioles) during life. The functional aspects began to be explored in the 1940s by experiments in cats and humans, which showed that acute hypoxia (10% O2 in N2) elicits pulmonary vasoconstriction (10–12). In 1951, Dresdale, Michtom, and Schultz (13) took the opposite tack (i.e., to relieve pulmonary hypertension): in patients with PPH they showed that tolazoline (Priscoline), a pulmonary vasodilator, relieved pulmonary hypertension. However, the observation was not entirely convincing because tolazoline is not only a pulmonary vasodilator but also a systemic vasodilator, raising the possibility that the effect on the pulmonary circulation was secondary to systemic vasodilation.
To eliminate this uncertainty, Harris et al. resorted to the intravenous injection of acetylcholine, which is destroyed during a single passage through the lungs (14,15). They found that acetylcholine was virtually without effect on the pulmonary circulation during normoxia (i.e., while breathing ambient air) but elicited pulmonary vasodilation if pulmonary vascular tone was previously increased by exposing the subject to a hypoxic-inspired air mixture. Soon thereafter, Wood et al. (16) showed that the intravenous injection of acetylcholine also elicited pulmonary vasodilation in patients with pulmonary hypertension secondary to mitral stenosis.
Such was the state of morphological and physiological knowledge relating to PPH when the epidemic of aminorex-induced pulmonary hypertension broke out in the late 1960s (17). Aminorex fumarate (2-amino-5-phenyl-2-oxazoline) is a catechol derivative, which was sold as an over-the-counter appetite suppressant to promote weight loss. Its actions include release of norepinephrine at nerve endings and an increase in levels of serotonin in the circulation. The drug was introduced on the Swiss, German, and Austrian markets in November 1965 and was withdrawn in October 1968 because it was held responsible for an epidemic of pulmonary hypertension. In patients who died from aminorex pulmonary hypertension, the pulmonary vascular lesions were identical with those of PPH. The aminorex outbreak presented two major questions about the pathogenesis of PPH. The first, stemming from the fact that only a few individuals who took the drug developed pulmonary hypertension, raised the possibility that genetic predisposition played a role in the pathogenesis of the disease (18). The second question was concerned with uncertainties about initiating and pathogenetic mechanisms.
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The first World Health Organization (WHO) meeting, Geneva, 1973
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Prompted by the outbreak of aminorex-induced pulmonary hypertension, the WHO convened a group of experts in 1973 to assess the state of knowledge about PPH and to standardize clinical and pathological nomenclature (19). In addition to accomplishing these goals, the 1973 meeting called for an international registry that would gather standardized data about the rare disease.
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The National Registry, 1981
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The international registry did not materialize. However, in 1981, the National Heart, Lung and Blood Institute of the National Institutes of Health created a National Registry of Patients with PPH (20). The Registry consisted of three components: a statistical-epidemiological core, a pathology core, and 32 clinical centers. By the time the Registry closed in 1987, it had accomplished more than anticipated with respect to the elucidation of the clinical, pathophysiologic, and morphologic features of the disease (21). Moreover, the participants, gratified by the success of this collaborative effort, subsequently embarked upon other clinical trials.
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The second WHO meeting, Evian, France, 1998
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The second WHO meeting, on the 25th anniversary of the original meeting in Geneva, went beyond the confines of PPH. Instead, it undertook to compile a classification of all pulmonary hypertensive diseases. The detailed classification appears in Table 1. Here it will suffice to indicate that it sorts all types of pulmonary hypertensive diseases into five categories: 1) PAH 2) pulmonary venous hypertension, 3) PAH associated with disorders of the respiratory system or hypoxemia, 4) PAH caused by chronic thrombotic or embolic disease, and 5) PAH cased by disorders of the pulmonary vasculature (22–27).
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The third World Symposium on pulmonary arterial hypertension, Venice, 2003
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The third World Symposium on PAH was prompted by a remarkable surge in the understanding of the mechanisms involved in the pathogenesis of pulmonary hypertension that occurred during the few years after the 1998 session. These advances covered a broad span, ranging from molecular biology, developmental biology, and genetics on the one hand, to clinical trials, natural history, and epidemiology on the other.
The third World Symposium on PAH also provided an opportunity to review the effectiveness of the Evian diagnostic classification. To this end, 14 experts from the U.S. and abroad were asked to review critically the Evian diagnostic classification with respect to its value for clinical, research, and epidemiologic purposes. Virtually all participants agreed that the classification was primarily useful for clinical and epidemiologic purposes and less so for research. This pattern of response was not unexpected as research has become increasingly devoted to the molecular and developmental aspects of the disease, whereas the classification is focused on diagnosis and treatment.
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Concluding comments
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Progress in the understanding of PPH has catalyzed the classification of all pulmonary hypertensive diseases. The etiologic basis for the classification enhances the prospects for a unified approach to diagnosis and therapy.
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References
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Abstract
The first World Health...
