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Pulmonary hypertension – historical development, current state of therapy and outlook

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M.  M.  Hoeper Department of Pulmonology, Hannover Medical School, Hanover
Further Information[spacer height=”20px”]
This is the English translation of the original article of:   Hoeper MM. Die pulmonale Hypertonie – historische Entwicklung, derzeitiger Stand der Therapie und Ausblick. Pneumologie. 2010;64(09):577-582. doi:10.1055/s-0030-1255681

Summary

This article provides a brief overview of the history of pulmonary hypertension, starting with the first descriptions of the corresponding pulmonary vascular changes by Ernst von Romberg and Victor Eisenmenger at the end of the 19th century. Some of the histopathological changes we know today in the various forms of pulmonary hypertension were already characterized in the first half of the 20th century, but it was not until the 50s that catheterization of the right heart and pulmonary vessels succeeded, especially through the pioneering achievements of Forßmann and Cournand. Only then did it become possible to investigate the clinical spectrum of this disease entity and the effects of therapeutic interventions. The first treatment attempts with vasodilators were mostly unsuccessful and it was not until the 80s of the last century that an effective therapy of at least one variant of pulmonary hypertension was available with intravenous prostacyclin. In the meantime, the understanding of the pathogenesis of pulmonary hypertension has increased significantly. The same applies to the number of available therapies and Germany now has a well-established care structure for this disease. However, there are still no curative treatment options for most forms of pulmonary hypertension and there are still many unresolved questions.

Abstract

This article provides a brief overview on the history of pulmonary hypertension, starting with the first descriptions of the accompanying pulmonary vascular lesions by Ernst von Romberg and Victor Eisenmenger at the end of the 19Th Century. Many of the histopathological changes in the pulmonary vasculature found in the various forms of pulmonary hypertension had already been described in the first half of the 20Th Century. However, only through the pioneering work by Forßmann and Cournand during the middle of the 20Th century was it finally possible to catheterise the right ventricle and the pulmonary arteries. After this, it became feasible to study the clinical spectrum of the various forms of pulmonary hypertension as well as the effects of therapeutic interventions. Early treatment attempts with vasodilators, however, were not successful. Intravenous prostacyclin, used to treat some forms of pulmonary hypertension since 1980, became the first effective treatment. Since that time, our understanding of the pathogenesis of pulmonary hypertension has increased substantially, as has the number of effective therapies, at least for some forms of pulmonary hypertension. Many aspects of the disease, however, remain poorly understood and a cure is still not achievable for the majority of the affected patients. Historical development of the clinical picture The first mention of the clinical picture, which we now call pulmonary hypertension, probably goes back to the German internist Ernst von Romberg, who described the “isolated sclerosis of the pulmonary arteries” in 1891 while working in Leipzig [1]. Only a few years later, in 1897, the Viennese physician Victor Eisenmenger reported similar histopathological changes in a patient with a ventricular septal defect [2]. This symptom complex, consisting of a primary left-right shunt and the resulting pulmonary vascular changes with consecutive pulmonary hypertension and shunt reversal, would later bear Eisenmenger’s name [3]. Initially, there were no clear ideas about the pathogenesis of these changes. In 1902, Abel Ayerza of the University of Buenos Aires suggested that the disease with cyanosis, dyspnea, polyglobulia and sclerosis of the pulmonary arteries, which was later temporarily named after him, was the result of syphilis (the first publication introducing the term “Ayerza’s disease” did not come from himself, but from one of his students [4]). The supposed existence of syphilitic pulmonary vasculopathy has been in the medical literature for quite a long time, although no convincing reports of a possible connection between syphilis and pulmonary hypertension have been published to date. A detailed description of the histopathological changes in clinical pictures, which we summarize under the term pulmonary hypertension, was carried out in the 40s by Brenner and colleagues [5]. Here, for the first time, the concentric and plexiform lesions as well as the thrombotic changes were described, which were later systematically analyzed by Heath and Edwards as well as by the Wagenvoort couple [6] [7] [8]. Brenner was probably also the one who introduced the concept of primary pulmonary hypertension and demanded as histological (autoptic) criteria that there should be no other cause for sclerosis of the pulmonary arteries and that there must be a pronounced right ventricular hypertrophy at the same time [9]. A clinical diagnosis of pulmonary hypertension was not possible at that time, as catheterization of the small circulation was still unknown. This possibility only arose through the pioneering work of André Cournand, who in the 50s, inspired by the self-experiments of Werner Forßmann (1929 as an assistant physician in Eberswalde), brought the diagnostic catheterization of the right heart and pulmonary vessels to clinical application [10]. Cournand was awarded the Nobel Prize in Medicine in 1956 together with Forßmann and his boss Dickinson Woodruff Richards. About 10 years after Cournand’s work, London cardiologist Paul Wood presented his groundbreaking research into the physiology of pulmonary circulation. He was the first to systematically carry out haemodynamic examinations of the small circulation and determined the upper normal value of the mean pulmonary arterial pressure at 20 mmHg [11]. This value has endured to this day [12] [13] [14]. Through his intensive research, but also through his impressive, quite controversial personality, Wood became a formative figure in the field of pulmonary circulation until his early death in 1962. For the first time, pulmonary hypertension came into the focus of a wider public in the context of the “Menocil epidemic”, in which an accumulation of cases of severe pulmonary hypertension was observed in Germany, Austria and Switzerland after the appetite suppressant Menocil® (active ingredient Aminorex) came onto the market in 1965 [15] [16]. The frequency of pulmonary hypertension did not decline until after the drug was withdrawn from the market in 1968. Doubts about human learning were also confirmed in subsequent years by the emergence of other appetite suppressants with a similar mechanism of action, which in turn led to an increase in cases of severe pulmonary hypertension [17] [18] [19]. In the wake of the “Menocil epidemic”, a WHO conference on pulmonary hypertension was held in 1971. At this conference, among other things, the first generally accepted hemodynamic definition of pulmonary hypertension was adopted. Although it was known from numerous studies by Paul Wood and others that the upper normal value of the mean pulmonary arterial pressure was 20 mmHg, the limit value for the presence of pulmonary hypertension was set at that time above 25 mmHg at rest or 30 mmHg under exercise. Contemporary witnesses report that the definition of the retirement value was preceded by an hour-long, sometimes heated and controversial discussion and that the definition of the stress value was ultimately regarded as the result of general exhaustion. It will be difficult to determine to what extent these reports are true, especially since the original documents of this meeting are difficult to access. The next and, for the time being, last WHO conference took place in 1998 in Evian, France. Here, for the first time, the classification of pulmonary hypertension into 5 groups was defined (Group I: Pulmonary arterial hypertension (PAH); Group II: Pulmonary hypertension in left heart disease; Group III: Pulmonary hypertension in pulmonary diseases; Group IV: chronic thromboembolic forms and group V: other forms). The exact prevalence of each form of pulmonary hypertension is not known exactly. The number of patients with PAH in Germany is probably between 2000 and 3000 and the prevalence of chronic thromboembolic pulmonary hypertension (CTEPH) is probably slightly lower [20]. Pulmonary hypertension is much more common in left heart disease and chronic lung disease [21]. The majority of patients with systolic or diastolic dysfunction of the left ventricle develop pulmonary hypertension during the course of their disease [22] [23]. The same applies to patients with progressive obstructive or restrictive pulmonary disease [24] [25]. Overall, at least a 5-digit number of patients in Germany are likely to be affected by these forms of pulmonary hypertension. This Evian classification was modified in some details during the subsequent World Symposia on pulmonary hypertension in Venice in 2003 and Dana Point, California, in 2008, which are no longer sponsored by the WHO, but was retained in its framework ([Table 1]) [26] [27].
Table 1 Current clinical classification of pulmonary hypertension (Dana Point 2008 and ESC/ERS guidelines 2009) [13] [14] [27].
In Venice, the concept of primary pulmonary hypertension was replaced by that of idiopathic PAH, not least to replace the less precise concept of secondary pulmonary hypertension with more specific terminology. At the Dana Point Conference in 2008, the hemodynamic definition of pulmonary hypertension was modified for the first time since 1971, after an extensive evaluation of the available literature had shown that the previous definition of pulmonary hypertension under stress (mean pulmonary artery pressure > 30 mmHg) had no sufficient basis and that significantly higher values can be physiological, especially in older people [12]. Accordingly, the exposure limits were removed from the hemodynamic definition of pulmonary hypertension while maintaining the limit of 25 mmHg at rest [13] [14] [28] [29]. Anecdotally, it should be noted that the attentive observer may have noticed that recent European guidelines no longer set this limit at > 25 mmHg, but at ≥ 25 mmHg [13] [14]. Initially, this was a transcription error, but the members of the Guideline Commission finally agreed to stick to this originally accidental change.

Historical development of therapy

The first attempts to treat pulmonary hypertension were carried out with vasodilators after Paul Wood had hypothesized that the disease was initially initiated by vasoconstrictive factors and that the typical vascular remodeling processes would only occur in the further course of the disease [11]. Initial attempts to lower pulmonary pressure with vasodilators were made as early as 1954 by Dresdale et al. [30]. In the 70s and 80s, virtually all available vasodilators were studied for their effectiveness in pulmonary hypertension, without it being possible to positively influence the course of the disease. Only Stuart Rich of the University of Chicago succeeded in demonstrating that only a small proportion of patients with “primary pulmonary hypertension” are extremely vasoreagible and can be successfully treated with high-dose calcium antagonists [30] [31] [32] [33]. This assessment is still valid today; however, the proportion of patients who can be treated accordingly is negligible at < 5% of the total patient population [34] [35]. The hypothesis that PAH is a disease based on pulmonary vasoconstriction is now considered to be refuted, at the latest after the gene of the familial or hereditary form of PAH has been identified. This is BMPR-II (bone morphogenetic protein receptor-II) [36] [37], which is involved in the regulation of vascular remodeling processes. Not least because of this discovery, a paradigm shift has occurred, so that PAH is now regarded as a disease that is primarily caused by remodeling processes in the pulmonary pathway ([Fig. 1]), whose pathogenesis is still not understood in detail, but which has certain similarities with malignant diseases at the cellular level ([Fig. 2]) [38] [39].
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Fig. 1 Vascular changes of pulmonary arterial hypertension and their hemodynamic consequences (modified according to [65]). In the upper half of the figure, the dominant histopathological changes in pulmonary arterial hypertension are schematically shown. Hypertrophy of the media, intimaproliferation and thrombotic changes lead to progressive obliteration of the pulmonary pathway. In the lower section, the hemodynamic consequences are shown. The right heart counters the increased flow resistance with an increase in pulmonary arterial pressure (PAP). As a result, cardiac output (HCV) initially remains normal at rest, but cannot be adequately increased under stress. In the late stages of the disease, there is an insufficiency of the right heart with a decrease in cardiac output even at rest, and occasionally even a decrease in pulmonary pressure as a manifestation of the contractile weakness of the right ventricle.
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Fig. 2 Hypothesis on the pathogenesis of pulmonary arterial hypertension (simplified presentation). At the center of current considerations is the pulmonary vascular endothelial cell, which can be damaged by numerous, mostly still unknown, noxious substances. The development of pulmonary arterial hypertension apparently includes a genetic disposition. Some of the genes responsible have already been identified. Apparently, on the one hand, apoptosis of the endothelial cells occurs in the affected patients with subsequent proliferation of apoptosis-resistant endothelial cells, which are partly responsible for intimaproliferation. At the same time, imbalance of vasoactive mediators develops, resulting in increased vasoconstriction and proliferation of smooth muscle cells. Once set in motion, these processes perpetuate themselves due to the increased pressure and the increased shear stress in the pulmonary circulation. BMPR-II, bone morphogenetic protein receptor-II; ALK-1, aktivin-like kinase-I; EC, endothelial cell; NO, nitric oxide; PGI2, Prostacyclin; VIP, vasoactive intestinal peptide, PDE-5, phosphodiesterase-5; ET-1 Endothelin-1; RTK, receptor tyrosine kinases; VSMC, vascular smooth muscle cells.
Modern therapy of this disease began with the introduction of intravenous prostacyclin (epoprostenol) in 1980/1981 [40] [41]. At the same time, the first successful heart-lung transplants were performed in patients with pulmonary hypertension [42] and epoprostenol therapy was initially intended only as a bridge to transplantation. However, some of the patients treated in this way improved significantly, so that in many cases a transplant was no longer necessary. Intravenous epoprostenol therapy improved the prognosis of patients with PAH for the first time [43] and it was speculated whether the effects of this therapy went beyond pure pulmonary vasodilation or whether effects on pulmonary vascular remodeling processes were also partly responsible for the long-term therapy effect. In the following years, the treatment of PAH was further improved by the introduction of endothelin receptor antagonists, phosphodiesterase 5 inhibitors, as well as newer prostacyclin analogues [44] [45] [46] [47]. In 2000, there was no approved therapy for PAH in Germany, but there are now 7 preparations from 3 substance classes available [48]. At the same time, a solid infrastructure for the care of patients with pulmonary hypertension has developed. There are some established and internationally renowned centers of excellence for this disease and the first regional networks, so that comprehensive care for these patients is guaranteed. This applies not only to drug therapy, but also to other therapeutic procedures such as pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension [20] [49] or lung or heart-lung transplantation for patients with refractory courses [42].

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Many of these developments, especially in recent years, have been decisively influenced by German centres, above all by Werner Seeger’s working group in Giessen [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60]. This also applies to the development of new therapeutic approaches that are currently in clinical trials [61] [62] [63]. Of particular importance may be the tyrosine kinase inhibitors, which for the first time open up the prospect of at least partial regression of the obliterative vascular lesions in patients with PAH [58] [62] [64]. This approach impressively illustrates the fruits of the interaction of basic research and clinical science, which has been as dynamic and successful in recent years in hardly any other field as in that of pulmonary hypertension. At the same time, the paradigm shift in the understanding of pathogenesis described above will be traced and research in the coming years is likely to be more dedicated than ever to understanding the vascular remodeling processes in the various forms of pulmonary hypertension with the aim of bringing them back to regression in the long term. In addition to PAH and CTEPH, the other groups of pulmonary hypertension are now also becoming the focus of clinical research [20] [24] [25]. These forms of pulmonary hypertension are much more common than PAH, but so far it is completely unclear whether, when and how they should be treated.

Concluding remarks and acknowledgments

I am not a medical historian and, despite all due care, I cannot rule out the possibility that some of the historical information as well as the sources in this text are not always entirely accurate. If this is the case, I would ask for corrective remarks, but at the same time for your indulgence. The same applies to all the achievements and achievements that I have not discussed for reasons of space. I would like to thank my esteemed colleague Prof. Robert Naeije from the Erasmus University of Brussels, who has been following the events in the field of pulmonary hypertension as a contemporary witness for longer than I have and has given me invaluable help in writing this article.

Conflicts

The author has received speaking and consulting fees from Actelion, Bayer, Gilead, GSK, Lilly, LungRx, Novartis and Pfizer. #

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Prof. Dr. med. Marius M. Hoeper Department of Pulmonology Hannover Medical School Carl-Neuberg-Str. 1 30625 Hannover Email: hoeper.marius@mh-hannover.de
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