Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a rare, progressive disease in which high blood pressure affects the arteries of the lungs (pulmonary arteries). Symptoms characterizing PAH include dyspnea (shortness of breath), chest pain, and syncopal (fainting) episodes. Due to high blood pressure in the pulmonary arteries, the right side of the heart must work harder to pump the blood through these arteries to the lungs which may result in right-sided heart failure.¹

PAH Disease History

In 1891, German physician, Ernst von Romberg, discovered evidence of PAH during an autopsy which revealed increased thickness of the pulmonary arteries which he termed “pulmonary vascular sclerosis”. Dr. von Romberg remained bewildered as to the etiology of this pulmonary artery thickening as he could not confirm any co-existing lung or cardiac disease which contributed to this development.²

In 1901, Dr. Abel Ayerza, a professor teaching medicine at the University of Buenos Aires in Argentina, lectured on a clinical syndrome that closely corresponded with Dr. von Romberg’s discovery. This syndrome consisted of dyspnea, chronic cyanosis, and polycythemia which correlated to thickening of the pulmonary artery. One of Dr. Ayerza’s students, Dr. F. C. Arrillaga, later eponymously named the syndrome, Ayerza’s disease, after his teacher. Dr. Arrillaga continued to research this syndrome, speculating incorrectly in 1913 that syphilitic pulmonary endarteritis caused the disease.²

After twenty years of confusion caused by Dr. Arrillaga’s speculation, Dr. Oscar Brenner, a British physician, scoured the medical literature in the Pathology Department at Massachusetts General Hospital, accurately confirming that Ayerza’s disease resulted from heart failure ultimately caused by pulmonary disease. Pathological evidence of right ventricular hypertrophy, moderate pulmonary artery sclerosis, and chronic lung disease supported Dr. Brenner’s conclusion.^2,3 However, he failed to correlate the pulmonary vascular disease with the right ventricular hypertrophy, attributing them separately to unknown causes. It took another 50 years before the connection between pulmonary artery sclerosis and right ventricular hypertrophy became clear.²

Autopsies throughout the 1930s overlooked the functional aspects of pulmonary vascular disease which researchers began to explore in the 1940s through animal and human experimentation. This experimentation confirmed that acute hypoxia caused the pulmonary vasoconstriction which in turn increased the blood pressure in the vessels.^2,4,5,6 

In 1954, Dresdale, Michtom, and Schultz published their findings after researching the effects of a pulmonary vasodilator (tolazoline) which successfully relieved symptoms of pulmonary hypertension in their patients.⁷ Scientists remained skeptical about these results since tolazoline also worked systemically as a vasodilator instead of strictly acting on the pulmonary vasculature.²

To disprove this skepticism, Harris and colleagues injected acetylcholine intravenously, knowing destruction of the acetylcholine would occur in transit through the lungs. This team of researchers observed that acetylcholine had no effect on pulmonary vessels while breathing environmental air, but acetylcholine caused pulmonary vasodilation if previous exposure to hypoxic air increased vascular tone in the pulmonary arteries.^8,9 Wood and colleagues repeated the experiment with acetylcholine causing vasodilation in patients with pulmonary hypertension caused by mitral valve stenosis.^2,10

In the late 1960s, an epidemic of PAH occurred following consumption of aminorex fumarate, a catechol derivative sold over the counter as an appetite suppressant for weight loss. The drug was released first in Austrian, Swiss, and German markets in November of 1965 and was recalled in October of 1968 due to the PAH epidemic in its wake. Half of the patients died within 10 years following the epidemic.^2,11 

Aminorex fumarate releases norepinephrine from nerve endings, resulting in increased concentrations of serotonin in the blood.² Serotonin stimulates growth in the pulmonary artery smooth muscle cells.¹¹ This excessive growth caused chronic precapillary vascular obstruction due to plexogenic pulmonary arteriopathy, resulting in pulmonary hypertension.¹² This event led to further questions regarding the pathogenesis of PAH, including the likelihood of genetic predisposition and the triggers and mechanisms causing the disease.² 

Following this outbreak, the World Health Organization (WHO) convened experts in Geneva in 1973 to clearly define the disease known as “primary pulmonary hypertension” or PPH.¹³ They attempted to form an international registry to procure standardized information about the disease.² 

While the international registry was not formed, the National Heart, Lung, and Blood Institute of the National Institutes of Health established the National Registry of Patients with PPH in 1981. Thirty-two clinical centers, a statistical-epidemiological core, and a pathology core comprised this National Registry which gathered and disseminated information about the pathophysiology, clinical manifestations, and morphological characteristics of PAH until 1987 when the Registry disbanded.^2,14,15

In 1998, WHO convened a second time in Evian, France, exactly 25 years after the first meeting in Geneva. The agenda for this second meeting involved classifying all pulmonary hypertensive diseases. Five categories of pulmonary hypertensive diseases evolved, including 

• PAH
• Pulmonary venous hypertension
• PAH associated with respiratory disorders or hypoxemia
• PAH associated with chronic thrombotic or embolic disease, and
• PAH related to pulmonary vasculature disorders.^2,16

In 2003, increased comprehension of the mechanisms behind PAH pathogenesis sparked the third World Symposium in Venice, Italy.¹⁷ Experts at this symposium reviewed the 5 Evian diagnostic classifications, deeming them effective for clinical and epidemiological reasons but not as much for research. Research at the time focused more on the molecular and pathogenetic underpinnings of PAH and less on diagnosis and treatment.²

PAH Treatment History

In 1981, Norman Shumway, John Wallwork, and Bruce Reitz, doctors at Stanford University, performed the first heart-lung transplantation as a surgical intervention for PAH.¹⁸ 

Epoprostenol (Flolan) was the first drug approved by the US Food and Drug Administration (FDA) to treat PAH in 1995.¹⁹ Over the past almost three decades, the FDA has approved 12 drugs to treat PAH including phosphodiesterase-5 (PDE-5) inhibitors, soluble guanylate cyclase (sGC) stimulators, endothelin receptor blockers (ERBs), and prostacyclins.²⁰ These include tadalafil (Adcirca), riociguat (Adempas), ambrisentan (Letairis), macitentan (Opsumit), Treprostinil (Remodulin), bosentan (Tracleer), selexipag (Uptravi), and an inhaled Treprostinil solution (Tyvaso).²¹  

Other medications that supplement treatments for patients with PAH include oxygen therapy, diuretics, calcium channel blockers, and coumadin (Warfarin).²⁰

References

1. Pulmonary arterial hypertension. NORD (National Organization for Rare Disorders). Accessed March 18, 2022.
2. Fishman AP.  Primary pulmonary arterial hypertension: A look back. J Am Coll Cardiol. 2004;43(12, Supplement):S2-S4. doi:10.1016/j.jacc.2004.03.019
3. Brenner O. Pathology of the vessels of the pulmonary circulation: Part I. Arch Intern Med. 1935;56(2):211-237. doi:10.1001/archinte.1935.03920020003001
4. Euler U, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand. 2008;12:301-320. doi:10.1111/j.1748-1716.1946.tb00389.x
5. Motley HL, Cournand A, Werko L, Himmelstein A, Dresdale D. The influence of short periods of induced acute anoxia upon pulmonary artery pressures in man. Am J Physiol-Legacy Content. 1947;150(2):315-320. doi:10.1152/ajplegacy.1947.150.2.315
6. Fishman AP. Respiratory gases in the regulation of the pulmonary circulation. Physiol Rev. 1961;41(1):214-280. doi:10.1152/physrev.1961.41.1.214
7. Dresdale DT, Michtom RJ, Schultz M. Recent studies in primary pulmonary hypertension including pharmacodynamic observations on pulmonary vascular resistance. Bull NY Acad Med. 1954;30(3):195.
8. Harris P. Influence of acetylcholine on the pulmonary arterial pressure. Heart. 1957;19(2):272-278. doi:10.1136/hrt.19.2.272
9. Fritts HW, Harris P, Clauss RH, Odell JE, Cournand A. The effect of acetylcholine on the human pulmonary circulation under normal and hypoxic conditions. J Clin Invest. 1958;37(1):99-110. doi:10.1172/JCI103590
10. Wood P, Besterman EM, Towers MK, McIlroy MB. The effect of acetylcholine on pulmonary vascular resistance and left atrial pressure in mitral stenosis. Heart. 1957;19(2):279-286. doi:10.1136/hrt.19.2.279
11. Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev. 2013;22(129):244-250. doi:10.1183/09059180.00003313
12. Gurtner HP. Amiriorex pulmonary hypertension. In: 29. Amiriorex Pulmonary Hypertension. University of Pennsylvania Press; 2016:397-412. doi:10.9783/9781512801736-031
13. Hatano S, Strasser R. Editors. Primary pulmonary hypertension: Report on a WHO meeting. World Health Organization. Geneva; 1975.
14. Fishman AP. Introduction to the National Registry on primary pulmonary hypertension. In: 31. Introduction to the National Registry on Primary Pulmonary Hypertension. University of Pennsylvania Press; 2016:437-440. doi:10.9783/9781512801736-033
15. Pietra GG. The histopathology of primary pulmonary hypertension. In: 34. The Histopathology of Primary Pulmonary Hypertension. University of Pennsylvania Press; 2016:459-472. doi:10.9783/9781512801736-036
16. Rich, S. Editor. Primary pulmonary hypertension: Executive summary from the World Symposium on primary pulmonary hypertension-1998-Evian-France. Accessed March 18, 2022. 
17. Galiè N, Rubin LJ. Introduction: new insights into a challenging disease: A review of the third world symposium on pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12, Supplement):S1. doi:10.1016/j.jacc.2004.03.003
18. George MP, Champion HC, Pilewski JM. Lung transplantation for pulmonary hypertension. Pulmonary Circulation. 2011;1(2):182. doi:10.4103/2045-8932.83455
19. Treating pulmonary arterial hypertension. WebMD. Accessed March 18, 2022.
20. Pulmonary hypertension medical management and treatment. UPMC | Life Changing Medicine. Accessed March 18, 2022.
21. Pulmonary arterial hypertension. FDA Approved Drugs | CenterWatch. Accessed March 18, 2022. 

Reviewed by Kyle Habet, MD, on 3/31/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.