The study of circulatory system dates back to the Ancient Greeks with most significant contribution accredited to studies by Galen [1, 2]. Born in 129 AD in Pergamum, Asia Minor (currently Bergama, western Turkey) during the rule of the Roman Empire, he acquired training when he was appointed as the surgeon to the gladiators. His reputation as the leading medical authority quickly rose where he was ultimately appointed as Physician to the Emperor. Through his experiments with animals and experiences in the field treating soldiers, he formulated a series of observations of the circulation and physiology. He claimed that the cardiovascular function was an open-ended system being comprised of two distinct networks of arteries and veins, where blood and air dissipated at the ends of arteries and veins according to the needs of the local tissues [1, 3].

This belief was held firm for 15 centuries until challenged by the scientific findings of William Harvey with his historic publication of Exercitatio Anatomica de Motu Cordis et sanguinis in Animabilus in 1628 [3–5]. In this monumental work written from his observations and experiments, Harvey correctly portrayed the circulatory system as a closed system where the blood circulates from the heart to the tissues via arteries and back to the heart through the veins and the lungs. Furthermore, he also surmised that there were pores in the lungs that allowed the blood to return to the heart. Indeed, these pores were later shown to be vascular capillaries once microscopy was available by Malpighi in 1661 [6]. He also had the incredible insight to differentiate the functions of the two ventricles as he stated: “So it appears that whereas one ventricle, the left, suffices for distributing the blood to the body and drawing it from the vena cava, as is the case in all animals lacking lungs, nature was compelled when she wished to filter blood through the lungs to add the right ventricle…Thus the right ventricle may be said to be made for the sake of transmitting blood through the lungs, not for nourishing them.” Harvey’s astute observations on human circulatory system started the beginnings of modern cardiology [5].

For the next few centuries, medical community was intrigued by reports from autopsy findings of abnormalities in pulmonary arteries and it was being accepted that pulmonary arteriosclerosis was morphological evidence of chronic pulmonary hypertension. However, the etiological basis for these findings remained a mystery. In 1891, a German physician and pathologist named Ernst von Romberg proceeded to categorize the abnormal findings in pulmonary arteries during autopsy simply as “pulmonary vascular sclerosis”, providing the first name of many to follow for this elusive disease [7–9].

The first few decades of 1900s witnessed emergence of several different explanations as the cause for pulmonary hypertension. One notable contributor in furthering the field was Dr. Abel Ayerza, professor of medicine at the University of Buenos Aires, Argentina, when he delivered his key clinical descriptions in a landmark lecture to his students on August 20, 1901 [10]. He described 38-year-old male who had suffered from pneumonia at 20 and 32 years of age and subsequently developed chronic respiratory symptoms. He presented with constellation of findings comprising of chronic cough and sputum production, dyspnea at rest, central cyanosis, clubbed fingers and tachypnea. The examination was significant for blood pressure of 150 mmHg (diastolic blood pressure was not able to be determined at that time), heart rate of 112 beats per minute, wet crackles and wheezing in the lungs with cardiovascular examination showing features of right heart failure (jugular venous distention, hepatomegaly, hepatojugular reflux, ascites and lower extremity edema). The laboratory findings revealed polycythemia of 6,560,000 red blood cells per mm³ and white blood cells were 5,250 cells per mm³. The patient died 24 days after admission to the hospital. His autopsy findings showed enlarged heart with thickened right ventricular wall, dilated right atrium, and normal left atrium and ventricle. Histological examinations of the pulmonary arteries revealed hyperplasia of the middle layer and intima, along with thrombus obstructing flow. Dr. Ayerza called this condition “cardiac negro” (black cardiac) to differentiate from other diseases due to the extreme degree of cyanosis seen in these patients.

This clinical and pathologic correlative description created marked interest among physicians worldwide and speculations started to emerge regarding the etiology [9, 10]. In 1905, Pedro Escudero proposed that “black cardiac” was secondary to a chronic pulmonary process and subsequently attributed the disease to complications of syphilis causing obliterating sclerosis of the pulmonary artery [9–11]. This misconception resulted in a considerable amount of debate of the role of the spirochete that lasted for two decades. In the midst of the controversy, Dr. F.C. Arrillaga, a student of Dr. Ayerza, focused on collecting information on patients with similar presentations who were described as “black cardiac”. In 1913, he published his findings that consisted of a review of a selected group of 11 patients, including the first patient described by Dr. Ayerza, covering the varied causes, pathology and clinical manifestations [10, 12]. As a result, the disease became known worldwide as “Ayerza’s disease.” Dr. A.S. Warthin of University of Michigan described the first case in USA at the 34th Annual Meeting of the American Society for Medicine in 1919 as “A case of Ayerza’s disease: chronic cyanosis, dyspnea, and erythema associated with syphilitic arteriosclerosis of the pulmonary artery” [13].

Despite his role in propagating the misconception of syphilis as the etiology, Dr. Arrillaga formulated a critical concept that shaped the nomenclature and classification of pulmonary hypertension by stating “sclerosis of the pulmonary artery was always primary and that it could be isolated or secondary to chronic pulmonary process” [10, 14]. Thus the theory of sclerosis of the pulmonary artery being the primary cause of Ayerza’s disease, independent of a chronic lung process, initiated the practice of classifying the condition as “primary” pulmonary hypertension, now known as “idiopathic”.

The notion of syphilitis being the cause of pulmonary hypertension was ultimately dispelled by a British physician named Dr. Oscar Brenner in 1935. As the Rockefeller Traveling Fellow at Massachusetts General Hospital (MGH), he reviewed 100 case reports of PH in the MGH autopsy files, of which 25 were categorized as “Ayerza’s disease.” He correctly arrived at the conclusion that that syphilis was not the cause but that clinical manifestations of the disease were due to heart failure secondary to pulmonary disease [15]. He made a significant contribution to the field by noting the presence of small muscular arteries and arterioles as the source of pulmonary hypertension. However, being mainly a histopathologist, he failed to recognize the role of vasoconstriction in the pathogenesis of pulmonary hypertension and its effect in the pathophysiology between pulmonary vascular lesions and right ventricular hypertrophy, viewing each as a separate entity due to an “unknown cause” [9, 15, 16].

The start of the twentieth century marked the birth of modern cardiopulmonary medicine with advances in understanding of physiology of pulmonary hemodynamics through innovations in technology to directly measure pulmonary circulation, which until then had been inaccessible. The initial studies were performed by measuring pulmonary arterial pressures in anesthesthetized, open-chest animals under artificial respiratory support [5, 17]. These experiments allowed development of accurate readings pulmonary pressures and methods to calculate pulmonary vascular resistance and the measurement of left arterial pressures. Among the key contributors in the study of pulmonary hemodynamics and physiology include Otto Frank (1865–1944) and Ernest Henry Starling (1866–1927) whose heart-lung preparations resulted in series of experiments under controlled setting to measure cardiac mechanical and physiologic causes and effect which led to the discovery of Frank-Starling law of the heart [15].

The other major discovery involved figuring out ways to measure pulmonary blood flow. August Krogh and Johannes Lindhard were the first to obtain indirect pulmonary blood flow measurement by using nitrous oxide gas uptake method in humans in 1912 [18]. To overcome limitations present in using the gas exchange technique, a direct approach to measure cardiac output was proposed by Adolph Fick in 1870 [5, 19]. It would take several decades for Fick’s principles to be applied to measure cardiac output in humans due to many complexities inherent in its application, one of which included obtaining mixed venous blood. Werner Forssman made this possible by being the first to demonstrate the feasibility of obtaining direct cardiac measurements in humans by catheterizing himself via the antecubital vein and obtaining a radiographic picture of his heart in 1929 [20]. By showing that the right side of the heart could be safely catheterized by peripheral vein, Forssman disapproved the widely held belief that was prevalent in the medical community that placement of catheter in cardiac chambers would result in morbid or fatal complication. Although his courageous self-experiment propelled the field of invasive cardiology, his actions resulted in criticism and condemnation by his colleagues and administrators [5, 15, 21]. His contribution made it feasible to obtain cardiac output and pulmonary vascular resistance measurements which are critical components to define pulmonary arterial hypertension.

The potential applications of assessing right-sided hemodynamics were quickly realized throughout Europe, South American and United States. Dickinson W. Richards and Andre F. Cournand of the Bellevue Service of Columbia University College of Physicians and Surgeons began experiments placing catheters in the right atrium first in large animals and finally in humans by 1940 [22, 23]. Many discoveries were made by the team led by Cournand and Richards during the next couple of decades that included establishing the wide range of variations in pressure and flow seen in health and disease states and hemodynamics associated with congenital heart defects and valvular disease [23–25]. Forssman, Cournand and Richards won the Nobel Prize in 1956 in physiology and/or medicine for their contributions to the discovery of circulatory and cardiopulmonary system [21, 24, 25]. Advances in science and technology, including development of a flow-directed catheter with an inflatable balloon to measure left atrial pressure in animals followed by a modified technique of measuring pulmonary “capillary” pressure in humans, set the stage for wide use of right sided catheterizations in laboratories across the country [26, 27]. In 1970, William Ganz and Harold J C Swan introduced a multi-lumen, balloon tipped catheter that enabled the procedure to be performed from the fluoroscopy suite to the bedside [28].

The rapid advances in technology in the field of invasive hemodynamics in the twentieth century created a marked interest that propelled research in the field of cardiopulmonary medicine that resulted in the start of formal nomenclature and classification for pulmonary hypertension. David Dresdale, a trainee of Cournand and Richards, was the first to report in 1951 hemodynamic profiles of patients with pulmonary hypertension without evident etiology and coined the name “primary pulmonary hypertension (PPH)” [29]. This was a significant event since prior to this, PPH did not have an accepted terminology which impeded effective communication and research relating to the condition. Furthermore, Dresdale also contributed to the key concept on the role of vasoconstriction in the pathophysiology of pulmonary hypertension and the effects of vasodilators. He performed functional studies in animals that demonstrated acute hypoxia elicited pulmonary vasoconstriction and that administration of a pulmonary vasodilator tolazoline relieved pulmonary hypertension in patients with PPH [30, 31]. However, this resulted in some controversy because tolazoline also produces systemic vasodilatory effects, which raised the question if the effect on the pulmonary circulation was due to systemic vasodilation [9].

Another key contributor furthering the field of cardiopulmonary physiology was Paul Wood by performing a wide range of hemodynamic studies in his patients with valvular heart disease, congenital heart disease and pulmonary hypertension. In his seminal publication of “Pulmonary Hypertension with Special Reference to the Vasoconstrictive Factor”, he outlined many seminal, critically important physiologic principles. First, he defined normal pulmonary hemodynamics from his laboratory at the Institute of Cardiology and at the Brompton Hospital: “The normal pulmonary pressure in a series of 60 normal controls….was 16/7 mm Hg…with mean being 11 mm. and the range 8/2-28/14 mm. The mean cardiac output was 8 liters a minute, and the common range 5.5 to 10.5 liters a minute.” He also gave a definition of pulmonary hypertension stating: “Pulmonary hypertension literally implies a pulmonary blood pressure above 30/15 mm. which is the upper limit of the normal range. In practice serious pulmonary hypertension usually means a pressure at or around systemic level, but rarely in excess of 150 mm” [32]. Furthermore, he proposed a “working classification of pulmonary hypertension” based on physiologic distinctions differentiating into five types: Passive, Hyerkinetic, Obstructive, Obliterative, Vasoconstrictive, Polygenic, with a claimer stating that “…it may help to add a sixth (polygenic), to describe cases of mixed etiology” [32]. He also described the significance and meanings behind “reactive” versus “passive”, with discussions centered around what he had learned from his experiments with intravenous injection of acetylcholine. This substance, being eliminated during a single passage through the pulmonary circulation, demonstrated the effect of a selective pulmonary vasodilator in that it decreased pulmonary pressures in his patients with pulmonary hypertension secondary to mitral stenosis [32, 33]. He confirmed the importance of the role of vasoconstriction in pulmonary hypertension, as well as the potent pulmonary vasodilatory effect of acetylcholine in patients who were subjected to pretreatment with hypoxic-inspired air [34, 35]. Furthermore, Paul Wood included 26 patients whom he labeled as “primary pulmonary hypertension”, 21 of them being female between the ages 9 and 48, similar to the cohort that would be described 20 years later in the NIH Registry [35, 36].

It is noteworthy that with introduction of the name “primary pulmonary hypertension” enabled the medical community to focus and publish their findings by having a common language. Paul Wood also led the studies on hemodynamics of pulmonary hypertension of different etiologies with his descriptions of Eisenmenger’s and mitral stenosis, which were corroborated by similar findings by other physicians in similar cohorts. Some of the critical works that emerged during this time include pathologic descriptions by Heath and Edwards in 1958 on Eisenmenger’s patients, and Wagenvoort and Wagenvoort in 1970, that provided a first detailed post mortem descriptions [37, 38]. The publication by the Wagenvoorts was a landmark work titled “Primary Pulmonary Hypertension. A Pathologic Study of the Lung Vessels in 156 Clinically Diagnosed Cases” of confirmed PPH cases from 51 medical centers and pathologic laboratories in 14 different countries [38].

Against the backdrop of a century of significant progress in the field of pulmonary hypertension, the epidemic of aminorex-induced PPH broke out in the late 1960s propelling this rare condition to the center stage [39]. Aminorex fumarate (Menocil®) shares similar chemical structures with epinephrine and amphetamines and its toxic effects have been reported to be predominately due to the release of catecholamines and norepinephrine [40, 41]. Aminorex became available as over-the-counter drug appetite suppressant to promote weight loss in 1965 in Switzerland, Austria, and Germany which was followed by a tenfold increase in the incidence of PPH reported in the three countries over the next 7 years [41].

The drug was withdrawn from the market in 1968 due to the alarming rate of PPH cases [9, 40]. However, important scientific advances resulted from this unfortunate event in that several key questions were raised followed by important observations regarding PPH which pushed the field forward. For one, it was observed that only 2 % of those who took aminorex developed PPH suggesting genetic predisposition playing an important role. Follow up experiments in animals to reproduce PPH were largely unsuccessful, which further supported the concept of genetic basis playing an important factor. The time frame of disease progression was also uncovered with appreciation of the latent period between the start of aminorex ingestion and onset of clinical manifestations, which appeared to peak at 6 months. In addition, it was observed that the changes related to PPH often progressed after the drug had been stopped and that in 12 of 20 patients who were followed for >17 years, the disease regressed demonstrating that in some patients PPH seemed reversible [9, 39, 41].

Culminating from the urgent need to that rose by the epidemic and the many imminent questions that surfaced, the World Health Organization (WHO) convened its first meeting on PPH that took place on October 15–17, 1973 in Geneva, Switzerland. There were 19 attendees representing 10 countries (5 from USA and Switzerland, each, with largest number of participants). The “Primary Pulmonary Hypertension: Report on a WHO meeting” contains an account of the meeting based on the papers submitted by the participants, as well as their discussions. Of note, the introduction of the report starts with mention of the first WHO meeting on pulmonary circulation on cor pulmonale that was held on 1960 (Table 1.2). In the Classification of Chronic Cor Pulmonale According to Causative Disease, PPH is listed in the 3rd group among the “Diseases primarily affecting the pulmonary vasculature”, which is most likely the first formal proposed classification [42].

Among the many important discussions that took place during that seminal meeting, one lengthy deliberation was centered on the dilemma surrounding the nomenclature of the term “primary pulmonary hypertension” being used in two distinct ways. Clinically, PPH referred to “indicate the presence of elevated pulmonary arterial pressures in the absence of discernable cause”. Its meaning also designated morphological changes found in pulmonary vascular pattern of PPH, namely concentric intimal fibrosis, necrotizing arteritis, and plexiform lesions. The group came to a consensus that it was not practical to abolish the term “primary pulmonary hypertension” due to its wide acceptance and use. Instead, they agreed to the term “primary pulmonary hypertension” to be used only to mean “pulmonary hypertension of unknown cause” and that the term “plexogenic pulmonary arteriopathy” be used to designate the constellation of morphologic changes associated with PPH [43]. It is interesting to note that this same debate will be held 25 and 30 years later at the next two subsequent WHO meetings.

The participants also discussed the definition of the disease that was initially reported during the WHO Expert Committee on Chronic Cor Pulmonale, stating “The mean pressure in the pulmonary artery does not normally exceed 15 mm Hg when the subject is at rest in a lying position. This value is little affected by age and never exceeds 20 mm Hg. Hypertension is definitely present if the pressure exceeds 25 mm Hg” [42, 43]. The group confirmed the findings initially stated by Paul Wood and set a formal cutoff value to define pulmonary hypertension which is used to present day. Discussion on left sided filling pressure was also held, with the group agreeing that the normal range is 6–9 mmHg and “may even reach 12 mm Hg” based on the measurements in normal individuals [43, 44]. It is noteworthy that the current upper limit range of 15 mmHg. used to define pulmonary arterial hypertension (PAH) was not set at the first WHO meeting. Other topics that were discussed include the value of end diastolic pressure of the pulmonary artery as an indicator of the left ventricular end diastolic pressure, with the group concluding that end diastolic pressures were not reliable in reflecting the left sided filling pressure in those with pulmonary vascular disease [43, 45]. The controversy surrounding relevance and accuracy of diastolic pulmonary gradient in patients with pulmonary hypertension due to left heart disease is ongoing to present day and studies are being conducted to help answer the question [46]. The effect of exercise on pulmonary pressures were also a major item of discussion: “Some forms of pulmonary hypertension are latent and become apparent only when there is an increase in blood flow. It is therefore important to know the response of the normal pulmonary circulation to effort” [43]. The participants pointed out that for “…an output of 20 liters or more, the mean pulmonary artery pressure does not normally exceed 30 mm Hg” based on prior study on hemodynamics during exercise, the value used as a cut off to define “exercise-induced pulmonary hypertension” formally stated during the 2003 Evian meeting was later retracted at the 2008 Dana Point meeting due to insufficient data to justify the definition [47–49]. Indeed, similar questions relating to effects of age and state of physical conditioning affecting pulmonary pressures with exercise were raised during the Geneva meeting as would be raised in others to follow. The recommendation that “…more information needs to be obtained on the various pressures and the resistance in the lesser circulation under clearly defined exercise conditions” set forth by the members would be restated during the Dana Point meeting [49].

The most significant outcome that resulted from the 1st WHO meeting was based on the series of proposed recommendations, one of which called for the “establishment of a central register of patients with primary pulmonary hypertension seen in centers throughout the world” [43]. In place of an international registry, the National Heart, Lung and Blood Institute (NHLBI) of the National Institute of Health (NIH) created a National Registry of Patients with PPH in 1981 [50]. The Registry had three core groups, namely one focusing on statistics and epidemiology, a core dedicated to pathology, and 32 clinical centers collaborating to collect patient information. The Registry completed its 194 patient enrollment in 1987, a historic accomplishment resulting in contributing critical information on the natural history, epidemiology, and clinical features of the disease that led the participants in future collaborations in clinical trials [9, 50, 51].